CN106661091A - 流行性感冒病毒疫苗及其用途 - Google Patents

流行性感冒病毒疫苗及其用途 Download PDF

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CN106661091A
CN106661091A CN201580036947.0A CN201580036947A CN106661091A CN 106661091 A CN106661091 A CN 106661091A CN 201580036947 A CN201580036947 A CN 201580036947A CN 106661091 A CN106661091 A CN 106661091A
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A·因帕利亚佐
J·W·梅博阁
K·拉多塞维奇
M·瓦格纳
Z·丁
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Abstract

此处提供了多种流行性感冒血球凝集素主干域多肽，提供多种血球凝集素主干域多肽的方法，包括这些多肽的组合物，包括这些多肽的疫苗及其使用方法，特别是在流行性感冒的检测、预防和/或治疗中的使用。

Description

流行性感冒病毒疫苗及其用途
引言
本发明涉及医学领域。此处提供了多种流行性感冒血球凝集素主干域多肽，提供多种血球凝集素主干域多肽的方法，包括这些多肽的组合物，包括这些多肽的疫苗及其使用方法，特别是在流行性感冒的检测、预防和/或治疗中的使用。
背景
流行性感冒病毒是主要的人病原体，引起呼吸系统疾病(通常称为“流行性感冒”或“流感”)，其严重性范围为从亚临床感染至可导致死亡的原发性病毒性肺炎。感染的临床影响随着流行性感冒株的毒力和宿主的暴露、病史、年龄、以及免疫状态而变化。全世界每年估计大约10亿的人经受流行性感冒病毒感染，导致3-5百万例严重疾病以及估计300,000至500,000例流行性感冒相关死亡。这些感染大多数可能归因于携带H1或H3血球凝集素亚型的甲型流行性感冒病毒，较少程度由乙型流行性感冒病毒促成，并且因此所有三种的代表包括在季节性疫苗中。当前免疫实践依赖于流行的流行性感冒病毒的早期鉴别以允许及时生产有效的季节性流行性感冒疫苗。除了在预测将在下一季中占主导的毒株方面的固有困难之外，抗病毒耐受性以及免疫逃逸也在当前疫苗在防止发病率和死亡率上的失败中发挥作用。除此外，由起源于动物贮器的高毒力病毒株引起大流行并且重配而增加人与人传播的可能性构成了对全球健康的显著且现实的威胁。
甲型流行性感冒病毒广泛分布于自然中并且可感染多种鸟类以及哺乳动物。流行性感冒病毒是属于正粘病毒科的包膜RNA病毒。其基因组由八个单链RNA区段组成，这些区段编码11种不同的蛋白、一种核蛋白(NP)、三种聚合酶蛋白(PA、PB1、以及PB2)、两种基质蛋白(M1以及M2)、三种非结构性蛋白(NS1、NS2、以及PB1-F2)、以及两种外膜糖蛋白：血球凝集素(HA)以及神经氨酸酶(NA)。这些病毒是基于HA以及NA蛋白的抗原结构的区别而分类的，其不同组合表示独特的病毒亚型，这些亚型进一步被分类为特异的流行性感冒病毒株。尽管所有已知的亚型都可以在鸟类中发现，当前流行的人甲型流行性感冒亚型是H1N1以及H3N2。系统发育分析已证实血球凝集素细分为两个主要的组：尤其在系统发育组1中的H1、H2、H5以及H9亚型，以及尤其系统发育组2中的H3、H4以及H7亚型。
乙型流行性感冒病毒株是严格地针对人的。乙型流行性感冒病毒株内的HA中的抗原变化小于甲型株内观察到的那些。乙型流行性感冒病毒的两个遗传上和抗原性上不同的谱系在人中流行，如由B/山形/16/88(也称为B/山形)以及B/维多利亚/2/87(B/维多利亚)谱系(弗格森(Ferguson)等人，2003)代表的。尽管由乙型流行性感冒病毒引起的疾病的光谱通常比由甲型流行性感冒病毒引起的更加温和，仍频繁观察到需要住院治疗的严重疾病具有乙型流行性感冒感染。
已知中和该流行性感冒病毒的抗体主要针对血球凝集素(HA)。血球凝集素或HA是一种三聚体糖蛋白，其被锚定到病毒衣并且具有双功能：它负责结合到细胞表面受体唾液酸并且摄取之后它介导病毒和内涵体膜的融合，导致在该细胞的胞液中释放病毒RNA。HA包括大的头部域以及较小的主干域。附接至该病毒膜是通过连接至该主干域的C-末端锚定序列介导的。该蛋白在指定的环中被翻译后切割以产生两种多肽，即HA1和HA2(全长序列被称为HA0)。膜远端头部区主要源自于HA1，并且膜近端主干区主要来自HA2(图1)。
季节性流行性感冒疫苗必须每年更新的原因是该病毒的大的可变性。在血球凝集素分子中，此变化具体地显现在头部域，其中抗原漂移和移位导致大量的不同变体。由于这也是免疫显性的区域，大部分中和抗体是针对此域并且通过干扰受体结合起作用。该头部域的免疫显性和大的变化的组合也解释了用具体株进行感染为什么不会导致对其他株的免疫：通过第一次感染引发的抗体仅识别有限数目的与原发性感染的病毒紧密相关的毒株。
近来，已描述了缺少所有或基本上所有流行性感冒血球凝集素球状头部域的流行性感冒血球凝集素主干域多肽，并且将其用于产生对该主干域多肽的一个或多个保守表位的免疫应答。认为该主干域多肽的表位比球状头部域的高免疫原性区域具有较小免疫原性，因此在该主干域多肽中缺少球状头部域可能允许发展针对该主干域多肽的一个或多个表位的免疫应答(斯蒂尔(Steel)等人，2010)。斯蒂尔(Steel)等人因此通过使A/波多黎各/8/1934(H1N1)以及A/香港/1968(H3N2)株的来自HA一级序列的HA1的氨基酸残基53至276缺失并且将其用短的柔性连接序列GGGG替代而建立了新的分子。用H3HK68构建体对小鼠进行疫苗接种不会引发与组1HA具有交叉反应性的抗血清。此外，如示于PCT/EP 2012/073706，这些主干域多肽是高度不稳定的并且不会采取如通过缺少抗体结合(显示结合到该主干区中的保守表位)证明的正确构象。
此外，博姆玛坎蒂(Bommakanti)等人(2010)描述了基于HA2的多肽，其包括HA2的氨基酸残基1-172、7-氨基酸接头(GSAGSAG)、HA1的氨基酸残基7-46、6-氨基酸接头GSAGSA，随后为HA1的残基290-321，在HA1中具有突变V297T、I300E、Y302T以及C305T。该设计是基于H3HA的序列(A/香港/1968)。该多肽仅提供针对H3亚型(A/Phil/2/82)内的另一个流行性感冒病毒株的交叉保护，而不提供针对H1亚型(A/PR/8/34)的交叉保护。在博姆玛坎蒂(Bommakanti)等人(2012)的一篇更近的论文中，描述了来自H1N1A/波多黎各/8/1934(H1HA0HA6)的基于HA的主干域序列。在此多肽中，残基55至302的等价物已经缺失，并且已经进行了突变I311T、V314T、I316N、C319S、F406D、F409T、以及L416D。基于H3的多肽和基于HA的多肽两者都表达于大肠杆菌，并且因此缺少作为天然存在的HA蛋白的部分的聚醣。当表达于大肠杆菌中时，该多肽主要作为高分子量聚集体和小单体部分回收。以两个表观解离常数即9和0.2μM，该多肽结合CR6261。作者们显示用佐以100μg的CpG7909的20μg的蛋白免疫(两次，4周间隔)之后，小鼠可幸存于用同源H1N1A/波多黎各/8/1934病毒的1LD90进行的激发。作者们也描述了循环置换的多肽可比得上以上针对A/香港/1/1968衍生的多肽所述的那些。这些多肽是源自于来自H1N1A/波多黎各/8/1934、H1N1A/北卡罗来纳州/20/99或H1N1A/加利福尼亚/07/2009的HA，并且在H1N1A/波多黎各/8/1934(即相同亚型内)的小鼠的温和激发(1LD90)模型中可提供部分保护。当在中和测定中测试时，来自用这些多肽免疫的豚鼠的血清未展现可检测水平的中和。
最近，陆(Lu)等人(2013)也描述了来源于H1N1A/加利福尼亚/05/2009的HA的可溶主干域(stem domain)多肽。在最终设计中，残基54-303的等价物(根据SEQ ID NO:1编号)已经被缺失(前导序列，残基1-17也是不存在的)，并且已经在该蛋白质的B环中引入了两个突变，即F407D和L413D。此外，该多肽包含C-末端三聚域(折叠子)。此外，还引入了两个内部单体二硫桥，一个在三聚折叠子域的区域内，并且一个在位置430和431处。该多肽在基于大肠杆菌的无细胞系统中产生(因此缺乏作为天然存在的HA蛋白的一部分的聚糖)，并且以变性形式回收，它需要在使用前重折叠。没有显示来自流行性感冒激发数据的免疫学或保护。
在最近的一篇论文中，马拉乔斯宇拉(Mallajosyula)等人(2014)也报道了主干域多肽。在此设计中，基于来自H1N1A/波多黎各/8/1934的HA，不仅HA1序列的很大一部分被缺失(残基42至289，根据SEQ ID NO:1编号)，还有HA2的N-末端和C-末端序列的很大一部分(分别为残基344至383和457至565)也被缺失。该多肽在C-末端包含折叠子三聚域，并也在大肠杆菌中产生，所以在病毒的HA上缺乏天然存在的聚糖。该多肽结合广泛中和性抗体CR6261、F10和FI6v3。该多肽也在流行性感冒激发模型(H1N1A/波多黎各/8/1934的1LD90)中进行测试，并能保护小鼠免于死亡。来源于H1N1A/新喀里多尼亚/20/1999和H1N1A/加利福尼亚/04/2009的HA的等价多肽也可以部分地保护。来源于H5N1A/越南/1203/2004的多肽在这种激发模式中只给出有限的保护。此外，以相对低剂量给予时所使用的激发模型是温和的(1-2LD90)。
因此仍存在对安全且有效的通用疫苗的需要，该疫苗刺激产生稳固的广泛中和抗体应答，并且提供针对当前和未来流行性感冒病毒株(季节性和大流行两者)的广泛集合的保护，具体而言提供针对系统发育组1和/或组2内一个或多个甲型流行性感冒病毒亚型的保护，以有效预防和治疗流行性感冒。
概述
此处提供了多种流行性感冒血球凝集素主干域多肽，提供多种主干域多肽的方法，包括这些多肽的组合物，包括这些多肽的疫苗及其使用方法。
在第一方面，本发明提供了新的免疫原性多肽，这些多肽包括流行性感冒血球凝集素主干域并且缺少球状头部，称为流行性感冒血球凝集素(HA)主干域多肽。当给予至受试者(具体而言人类受试者)时，这些多肽能够诱导免疫应答。在不存在优势表位(存在于膜远端头部域中)的情况下，本发明的多肽将膜近端主干域HA分子的保守表位呈现给免疫系统。为此，构成该头部域的HA0蛋白的一级序列的部分被去除，并且剩下的氨基酸序列直接地或在一些实施例中通过引入短的柔性连接序列(‘接头’)再连接以恢复氨基酸链的连续性。所得到的序列通过引入特定突变被进一步修饰，这些特定突变稳定了该HA0分子的剩下部分的天然3-维结构。这些免疫原性多肽不包括流行性感冒病毒的全长HA1域。
本发明提供了新颖的流行性感冒血球凝集素主干域多肽，包含：(a)一种流行性感冒血球凝集素HA1域，该HA1域包含HA1N-末端主干区段，该HA1N-末端主干区段通过具有0-50个氨基酸残基的连接序列共价连接至HA1C-末端主干区段，所述HA1C-末端区段被连接到(b)一种流行性感冒血球凝集素HA2域，其中该HA1域和HA2域来源于包括H1亚型的HA的甲型流行性感冒病毒亚型；并且
(c)其中该多肽不包括在HA1域和HA2域之间的接合处的蛋白酶切割位点；
(d)其中所述HA1N-末端区段包含HA1的氨基酸1-X，优选地是HA1的氨基酸p-x，并且其中该HA1C-末端主干区段包含HA1的氨基酸y-C-末端氨基酸，其中x＝SEQ ID NO:1的位置52(或在另一个血球凝集素中的等价位置)上的氨基酸，p＝SEQ ID NO:1的位置18(或在另一个血球凝集素中的等价位置)上的氨基酸并且y＝SEQ ID NO:1的位置321(或在另一个血球凝集素中的等价位置)上的氨基酸；
(e)其中包括氨基酸残基402-418的区域包含氨基酸序列X1NTQX2TAX3GKEX4N(H/K)X5E(K/R)(SEQ ID NO:8)，其中：
X1是选自下组的氨基酸，该组由以下各项组成：M、E、K、V、R以及T，
X2是选自下组的氨基酸，该组由以下各项组成：F、I、N、T、H、L以及Y，优选I、L或Y，
X3是选自下组的氨基酸，该组由以下各项组成：V、A、G、I、R、F以及S，优选A、I或F，
X4是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、E、K、M、以及V，优选I、Y、M或V，
X5是选自下组的氨基酸，该组由以下各项组成：L、H、I、N、R，优选I；
(f)其中位置337上的氨基酸残基(HA1域)选自下组，该组由以下各项组成：I、E、K、V、A、以及T，
位置340上的氨基酸残基(HA1域)选自下组，该组由以下各项组成：I、K、R、T、F、N、S以及Y，
位置352上的氨基酸残基(HA2域)选自下组，该组由以下各项组成：D、V、Y、A、I、N、S、以及T，并且
位置353上的氨基酸残基(HA2域)选自下组，该组由以下各项组成：K、R、T、E、G、以及V；并且
(g)其中该多肽进一步包含位置324上的氨基酸和位置436上的氨基酸之间的二硫桥；并且
(h)其中另外的氨基酸序列RMKQIEDKIEEIESK(SEQ ID NO:20)已经引入位置419-433处，或其中序列RMKQIEDKIEEIESKQK(SEQ ID NO:21)已经引入位置417-433处。
在某些实施例中，这些多肽包含完整的HA2域，即该HA2域包括跨膜域和细胞内序列。在某些实施例中，该HA2域已被截短。因此，在某些实施例中，本发明的多肽不包含HA的细胞内序列以及跨膜域。在某些实施例中，从该HA2域的位置514、515、516、517、518、519、520、521、522、523、524、525、526、527、526、528、529、或530(或等价物)至该HA2域的C末端的氨基酸序列已被去除。
根据本发明，该HA1C-末端主干区段的C-末端氨基酸连接至HA2域的N-末端氨基酸，从而形成了HA1域和HA2域之间的接合处。本发明的这些多肽不包含在HA1和HA2域之间的接合处的蛋白酶切割位点。在某些实施例中，该HA1C-末端主干区段的C-末端氨基酸残基(SEQ ID NO:1中的氨基酸343)是除了精氨酸(R)或赖氨酸(K)，优选地是谷氨酰胺(Q)的任何氨基酸。
本发明的这些多肽实质上比HA0小，优选地缺少所有或基本上所有的HA的球状头部。优选地，这些免疫原性多肽长度上不超过360，优选地不超过350、340、330、320、310、305、300、295、290、285、280、275、或270个氨基酸。在某些实施例中，这些免疫原性多肽长度上是从约250至约350，优选地从约260至约340，优选地从约270至约330，优选地从约270至约330个氨基酸。
本发明的多肽包括组1交叉中和抗体CR6261(如披露于WO 2008/028946)和/或抗体CR9114(如描述于WO 2013/007770)的保守主干域表位，该抗体CR9114是能够结合到并且中和组1和组2甲型流行性感冒病毒两者、连同乙型流行性感冒病毒的一种抗体。因此本发明的另一个方面是提供多种HA主干域多肽，其中所述多肽稳定地呈现抗体CR6261和/或CR9114的表位，如通过所述一个抗体或多个抗体结合至所述多肽表明的。在一个实施例中，这些多肽不结合到CR8020以及CR8057(描述于WO 2010/130636)，它们是仅结合到H3流行性感冒病毒的单克隆抗体。
此处提供的流行性感冒血球凝集素主干域多肽适合用于能够针对一个或多个甲型和/或乙型流行性感冒病毒株，具体针对H1亚型的流行性感冒病毒发生免疫应答的免疫原性组合物(例如疫苗)中。在一个实施例中，这些流行性感冒血球凝集素主干域多肽能够针对系统发育组1和/或组2的甲型流行性感冒病毒株发生免疫应答，特别是针对系统发育组1和组2两者的流行性感冒病毒株。在一个实施例中，这些多肽能够针对同源流行性感冒病毒株发生免疫应答。在一个实施例中，这些多肽能够针对相同和/或不同亚型的异源流行性感冒病毒株发生免疫应答。在另一个实施例中，这些多肽能够对系统发育组1和组2两者的流行性感冒病毒株以及乙型流行性感冒病毒株发生免疫应答。
根据本发明的多肽可用于例如孤立型治疗和/或预防和/或诊断由流行性感冒病毒、特别是系统发育组1或2甲型流行性感冒病毒和/或乙型流行性感冒病毒引起的一种疾病或病况，或与其他预防和/或治疗性处理诸如(现存的或未来的)疫苗、抗病毒剂和/或单克隆抗体组合。
在另一个方面，本发明提供编码这些流行性感冒HA主干域多肽的核酸分子。在又另一个方面，本发明提供包括编码这些免疫原性多肽的核酸的载体。
在另一个方面，本发明提供在受试者中诱导免疫应答的方法，该方法包括向该受试者给予根据本发明的多肽和/或核酸分子和/或载体。
在另一个方面，本发明提供包括根据本发明的多肽和/或核酸分子和/或载体的组合物。该组合物优选地是免疫原性组合物。此处提供的这些组合物可以处于任何允许将这些组合物给予至受试者例如小鼠、白鼬或人的形式。在特定实施例中，这些组合物适合于人给药。这些多肽、核酸分子以及组合物可用于预防和/或治疗流行性感冒病毒疾病的方法中和/或用于诊断目的。这些组合物可进一步包括药学上可接受的载体或赋形剂。在某些实施例中，此处描述的组合物包括佐剂或与佐剂组合给予。
在另一个方面，本发明提供用作疫苗的多肽、核酸和/或载体。本发明具体而言涉及在预防和/或治疗由系统发育组1和/或2的甲型流行性感冒病毒亚型和/或乙型流行性感冒病毒引起的一种疾病或病况，具体由包含该H1亚型的HA的流行性感冒病毒引起的疾病或病况中，用作疫苗的免疫原性多肽、核酸和/或载体。
根据本发明的多肽的不同实施例以及用途将从以下本发明的详细描述中变得清晰。
附图简要说明
图1显示了如以天然三聚体存在的处于融合前状态的HA单体的模型。HA1是以浅灰色显示，HA2是以深灰色显示。指明了螺旋A(CR6261的表位的重要部分)以及螺旋CD(三聚体接口的部分)，还指明了连接这些二级结构元素的环。也指明了HA1的C-末端以及HA2的N-末端。融合肽位于HA2的N-末端。
图2.针对表达SEQ ID NO:65至71和SEQ ID NO:76至78(在PCT/EP 2014/060997中披露)的培养物的上清液而获得的夹心Elisa结果。捕获和检测抗体示于图上方。Mini-HA是指SEQ ID NO:2的可溶形式，其中残基519-565的等价物已被RSLVPRGSPGHHHHHH取代；FL-HA-FFH是指SEQ ID NO:1的可溶形式，它包含从位置520的C末端Flag-凝血酶-折叠子-His序列(SEQ ID NO:4)；FL-HA-7xHis是指SEQ ID NO:1的可溶形式，它包含从位置530的C末端序列EGRHHHHHHH。
图3.针对表达本发明的多肽的培养物的上清液而获得的夹心Elisa结果，本发明的这些多肽包含在位置419-433处的GCN4衍生序列RMKQIEDKIEEIESK(SEQ ID NO:20)(t2变体)。捕获和检测抗体示于图上方。Mini-HA-t2来源于通过在位置419-433处引入SEQ IDNO:20的Mini-HA；FL-HA-FFH、FL-HA-7xHis，如上。
图4.针对表达本发明的多肽的培养物的上清液而获得的夹心Elisa结果，本发明的这些多肽包含在位置417-433处的GCN4衍生序列RMKQIEDKIEEIESKQK(SEQ ID NO:21)(t3变体)。捕获和检测抗体示于图上方。Mini-HA-t3来源于通过在位置417-433处引入SEQ IDNO:21的Mini-HA；FL-HA-FFH、FL-HA-7xHis，如上。
图5.来自纯化过程中的最后一步的Superdex 200尺寸排阻柱的s55G7-t2、s127H1-t2和s86B4-T2的洗脱曲线。色谱下的编号线表示在洗脱过程中收集的级分。
图6.对在Superdex 200尺寸排阻柱的洗脱过程中收集的级分的SDS-PAGE和蛋白质印迹分析。对应于这些级分的编号示于图5中。对于蛋白质印迹上的检测，使用识别C-末端his标签的抗体。
图7.在广谱中和抗体CR9114、CR6261、和CR8020的Fab片段的存在和不存在的情况下，s127H1-T2的尺寸排阻色谱(Tosoh(东曹)G2000分析柱)。在从柱上洗脱期间通过多角度光散射来确定个体蛋白质和/或复合物的分子量，并列于表8中。
图8.使用生物膜层干涉技术将本发明的多肽s127H1-t2结合至单克隆抗体CR6261和CR9114上。顶图显示暴露于变化浓度的s127H1-t2的固定化单克隆抗体的个体结合曲线，底图显示用以估计Kd的稳态分析。
图9.阴性对照(PBS，按3周间隔3次免疫)和阳性对照(15mg/kg CR6261，激发前1天)组的存活率(A)、体重减轻(B)和临床得分(C)。在最后一次免疫后四周，用致死剂量(25xLD50)的H1N1A/波多黎各/8/34激发小鼠并监测21天。误差条表示95％置信区间(B)或四分位数间距(C)。
图10.在10μg基质-M存在抑或不存在的情况下，用10μg s127H1-t2免疫的实验组(3周间隔3次免疫)的存活率(A)、体重减轻(B)和临床得分(C)。在最后一次免疫后四周，用致死剂量(25x LD50)的H1N1A/波多黎各/8/34激发小鼠并监测21天。出于比较的原因，还显示了阴性对照组(PBS)。误差条表示95％置信区间(B)或四分位数间距(C)
图11.使用s127H1-t2(A)或全长HA(B)的可溶形式作为抗原，阴性对照组和的实验组的血清的Elisa结果。条表示中值。
图12.用本发明的包含佐剂的多肽s127H1-t2免疫后诱导的抗体能够在竞争ELISA(A)中与CR9114针对结合来自H1N1A/布里斯班/59/07的全长HA进行竞争。出于比较的原因，在分开的图中指明了未标记的CR9114(即自我竞争)和非结合单克隆抗体CR8020和CR-JB(两者都从5μg/ml起始浓度连续稀释)的竞争水平。
图13.阴性对照(PBS，按3周间隔3次免疫)和阳性对照(15mg/kg CR6261，激发前1天)组的存活率(A)、相对体重减轻(B)和临床得分(C)。在最后一次免疫后四周，用致死剂量(25x LD50)的H1N1A/波多黎各/8/34激发小鼠并监测21天。误差条表示95％置信区间(B)或四分位数间距(C)。
图14.在10μg基质-M存在下，用30μg s127H1-t2-cl18长进行免疫1次(A)、2次(B)、或3次(C)的组的存活率。在最后一次免疫后四周，用致死剂量(25x LD50)的H1N1A/波多黎各/8/34激发小鼠并监测21天。出于比较的原因，还显示了阴性对照组(PBS)。
图15.在10μg基质-M存在下，用30μg s127H1-t2-cl18长进行免疫1次(A)、2次(B)、或3次的组的相对体重变化。在最后一次免疫后四周，用致死剂量(25x LD50)的H1N1A/波多黎各/8/34激发小鼠并监测21天。出于比较的原因，还显示了阴性对照组(PBS)。误差条表示95％置信区间。
图16.在10μg基质-M存在下，用30μg s127H1-t2-cl18长进行免疫1次(A)、2次(B)、或3次的组的临床得分。在最后一次免疫后四周，用致死剂量(25x LD50)的H1N1A/波多黎各/8/34激发小鼠并监测21天。出于比较的原因，还显示了阴性对照组(PBS)。误差条表示四分位数间距。
图17.使用s127H1-t2-cl18长(A)或全长HA(B)的可溶形式作为抗原，阴性对照组和的实验组的激发前血清(最后一次免疫后4周)的ELISA结果。条表示中值。
图18.用本发明的佐有基质-M的多肽s127H1-t2-cl18长免疫后诱导的抗体能够在竞争ELISA(A)中与CR9114针对结合来自H1N1A/布里斯班/59/07的全长HA进行竞争。出于比较的原因，在独立的图(B)中指明了未标记的CR9114(即自我竞争)和非结合单克隆抗体CR8020(两者都从5μg/ml起始浓度连续稀释)的竞争水平。条表示中值。
图19.阴性对照(PBS，按3周间隔3次免疫)和阳性对照(15mg/kg CR6261，激发前1天)组的(A)存活率。在最后一次免疫后四周，用致死剂量(12.5x LD50)的H5N1A/香港/156/97激发小鼠。在10μg基质-M存在下，用30μg s127H1-t2免疫3次的组的(B)存活率、(C)相对体重变化和(D)中值临床得分。误差条表示95％置信区间(C)或四分位数间距(D)。在最后一次免疫后四周，用致死剂量(12.5x LD50)的H5N1A/香港/156/97激发小鼠并监测21天。出于比较的原因，阴性对照组(PBS)还示于B、C、D中。
图20.使用来自多个组1(H1、H5和H9)和组II(H3和H7)流行性感冒株的全长HA作为抗原，如实例5中所述的用本发明的多肽s127H1-t2免疫3次的小鼠的血清的Elisa结果。诱导的抗体识别所有来自组1的测试的FL HA。
图21.阴性对照(PBS，按3周间隔3次免疫)和阳性对照(15mg/kg CR6261，激发前1天)组的(A)存活率。在最后一次免疫后四周，用致死剂量(12.5x LD50)的H1N1A/布里斯班/59/2007激发小鼠。在10μg基质-M存在下，用30μg s127H1-t2免疫3次的组的(B)存活率、(C)相对体重变化和(D)中值临床得分。误差条表示95％置信区间(C)或四分位数间距(D)。在最后一次免疫后四周，用致死剂量(12.5x LD50)的H1N1A/布里斯班/59/2007激发小鼠并监测21天。出于比较的原因，阴性对照组(PBS)还示于B、C、D中。
图22.使用来自用本发明的多肽s127H1-t2或PBS免疫的小鼠的血清的拟颗粒中和测定。
图23.抗体依赖性细胞毒性(ADCC)替代测定。使用来自H5N1A/香港/156/97(A)或与H1N1A/布里斯班/59/07(B)的FL HA转染的靶细胞作为抗原的来源，来自用本发明的多肽s127H1-t2免疫的小鼠的血清展示在最高血清浓度下的FcγRIV信号转导活性的30-40倍诱导。
图24.血清转移和用如实例9中所述的H5N1A/香港/156/97激发后的小鼠的存活率(A)和％体重变化(B)。
图25.第70天的供体小鼠(D)和血清转移(-4天)或激发(第0天)之前的受体小鼠(R)的全长HA(H1N1A/布里斯班/59/2007)ELISA效价。使用基于斜率的加权平均方法分析数据。开放符号表示LOD处的测量。条表示中值。
图26.用如实例10中所述的H1N1A/NL/602/09免疫和激发后的小鼠的存活率(A)和％体重变化(B)。
图27.(A)：如实例10中所述进行免疫的小鼠的全长HA(H1N1A/布里斯班/59/2007)ELISA效价。使用基于斜率的加权平均方法分析数据。开放符号表示LOD处的测量。条表示中值。(B)：如实例10中所述小鼠免疫后获得的血清IgG CR9114竞争结合。将来自H1N1A/布里斯班/59/2007的FL HA用作抗原。显示的数据是组中值，误差条表示四分位数间距。表示了起始于5μg/ml溶液并以同一方式稀释作为血清样品的CR9114和CR8020的数据。
图28.总共10472个克隆的初级筛选(分别来自组1和组2的5544个和4928个)，数据被归一化为包含于实验中的FL HA结合和表达的平均值。在CR9114夹心测定(图A)中的前20％克隆也展现了FL HA表达的>50％表达与针对FL HA(小图B)所观察到的信号的CR6261>80％的结合信号被认为是命中；此过程产生了703个命中(分别来自库1和库2的596个和107个)。
图29.本发明的多肽的CR9114夹心ELISA结果：(A)SEQ ID NO:158至162，全部包含C-末端Flag-折叠子-his序列(B)SEQ ID NO:163至166，全部包含C-末端TCS-his序列。
图30.在存在和不存在CR9114(指示为CRF9114)或CR6261(表示为CRF6261)的Fab片段情况下，SEQ ID NO:158的SEC MALS结果。来源于多角度光散射分析的分子量在实例12中给出并且表示以每本发明的多肽的三聚体3个Fab片段形成复合物。
图31.用如实例13中所述的H1N1A/布里斯班/59/07免疫和激发后的小鼠的存活率(A)和％体重变化(B)。
图32.(A)：如实例13中所述进行免疫的小鼠的全长HA(H1N1A/布里斯班/59/2007)ELISA效价。使用基于斜率的加权平均方法分析数据。开放符号表示LOD处的测量。条表示中值。(B)：如实例18中所述小鼠免疫后获得的血清IgG CR9114竞争结合。将来自H1N1A/布里斯班/59/2007的FL HA用作抗原。显示的数据是组中值，误差条表示四分位数间距。表示了起始于5μg/ml溶液并以同一方式稀释作为血清样品的CR9114和CR8020的水平。
图33.用如实例14中所述的H5N1A/香港/156/97免疫和激发后的小鼠的存活率(A)和％体重变化(B)。
图34.(A)：如实例14中所述进行免疫的小鼠的全长HA(H1N1A/布里斯班/59/2007)ELISA效价。使用基于斜率的加权平均方法分析数据。开放符号表示LOD处的测量。条表示中值。(B)：如实例18中所述小鼠免疫后获得的血清IgG CR9114竞争结合。将来自H1N1A/布里斯班/59/2007的FL HA用作抗原。显示的数据是组中值，误差条表示四分位数间距。表示了起始于5μg/ml溶液并以同一方式稀释作为血清样品的CR9114和CR8020的水平。
图35.用如实例15中所述的H1N1A/波多黎各/8/1934免疫和激发后的小鼠的存活率(A)和％体重变化(B)。
图36.(A)：如实例15中所述进行免疫的小鼠的全长HA(H1N1A/布里斯班/59/2007)ELISA效价。使用基于斜率的加权平均方法分析数据。开放符号表示LOD处的测量。条表示中值。(B)：如实例18中所述小鼠免疫后获得的血清IgG CR9114竞争结合。将来自H1N1A/布里斯班/59/2007的FL HA用作抗原。显示的数据是组中值，误差条表示四分位数间距。表示了起始于5μg/ml溶液并以同一方式稀释作为血清样品的CR9114和CR8020的水平。
定义
以下给出如本发明中所用的术语的定义。
根据本发明的氨基酸可以是二十种天然存在(或‘标准’氨基酸)的任一种或其变体，比如例如D-脯氨酸(脯氨酸的D-对映体)或在蛋白质中未天然发现的任何变体，比如例如正亮氨酸。这些标准氨基酸可以基于其性质分成若干群组。重要因素是电荷、亲水性或疏水性、尺寸以及官能团。这些性质对于蛋白质结构和蛋白质-蛋白质相互作用来说是重要的。一些氨基酸具有特殊的性质，例如可以与其他半胱氨酸残基形成共价二硫键(或二硫桥)的半胱氨酸，形成到多肽主链的环的脯氨酸，以及比其他氨基酸更灵活的甘氨酸。表2展示这些标准氨基酸的缩写和性质。
术语“氨基酸序列一致性”是指一对对齐的氨基酸序列之间的一致性或相似性程度，通常表示为百分比。百分比同一性是以下候选序列中的氨基酸残基百分比，该候选序列与在比对序列并且引入缺口(如果必要的话，以实现最大序列同源性百分比)之后该肽中的对应氨基酸残基是相同的(即，比对中在给出位置处的氨基酸残基是相同的残基)或相似的(即，比对中在给出位置处的氨基酸取代是保守性取代，如以下讨论的)。序列同源性包括序列一致性以及相似性的百分比是使用本领域中熟知的序列比对技术确定的，诸如通过目测以及数学计算，或更优选地，该比较是通过使用计算机程序比较序列信息进行的。一个示例性的、优选的计算机程序是遗传学计算机组(GCG；麦迪逊，威斯康星州)威斯康星程序包版本10.0的程序，‘GAP’(德弗罗(Devereux)等人(1984))。
“保守性取代”是指一类的氨基酸被相同类的另一个氨基酸替代。在具体的实施例中，保守性取代不改变多肽的结构或功能，或两者。用于保守性取代目的的氨基酸类别包括疏水的(例如Met，Ala，Val，Leu)、中性亲水(例如Cys，Ser，Thr)、酸性(例如Asp，Glu)、碱性(例如Asn，Gln，His，Lys，Arg)、构象打断者(例如Gly，Pro)以及芳香族的(例如Trp，Tyr，Phe)。
如此处使用的，术语“疾病”以及“障碍”可互换地使用，以指代受试者中的病况。在一些实施例中，该病况是病毒感染，特别是流行性感冒病毒感染。在特定实施例中，术语“疾病”是指由于病毒在细胞或受试者中的存在、或通过该病毒对细胞或受试者的侵染导致的病理状态。在某些实施例中，该病况是受试者中的疾病，其严重性通过给予免疫原性组合物来诱导该受试者中的免疫应答而被降低。
如此处使用的，在向受试者给予治疗的背景下术语“有效量”是指具有一个或多个预防和/或治疗效果的治疗的量。在某些实施例中，在向受试者给予治疗的背景下术语“有效量”是指足够实现如下的治疗量：流行性感冒病毒感染、与其相关的疾病或症状的严重性的减少或改善，诸如但不限于流行性感冒病毒感染、与其相关的疾病或症状的持续时间减少，对流行性感冒病毒感染、与其相关的疾病或症状的进展的预防，对流行性感冒病毒感染、与其相关的疾病或症状的发展或发作或复发的预防，流行性感冒病毒从一个受试者传播至另一个受试者的情况的预防或减少，受试者住院和/或住院时间长短的减少，患有流行性感冒病毒感染或与其相关的疾病的受试者的存活率的增加，流行性感冒病毒感染或与其相关的疾病的消除，流行性感冒病毒复制的抑制或减少，流行性感冒病毒滴度的减少；和/或另一种治疗的一个或多个预防或治疗作用的增强和/或改善。在某些实施例中，该有效量不导致免受流行性感冒病毒疾病的完全保护，但比较于未治疗的受试者导致更低的滴度或减少数目的流行性感冒病毒。流行性感冒病毒的滴度、数目或总负担上的减少的益处包括但不限于该感染的严重症状更少，该感染的症状更少，并且与该感染关联的疾病的时间长短上减少。
如在此所用，术语“宿主”意欲指已经引入了载体(诸如克隆载体或表达载体)的生物体或细胞。生物体或细胞可以是原核或真核的。优选地，宿主包括被分离的宿主细胞，例如培养物中的宿主细胞。术语“宿主细胞”仅意味着这些细胞被修饰以(过度)-表达本发明的多肽。应理解，术语宿主意欲不仅指具体主题生物体或细胞，而且还指此类生物体或细胞的子代。因为某些修饰可以由于或者突变或者环境影响而在后代中发生，所以此类子代可以实际上与亲本生物体或细胞不相同，但仍包括在如在此所用的术语“宿主”的范围内。
如在此所用，术语“包括(included)”或“包括着(including)”被视为后面有措辞“无限制”。
如此处使用的，术语“感染”意指通过病毒在细胞或受试者中的扩增和/或存在进行的侵染。在一个实施例中，感染是“活性”感染，即其中病毒在细胞或受试者中复制的一种感染。这样的感染是通过该病毒从最初被该病毒感染的细胞、组织、和/或器官传播至其他细胞、组织、和/或器官来表征。感染也可以是潜伏感染，即其中该病毒未复制的一种感染。在某些实施例中，感染是指由于病毒在细胞或受试者中的存在、或通过该病毒对细胞或受试者的侵染导致的病理状态。
流行性感冒病毒被分类为流行性感冒病毒类型：甲型、乙型和丙型。如此处使用的术语“流行性感冒病毒亚型”是指甲型流行性感冒病毒变体，其通过血球凝集素(H)以及神经氨酸酶(N)病毒表面蛋白的组合来表征。根据本发明，流行性感冒病毒亚型可以通过其H数目被称为诸如，如“包括H3亚型的HA的流行性感冒病毒”、“H3亚型的流行性感冒病毒”或“H3流行性感冒”，或通过H数目以及N数目的组合被称为诸如，如“流行性感冒病毒亚型H3N2”或“H3N2”。术语“亚型”确切地包括每个亚型内的所有个体“株”，其通常从突变产生并且显示不同病原谱，包括天然分离体连同人工突变体或重配体等。此类株也可称为病毒亚型的不同“分离体”。因此，如在此所用，术语“株”和“分离体”能可互换地使用。人流行性感冒病毒株或分离体的当前命名法包括病毒的类型(属)，即甲型、乙型或丙型，第一次分离的地理定位，株编号以及分离年份，通常在括号中给出HA以及NA的抗原说明，例如A/莫斯科/10/00(H3N2)。在该命名法中非人株也包括起源宿主。甲型流行性感冒病毒亚型可通过参照其系统发育组进一步分类。系统发育分析已证实血球凝集素细分为两个主要的组：尤其在系统发育组1(“组1”流行性感冒病毒)中的H1、H2、H5以及H9亚型，以及尤其系统发育组2(“组2”流行性感冒病毒)中的H3、H4、H7以及H10亚型。
如此处使用的，术语“流行性感冒病毒疾病”是指由于流行性感冒病毒(例如甲型或乙型流行性感冒病毒)在细胞或受试者中的存在或流行性感冒病毒对细胞或受试者的侵染导致的病理状态。在特定的实施例中，该术语是指由流行性感冒病毒引起的呼吸系统疾病。
如此处使用的，术语“核酸”旨在包括DNA分子(例如，cDNA或基因组DNA)以及RNA分子(例如，mRNA)以及使用核苷酸类似物产生的DNA或RNA的类似物。该核酸可以是单链或双链。核酸分子可以被化学或生物化学修饰，或可以包含非天然或衍生化的核苷酸碱基，如本领域的技术人员将容易了解。此类修饰包括例如标记；甲基化；用一种类似物取代天然存在的核苷酸中的一者或多者；核苷酸间修饰，诸如不带电的键(例如甲基膦酸酯、磷酸三酯、氨基磷酸酯、氨基甲酸酯等)，带电的键(例如硫代磷酸酯、二硫代磷酸酯等)；侧位部分(例如多肽)；嵌入剂(例如吖啶、补骨脂素等)；螯合剂；烷基化剂；以及被修饰的键(例如α异头核酸等)。除非另外规定，否则对核酸序列的提及涵盖其互补序列。因此，对具有具体序列的核酸分子的提及应理解为涵盖其互补链与其互补序列。互补链还可用于例如反义疗法、杂交探针以及PCR引物。
如此处使用的，在某些实施例中，HA中氨基酸的编号是基于野生型流行性感冒病毒的HA0中氨基酸的编号，例如H1N1流行性感冒株A/布里斯班/59/2007(SEQ ID NO:1)的氨基酸的编号。如在本发明中所使用，措辞“在HA中位置“x”处的氨基酸”因此意指与具体野生型流行性感冒病毒(例如A/布里斯班/59/2007)(SEQ ID NO:1，其中HA2域的氨基酸已经以斜体指示)的HA0中位置x处的氨基酸相对应的氨基酸。技术人员会理解，其他流行性感冒病毒株和/或亚型中的等价氨基酸可以通过多重序列比对确定。注意，在本申请中所使用的编号系统中，1是指未成熟HA0蛋白质的N-末端氨基酸(SEQ ID NO:1)。该成熟序列起始于例如SEQ ID NO:1的位置18。本领域的普通技术人员会理解，在生产过程中指导蛋白(例如对应于SEQ ID NO:1的氨基酸1-17)的转运的前导序列(或信号序列)通常不存在于例如在疫苗中使用的最终多肽中。在某些实施例中，根据本发明的多肽因此包括不具有前导序列的氨基酸序列，即该氨基酸序列是基于HA0的不具有信号序列的氨基酸序列。
如本领域的普通技术人员已知的，“多肽”是指通过酰胺键连接的氨基酸的多聚体。如此处使用的，该术语可以是指通过共价酰胺键连接的单个多肽链。术语也可以是指通过非共价相互作用诸如离子接触、氢键、范德瓦尔斯接触以及疏水接触相关联的多个多肽链。本领域的普通技术人员会意识到，该术语包括已被修饰的多肽，例如通过翻译后加工诸如信号肽切割、二硫键形成、糖基化(例如，N-连接的以及O-连接的糖基化)、蛋白酶切割以及脂质修饰(例如S-棕榈酰化)来修饰。
“主干域多肽”是指包括组成天然存在的(或野生型)血球凝集素(HA)的主干域的一个或多个多肽链的多肽。典型地，主干域多肽是单个多肽链(即对应于血球凝集素HA0多肽的主干域)或两个多肽链(即对应于与血球凝集素HA2多肽相关的血球凝集素HA1多肽的主干域)。根据本发明，与野生型HA分子比较，主干域多肽包括一个或多个突变，具体而言野生型HA的一个或多个氨基酸残基可能已被其他在具体野生型HA中对应位置上非天然存在的氨基酸取代。根据本发明的主干域多肽可另外包括一个或多个连接序列，如下所述。
术语“载体”表示可以插入第二核酸分子以便引入到宿主中的核酸分子，在该宿主中它将被复制并且在一些情况下被表达。换句话说，载体能够输送它所已经连接的核酸分子。如在此所用，术语“载体”涵盖克隆以及表达载体。载体包括但不限于质粒、粘粒、细菌人工染色体(BAC)和酵母人工染色体(YAC)以及来源于细菌噬菌体或植物或动物(包括人类)病毒的载体。载体包含由所提议的宿主识别的复制起点，并且在表达载体情况下是启动子；和由宿主识别的其他调节区。某些载体能够在它们被引入到其中的宿主中自主复制(例如具有细菌复制起点的载体可以在细菌中复制)。其他载体可以在被引入到宿主中后被整合到宿主的基因组中，并且从而与宿主基因组一起复制。
如此处使用的，在病毒的背景下术语“野生型”是指流行的、天然流行的并且产生典型的疾病爆发的流行性感冒病毒。
详细说明
流行性感冒病毒对全球公共健康具有显著影响，每年引起数百万例严重疾病、数千例死亡、以及相当大的经济损失。当前三价流行性感冒疫苗引发对疫苗株以及紧密相关的分离体的强力中和抗体应答，但很少扩大到一个亚型内更发散的株或扩大到其他亚型。此外，选择适合的疫苗株呈现许多挑战并且经常导致次佳保护。另外，目前不可以预测下一个大流行病毒的亚型，包括它将会出现的时间和地点。
血球凝集素(HA)是来自甲型流行性感冒病毒的主要包膜糖蛋白，其是中和抗体的主要靶标。血球凝集素在进入过程中具有两个主要功能。第一，血球凝集素通过与唾液酸受体的相互作用介导病毒附接至靶细胞的表面。第二，病毒的内吞作用之后，血球凝集素随后触发病毒和内涵体膜的融合以将其基因组释放至靶细胞的细胞质中。HA包括约500个氨基酸的大的胞外域，其被宿主衍生的酶切割以产生通过二硫键保持连接的2个多肽。N-末端片段(HA1，320-330个氨基酸)的大多数形成膜远端球状域，该膜远端球状域包含受体-结合位点以及由病毒-中和抗体识别的大部分决定簇。较小的C-末端部分(HA2，约180个氨基酸)形成茎状结构，该茎状结构将该球状域锚定至细胞膜或病毒膜。在HA1多肽(亚型之间34％-59％同源性)中亚型之间的序列同源性的程度小于在HA2多肽中的(51％-80％同源性)。大部分保守区是切割位点附近的序列，具体地HA2N-末端23个氨基酸，其在所有甲型流行性感冒病毒亚型中是保守的(洛瑞尤(Lorieau)等人，2010)。此区域的部分在HA前体分子(HA0)中作为表面环暴露，但当HA0被切割为HA1和HA2时变得不可及。
大部分中和抗体结合到围绕该受体结合位点的环，并干扰受体结合以及附接。由于这些环是高度可变的，靶向这些区域的大部分抗体是株-特异性的，解释了为什么当前疫苗引发这种受限的、株-特异性的免疫。然而，近来，产生了针对流行性感冒病毒血球凝集素的具有广泛的交叉中和效力的完全人类单克隆抗体。功能性以及结构性分析已经揭示，这些抗体干扰膜融合过程，并且是针对流行性感冒HA蛋白的主干域中的高度保守的表位(斯罗索比(Throsby)等人，2008；艾基尔特(Ekiert)等人2009，WO 2008/028946，WO 2010/130636，WO 2013/007770)。
稳定呈现这些抗体的表位的主干域多肽描述于共同未决专利申请PCT/EP 2012/073706中。至少一些此处描述的主干域多肽稳定地呈现CR6261和/或CR9114的表位，并且在小鼠中是免疫原性的。在共同未决的专利申请PCT/EP 2014/060997中已经描述了稳定地呈现CR6261和/或CR9114的表位的另外的免疫原性主干域多肽。
根据本发明，已经设计了呈现这些表位的新的HA主干域多肽。这些多肽可用于建立通用的基于表位的疫苗，该疫苗诱导针对广范围的流行性感冒株的保护。像在之前所述的主干域多肽中一样，该高度可变的和免疫显性的部分(即头部域)被首先从该全长HA分子去除以建立主干域多肽，也称为迷你-HA，从而将免疫应答向着广泛中和抗体的表位所处的主干域重定向。以上提到的广泛中和抗体用于探查新建立的分子的正确折叠，并且证实中和表位的存在。
相比于那些抗体与前面所述的主干多肽的结合(PCT/EP 2012/073706和PCT/EP2014/060997)，本发明的新的主干域多肽显示抗体(具体为CR6261和/或CR9114)的增加的结合、和/或对多聚化的增加的倾向和增加的稳定性。
在不存在优势表位(存在于膜远端头部域中)的情况下，本发明的主干域多肽能够将膜近端主干域HA分子的保守表位呈现给免疫系统。为此，构成该头部域的HA0蛋白的一级序列的部分被去除，并且直接地或在一些实施例中通过引入短的柔性连接序列(‘接头’)再连接以恢复多肽链的连续性。所得到的多肽序列通过引入特定突变被进一步修饰，这些特定突变稳定了该HA0分子的剩下部分的天然3-维结构。
本发明具体提供了流行性感冒血球凝集素主干域多肽，包含：
(a)一种流行性感冒血球凝集素HA1域，该HA1域包含HA1N-末端主干区段，该HA1N-末端主干区段通过具有0-50个氨基酸残基的连接序列共价连接至HA1C-末端主干区段，所述HA1C-末端区段被连接到(b)一种流行性感冒血球凝集素HA2域，其中该HA1域和HA2域来源于包括H1亚型的HA的甲型流行性感冒病毒亚型；
(c)其中该多肽不包括在HA1和HA2域之间的接合处的蛋白酶切割位点；
(d)其中所述HA1N-末端区段包含HA1的氨基酸1-x，
优选地是HA1的氨基酸p-x，并且其中该HA1C-末端主干区段包含HA1的氨基酸y-C-末端氨基酸，其中x＝SEQ ID NO:1的位置52(或在另一个流行性感冒病毒株的血球凝集素中的等价位置)上的氨基酸，p＝SEQ ID NO:1的位置18(或在另一个流行性感冒病毒的血球凝集素中的等价位置)上的氨基酸并且y＝SEQ ID NO:1的位置321(或在另一个血球凝集素中的等价位置)上的氨基酸；
(e)其中包括氨基酸残基402-418的区域包含氨基酸序列X1NTQX2TAX3GKEX4N(H/K)X5E(K/R)(SEQ ID NO:8)，
其中：
X1是选自下组的氨基酸，该组由以下各项组成：M、E、K、V、R以及T，
X2是选自下组的氨基酸，该组由以下各项组成：F、I、N、T、H、L以及Y，优选I、L或Y，
X3是选自下组的氨基酸，该组由以下各项组成：V、A、G、I、R、F以及S，优选A、I或F，
X4是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、E、K、M、以及V，优选I、Y、M或V，
X5是选自下组的氨基酸，该组由以下各项组成：L、H、I、N、R，优选I；
(f)其中位置337上的氨基酸残基(HA1域)选自下组，该组由以下各项组成：I、E、K、V、A、以及T，
位置340上的氨基酸残基(HA1域)选自下组，该组由以下各项组成：I、K、R、T、F、N、S以及Y，
位置352上的氨基酸残基(HA2域)选自下组，该组由以下各项组成：D、V、Y、A、I、N、S、以及T，并且
位置353上的氨基酸残基(HA2域)选自下组，该组由以下各项组成：K、R、T、E、G、以及V；并且
(g)其中该多肽进一步包含位置324上的氨基酸和位置436上的氨基酸之间的二硫桥；并且
(h)其中氨基酸序列RMKQIEDKIEEIESK(SEQ ID NO:20)已经引入位置419-433处，或其中序列RMKQIEDKIEEIESKQK(SEQ ID NO:21)已经引入位置417-433处。
因此，本发明提供了模拟天然血球凝集素分子的主干的三维构象的稳定的血球凝集素主干多肽。
本发明的多肽不包括全长HA1域。
因此，这些多肽实质上比HA0小，优选地缺少所有或基本上所有的HA的球状头部。优选地，这些免疫原性多肽长度上不超过360，优选地不超过350、340、330、320、310、305、300、295、290、285、280、275、或270个氨基酸。在某些实施例中，这些免疫原性多肽长度上是从约250至约350，优选地从约260至约340，优选地从约270至约330，优选地从约270至约330个氨基酸。
根据本发明，该“HA1N-末端区段”是指对应于流行性感冒血球凝集素(HA)分子的HA1域的氨基-末端部分的多肽区段。该HA1N-末端多肽区段包括从该HA1域的位置1至位置x的氨基酸，其中位置x上的氨基酸是HA1内的氨基酸残基。术语“HA1C-末端区段”是指对应于流行性感冒血球凝集素HA1域的羧基-末端部分的多肽区段。该HA1C-末端多肽区段包括从该HA1域的位置y的氨基酸至C-末端氨基酸并且包括C-末端氨基酸，其中位置y上的氨基酸是HA1内的氨基酸残基。根据本发明，y是大于x，因此该HA1N-末端区段和该HA1C-末端区段之间，即HA1的位置x上的氨基酸和位置y上的氨基酸之间的HA1域的区段已经缺失，并且在一些实施例中，由连接序列替代。因此，在某些实施例中，该HA1区段中的缺失包括从在位置x+1处的氨基酸直至在位置y-1处的氨基酸并且包括在位置y-1处的氨基酸的氨基酸序列。
在某些实施例中，这些多肽不包括信号序列。因此在某些实施例中，该HA1N-末端区段包括HA1的氨基酸p-x，其中p是该成熟HA分子的第一氨基酸(例如在SEQ ID NO:1的情况下p＝18)。普通技术人员将能够确定在其他血球凝集素中的等价的氨基酸并且以制备不含信号肽的本文所述的多肽(例如SEQ ID NO:1的氨基酸1-17，或其他H1流行性感冒病毒株的等效位置(参见，例如，表2))，至HA1域的位置x。
根据本发明，该HA1N-末端区段包括氨基酸1-x，优选地是HA1域的p-x，其中在SEQID NO:1中x＝52并且p＝18，或H1亚型的其他HA序列中的等效氨基酸位置。
根据本发明，该HA1C-末端多肽区段包括从位置y的氨基酸并且包括H1HA1域的C-末端氨基酸，其中y是321或H1亚型的其他HA序列中的等效氨基酸位置。
根据本发明，因此该HA1N-末端主干区段包括HA1的氨基酸残基1-52、优选地HA1的氨基酸残基18-52，并且该HA1C-末端主干区段包括HA1的氨基酸残基321-343。在某些实施例中，该HA1N-末端主干区段由HA1的氨基酸残基1-52、优选地HA1的氨基酸残基18-52组成，并且该HA1C-末端主干区段由HA1的氨基酸残基321-343组成。
根据本发明，这些多肽不包含在HA1和HA2域之间的接合处的蛋白酶切割位点。因此，这些血球凝集素主干域多肽对HA1和HA2之间的接合处的蛋白酶切割具有抗性。本领域的普通技术人员已知，跨越HA1和HA2的Arg(R)-Gly(G)序列(即，SEQ ID NO:1中的氨基酸位置343和344)是胰蛋白酶和胰蛋白酶样蛋白酶的识别位点，并且典型地被切割用于血球凝集素激活。由于此处描述的这些HA主干域多肽不应该被激活，本发明的流行性感冒血球凝集素主干域多肽对蛋白酶切割具有抗性。根据本发明，因此该蛋白酶切割位点已被去除以便防止在HA1和HA2域之间的切割位点处的多肽的切割。在某些实施例中，该蛋白酶切割位点已经通过C-末端HA1区段的C-末端氨基酸的突变和/或HA2域的N-末端氨基酸的突变来去除，以获得抗蛋白酶切割的序列。在某些实施例中，在某些实施例中的HA1和HA2之间的切割位点的去除可以通过使在P1位置的R(在少数情况下为K)突变为Q来实现(参见例如孙(Sun)等人，2010，切割位点(SEQ ID NO:1中位置343)的命名法解释)。因此，在某些实施例中，该HA1C-末端主干区段的C-末端氨基酸残基是除了精氨酸(R)或赖氨酸(K)的任何氨基酸。在某些实施例中，该HA1C-末端氨基酸是谷氨酰胺(Q)、丝氨酸(S)、苏氨酸(T)、天冬酰胺(N)、天冬氨酸(D)或谷氨酸(E)。在某些实施例中，该HA1C-末端主干区段的C-末端氨基酸残基是谷氨酰胺(Q)。
根据本发明，这些多肽来源于或基于H1HA，即包括来自H1亚型的流行性感冒病毒的氨基酸序列的HA。在具体实施例中，这些多肽包括血球凝集素主干域，该血球凝集素主干域来自或基于甲型流行性感冒病毒的HA，包括H1亚型的HA，诸如来自甲型流行性感冒病毒/布里斯班/59/2007(H1N1)(SEQ ID NO:1)，如下所述。技术人员会理解，根据本发明也可使用其他包括H1亚型的HA的甲型流行性感冒病毒。在某些实施例中，这些多肽包括来源于或基于选自表2的甲型流行性感冒H1病毒的HA的血球凝集素主干域。用“来源于”或“基于”意指，该HA1域和/或该HA2域的N-末端区段和/或C-末端区段与本领域的技术人员已知的或后来发现的H1亚型的天然存在的流行性感冒血球凝集素的HA1和/或HA2域的对应N-末端和/或C-末端区段具有至少70％、75％、80％、85％、90％、95％、96％、97％、98％、或99％的氨基酸序列一致性。
根据本发明，该HA2域包括将螺旋A的C-末端残基连接至螺旋CD的N-末端残基的HA2氨基酸序列中的一个或多个突变(图1)。连接螺旋A的C-末端残基和螺旋CD的N-末端残基的H1HA2氨基酸序列包括如下氨基酸序列，其包括流行性感冒HA(根据SEQ ID NO:1编号)的残基402-418，包括氨基酸序列MNTQFTAVGKEFN(H/K)LE(K/R)(SEQ ID NO:7)。
在某些实施例中，将螺旋A的C-末端残基连接到螺旋CD的N-末端残基的氨基酸序列，即包括血清型H1的流行性感冒HA的氨基酸残基402-418(根据SEQ ID NO:1编号)的区域，包括以下氨基酸序列
X1NTQX2TAX3GKEX4N(H/K)X5E(K/R)(SEQ ID NO:8)。
根据本发明，位置402、406、409、413以及416(编号参考SEQ ID NO:1)上的一个或多个氨基酸，即氨基酸X1、X2、X3、X4以及X5中一个或多个已经突变，即包括在该主干多肽基于的野生型流行性感冒病毒中的那些位置处不存在的氨基酸。
在某些实施例中，位置402上的突变氨基酸，即X1，是选自下组的氨基酸，该组由以下各项组成：M、E、K、V、R以及T。
在某些实施例中，位置406上的突变氨基酸，即X2，是选自下组的氨基酸，该组由以下各项组成：F、I、N、T、H、L以及Y，优选I、L或Y。
在某些实施例中，位置409上的突变氨基酸，即X3，是选自下组的氨基酸，该组由以下各项组成：V、A、G、I、R、F以及S，优选A、I或F。
在某些实施例中，位置413上的突变氨基酸，即X4，是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、E、K、M、以及V，优选I、Y、M或V。
在某些实施例中，位置416上的突变氨基酸，即X5，是选自下组的氨基酸，该组由以下各项组成：L、H、I、N、R，优选I。
这些突变的组合也是可能的。
在某些实施例中，X1是M，X2是Y，X3是I，X4是Y并且X5是S。
根据本发明，相比于对应的野生型流行性感冒病毒HA1和/或HA2域(即这些主干多肽基于的流行性感冒病毒)的氨基酸序列，这些主干多肽在该HA1域和/或该HA2域中包括一个或多个另外的突变，即氨基酸取代。
在某些实施例中，接近于HA0切割位点(SEQ ID NO:1中残基343)的一个或多个氨基酸残基已经突变。在某些实施例中，SEQ ID NO:1的位置337、340、352、或353上、或其他流行性感冒病毒中的等价位置上的一个或多个氨基酸残基已经突变，即被在该主干多肽基于的野生型流行性感冒病毒的HA的氨基酸序列中的对应位置处不存在的氨基酸取代。表6显示天然存在的氨基酸变化。
在某些实施例中，本发明的多肽包括SEQ ID NO:1的位置352上、或其他流行性感冒病毒的等价位置上的至少一个突变。
在某些实施例中，本发明的多肽包括SEQ ID NO:1的位置353上、或其他流行性感冒病毒的等价位置上的至少一个突变。
在某些实施例中，本发明的多肽包括SEQ ID NO:1的位置337上、或其他流行性感冒病毒的等价位置上的至少一个突变。
在某些实施例中，本发明的多肽包括SEQ ID NO:1的位置340上、或其他流行性感冒病毒的等价位置上的至少一个突变。
在某些实施例中，位置337上的突变氨基酸残基(HA1域)是选自下组，该组由以下各项组成：I、E、K、V、A、以及T。
在某些实施例中，位置340上的突变氨基酸残基(HA1域)是选自下组，该组由以下各项组成：I、K、R、T、F、N、S以及Y。
在某些实施例中，位置352上的突变氨基酸残基(HA2域)是选自下组，该组由以下各项组成：D、V、Y、A、I、N、S、以及T。
在某些实施例中，位置353上的突变氨基酸残基(HA2域)是选自下组，该组由以下各项组成：K、R、T、E、G、以及V。
在某些实施例中，该突变的氨基酸在该序列中引入共有N-糖基化，例如N-X-T/S(此处X是任何天然存在的氨基酸，除了P)，如同例如对于I340N在SEQ ID NO:6中的情况。
在某些实施例中，该突变的氨基酸是相同亚型的序列中不会天然存在的氨基酸。
在某些实施例中，在位置337(HA1域)上突变的氨基酸残基是K。
在某些实施例中，在位置340(HA1域)上突变的氨基酸残基是K。
在某些实施例中，在位置352(HA2域)上突变的氨基酸残基是F。
在某些实施例中，在位置353(HA2域)上突变的氨基酸残基是T。
再次指出，贯穿本申请，氨基酸的编号是基于H1HA0中氨基酸的编号，具体而言H1N1甲型流行性感冒株/布里斯班/59/2007(SEQ ID NO:1)的氨基酸的编号。普通技术人员将能够确定其他流行性感冒病毒的HA中的等价(或对应)氨基酸，并且因此将能够确定等价突变，参见例如表2的不同H1流行性感冒病毒的序列比对。
根据本发明，这些多肽进一步包含位置324上的氨基酸和位置436上的氨基酸之间的二硫桥。因此，根据本发明，至少一个二硫桥已被引入这些主干域多肽中，优选地在H1A/布里斯班/59/2007(SEQ ID NO:1)中位置324和436(或等价物)的氨基酸之间。在某些实施例中，这些多肽因此进一步包括该HA1域中的突变R324C以及该HA2域中的T436C。本领域的普通技术人员可以使用适合的算法诸如Clustal、Muscle等，通过比对序列容易地确定等价位置。工程化的二硫桥是通过使至少一个(如果另一个已经是半胱氨酸)、但通常是空间上接近的两个残基突变为半胱氨酸来建立的，该突变将自发地或通过活性氧化在这些残基的硫原子之间形成共价键。
在某些实施例中，相比于衍生该HA1和HA2域的HA的氨基酸序列，这些多肽进一步在该HA1和/或HA2域中包括一个或多个另外的突变。因此，这些主干多肽的稳定性进一步增加。
申请人之前已经鉴定了从来自接种疫苗的个体的初级人B-细胞分离的广泛中和抗体，它们中的一些对于组1是特异性的(例如CR6261，如WO 2008/028946中所述)，并且它们中的一些对于组2流行性感冒病毒是特异性的(例如CR8020，如WO 2010/130636中所述)。这些单克隆抗体的表位的详细分析已经揭示了这些特异抗体缺少交叉反应性的原因。在两种情况下，组1或组2HA分子中不同位置上聚醣的存在至少部分地解释了以下事实：这些抗体是组特异性的。在鉴别与许多组1和2HA分子交叉反应的CR9114样抗体的情况下，如下所述的，变得明了的是人免疫系统可能针对流行性感冒病毒引发非常广泛的中和抗体。然而，在考虑对于年度疫苗接种方案的需要时，在亚型H1和/或H3的(季节性)流行性感冒病毒的感染或疫苗接种之后，这些抗体显然不会或仅非常低程度地被引发。
根据本发明，提供了以下多肽，这些多肽模拟CR6261和/或CR9114的特异表位，并且可被用作免疫原性多肽，例如当独自或与其他预防和/或治疗处理组合来体内给予时引发交叉中和抗体。对于“交叉中和抗体”，意指该抗体能够中和系统发育组1的甲型流行性感冒病毒的至少两个、优选至少三个、四个、或五个不同亚型，和/或系统发育组2的甲型流行性感冒病毒的至少两个、优选至少三个、四个、或五个不同亚型，和/或乙型流行性感冒病毒的至少两个不同亚型，特别是至少所有被CR6261和CR9114中和的病毒株。
本发明的这些多肽包含主干结合的流行性感冒中和性抗体CR6261和/或CR9114的表位。在某些实施例中，因此这些多肽选择性地结合到抗体CR6261和/或CR9114。在某些实施例中，本发明的这些多肽不结合抗体CR8020和/或CR8057。如在本发明中所使用的，CR6261包括包含SEQ ID NO:9的氨基酸序列的重链可变区和包含SEQ ID NO:10的氨基酸序列的轻链可变区；CR9114包括包含SEQ ID NO:11的氨基酸序列的重链可变区和包含SEQ IDNO:12的氨基酸序列的轻链可变区。CR8057包括包含SEQ ID NO:13的氨基酸序列的重链可变区和包含SEQ ID NO:14的氨基酸序列的轻链可变区。CR8020包括包含SEQ ID NO:17的氨基酸序列的重链可变区和包含SEQ ID NO:18的氨基酸序列的轻链可变区。
如上所述的，这些多肽包括流行性感冒血球凝集素HA1域，其包括通过具有0-50个氨基酸残基的连接序列共价连接至HA1C-末端主干区段的HA1N-末端主干区段。该连接序列(如果存在)不存在于天然存在的或野生型HA中。在某些实施例中，该接头是肽，该肽包括一个氨基酸残基、两个或更少的氨基酸残基、三个或更少的氨基酸残基、四个或更少的氨基酸残基、五个或更少的氨基酸残基、十个或更少的氨基酸残基、15个或更少的氨基酸残基、或20个或更少的氨基酸残基，或30个或更少的氨基酸残基，或40个或更少的氨基酸残基，或50个或更少的氨基酸残基。在一个特定实施例中，该连接序列是选自下组的序列，该组由以下各项组成：G、GS、GGG、GSG、GSA、GSGS、GSAG、GGGG、GSAGS、GSGSG、GSAGSA、GSAGSAG、以及GSGSGSG。
在某些实施例中，该HA1N-末端区段直接连接至HA1C-末端区段，即这些多肽不包括连接序列。
处于其天然形式的流行性感冒HA在细胞或病毒膜上作为三聚体存在。在某些实施例中，该细胞内和跨膜序列被去除以使得在细胞中表达后产生分泌的(可溶的)多肽。已经描述表达以及纯化HA的分泌胞外域的方法(参见例如多普海德(Dopheide)等人2009；艾基尔特(Ekiert)等人2009，2011；史蒂文斯(Stevens)等人2004，2006；威尔逊(Wilson)等人1981)。本领域的普通技术人员会理解，这些方法也可直接应用到本发明的主干域多肽以实现分泌(可溶的)多肽的表达。因此这些多肽也包括在本发明中。
在某些实施例中，这些多肽包含全部HA2域，因此包括跨膜序列和胞细内序列。在其他实施例中，本发明的多肽不包括HA的细胞内序列以及跨膜域。在某些实施例中，这些多肽包含截短的HA2域。在某些实施例中，这些细胞内序列以及跨膜序列，例如从该HA2域的位置514、515、516、517、518、519、520、521、522、523、524、525、526、527、526、528、529、或530(或等价物)至该HA2域的C-末端的氨基酸序列(根据SEQ ID NO:1编号)已被去除以在细胞中表达之后产生可溶的多肽。
在某些实施例中，从位置519到C末端氨基酸的HA2域的C-末端部分已被缺失。在另外的实施例中，从位置530到C末端氨基酸的HA2域的C-末端部分已被缺失。
任选地，可以将his-标签序列(HHHHHH(SEQ ID NO:15)或HHHHHHH(SEQ ID NO:16))连接至(任选地截短的)HA2域用于纯化目的，任选地通过接头连接。任选地该接头可包含蛋白分解切割位点以在纯化之后酶促地去除该his-标签。
在某些实施例中，通过在HA2的C-末端处引入已知会形成三聚体结构的序列，即GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID NO:3)，任选地通过接头连接，这些多肽进一步稳定化。因此，在某些实施例中，HA2域的C-末端部分已被氨基酸序列GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID NO:3)替代，任选通过接头连接。该接头可任选地包含切割位点用于之后根据本领域的普通技术人员熟知的方案进行加工。为了促进该可溶形式的纯化，可添加标签序列，例如his标签(HHHHHH(SEQ ID NO:15)或HHHHHHH(SEQ ID NO:16))或FLAG标签(DYKDDDDK)(SEQ ID NO:22)或这些的组合，任选地通过短接头连接。该接头可任选地包含(部分的)蛋白分解切割位点，例如IEGR(SEQ ID NO:24)(因子X)或LVPRGS(SEQ ID NO:23)(凝血酶)，用于之后根据本领域的普通技术人员熟知的方案进行加工。加工的蛋白也包括在本发明中。
在某些实施例中，该HA2域的C-末端部分从位置519-565已经缺失(根据SEQ IDNO:1编号)并且被以下替代：SGRDYKDDDDKLVPRGSPGSGYIPEAPRDGQAYVRKDGEWVLLSTFLGHHHHHH(SEQ ID NO:4)。
在某些实施例中，该HA2域的C-末端部分从位置530-565已经缺失(根据SEQ IDNO:1编号)并且被以下替代：SGRDYKDDDDKLVPRGSPGSGYIPEAPRDGQAYVRKDGEWVLLSTFLGHHHHHH(SEQ ID NO:4)。
该天然HA在细胞表面上作为三聚体存在。将三聚体保持在一起的个体单体之间的相互作用的大部分处于头部域，而在主干域中，三聚体化是通过三聚体叠螺旋基序的形成介导的。去除该头部之后，该三级结构去稳定并且因此需要修饰以增加蛋白稳定性。通过加强该螺旋CD的螺旋倾向，可以建立更稳定的蛋白。
在共同未决的申请PCT/EP 2014/060997中所描述的多肽中，序列MKQIEDKIEEIESKQ(SEQ ID NO:5)，来源于酵母转录激活因子蛋白GCN4并且已知会在位置419-433处(的等价物)的CD螺旋中引入三聚。该序列具有形成螺旋二级结构的高倾向，并且可以按这种方式增强本发明的多肽的整体稳定性。
根据本发明，已经令人惊讶地显示，该多肽的稳定性和多聚化状态取决于本发明的多肽的一级序列中的GCN4衍生序列的确切位置和顺序。
因此，根据本发明，将序列RMKQIEDKIEEIESK(SEQ ID NO:20)引入位置419-433处(根据SEQ ID NO:1编号)，或将序列RMKQIEDKIEEIESKQK(SEQ ID NO:21)引入位置417-433处。
在某些实施例中，这些多肽是糖基化的。
在产生本发明的研究中，使用本领域的普通技术人员熟知的分子生物学技术，例如对共同未决的专利申请PCT/EP 2014/060997中所描述的s74H9(SEQ ID NO:65)、s127H1(SEQ ID NO:66)、s71H2(SEQ ID NO:71)、s86B4(SEQ ID NO:67)、s115A1(SEQ ID NO:70)、s2201C9(SEQ ID NO:77)、s55G7(SEQ ID NO:68)、s113E7(SEQ ID NO:78)、s6E12(SEQ IDNO:69)、s181H9(SEQ ID NO:76)进行修饰，以建立在位置419-433处包含序列RMKQIEDKIEEIESK(SEQID NO:20)的序列s74H9-t2(SEQ ID NO:93)、s127H1-t2(SEQ ID NO:91)、s71H2-t2(SEQ ID NO:97)、s86B4-t2(SEQ ID NO:92)、s115A1-t2(SEQ ID NO:96)、s220C9-t2(SEQ ID NO:99)、s55G7-t2(SEQ ID NO:95)、s113E7-t2(SEQ ID NO:100)、s6E12-t2(SEQ ID NO:94)、s181H9-t2(SEQ ID NO:98)。
以类似的方式，建立在位置417-433处包含序列RMKQIEDKIEEIESKQK(SEQ ID NO:21)的多肽s74H9-t3(SEQ ID NO:123)、s127H1-t3(SEQ ID NO:121)、s71H2-t3(SEQ ID NO:127)、s86B4-t3(SEQ ID NO:122)、s115A1-t3(SEQ ID NO:126)、s2201C9-t3(SEQ ID NO:129)、s55G7-t3(SEQ ID NO:125)、s113E7-t3(SEQ ID NO:130)、s6E12-t3(SEQID NO:124)、s181H9-t3(SEQ ID NO:128)。
相比于前面(PCT/EP 2012/073706和PCT/EP 2014/060997)所述的主干多肽，本发明的这些多肽显示流行性感冒抗体(具体为CR6261和/或CR9114)的增加的结合、和/或对多聚化的增加的倾向和/或增加的稳定性。
在某些实施例中，这些多肽包括以下氨基酸序列：
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNX1PSX2QSQGLFGAIAGX3X4EGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKX5NTQX6TAX7GKEX8NKX9ERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVSGRDYKDDDDKLVPRGSPGSGYIPEAPRDGQAYVRKDGEWVLLSTFLGHHHHHH(SEQ ID NO:145)，
其中X1是选自下组的氨基酸，该组由以下各项组成：E、I、K、V、A、以及T；
X2是选自下组的氨基酸，该组由以下各项组成：I、K、R、T、F、N、S以及Y；
X3是选自下组的氨基酸，该组由以下各项组成：D、F、V、Y、A、I、N、S、以及T；
X4是选自下组的氨基酸，该组由以下各项组成：I、K、R、T、E、G以及V；
X5是选自下组的氨基酸，该组由以下各项组成：M、E、K、V、R、T；
X6是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、H、以及L；
X7是选自下组的氨基酸，该组由以下各项组成：A、G、I、R、T、V、F、以及S；
X8是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、G、E、K、M、以及V；并且
X9是选自下组的氨基酸，该组由以下各项组成：H、I、L、N、R、以及S。
在某些实施例中，这些多肽包括以下氨基酸序列：
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNX1PSX2QSQGLFGAIAGX3X4EGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKX5NTQX6TAX7GKEX8NKX9ERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDG(SEQ ID NO:146)，
其中X1是选自下组的氨基酸，该组由以下各项组成：E、I、K、V、A、以及T；
X2是选自下组的氨基酸，该组由以下各项组成：I、K、R、T、F、N、S以及Y；
X3是选自下组的氨基酸，该组由以下各项组成：D、F、V、Y、A、I、N、S、以及T；
X4是选自下组的氨基酸，该组由以下各项组成：I、K、R、T、E、G以及V；
X5是选自下组的氨基酸，该组由以下各项组成：M、E、K、V、R、T；
X6是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、H、以及L；
X7是选自下组的氨基酸，该组由以下各项组成：A、G、I、R、T、V、F、以及S；
X8是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、G、E、K、M、以及V；并且
X9是选自下组的氨基酸，该组由以下各项组成：H、I、L、N、R、以及S。
在某些实施例中，这些多肽包括以下氨基酸序列：
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNX1PSX2QSQGLFGAIAGX3X4EGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKX5NTQX6TAX7GKEX8NKX9ERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG(SEQ ID NO:147)，
其中X1是选自下组的氨基酸，该组由以下各项组成：E、I、K、V、A、以及T；
X2是选自下组的氨基酸，该组由以下各项组成：I、K、R、T、F、N、S以及Y；
X3是选自下组的氨基酸，该组由以下各项组成：D、F、V、Y、A、I、N、S、以及T；
X4是选自下组的氨基酸，该组由以下各项组成：I、K、R、T、E、G以及V；
X5是选自下组的氨基酸，该组由以下各项组成：M、E、K、V、R、T；
X6是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、H、以及L；
X7是选自下组的氨基酸，该组由以下各项组成：A、G、I、R、T、V、F、以及S；
X8是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、G、E、K、M以及V；并且
X9是选自下组的氨基酸，该组由以下各项组成：H、I、L、N、R、以及S。
在某些实施例中，这些多肽包括以下氨基酸序列：
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNX1PSX2QSQGLFGAIAGX3X4EGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKX5NTQX6TAX7GKEX8NKX9ERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI(SEQ IDNO:148)，
其中X1是选自下组的氨基酸，该组由以下各项组成：E、I、K、V、A、以及T；
X2是选自下组的氨基酸，该组由以下各项组成：I、K、R、T、F、N、S以及Y；
X3是选自下组的氨基酸，该组由以下各项组成：D、F、V、Y、A、I、N、S、以及T；
X4是选自下组的氨基酸，该组由以下各项组成：I、K、R、T、E、G以及V；
X5是选自下组的氨基酸，该组由以下各项组成：M、E、K、V、R、T；
X6是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、H、以及L；
X7是选自下组的氨基酸，该组由以下各项组成：A、G、I、R、T、V、F、以及S；
X8是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、G、E、K、M以及V；并且
X9是选自下组的氨基酸，该组由以下各项组成：H、I、L、N、R、以及S。
在某些实施例中，在SEQ ID NO:145-148中X1是K，X2是K，X3是F，X4是T，X5是M，X6是Y，X7是I，X8是Y，并且X9是S。
这些流行性感冒血球凝集素主干域多肽可以根据任何被认为适合技术人员的技术来制备，包括以下所述的技术。
因此，本发明的免疫原性多肽可通过本领域中已知的标准方法，使用适合的限制性内切酶以及本领域已知的方法被合成为DNA序列，并且被克隆并随后体外或体内表达。本发明因此也涉及编码上述多肽的核酸分子。本发明进一步涉及包括编码本发明的多肽的核酸的载体。在某些实施例中，根据本发明的核酸分子为载体(例如质粒)的一部分。这些载体可以通过本领域的普通技术人员众所周知的方法容易地操纵，并且可以例如被设计成能够在原核和/或真核细胞中复制。另外，许多载体可以直接或以从其分离的希望片段的形式用于真核细胞的转化并且将完全或部分地整合到这些细胞的基因组中，产生在其基因组中包含所需核酸的稳定的宿主细胞。所用的载体可以是适于克隆DNA并且可以用于感兴趣核酸的转录的任何载体。当使用宿主细胞时，优选的是该载体是整合型载体。可替代地，该载体可以是游离型复制载体。
本领域的普通技术人员能够选择适合的表达载体，并且以一种功能性方式插入本发明的核酸序列。为了获得编码多肽的核酸序列的表达，本领域的普通技术人员熟知能够驱动表达的序列可以功能性地连接至编码该多肽的核酸序列，得到可表达形式的编码蛋白或多肽的重组核酸分子。总的来说，该启动子序列被放置在应该表达的序列的上游。许多表达载体在本领域中可获得，例如英杰公司的pcDNA和pEF载体系列、碧迪科学公司(BDSciences)的pMSCV和pTK-Hyg、来自斯曲杰公司(Stratagene)的pCMV-Script等，它们可以用于获得适合的启动子和/或转录终止子序列、polyA序列等等。参照控制编码多肽的转录和翻译的序列，在适当插入编码感兴趣多肽的序列的情况下，得到的表达盒可用于产生感兴趣多肽，称为表达。驱动表达的序列可包括启动子、增强子等，以及其组合。这些应能够在宿主细胞中起作用，从而驱动与它们功能性连接的核酸序列的表达。本领域的普通技术人员知道不同的启动子可以用于获得宿主细胞中一种基因的表达。启动子可以是组成型的或调节型的，并且可以从不同的来源中，包括病毒、原核或真核来源获得，或是人工设计的。感兴趣的核酸的表达可来自天然启动子或其衍生物或来自完全异源的启动子(考夫曼(Kaufman)，2000)。一些熟知的并且多用于在真核细胞中表达的启动子包括源自于病毒(诸如腺病毒)的启动子(例如E1A启动子)、源自于巨细胞病毒(CMV)的启动子(诸如CMV即刻早期(IE)启动子(此处称为CMV启动子)(例如可从pcDNA，英杰公司(Invitrogen)获得))、源自于猴病毒40(SV40)的启动子(达斯(Das)等人，1985)等。适合的启动子也可源自于真核细胞，诸如金属硫蛋白(MT)启动子、延长因子1α(EF-1α)启动子(吉尔(Gill)等人，2001)、泛素C或UB6启动子(吉尔(Gill)等人，2001)、肌动蛋白启动子、免疫球蛋白启动子、热休克启动子等。对启动子功能和启动子强度进行测试是本领域的普通技术人员的例行途径，并且总的来说可例如包括克隆该启动子序列后的测试基因(诸如lacZ、荧光素酶、GFP等)，并且对该测试基因的表达进行测试。当然，启动子可通过其中的序列的缺失、添加、突变而被改变，并且针对功能性进行测试以找到新的、减毒的、或改善的启动子序列。根据本发明，在所选择的真核细胞中给出高转录水平的强启动子是优选的。
使用本领域的普通技术人员熟知的方法，这些构建体可被转染到真核细胞(例如植物、真菌、酵母或动物细胞)或适合的原核生物表达系统像大肠杆菌中。在一些情况下，可将适合的‘标签’序列(例如，如但不限于his-、myc-、strep-、或flag-标签)或完全蛋白(例如，如但不限于麦芽糖结合蛋白或谷胱甘肽S转移酶)添加到本发明的序列中以允许从这些细胞或上清液纯化和/或鉴定这些多肽。任选地，可以包括包含特异蛋白分解位点的序列以在之后通过蛋白分解消化去除该标签。
纯化多肽可以通过本领域中已知的光谱法(例如圆二色谱法、傅里叶变换红外光谱法以及NMR光谱法或X射线晶体分析法)进行分析以调查所希望的结构像螺旋以及β片层的存在。ELISA、Octet以及FACS等可用于调查本发明的多肽与之前所述的广泛中和抗体(CR6261、CR9114、CR8057)的结合。因此，可以选择根据本发明的具有正确构象的多肽。
本发明进一步涉及免疫原性组合物，其包括治疗有效量的本发明的多肽和/或核酸中的至少一个。这些免疫原性组合物优选地进一步包括一种药学上可接受的载体。在本发明的上下文中，术语“药学上可接受的”意思指载体在所用剂量和浓度下不会在给予它们的受试者中造成不希望有的或有害的影响。这些医药学上可接受的载剂和赋形剂是本领域中熟知的(参见雷明登氏制药科学(Remington’s Pharmaceutical Sciences)，第18版，A.R.热纳罗(Gennaro)编，马克出版社(Mack Publishing Company)[1990]；肽和蛋白质的医药配制品发展(Pharmaceutical Formulation Development of Peptides andProteins)，S.弗罗加尔(Frokjaer)和L.霍夫高(Hovgaard)编，泰勒弗朗西斯集团(Taylor&Francis)[2000]；以及医药赋形剂手册(Handbook of Pharmaceutical Excipients)，第3版，A.凯博(Kibbe)编，医药出版社(Pharmaceutical Press)[2000])。术语“载体”是指与组合物一起给予的稀释剂、佐剂、赋形剂或运载体。盐水溶液以及葡萄糖和甘油水溶液可以例如用作液体载体，特别是对于可注射溶液而言。精确的配制品可适应给予模型。这些多肽和/或核酸分子优选地呈无菌溶液形式被配制和给予。无菌溶液是通过无菌过滤或通过本领域中自身已知的其他方法制备。这些溶液可接着被冻干或填充到药物剂量容器中。溶液的pH通常在pH 3.0到9.5、例如pH 5.0到7.5范围内。
本发明也涉及如上所述的流行性感冒HA主干域多肽、核酸分子和/或载体以用于诱导针对流行性感冒HA蛋白的免疫应答。本发明也涉及在受试者中诱导免疫应答的方法，该方法包括向受试者给予如上所述的多肽、核酸分子和/或免疫原性组合物。根据本发明的受试者优选地是能够被引起传染病的药剂(具体而言流行性感冒病毒)感染的哺乳动物，或另外可以从免疫应答的诱导受益，此类受试者例如是啮齿动物，例如小鼠、白鼬、或家畜或农畜，或非人的灵长类，或人。优选地，该受试者为一个人类受试者。本发明因此提供了利用此处描述的多肽、核酸和/或免疫原性组合物，用于在受试者中诱导对具体地组1和/或组2甲型流行性感冒病毒(诸如包括H1、H2、H3、H4、H5、H7和/或H10亚型的HA的流行性感冒病毒)和/或乙型流行性感冒病毒的流行性感冒病毒血球凝集素(HA)的免疫应答的方法。在一些实施例中，本发明提供了用于在受试者中利用本文所述的多肽、核酸和/或免疫原性组合物来诱导对包含H1亚型的HA的流行性感冒病毒的免疫应答的方法。
在一些实施例中，诱导的免疫应答有效于预防和/或治疗由组1和/或组2甲型流行性感冒病毒亚型和/或乙型流行性感冒病毒引起的流行性感冒病毒感染。在一些实施例中，由此处描述的多肽、核酸和/或免疫原性组合物诱导的免疫应答有效于预防和/或治疗由甲型和/或乙型流行性感冒病毒的两个、三个、四个、五个或六个亚型引起的甲型和/或乙型流行性感冒病毒感染。在一些实施例中，诱导的免疫应答是有效地预防和/或治疗由包含H1亚型的HA的流行性感冒病毒引起的流行性感冒病毒感染。
由于熟知的是小蛋白和/或核酸分子不会总是有效地诱导强力的免疫应答，可能必要的是通过添加佐剂增加这些多肽和/或核酸分子的免疫原性。在某些实施例中，此处描述的免疫原性组合物包括佐剂或与佐剂组合给予。用于与此处描述的组合物组合给予的佐剂可在给予所述组合物之前、伴随、或之后给予。适合的佐剂的实例包括铝盐，诸如氢氧化铝和/或磷酸铝；油-乳剂组合物(或水包油组合物)，包括鲨烯-水乳液，诸如MF59(参见例如WO 90/14837)；皂苷配制品，诸如，如QS21和免疫刺激复合物(ISCOMS)(参见例如US 5,057,540；WO 90/03184、WO 96/11711、WO 2004/004762、WO 2005/002620)；细菌或微生物衍生物，它们的实例是脂质A(MPL)、3-O-脱酰的MPL(3dMPL)、包含寡核苷酸的CpG-基序、ADP-核糖基化细菌毒素或其突变体，诸如大肠杆菌不耐热肠毒素LT、霍乱毒素CT、百日咳毒素PT、或破伤风类毒素TT，基质M(伊斯康诺瓦(Isconova))。此外，可以使用已知的免疫增强技术，诸如将本发明的多肽融合至本领域中已知的蛋白以增强免疫应答(例如破伤风类毒素、CRM197、rCTB、细菌鞭毛蛋白或其他的)或包括病毒体中的多肽，或其组合。可使用的其他非限制实例是例如科夫曼(Coffman)等人(2010)披露的。
在一个实施例中，本发明的流行性感冒血球凝集素主干域多肽结合至病毒样颗粒(VLP)载体。VLP通常包括典型地源自于病毒的一种或多种结构蛋白质的一种或多种病毒多肽。优选地，这些VLP不能够复制。在某些实施例中，这些VLP可缺少病毒的完全基因组或包括病毒的基因组的部分。在一些实施例中，这些VLP不能够感染细胞。在一些实施例中，这些VLP表达其表面上的本领域普通技术人员已知的一个或多个病毒(例如，病毒表面糖蛋白)或非病毒(例如，抗体或蛋白)靶向部分。
在一个特定实施例中，本发明的多肽结合至病毒体中。可使用本领域的普通技术人员已知的技术产生包含根据本发明的多肽的病毒体。例如，可通过如下产生病毒体：破坏纯化病毒、提取基因组、并且用病毒蛋白(例如，流行性感冒血球凝集素主干域多肽)以及脂质重新装配颗粒以形成包含病毒蛋白的脂质颗粒。
本发明也涉及用于在受试者中诱导针对流行性感冒HA的免疫应答，具体而言用于用作疫苗的上述的多肽、核酸和/或免疫原性组合物。此处描述的流行性感冒血球凝集素主干域多肽、编码此类多肽的核酸、或包括此类核酸或多肽的载体因此可被用于引发针对流行性感冒病毒，例如针对流行性感冒病毒血球凝集素的主干区的中和抗体。本发明具体而言涉及如上所述的用于在预防和/或治疗由系统发育组1和/或系统发育组2的甲型流行性感冒病毒和/或乙型流行性感冒病毒引起的疾病或病况中用作疫苗的多肽、核酸和/或免疫原性组合物。在一个实施例中，该疫苗可被用于预防和/或治疗由系统发育组1和/或2的两个、三个、四个、五个、六个或更多个不同亚型和/或乙型流行性感冒病毒引起的疾病。在一个实施例中，该疫苗可以用于预防和/或治疗由包含H1亚型的HA的流行性感冒病毒引起的流行性感冒感染。
本发明的多肽可在合成之后在体外或在适合的细胞表达系统(包括细菌和真核细胞)中使用，或可替代地，可在需要其的受试者中体内表达，通过表达编码免疫原性多肽的核酸。此类核酸疫苗可采取任何形式，包括裸DNA、质粒、或病毒载体(包括腺病毒载体)。
根据本发明的多肽、核酸分子、和/或免疫原性组合物的给予可以使用标准给予途径执行。非限制性实例包括肠胃外给予，诸如静脉内、皮内、经皮、肌肉内、皮下等或粘膜给予，例如鼻内、经口等等。本领域的普通技术人员能够确定给予根据本发明的多肽、核酸分子、和/或免疫原性组合物以诱导免疫应答的不同可能性。在某些实施例中，超过一次给予该多肽、核酸分子、和/或免疫原性组合物(或疫苗)，即所谓的同源初免-加强免疫接种方案。在某些实施例中，其中超过一次给予多肽、核酸分子、和/或免疫原性组合物，给予第二剂量可以在例如给予第一剂量之后一周或更长时间、给予第一剂量之后两周或更长时间、给予第一剂量之后三周或更长时间、给予第一剂量之后一个月或更长时间、给予第一剂量之后六周或更长时间、给予第一剂量之后两个月或更长时间、给予第一剂量之后3个月或更长时间、给予第一剂量之后4个月或更长时间等等直至给予第一剂量的多肽、核酸分子、和/或免疫原性组合物之后若干年的时间间隔之后进行。也可能超过两次，例如三次、四次等给予该疫苗，以使得第一次初免给药随后为超过一次的加强给药。在其他实施例中，仅一次给予根据本发明的多肽、核酸分子、和/或免疫原性组合物。
多肽、核酸分子和/或免疫原性组合物还可以在一种异源初免-加强方案中作为初免或者作为加强来给予。
本发明进一步提供了在受试者中利用此处描述的多肽、核酸和/或组合物预防和/或治疗流行性感冒病毒疾病的方法。在一个特定实施例中，用于在受试者中预防和/或治疗流行性感冒病毒疾病的方法包括向有需要的受试者给予有效量的如上所述的多肽、核酸和/或免疫原性组合物。治疗有效量是指如此处定义的多肽、核酸或组合物有效用于预防、缓解和/或治疗由被组1或2甲型流行性感冒病毒和/或乙型流行性感冒病毒感染所引起的疾病或病况，优选地由包含H1亚型的HA的甲型流行性感冒病毒感染引起的疾病的量。预防涵盖抑制或减少流行性感冒病毒的传播或抑制或减少与被流行性感冒病毒感染有关的一种或多种症状的发作、发展或进展。如在此使用的缓解可以指减少可见或可察觉的疾病症状、病毒血症或任何其他可测量的流行性感冒感染表现。
需要治疗的那些包括已经患上由组1或组2甲型流行性感冒病毒或乙型流行性感冒病毒感染引起的病况的那些以及其中流行性感冒病毒感染有待预防的那些。本发明的多肽、核酸和/或组合物因此可被给予至一个初试受试者，即不具有由流行性感冒病毒感染引起的疾病或尚未被感染以及当前未被流行性感冒病毒感染的受试者，或给予至已经被流行性感冒病毒感染的和/或已经感染过流行性感冒病毒的受试者。
在一个实施例中，预防和/或治疗可以靶向易受流行性感冒病毒感染的患者群组。这些患者群组包括但不限于例如老年人(例如≥50岁、≥60岁以及优选地≥65岁)、幼童(例如≤5岁、≤1岁)、就医患者以及已经用一种抗病毒化合物治疗但已经展示一种不足的抗病毒反应的患者。
在另一个实施例中，这些多肽、核酸和/或免疫原性组合物可与一种或多种其他活性剂诸如现存的或未来的流行性感冒疫苗、单克隆抗体和/或抗病毒剂、和/或抗细菌剂和/或免疫调节剂组合给予至受试者。这一种或多种其他活性剂可有益于治疗和/或预防流行性感冒病毒疾病或可缓解与流行性感冒病毒疾病关联的症状或病况。在一些实施例中，这一种或多种其他活性剂是止痛药、退烧药物治疗、或缓解或协助呼吸的疗法。
可以调节本发明的多肽和/或核酸分子的剂量方案以提供最优的所希望的反应(例如治疗反应)。一种适合的剂量范围可以是例如0.1-100mg/kg体重，优选1-50mg/kg体重，优选0.5-15mg/kg体重。采用的多肽和/或核酸分子的精确剂量将例如取决于给药途径和该感染及由其引起的疾病的严重性，并且应当根据执业医师的判断和每一受试者的情况来决定。例如，有效剂量依赖靶位点、该患者的生理学状态(包括年龄、体重、健康)、以及治疗是预防性的还是治疗性的而变化。通常，该患者是人，但也可治疗非人哺乳动物(包括转基因的哺乳动物)。治疗剂量最佳地用滴定法测量以优化安全性和有效性。
本发明的多肽也可用于证实鉴定为潜在的治疗候选者的单克隆抗体的结合。另外，本发明的多肽可以用作诊断工具，例如以通过确定一名个体的血清中是否存在能够结合于本发明多肽的抗体来测试该个体的免疫状态。本发明因此还涉及了一种用于检测患者中流行性感冒感染的存在的体外诊断方法，所述方法包括以下步骤：a)使从所述患者中获得的生物样品与根据本发明的多肽接触；并且b)检测抗体-抗原复合物的存在。
本发明的多肽也可用于鉴定新的结合分子或改善现存的结合分子，诸如单克隆抗体以及抗病毒剂。
在以下实例和图式中进一步展示本发明。这些实例并不意在以任何方式限制本发明的范围。
实例
实例1：如在PCT/EP 2014/060997中所述的基于主干的多肽
PCT/EP 2012/073706披露了流行性感冒血球凝集素主干域多肽、组合物和疫苗以及在预防和/或治疗流行性感冒的领域中使用它们的方法。PCT/EP 2014/060997披露了来源于H1N1A/布里斯班/59/2007的全长HA的主干域多肽的另外的序列(SEQ ID NO:1)，它是通过H1-mini2-簇1+5+6-GCN4(SEQ ID NO:2)的定向突变获得的，并且它也稳定地呈现CR6261(斯罗索比(Throsby)等人，2009；艾基尔特(Ekiert)等人，2010)和/或CR9114的广泛中和表位。
H1-mini2-簇1+5+6-GCN4(SEQ ID NO:2)是源自于H1N1A/布里斯班/59/2007(SEQID NO:1)的全长HA，采取以下步骤：
1.去除HA0中的切割位点。在此位点对野生型HA的切割得到HA1和HA2。该去除可以通过使在P1位置(SEQ ID NO:1中位置343)的R突变为Q来实现(参见例如孙(Sun)等人，2010，切割位点的命名法解释)。
2.通过使氨基酸53至320从SEQ ID NO:1缺失而去除头部域。通过四残基柔性接头GGGG连接该序列剩下的N-以及C-末端部分。
3.增加由H1A/布里斯班/59/2007(SEQ ID NO:1)中的残基402至418(或等价物)形成的环(A-螺旋以及CD螺旋之间)的溶解度以增加融合前构象的稳定性并且使修饰的HA的融合后构象两者去稳定化。在H1-mini2-簇1+5+6-GCN4(SEQ ID NO:2)中引入突变F406S、V409T、F413G和L416S(编号参照SEQ ID NO:1)
4.在H1A/布里斯班/59/2007中的位置324和436处的氨基酸之间引入二硫桥；这是通过引入突变R324C和Y436C实现的。(编号参照SEQ ID NO:1)
5.在位置419-433处(编号参照SEQ ID NO:1)引入已知会三聚体化的GCN4衍生的序列MKQIEDKIEEIESKQ(SEQ ID NO:5)。
在某些实施例中，将跨膜和胞内域的序列从HA2的位置514、515、516、517、518、519、520、521、522、523、524、525、526、526、527、528、529、或530(或其等价位置，如从序列比对测定的)至HA2的C-末端(根据SEQ ID NO:1编号)缺失，以使得在细胞中表达之后产生分泌的(可溶的)多肽。该可溶的多肽通过引入已知形成三聚体结构的序列，即折叠子序列GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID NO:3)而进一步稳定化，任选地通过短接头连接，如上所述。该接头可任选地包含切割位点用于之后根据本领域的普通技术人员熟知的方案进行加工。为了促进该可溶形式的纯化和检测，可以任选地添加标签序列，例如组氨酸标签(HHHHHH(SEQ ID NO:15)或HHHHHHH(SEQ ID NO:16)或FLAG标签(DYKDDDDK；SEQ ID NO:22)或这些的组合，任选地通过短接头连接。该接头可任选地包含(部分的)蛋白分解切割位点，例如LVPRGS(SEQ ID NO:23)(凝血酶)或IEGR(SEQ ID NO:24)(因子X)，用于之后根据本领域的普通技术人员熟知的方案进行加工。加工的蛋白也包括在本发明中。
这样的组合了FLAG-标签、凝血酶切割位点、折叠子、以及His序列的C-末端序列的实例是SEQ ID NO:4FLAG-凝血酶-折叠子-His。将此序列与可溶形式的H1-mini2-簇1+5+6-GCN4(SEQ ID NO:2)序列组合以建立亲本序列(SEQ ID NO:6)，该序列被用于通过诱变建立本发明的新颖多肽。此序列不包含对应于SEQ ID NO:1和2的氨基酸1-17的前导序列。
因此，这些主干域多肽是通过以下方式来建立的：使编码该分子头部域的该血球凝集素序列的部分缺失，并且通过如描述于PCT/2012/073706以及上述的接头在该缺失的任一侧上重连接该序列的N-和C-末端部分。去除该头部域留下了之前从暴露的水性溶剂屏蔽的分子的部分，潜在地去稳定化本发明的多肽的结构。出于此原因，使用亲本序列SEQ IDNO:6作为起始点，B-环(具体而言氨基酸残基406(SEQ ID NO:1和2中分别是F和S)、409(V和T)413(F和G)以及416(L和S))中的残基以不同组合突变。SEQ ID NO:6是通过去除前导序列并且用Flag-凝血酶-折叠子--his序列(SEQ ID NO:4)替代残基520-565而从H1-mini2-簇1+5+6-GCN4(SEQ ID NO:2)建立。
类似地，在该融合肽周围的区域中，数个疏水残基被暴露于该溶剂，这是由以下事实引起的，不像天然全长HA，这些多肽不能被切割，并且经受相关的构象变化，该构象变化将该疏水融合肽隐藏在该蛋白的内部。为了解决此问题，SEQ ID NO:2中残基I337、I340、F352以及I353中的一些或所有也突变。
通过这种方式，建立HA主干多肽的可溶形式74H9(SEQ ID NO:57)、127H1(SEQ IDNO:55)、71H2(SEQ ID NO:61)、86B4(SEQ ID NO:56)、115A1(SEQID NO:60)、2201C9(SEQ IDNO:63)、55G7(SEQ ID NO:59)、113E7(SEQ ID NO:64)、6E12(SEQ ID NO:58)、181H9(SEQ IDNO:62)。
使用本领域的普通技术人员熟知的方案，编码以上所述的多肽的DNA序列被转化到巴斯德毕赤酵母中或被转染到HEK293F细胞中。用于在哺乳动物细胞中表达的构建体包含HA前导序列(SEQ ID NO:1和2中的残基1-17)，而在用于在毕赤酵母中表达的构建体中，该HA前导序列被酵母α因子前导序列(SEQ ID NO:7)替代。以此方式，表达的蛋白向着该细胞培养基定向，从而允许待测定的本发明的多肽的结合和表达而不用进一步纯化。所有序列包含FLAG-折叠子-HIS C-末端序列(SEQ ID NO:4)。
结合这些多肽的单克隆抗体(CR6261、CR9114、CR8020)是通过ELISA确定的。为此，将ELISA板用2μg/ml单克隆抗体溶液(20μl/孔)在4℃处理过夜。在去除该抗体溶液之后，在室温下将剩下的表面用脱脂奶粉于PBS中的4％溶液封闭最少1h。在洗涤这些板之后，将20μl的细胞培养基(未搀水的或稀释的)添加到每个孔并且在室温下孵育至少1h。然后洗涤ELISA板并且添加20μl的抗-FLAG-HRP抗体溶液(西格玛A8952，在PBS-Tween中4％脱脂奶粉稀释2000倍)。孵育(在室温下1h)之后，将各板进行再一次洗涤，并且添加20μl发光底物(赛默飞世尔科技公司(Thermoscientific)C#34078)以使该信号显影。可替代地，可使用比色检测方法以使该信号显影。
从均相时间分辨荧光测定来测定本发明的多肽的表达(关于概述，参见例如德歌斯(Degorce)等人，当前化学基因组学(Curr.Chem.Genomics)2009 3:22-32)。为此，通过将210.5μl抗-FLAG-TB(储备液26μg/ml)以及1.68ml的抗-HIS-488(储备液50μg/ml)添加至培养基和50mM HEPES+0.1％BSA的80ml的1比1混合物中制备铽(Tb)标记的抗-FLAG单克隆抗体(供体)和Alexa488标记的抗-His单克隆抗体(受体)(HTRF溶液)的混合物。将19μl的HTRF溶液添加到ELISA板的每个孔中，并且添加1μl的培养基。在激发时并且在允许起源于其他化合物(蛋白，培养基组分等)的干扰性短期背景信号衰退的一个延迟之后，测定在520和665nm的荧光发射的比率。这是对样品中总蛋白含量的测量，并且用于归一化不同实验之间的mAb结合信号。
遵循本领域的普通技术人员熟知的方案，将在表3和4中列出的这些多肽表达于毕赤酵母。收集培养基并且使其结合到CR6261，如上所述测定这些主干域多肽的结合和表达。由于结合测定标度随着表达蛋白浓度进行响应，通过比较结合信号与针对每个表达序列的HTRF测定中的信号的比率，将ELISA结合信号针对蛋白表达进行归一化。相比于SEQ ID NO:6的亲本序列，所有表达的多肽展现了CR6261结合HTRF信号的更高比率。
此外，计算CR6261结合HTRF信号的比率，并且与针对亲本序列SEQ ID NO:6计算的比率进行比较。结果列于表3和4中的第5列；所有表达的蛋白展现更高比率，表明以上所述的主干多肽显示增加的CR6261结合。
实例2：本发明的多肽的设计以及表征
本发明的这些多肽在CD螺旋中包含来源于酵母转录激活因子蛋白GCN4的序列RMKQIEDKIEEIESK(SEQ ID NO:20)或RMKQIEDKIEEIESKQK(SEQ ID NO:21)。该序列具有高倾向形成螺旋二级结构，并且可以以这种方式增强本发明的多肽的整体稳定性。根据本发明，已令人惊讶地发现，本发明的这些多肽的稳定性和聚集状态取决于本发明的多肽的一级序列中的GCN4衍生序列的确切位置和顺序。
因此，在这里我们描述了本发明的一新组多肽，其中将序列RMKQIEDKIEEIESK(SEQID NO:20)引入位置419-433处(根据SEQ ID NO:1编号；例如SEQ ID NO.81至110)，或将序列RMKQIEDKIEEIESKQK(SEQ ID NO:21)引入位置417-433处(例如SEQ ID NO 111至140)。
为此，使用本领域的普通技术人员熟知的分子生物学技术，对实例1中所描述的多肽，即74H9(SEQ ID NO:57)、127H1(SEQ ID NO:55)、71H2(SEQ ID NO:61)、86B4(SEQ IDNO:56)、115A1(SEQ ID NO:60)、2201C9(SEQ ID NO:63)、55G7(SEQ ID NO:59)、113E7(SEQID NO:64)、6E12(SEQ ID NO:58)、181H9(SEQ ID NO:62)进行修饰，以建立在位置419-433处包含序列RMKQIEDKIEEIESK(SEQID NO:20)的序列74H9-t2(SEQ ID NO:83)、127H1-t2(SEQ ID NO:81)、71H2-t2(SEQ ID NO:87)、86B4-t2(SEQ ID NO:82)、115A1-t2(SEQ IDNO:86)、220C9-t2(SEQ ID NO:89)、55G7-t2(SEQ ID NO:85)、113E7-t2(SEQ ID NO:90)、6E12-t2(SEQ ID NO:84)、181H9-t2(SEQ ID NO:88)。
以类似的方式，建立在位置417-433处包含序列RMKQIEDKIEEIESKQK(SEQ ID NO:21)的序列74H9-t3(SEQ ID NO:113)、127H1-t3(SEQ ID NO:111)、71H2-t3(SEQ ID NO:117)、86B4-t3(SEQ ID NO:112)、115A1-t3(SEQ ID NO:116)、2201C9-t3(SEQ ID NO:119)、55G7-t3(SEQ ID NO:115)、113E7-t3(SEQ ID NO:120)、6E12-t3(SEQID NO:114)、181H9-t3(SEQ ID NO:118)。
可以在来自不同病毒株的HA分子的序列的基础上建立本发明的多肽。SEQ ID NO:149-155例如描述了基于H1N1A/加利福尼亚/07/09株的HA序列的本发明的多肽。
如前所述，可以通过去除基于例如从HA2域的残基519、520、521、522、523、524、525、526、527、526、528、529或530至HA2域的C-末端的序列(根据SEQ ID NO:1编号)的HA的C-末端部分来建立本发明的可溶多肽。
可以通过引入已知形成三聚体结构的序列，即GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQID NO:3)，任选地通过接头连接，这些多肽进一步稳定化。该接头可任选地包含切割位点用于之后根据本领域的普通技术人员熟知的方案进行加工。为了促进该可溶形式的纯化，可添加标签序列，例如his标签(HHHHHHH(SEQ ID NO:16)或HHHHHH(SEQ ID NO:15))或FLAG标签(DYKDDDDK)(SEQ ID NO:22)或这些的组合，任选地通过短接头连接。该接头可任选地包含(部分的)蛋白分解切割位点，例如IEGR(SEQ ID NO:24)(因子X)或LVPRGS(SEQ IDNO:23)(凝血酶)，用于之后根据本领域的普通技术人员熟知的方案进行加工。加工的蛋白也包括在本发明中。
通过用序列RSLVPRGSPGHHHHHH(包含修饰的凝血酶切割位点和一种6组氨酸标签(SEQ ID NO:15))替代残基519-565(编号参考SEQ ID NO:1)的等价物来建立SEQ ID NO55-64和81-90的多肽的可溶形式，并且遵循本领域的普通技术人员熟知的方案在HEK293F细胞中表达。
出于比较的原因，H1-mini2-簇1+5+6-GCN4t2(SEQ ID NO:52)和H1-mini2-簇1+5+6-GCN4t3(SEQ ID NO:53)的可溶形式。出于检测目的，收集培养基，并且通过夹心ELISA，使用被用来直接从培养基捕获本发明的多肽的包被的mAb CR6261或CR9114，以及针对C-末端his-标签的辣根过氧化物酶(HRP)轭合抗体，检测与CR6261、CR9114的结合。可替代地，将与HRP轭合的链霉亲和素组合的生物素化的CR9114用于在夹心ELISA中，检测CR9114捕获的本发明的多肽。这种形式允许检测本发明的多肽的多聚体形式的存在。如通过ELISA确定，测试的本发明的所有多肽都能够结合CR9114(图2A和B、图3A和B以及图4A和B)和CR6261(图2C和D、图3C和D以及图4C和D)。针对s55G7-t2(SEQ ID NO:95)、s86B4-t2(SEQ ID NO:92)、s115A1-t2(SEQ ID NO:96)、s127H1-t2(SEQ ID NO:91)、s113E7-t2(SEQ ID NO:100)、s220C9-t2(SEQ ID NO:99)、s71H2-t2(SEQ ID NO:127)、s127H1-t2(SEQ ID NO:121)、s74H9-t2(SEQ ID NO:123)观察到如通过CR9114捕获-生物素化的CR9114检测夹心ELISA来检测的多聚化的增加的水平，如图2E和F、图3E和F以及图4E和F中所示。
为了获得本发明的多肽的高纯度的制剂用于进一步表征，将HEK293F细胞用包含编码可溶形式的127H1-t2(SEQ ID NO:81)、86B4-t2(SEQ ID NO:82)和55G7-t2(SEQ IDNO:85)的基因的表达载体pcDNA2004转染。本领域的普通技术人员会理解，在生产过程中指导蛋白(对应于SEQ ID NO:1的氨基酸1-17)的转运的前导序列(或信号序列)不会存在于分泌的最终多肽中。
为了产生本发明的多肽，通过在300g向下自旋HEK293F细胞(英杰公司(Invitrogen))5min并且重悬于300mL预加温的FreestyleTM培养基/SF1000烧瓶中来种植1.0*106vc/mL。将此培养物在多极(multitron)孵育器中在37℃，10％CO2，110rpm下孵育1小时。1小时之后，将质粒DNA吸移在9.9mL Optimem培养基中达到在300mL培养体积1.0μg/mL的浓度。平行地将440μL吸移在9.9mL Optimem培养基中并且在室温下孵育5分钟。5分钟之后，将质粒DNA/Optimem混合物添加到混合物中，并且在室温下孵育20分钟。孵育之后，将质粒混合物逐滴添加至该细胞悬液中。将转染的培养物在多极(multitron)孵育器中在37℃，10％CO2，和110rpm下孵育。在第7天，通过离心(在3000g30分钟)从该培养基分离细胞，而将包含本发明的可溶多肽的上清液经0.2μm瓶顶过滤器过滤以用于进一步加工。
出于纯化目的，将1500ml(s127H1_t2)、1800ml(s86B4_t2)、和2400ml(s55G7_t2)的培养上清液施加至一个24ml镍琼脂糖凝胶HP柱上，在洗涤缓冲液(20mM TRIS、500mMNaCl，pH 7.8)中预平衡。用在洗涤缓冲液中的10mM咪唑进行的洗涤步骤之后，将本发明的结合多肽以在洗涤缓冲液中300mM咪唑的分步梯度进行洗脱。将各洗脱峰进行收集，浓缩，并且施加至尺寸排阻柱以进一步纯化(Superdex 200)。洗脱曲线示于图5中。为了如该图所示，收集、合并55G7-t2和127H1-t2级分，并且通过SDS-PAGE(图6)、ELISA和分析性尺寸排阻色谱与多角度光散射组合进行分析以估计分子量(SEC-MALS)。ELISA结果证实了本发明的多肽与CR6261和CR9114结合，但不与CR8020结合。SEC-MALS结果概述于表8中。
图5和表8表明，相比于s55G7-t2和s86B4-t2，本发明的多肽s127H1-t2具有更高产量(约30mg蛋白质/l培养上清液)。大多数蛋白展现62kDa的分子量，这是在对于单体或二聚体所预期的分子量之间。为了证实该蛋白质的聚集状态，在源自CR6261、CR9114和CR8020的Fab片段的存在下，重复SEC-MALS实验。结果示于图7中并且概述于表8中。
结果显示，在来自CR6261和CR9114、但无CR8020的Fab片段的存在下，本发明的可溶形式的多肽s127H1-t2形成复合物(如SEC色谱图中峰的位移所证明)。这与这些Fab片段的结合反应的特异性一致，由于CR6261和CR9114结合到源自组1的HA，而CR8020不会。该复合物的大小在表8中列出，并且这表示多肽s127H1-t2结合一到两个Fab片段，这表明本发明的纯化的多肽s127H1-t2的群体的至少一部分是处于二聚形式。
为了进一步分析本发明的多肽127H1-t2和mAb’s CR6261以及CR9114之间的结合反应，连同为了证实CR6261和CR9114的构象表位的存在，通过生物膜层干涉技术(OctetRed384，福特生物公司(Forte Bio))研究这些抗体与该纯化蛋白的复合。为此，将生物素化的CR6261、CR9114和CR8020固定于链霉亲和素涂覆的传感器上，随后将其首先暴露于本发明的纯化多肽的溶液以测量缔合率并且然后暴露于洗涤溶液以测量解离率。结果示于图8中。
固定的CR6261和CR9114两者识别本发明的多肽，如通过在暴露于可溶形式的127H1-t2之后的明显反应证明的(图8)。为了估计结合相互作用的解离常数，使用2倍稀释系列进行滴定。将包含固定的CR6261或CR9114的传感器暴露于浓度分别为40、20、10、5、2.5、1.3和0.63nM的可溶s127H1-t2溶液中，并且记录6600秒后的最终反应。该反应被绘制为该主干域多肽浓度的函数，并且进行至稳态1:1结合模型的拟合，得到对于CR6261/主干域多肽复合物的解离常数Kd为3.5nM和对于CR9114复合物的解离常数Kd为2.3nM(图8)。
总之，本发明的多肽s127H1-t2(SEQ ID NO:91)以高批量生产并且能够以高亲和性结合广泛中和性单克隆抗体CR6261和CR9114，证实了相应的中和表位在该主干域多肽中的存在。该多肽具有形成二聚结构的倾向。
实例3：在致命的流行性感冒激发模型中对本发明的多肽的保护效力的评价
为了评价本发明的多肽s127H1-t2(SEQ ID NO:91)在致命的流行性感冒激发模型中的保护效力，将具有10只雌性BALB/c小鼠(6-8周龄)的组以3周间隔用10μg的未佐有抑或佐有10μg基质-M的纯化s127H1-t2免疫3次。作为该激发模型的阳性对照，在激发之前1天肌肉内给予广泛中和抗体单克隆抗体CR6261(15mg/kg)，而用PBS进行免疫则充当阴性对照。在最后一次免疫后四周，将小鼠用25x LD50异源激发病毒(H1N1A/波多黎各/8/34)激发并且每天监测(存活率、重量、临床得分)持续3周。在ELISA测定中针对结合到用于免疫的本发明的多肽s127H1-t2(以证实正确的免疫)、结合到可溶的H1N1A/布里斯班/59/07全长HA(以证实全长HA的识别)、并且与广泛中和抗体单克隆抗体CR9114竞争结合到全长HA(以确定诱导的抗体是否极为贴近地结合广泛中和CR9114表位)，测试激发前血清。结果示于图9-12中。
这些结果显示，该实验是有效的，由于PBS对照组中的所有小鼠在激发后第7天屈从于感染，而阳性对照组(15mg/kg CR6261，激发前1天)被全面保护(图9)。与PBS处理的小鼠相对照，用未佐剂化的本发明的多肽s127H1-t2(SEQ ID NO:91)免疫的小鼠中3/10和用佐剂化的本发明的多肽免疫的小鼠中10/10幸存于该致命的激发(参见图10)。相比于PBS对照组，针对用本发明的多肽s127H1-t2免疫的组观察到增加的存活比例、增加的存活时间和减少的临床得分。差异对于接受本发明的佐剂化多肽的组是最显著的，但是针对接受未佐剂化多肽的组也观察到差异。
使用s127H1-t2或可溶的全长HA作为抗原的ELISA数据表明本发明的多肽s127H1是免疫原性的并且诱导无论是否使用佐剂，能够识别全长HA的抗体(图11A和B)。
为了进一步理解对免疫的免疫学应答，进行竞争结合ELISA。为此，将板结合的全长HA用连续稀释的血清样品孵育，之后在预定的滴定浓度添加CR9114-生物素。进一步孵育之后，遵循本领域中熟知的方案，使用链霉亲和素-轭合的辣根过氧化物酶对结合的CR9114-生物素的量进行定量。使用OD对log稀释度的线性回归来分析数据，表示为‘斜率OD’(ΔOD/10倍稀释)。该数据显示，通过用本发明的佐剂化多肽进行免疫来诱导可检测水平的能够与广泛中和抗体CR9114竞争结合的抗体，如通过在图12A中观察到的竞争水平的提升表明的。作为比较，在独立的图中指明了通过未标记的CR9114(即自我竞争)和非结合单克隆抗体CR8020和CR-JB(两者都从5μg/ml起始浓度连续稀释)诱导的水平。
总之，我们显示了用本发明的多肽s127H1-t2(SEQ ID NO:91)进行的免疫可保护小鼠对抗流行性感冒的致命的感染。该多肽是免疫原性的并且诱导可以结合全长HA的抗体。当本发明的多肽与佐剂组合使用时，至少部分诱导的可检测抗体在单克隆抗体CR9114的广泛中和表位的表位处结合或接近该表位处结合。
实例4：在致命的流行性感冒激发模型中对本发明的多肽的保护效力的评价
为了进一步评价本发明的多肽s127H1-t2(SEQ ID NO:91)在致命的流行性感冒激发模型中的保护效力，将具有10只雌性BALB/c小鼠(6-8周龄)的组以3周间隔用30μg的佐有10μg基质-M的纯化s127H1-t2免疫1次、2次和3次。作为该激发模型的阳性对照，在激发之前1天静脉内给予广泛中和抗体单克隆抗体CR6261(15mg/kg)，而用PBS进行免疫则充当阴性对照。在最后一次免疫后四周，将小鼠用25x LD50异源激发病毒(H1N1A/波多黎各/8/34)激发并且每天监测(存活率、重量、临床得分)持续3周。在ELISA测定中针对结合到用于免疫的本发明的多肽s127H1-t2(以证实正确的免疫)、结合到可溶的H1N1A/布里斯班/59/07全长HA(以证实全长HA的识别)、并且与广泛中和抗体单克隆抗体CR9114竞争结合到全长HA(以确定诱导的抗体是否极为贴近地结合广泛中和CR9114表位)，测试最后一次免疫后4周获得的激发前血清。结果示于图13-18中。
结果显示，该实验是有效的，由于PBS对照组中的所有小鼠在激发后第7天屈从于感染，而阳性对照组(15mg/kg CR6261，激发前1天)被全面保护(图13A)。用s127H1-t2(SEQID NO:91)免疫一次的小鼠在第7天和第9天之间都屈从于感染(图14A)。相比之下，在两次免疫后，8/10只小鼠存活，并且在3次免疫后，所有小鼠(10/10)幸存于该致命的激发(图14B、C)。对于多次免疫的组，体重减轻也减少，其中针对免疫三次的动物观察到最低百分比(图15B、C)。相比于PBS对照组，针对用本发明的多肽s127H1-t2免疫两次或三次的组观察到统计上显著增加的存活比例、增加的存活时间、减少的体重减轻和减少的临床得分(参见图16B、C)
来自使用s127H1-t2(图17A)或可溶全长HA(图17B)作为抗原的最终免疫后4周的激发前时间点的ELISA数据表明，本发明的多肽s127H1是免疫原性的并诱导能够识别全长HA的抗体，甚至在一次免疫后，虽然在两次和三次免疫后水平显著更高。使用上述CR9114竞争结合测定，在用本发明的多肽s127H1-t2(SEQ ID NO:91)进行两次和三次免疫后诱导能够竞争与广泛中和性抗体CR9114结合的可检测水平的抗体(图18A)。作为比较，在独立的图中指明了通过未标记的CR9114(即自我竞争)和非结合单克隆抗体CR8020和CR-JB(两者都从5μg/ml起始浓度连续稀释)诱导的水平(图18B)。
总之，我们显示了用本发明的多肽s127H1-t2(SEQ ID NO:91)进行的两次和三次免疫可保护小鼠对抗流行性感冒的致命的感染。该多肽是免疫原性的并且诱导可以结合全长HA的抗体。至少部分诱导的抗体在单克隆抗体CR9114的广泛中和表位的表位处结合或接近该表位处结合。
实例5：在致命的异源亚型H5N1流行性感冒激发模型中对本发明的多肽的保护效力的评价
为了进一步评价本发明的多肽s127H1-t2(SEQ ID NO:91)在致命的H5N1流行性感冒激发模型中的保护效力，将具有8-12只雌性BALB/c小鼠(6-8周龄)的组以3周间隔用30μg的佐有10μg基质-M的纯化s127H1-t2免疫3次。作为该激发模型的阳性对照，在激发之前1天静脉内给予广泛中和抗体单克隆抗体CR6261(15mg/kg)，而用PBS进行免疫则充当阴性对照。在最后一次免疫后四周，将小鼠用12.5x LD50异源亚型激发病毒(H5N1A/香港/156/97)激发并且每天监测(存活率、重量、临床得分)持续3周。
结果显示，该实验是有效的，由于PBS对照组中的所有小鼠在激发后8-10天之间屈从于感染，而阳性对照组(15mg/kg CR6261，激发前1天)被全面保护(图19A)。用s127H1-t2(SEQ ID NO:91)免疫的8/10只(80％)小鼠幸存于该致命的激发(图19B)。在第9天，平均体重减轻为大约15％，但存活的动物恢复并获得体重(图19C)。在第3-6天，中值临床得分为1.5，但从第8天开始，对于存活的小鼠没有观察到临床症状(图19D)。相比于PBS对照组，针对用本发明的多肽s127H1-t2免疫的组观察到统计学显著增加的存活比例、增加的存活时间、体重减轻的降低和减少的临床得分。总之，我们显示了用本发明的多肽s127H1-t2(SEQID NO:91)进行的免疫可保护小鼠对抗异源亚型H5N1流行性感冒株的致命的感染。
实例6：对通过用本发明的多肽免疫诱导的血清的结合宽度的评价
通过ELISA遵循本领域熟知的方法，还对来自如实例5所述免疫3次的小鼠的激发前血清来测试针对来自多个其他组1(H1、H5和H9)和组2(H3和H7)流行性感冒株的全长HA的结合(图20)。结果证实，用本发明的多肽s127H1-t2(SEQ ID NO:91)诱导的抗体有效地识别存在于FL HA的天然序列中的表位，并且抗体结合的这些表位在不同的组1流行性感冒株(包括H1、H5和H9HA)中是保守的。
实例7：在致命的H1N1A/布里斯班/59/2007流行性感冒激发模型中对本发明的多肽的保护效力的评价
为了进一步评价s127H1-t2(SEQ ID NO:91)在致命的H1N1流行性感冒激发模型中的保护效力，将具有8-18只雌性BALB/c小鼠(6-8周龄)的组以3周间隔用30μg的佐有10μg基质-M的纯化s127H1-t2免疫3次。作为该激发模型的阳性对照，在激发之前1天静脉内给予广泛中和抗体单克隆抗体CR6261(15mg/kg)，而用PBS进行免疫则充当阴性对照。在最后一次免疫后四周，将小鼠用12.5x LD50激发病毒(H1N1A/布里斯班/59/2007)激发并且每天监测(存活率、重量、临床得分)持续3周。
结果显示，该实验是有效的，由于PBS对照组中的所有小鼠在激发后7-10天之间屈从于感染，而阳性对照组(15mg/kg CR6261，激发前1天)被全面保护(图21A)。用s127H1-t2(SEQ ID NO:91)免疫的10/10只小鼠幸存于该致命的激发(图21B)。此外，感染后平均5天体重减轻约20％(图21C)，但在21天随访期内动物完全恢复。中值临床得分在感染后2至9天之间达到最高值3，但从感染后第16天返回到基线水平(0)(图21D)。相比于PBS对照组，对于用本发明的多肽s127H1-t2免疫的组观察到统计学显著增加的存活比例、增加的存活时间、体重减轻的降低和减少的临床得分
总之，我们显示了用本发明的多肽s127H1-t2(SEQ ID NO:91)进行的免疫可保护小鼠对抗H1N1A/布里斯班/59/2007的致命的感染。
实施例8：对用本发明的多肽免疫的小鼠的血清中流行性感冒中和抗体的存在的评价
为了进一步研究在针对流行性感冒的保护中起作用的抗体介导的效应机制，如下所述,使用源自H5N1A/越南/1194/04的拟颗粒,在拟颗粒中和测定(阿尔贝里尼(Alberini)等人，2009)中测试激发前血清。
拟颗粒中和测定
如前所述，生成表达FL HA的拟颗粒(Temperton等人，2007)。如先前(阿尔贝里尼等人，2009)所述，具有一些修改，使用单轮转导的HEK293细胞与编码荧光素酶报告基因的H5A/越南/1194/04拟颗粒来确定中和抗体。简言之，将热灭活(56℃下30分钟)的激发前血清样品3倍连续稀释于96孔平底培养板中的一式三份的生长培养基(MEM Eagle与EBSS(龙沙公司(Lonza)，巴塞尔，瑞士))中，该生长培养基补充有2mM L-谷氨酰胺(龙沙)、1％非必需氨基酸溶液(龙沙公司)、100U/ml的Pen/Strep(龙沙公司)和10％FBS(欧克隆(Euroclone)，佩罗，意大利))，并且添加滴定数的H5A/越南/1194/04拟颗粒(感染后产生106个相对发光单位(RLU))。在37℃、5％CO2下孵育1h后，每孔添加104个HEK293细胞。在37℃、5％CO2下孵育48h后，添加荧光素酶底物(Britelie Plus，珀金埃尔默公司(PerkinElmer)，沃尔瑟姆(Waltham)，马萨诸塞州)，并根据制造商的说明使用发光计(Mithras LB940，贝特霍尔德技术公司(Berthold Technologies)，德国)测量发光。
如实例5、6和7中所述，从用本发明的多肽s127H1-t2(SEQ ID NO:91)免疫的动物获得的激发前血清显示使用拟颗粒中和测定在高血清浓度下的可检测的中和(图22)。这证明了本发明的多肽用作免疫原时引发广泛中和抗体的能力。
除了直接的病毒中和以外，Fc介导的效应机制，例如抗体依赖性细胞毒性(ADCC)和抗体依赖性细胞吞噬作用(ADCP)，基本上有助于防止流行性感冒，伴随在这些机制中特别有效的主干定向的bnAb(丽罗(DiLillo)等人，2014)。为了测试用本发明的多肽s127H1-t2l18长(SEQ ID NO:186)免疫后引发的的抗体是否能够诱导ADCC，我们使用如以下所述的适于小鼠的ADCC替代测定(帕里克(Parekh)等人，2012；施钮日格(Schneuriger)等人2012；郑(Cheng)等人，2014)来测试激发前血清。
抗体依赖性细胞毒性(ADCC)替代测定
在37℃、10％CO2下，将人肺癌来源的A549上皮细胞(ATCC CCL-185)维持在补充有10％热灭活的胎牛血清的杜氏改良伊格尔培养基(DMEM)中。实验前两天，使用在Opti-MEM(英杰公司)中的Lipofectamine 2000(英杰公司)，用编码H5A/香港/156/97HA或H1A/布里斯班/59/2007HA的质粒DNA转染A549细胞。在该测定前一天，收获转染的细胞并在用于ADCC的白色96孔板(Costar)中和用于成像的黑色透明底96孔板(BD Falcon)中进行接种。24小时后，将样品稀释于RPMI 1640(Gibco)中的测定缓冲液(4％超低IgG FBS(Gibco))中并且在56℃下加热灭活30分钟，随后在测定缓冲液中连续稀释。对于ADCC生物测定，将A549细胞用新鲜的测定缓冲液和抗体稀释液重新装满，并且将表达小鼠Fcγ受体IV(FcγRIV；普洛麦格公司(Promega))的ADCC生物测定Jurkat效应细胞添加到这些细胞中，并且以1:4.5的靶效应比在37℃下孵育6小时。将细胞平衡至室温15分钟，之后添加Bio-Glo荧光素酶系统底物(普洛麦格公司)。10分钟后在Synergy Neo(Biotek)上读出发光。数据表示为在不存在血清下的信号的诱导倍数。
使用该测定，使用来自H5N1A/香港/156/97或H1N1A/布里斯班/59/07的FL HA转染的靶细胞作为抗原的来源，针对FcγRIV信号传导活性测试从用如在实例5、6、和7中所述的本发明的多肽s127H1-t2(SEQ ID NO:91)免疫的动物获得的激发前血清(图23)。在两种情况下，在测试的最高血清浓度下观察到30倍诱导，证实了本发明的多肽引发激活FcγRIV信号传导的抗体的能力，指示小鼠中ADCC/ADCP效应子功能。
示于实例5-8中的这些结果显示，本发明的多肽s127H1-t2(SEQ ID NO:91)能够引发主干靶向、中和以及ADCC介导的抗体，并且保护小鼠对抗同源、异源和异源亚型组I流行性感冒株的致命的激发的能力。
实例9：通过来自本发明的多肽免疫的小鼠的血清的被动转移来保护免受H5N1A/香港/156/97的致命的激发
为了确定由本发明的多肽诱导的抗体对所观察到的保护的贡献，进行转移研究。本研究的目的是评估来自用s127H1-t2(SEQ ID NO:91)和包含另外的His-标签的s127H1-t2长(SEQ ID NO:101)免疫三次的小鼠的血清的被动转移(多次给药)是否在佐剂(基质-M)存在下对H5N1流行性感冒A/香港/156/97的致命的激发赋予保护。
将雌性BALB/c供体小鼠(6-8周龄)以3周的间隔用30μg的s127H1-t2(SEQ ID NO:91)或s127H1-t2长(SEQ ID NO:101)(包含佐有10μg基质-M或PBS的C-末端His-标签)免疫3次。最后一次免疫后4周(d70)分离血清，合并每组并且在受体小鼠(雌性BALB/c，6-8周龄，每组n＝10)中转移。在激发前连续三天(d-3、-2和-1)使每只小鼠腹膜内接受400μl血清。在激发之前1天给予激发模型CR6261(15mg/kg)的阳性对照(n＝8)，而用PBS进行注射则充当阴性对照(n＝8)。在第0天，将小鼠用12.5x LD50激发病毒激发并且监测(存活率、重量、临床得分)3周。
为了验证在供体小鼠中本发明的多肽的免疫原性并且评估血清转移至受体小鼠后的HA特异性的抗体水平，在ELISA中针对与来自H1N1A/布里斯班/59/07的FL HA的结合来测试供体小鼠的肢端流血(d70)的合并的血清样品、血清转移前(d-4)的初始受体小鼠的合并的血清样品连同刚好在激发前(d0)的3次血清转移后的受体小鼠的个体血清样品。
结果
激发
-实验是有效的；PBS对照组中的所有小鼠在激发后(中值9.5天)第13天或之前屈从于感染，而阳性对照组(15mg/kg CR6261，激发前1天)被全面保护(p<0.001)。
-相比于PBS血清转移对照组，来自佐有基质-M的本发明的多肽SEQ ID NO:91的血清的三次血清转移至初始受体小鼠导致了存活时间显著增加(p＝0.007)和临床得分减少(p＝0.012)(图24)。
-相比于PBS血清转移对照组，来自佐有基质-M的本发明的多肽SEQ ID NO:101的血清的三次血清转移至初始受体小鼠导致了存活比例显著增加(p＝0.002)、存活时间增加(p<0.001)、体重减轻降低(p＝0.002)和临床得分减少(p<0.001)。(图24)
-对于本发明的多肽，在三次血清转移后测试FL HA A/布里斯班/59/07特异性抗体滴度，极少类似于主动免疫后获得的水平(图25)。
结论
通过用本发明的佐有基质-M的多肽SEQ ID NO:91和101免疫3次而诱导的血清组分(最可能是抗体)可以保护小鼠免受H5N1A/香港/156/97的致命的激发(存活百分比分别为30％和78％)。
例10：在小鼠的H1N1A/NL/602/09激发模型中本发明的多肽的体内保护效力
在H1N1A/NL/602/09激发模型中，相比于PBS对照组，确定具有基质-M的本发明的多肽s127H1-t2(SEQ ID NO:91)和包含另外的His-标签的s127H1-t2长(SEQ ID NO:101)的保护效力。
将具有10只雌性BALB/c小鼠(6-8周龄)的组用30μg的具有10μg基质-M的本发明的多肽以3周间隔免疫3次。在激发之前1天给予激发模型CR6261(15mg/kg)的阳性对照(n＝8)，而用PBS进行注射则充当阴性对照(n＝18)。在最后一次免疫后四周，将小鼠用12.5xLD50激发病毒激发并且监测(存活率、重量、临床得分)3周。
为了验证本发明的多肽的免疫原性，在ELISA测定中针对与来自H1N1A/布里斯班/59/07的FL HA的结合来测试激发前血清(-1天)。为了确定诱导的抗体是否在紧邻CR9114表位处结合，进行CR9114竞争ELISA。竞争数据表示为使用斜率OD以能够量化反应。
结果
-该实验是有效的；PBS对照组中的所有小鼠在激发后(中值5天)第8天或之前屈从于感染，而阳性对照组(15mg/kg CR6261，激发前1天)被全面保护(p<0.001)。
-相比于PBS对照组，用佐有基质-M的s127H1-t2(SEQ ID NO:91)和包含另外的His-标签的s127H1-t2长(SEQ ID NO:101)进行的三次免疫导致了存活比例显著增加(p<0.001)、存活时间增加(p<0.001)和临床得分减少(p<0.001)(图26)。
-相比于PBS对照组，用佐有基质-M的H1mini-HA变体s127H1-t2(SEQ ID NO:91)进行的三次免疫导致了体重显著降低(p<0.001)(图26)。
-对于所有测试的H1mini-HA变体，相比于PBS，由本发明的多肽诱导的对H1N1A/布里斯班/59/07FL HA的IgG抗体滴度显著更高(p<0.001)(图27A)。
-相比于包含另外的His-标签的s127H1-t2长(SEQ ID NO:101)，H1mini-HA变体s127H1-t2(SEQ ID NO:91)具有对H1N1A/布里斯班/59/07FL HA的显著更高IgG抗体滴度(p＝0.021)(图27A)。
-相比于PBS，测试的本发明的佐有基质-M的全部多肽具有显著更高的CR9114竞争滴度(p<0.001)(图27B)。
结论：
佐有基质-M的本发明的多肽s-127H1-t2(SEQ ID NO:91)和包含另外的His-标签的s127H1-t2长(SEQ ID NO:101)赋予针对H1N1A/NL/602/09的致命的激发的保护，被认为是生存比例、生存期的增加和临床得分的减少。此外，佐有基质-M的s127H1-t2(SEQ ID NO:91)也导致H1N1A/NL/602/09致命的激发后减少的体重减轻。
实例11：文库筛选
PCT/EP 2012/073706披露了流行性感冒血球凝集素主干域多肽、组合物和疫苗以及在预防和/或治疗流行性感冒的领域中使用它们的方法。此处我们描述了另外的源自于H1N1A/布里斯班/59/2007(SEQ ID NO:1)的全长HA的主干域多肽的序列。这些主干域多肽是通过H1-mini2-簇1+5+6-GCN4t2(SEQ ID NO:52)的定向突变获得，并且呈现CR6261的广泛流行性感冒中和表位(斯罗索比(Throsby)等人，2009；艾基尔特(Ekiert)等人2010)和/或CR9114。
H1-mini2-簇1+5+6-GCN4t2(SEQ ID NO:52)是源自于H1N1A/布里斯班/59/2007(SEQ ID NO:1)的全长HA，采取以下步骤：
-去除HA0中的切割位点。在此位点对野生型HA的切割得到HA1和HA2。该去除可以通过使在P1位置(SEQ ID NO:1中位置343)的R突变为Q来实现(参见例如孙(Sun)等人，2010，切割位点的命名法解释)。
-通过使氨基酸53至320从SEQ ID NO；1缺失而去除头部域。通过四残基柔性接头GGGG连接该序列剩下的N-以及C-末端部分。
-增加由H1A/布里斯班/59/2007(SEQ ID NO:1)中的残基402至418(或等价物)形成的环(A-螺旋以及CD螺旋之间)的溶解度以增加融合前构象的稳定性并且使修饰的HA的融合后构象两者去稳定化。在H1-mini2-簇1+5+6-GCN4(SEQ ID NO:2)中引入突变F406S、V409T、F413G和L416S(编号参照SEQ ID NO:1)
-在H1A/布里斯班/59/2007中的位置324和436处的氨基酸之间引入二硫桥；这是通过引入突变R324C和Y436C实现的。(编号参照SEQ ID NO:1)
-在位置419-433处(编号参照SEQ ID NO:1)引入已知会三聚体化的GCN4衍生的序列RMKQIEDKIEEIESK(SEQ ID NO:20)。
在某些实施例中，本发明的多肽包含HA的细胞内序列以及跨膜域。在其他实施例中，跨膜和胞内域的序列已从HA2的位置519、520、521、522、523、524、525、526、526、527、528、529、或530(或其等价位置，如从序列比对测定的)至HA2的C-末端(根据SEQ ID NO:1编号)缺失，以使得在细胞中表达之后产生分泌的(可溶的)多肽。该可溶的多肽可以通过引入已知形成三聚体结构的序列，即折叠子序列AYVRKDGEWVLL(SEQ ID NO:3)而进一步稳定化，任选地通过短接头连接，如上所述。该接头可任选地包含切割位点用于之后根据本领域的普通技术人员熟知的方案进行加工。为了促进该可溶形式的纯化和检测，可以任选地添加标签序列，例如组氨酸标签(HHHHHHH(SEQ ID NO:16)或HHHHHH(SEQ ID NO:15)或FLAG标签(DYKDDDDK；SEQ ID NO:22)或这些的组合，任选地通过短接头连接。该接头可任选地包含(部分的)蛋白分解切割位点，例如LVPRGS(SEQ ID NO:23)(凝血酶)或IEGR(SEQ ID NO:24)(因子X)，用于之后根据本领域的普通技术人员熟知的方案进行加工。加工的蛋白也包括在本发明中。
这样的组合了FLAG-标签、凝血酶切割位点、折叠子、以及His序列的C-末端序列的实例是SEQ ID NO:4FLAG-凝血酶-折叠子-His。将此序列与可溶形式的H1-mini2-簇1+5+6-GCN4t2(SEQ ID NO:51)序列组合以建立亲本序列(SEQ ID NO:156)，该序列被用于通过诱变建立本发明的新颖多肽。此序列不包含对应于SEQ ID NO:1和2的氨基酸1-17的前导序列。
这些主干域多肽是通过以下方式来建立的：使编码该分子头部域的该血球凝集素序列的部分缺失，并且通过如描述于PCT/2012/073706以及上述的接头在该缺失的任一侧上重连接该序列的N-和C-末端部分。去除该头部域留下了之前从暴露的水性溶剂屏蔽的分子的部分，潜在地去稳定化本发明的多肽的结构。出于此原因，使用亲本序列SEQ ID NO:156作为起始点，B-环(具体而言氨基酸残基406(SEQ ID NO:1和2中分别是F和S)、409(V和T)413(F和G)以及416(L和S))中的残基以不同组合突变。SEQ ID NO:156是通过去除前导序列并且用Flag-凝血酶-折叠子--his序列(SEQ ID NO:4)替代残基520-565而从H1-mini2-簇1+5+6-GCN4t2(SEQ ID NO:52)建立。
类似地，在该融合肽周围的区域中，数个疏水残基被暴露于该溶剂，这是由以下事实引起的，不像天然全长HA，本发明的多肽不能被切割，并且经受相关的构象变化，该构象变化将该疏水融合肽隐藏在该蛋白的内部。为了解决此问题，SEQ ID NO:156中残基I337、I340、F352以及I353中的一些或所有也突变。
突变体多肽的两个不同集合披露于表9中。在所有情况下，这些多肽在位置419-433处包含SEQ ID NO:20(编号参照SEQ ID NO:1)。
实例12：本发明的三聚体多肽的鉴定、纯化以及表征。
建立如实例11(组1和组2)中所述的多肽的文库，它在位置419-433处包含SEQ IDNO:20。单克隆进入HEK293F细胞，并且用于多聚体(CR9114夹心ELISA)、CR6261结合(ELISA)和蛋白质表达(HTRF测定)的筛选培养基被单独转染。基于CR9114夹心测定，CR9114、CR6261和CR8020ELISA，以及HTRF测定的命中得到证实和排序。
对通过用伯胺(存在于赖氨酸残基中)特异性交联剂BS3交联、随后进行SDS-PAGE(见下文)的多聚化进行评估。由于广泛的多聚化，用凝血酶切割位点和his-标签序列(TCShis)替代C-末端Flag-折叠子-His(FFH)标签序列。随后，重新证实了包含序列(CR9114夹心测定，BS3交联)的TCS-his的多聚化，并对克隆进行排序和选择。选择的克隆被表达、纯化和表征。
如下进行该交联测定：
·将交联剂BS3(双(磺基琥珀酰亚胺基)辛二酸酯)直接添加至培养基中
·在室温下孵育30分钟。
·收集培养基并在还原(R，5mM DTT)和非还原(NR)条件下通过SDS-PAGE/蛋白质印迹法进行分析
·在还原条件下，仅BS3交联的种类将保持共价连接
·经由蛋白质印迹法使用his-标签特异性mAb来检测mini-HA。
结果：
1.成功地建立了包含位置419-433处的SEQ ID NO:20和预期的序列变异(>97％随机化)的两个高质量文库(>90％的ORF正确的)
2.在初级筛选中评估总共10472个克隆(分别来自组1和组2的5544个和4928个)(图28)
3.展现出FL HA表达的>50％表达的克隆和信号与针对FL HA所观察到的信号的CR6261>80％的结合被认为是命中；此过程产生了703个命中(分别来自库1和库2的596个和107个)
4.确认筛选后保留703个命中中的658个命中
5.前20％命中(111)的交联测定表明更高级的多聚体的存在，这些多聚体可能潜在地干扰三聚体种类的纯化。
6.前20％确认的命中(111)被成功克隆以用TCS-his序列替代FFH C-末端，随后是CR9114夹心ELISA和交联测定评估
7.交联测定产生被认为是最有希望的三聚体候选物的9个克隆(SEQ ID NO:158至166，表11)。基于CR9114夹心ELISA(图29)，选择三个候选物(2个具有TCS-his，1个具有FFHC-末端)用于表达和纯化
8.选择的候选物中的两个表达不良好，并且不继续纯化。按照如实例4中所述的过程将候选物GW1.5E2.FFH(SEQ ID NO:158)纯化至同质性(7.6mg总蛋白；纯度>95％，HP-SEC)。
9.通过SEC-MALS分析对GW1.5E2.FFH(SEQ ID NO:158)的表征指示了溶液中的三聚体形成，其中每个三聚体结合CR9114或CR6261的3个Fab片段(图30和下表10)。如从双层干涉技术测量(Octet)针对CR6261和CR9114确定的Kd app是1nM。如所预期的，通过任一方法都不能检测CR8020(阴性对照)的结合。
结论：已经鉴定了以3:1化学计量的高亲和力结合bnAb CR6261和CR9114的本发明的非共价三聚体多肽(GW1.5E2.FFH，SEQ ID NO:158)。
实例13：在H1N1A/布里斯班/59/07小鼠模型中本发明的多肽sH1mini-HAGW1.5E2-FFH(SEQ ID NO:158)的保护效力
在H1N1A/布里斯班/59/07激发模型中，相比于PBS对照组，确定佐有基质-M的sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)的保护效力。
将具有10只雌性BALB/c小鼠(6-8周龄)的组用30μg的佐有10μg基质-M的sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)以3周间隔免疫3次。在激发之前1天给予激发模型CR6261(15mg/kg)的阳性对照(n＝8)，而用PBS进行注射则充当阴性对照(n＝16)。在最后一次免疫后四周，将小鼠用12.5x LD50激发病毒激发并且监测(存活率、重量、临床得分)3周。
为了验证sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)的免疫原性，在ELISA测定中针对与来自H1N1A/布里斯班/59/07的FL HA的结合来测试激发前血清(-1天)。为了确定本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)诱导的抗体是否在紧邻CR9114表位处结合，进行CR9114竞争ELISA。竞争数据可视化为“％竞争”，定义为(AP)/A x 100)，其中A是当不存在血清时CR9114与FL HA结合的最大OD信号，并且P是在以给定稀释度的血清存在下CR9114与FL Ha结合的OD信号或使用能够量化反应的斜率OD度量来表示；包括针对参考CR9114和CR8020(起始浓度5mg/ml)溶液。
结果：
-实验是有效的；PBS对照组(n＝16)中的所有小鼠在激发后(中值8天)第10天或之前屈从于感染，而阳性对照组(n＝8，15mg/kg CR6261，激发前1天)被全面保护(p<0.001)。
-相比于PBS对照组，用佐有基质-M的sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)进行的三次免疫导致了存活比例显著增加(p<0.001)、存活时间增加(p<0.001)、体重减轻降低(p<0.001)和临床得分减少(p<0.001)(图31)。
-相比于PBS，由sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)诱导的对H1N1A/布里斯班/59/07FL HA的激发前IgG抗体滴度显著更高(p≤0.001)(图32A)。
-两次免疫后，对H1N1A/布里斯班/59/07FL HA平台的IgG抗体滴度(未显示)。
-相比于PBS，本发明的佐有基质-M的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)诱导显著更高的CR9114竞争滴度(p<0.001)(图32B)。
结论：本发明的佐有基质-M的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)赋予针对H1N1A/布里斯班/59/07的致命的激发的保护。
实例14：在H5N1A/香港/156/97小鼠模型中本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)的保护效力
在H5N1A/香港/156/97激发模型中，相比于PBS对照组，测定佐有基质-M的主要的H1mini-HA变体的保护效力。
将具有10只雌性BALB/c小鼠(6-8周龄)的组用30μg的佐有10μg基质-M的本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)以3周间隔免疫3次。在激发之前1天给予激发模型CR6261(15mg/kg)的阳性对照(n＝8)，而用PBS进行注射则充当阴性对照(n＝16)。在最后一次免疫后四周，将小鼠用12.5x LD50激发病毒激发并且监测(存活率、重量、临床得分)3周。
为了验证本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)的免疫原性，在ELISA测定中针对与来自H1N1A/布里斯班/59/07的FL HA的结合来测试激发前血清(-1天)。为了确定mini-HA诱导的抗体是否在紧邻CR9114表位处结合，进行CR9114竞争ELISA。竞争数据可视化为“％竞争”，定义为(A-P)/A x 100)，其中A是当不存在血清时CR9114与FLHA结合的最大OD信号，并且P是在以给定稀释度的血清存在下CR9114与FL Ha结合的OD信号或使用能够量化反应的斜率OD度量来表示；包括针对参考CR9114和CR8020(起始浓度5μg/ml)溶液。
结果：
-实验是有效的；PBS对照组中的15/16只小鼠在激发后(中值9天)第9天或之前屈从于感染，而阳性对照组(n＝8，15mg/kg CR6261，激发前1天)被全面保护(p<0.001)。
-相比于PBS对照组，用佐有基质-M的本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQID NO:158)进行的三次免疫导致了存活比例显著增加(p<0.001)、存活时间增加(p<0.001)、体重减轻降低(p<0.001)和临床得分减少(p<0.001)(图33)。
-相比于PBS，由本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)诱导的对H1N1A/布里斯班/59/07FL HA的激发前IgG抗体滴度显著更高(p≤0.001)(图34A)。
-相比于PBS，本发明的佐有基质-M的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)诱导显著更高的CR9114竞争滴度(p<0.001)(图34B)。
结论：本发明的佐有基质-M的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)赋予针对H5N1A/香港/156/97的致命的激发的异源亚型保护。
实例15：在H1N1A/波多黎各/8/34小鼠模型中本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)的保护效力
在H1N1A/波多黎各/8/1934激发模型中，相比于PBS对照组，确定佐有基质-M的本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)的保护效力。
将具有10只雌性BALB/c小鼠(6-8周龄)的组用30μg的佐有10μg基质-M的本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)以3周间隔免疫3次。在激发之前1天给予激发模型CR6261(15mg/kg)的阳性对照(n＝8)，而用PBS进行3次免疫则充当阴性对照(n＝16)。在最后一次免疫后四周，将小鼠用25x LD50激发病毒激发并且监测(存活率、重量、临床得分)3周。
为了验证本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)的免疫原性，在ELISA测定中针对与来自H1N1A/布里斯班/59/07的FL HA的结合来测试激发前血清(-1天)。为了确定mini-HA诱导的抗体是否在紧邻CR9114表位处结合，进行CR9114竞争ELISA。竞争数据可视化为‘％竞争’，定义为(A-P)/A x 100)，其中A是当不存在血清时CR9114与FLHA结合的最大OD信号，并且P是在以给定稀释度的血清存在下CR9114与FL HA结合的OD信号或使用能够量化反应的斜率OD度量来表示；包括针对参考CR9114和CR8020(起始浓度5μg/ml)溶液。
结果
-实验是有效的；PBS对照组(n＝16)中的所有小鼠在激发后(中值8天)第9天或之前屈从于感染，而阳性对照组(n＝8，15mg/kg CR6261，激发前1天)被全面保护(p<0.001)。
-相比于PBS对照组，用佐有基质-M的本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQID NO:158)进行的三次免疫导致了存活比例显著增加(p<0.001)、存活时间增加(p<0.001)、体重减轻降低(p<0.001)和临床得分减少(p<0.001)(图35)。
-相比于PBS，由本发明的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)诱导的对H1N1A/布里斯班/59/07FL HA的激发前IgG抗体滴度显著更高(p<0.001)(图36A)。
-相比于PBS，本发明的佐有基质-M的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)诱导显著更高的CR9114竞争滴度(p<0.001)(图36B)。
结论：本发明的佐有基质-M的多肽sH1mini-HA GW1.5E2-FFH(SEQ ID NO:158)赋予针对H1N1A/波多黎各/8/34的致命的激发的保护。
表1.标准氨基酸、缩写以及特性
氨基酸 3字母 1字母 侧链极性 侧链电荷(pH 7.4)
丙氨酸 Ala A 非极性 中性
精氨酸 Arg R 极性 正性
天冬酰胺 Asn N 极性 中性
天冬氨酸 Asp D 极性 负性
半胱氨酸 Cys C 非极性 中性
谷氨酸 Glu E 极性 负性
谷氨酰胺 Gln Q 极性 中性
甘氨酸 Gly G 非极性 中性
组氨酸 His H 极性 正性(10％)中性(90％)
异亮氨酸 Ile I 非极性 中性
亮氨酸 Leu L 非极性 中性
赖氨酸 Lys K 极性 正性
甲硫氨酸 Met M 非极性 中性
苯丙氨酸 Phe F 非极性 中性
脯氨酸 Pro P 非极性 中性
丝氨酸 Ser S 极性 中性
苏氨酸 Thr T 极性 中性
色氨酸 Trp W 非极性 中性
酪氨酸 Tyr Y 极性 中性
缬氨酸 Val V 非极性 中性
表2.根据本发明的具体实施例的H1序列的序列比对
表3.毕赤酵母中表达的多肽。
如所述的测定表达和CR6261结合，并且计算结合和表达信号的比率。
表4.毕赤酵母中表达的多肽。如所述的测定表达和CR6261结合，并且计算结合和表达信号的比率。
表5. HEK293F中表达的多肽。
如所述的测定表达和CR6261结合，并且计算结合和表达信号的比率。每个克隆中包括的突变表明于表4以及5中。
表6.针对每个亚型以序列总数目的％计的在指示位置天然发生的序列变化
表7.多肽的mAb结合的纯化以及强度
表8.如通过SEC-MALS针对本发明的多肽及其与CR6261和CR9114的Fab片段的复合体确定的分子量。基于本发明的多肽的序列(假设单体)以及来自附接聚醣的大约10kDa的额外贡献来估计理论(theor)值。还通过SEC-MALS确定CR6261、CR9114以及CR8020的Fab片段的分子量，并且分别是48、49以及47kDa。
表9：SEQ ID NO:156中建立的突变。也表明了SEQ ID NO:1(全长，wt HA)和SEQ IDNO:52中的对应氨基酸。
集合1
集合2
表10.如通过SEC-MALS针对本发明的多肽及其与CR6261和CR9114的Fab片段的复合体确定的分子量。基于本发明的多肽的序列(假设三聚体)以及来自附接聚醣的大约10kDa的额外贡献来估计理论值(括号内给出)。还通过SEC-MALS确定CR6261、CR9114以及CR8020的Fab片段的分子量，并且分别是48、49以及47kDa。
*出于参考目的而包括的数据
**如从SEC MALS确定的；针对三聚体FL HA或SEQ ID NO:158和与3个Fab复合的三聚体FL HA或SEQ ID NO:158的理论值在括号之间给出
表11.源自SEQ ID NO:156并如实例11和12中所述而选择的本发明的多肽。仅表示在组1和组2中不同的残基，所有其他残基与SEQ ID NO 156相同。
参考文献
阿尔贝里尼(Alberini)等人(2009)，疫苗(Vaccine)27:5998-6003。
博姆玛坎蒂(Bommakanti)等人(2010)，PNAS 107(31):13701-13706。
博姆玛坎蒂(Bommakanti)等人(2012)，病毒学杂志(J Virol)86:13434。
郑(Cheng)等人(2014)，免疫方法杂志(J.Immunol.Methods)1-13.(doi:10.1016/j.jim.2014.07.010)
科夫曼(Coffman)等人(2010)，免疫(Immunity)33:492。
德弗罗(Devereux)等人(1984)，核酸研究(Nucl.Acids Res.)12:387。
狄丽罗(DiLillo)等人(2014)，自然医学(Nat Med)20,143。
多普海德(Dopheide)TA，沃德(Ward)CW.(1981)普通病毒学杂志(J Gen Virol.)367-370
艾基尔特(Ekiert)等人(2009)，科学(Science)324:246。
艾基尔特(Ekiert)等人(2011)，科学(Science)333:844。
弗格森(Ferguson)等人(2003)，自然(Nature)422:428-443。
洛瑞尤(Lorieau)等人，2010，美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)，107：11341。
陆(Lu)等人(2013)，www.pnas.org/cgi/doi/10.1073/pnas.1308701110。
马拉乔斯宇拉(Mallajosyula)等人(2014)，www.pnas.org/cgi/doi/10.1073/pnas.1402766111。
帕里克(Parekh)等人(2012)，mAbs 4:310。
施钮日格(Schnueriger)等人(2011)，分子免疫学(Molecular immunology)48:1512。
斯蒂尔(Steel)等人(2010)，mBio 1(1):1-9。
史蒂文(Steven)等人(2004)科学(Science)303:1866。
史蒂文(Steven)等人(2006)科学(Science)312:404。
Temperton等人(2007)，病毒(Viruses)1:105-12。
斯罗索比(Throsby)等人(2008)，公共科学图书馆-综合(Plos One)12(3):1-15。
威尔逊(Wilson)等人(1981)自然(Nature)289:366。
序列
SEQ ID NO 1：H1全长(A/布里斯班/59/2007)
SEQ ID NO:2:H1-mini2-簇1+5+6-GCN4
SEQ ID NO:3：折叠子
GYIPEAPRDGQAYVRKDGEWVLLSTFL
SEQ ID NO:4：FLAG-凝血酶-折叠子-HIS
SGRDYKDDDDKLVPRGSPGSGYIPEAPRDGQAYVRKDGEWVLLSTFLGHHHHHH
SEQ ID NO:5：
MKQIEDKIEEIESKQ
SEQ ID NO:6：H1-mini2-簇1+5+6-GCN4，不具有前导序列并且具有FLAG-凝血酶-折叠子-HIS
SEQ ID NO 7：H1共有序列残基402-418(根据SEQ ID NO:1编号)
402MNTQFTAVG KEFN(H/K)LE(K/R)418
>SC09-114VH蛋白(SEQ ID NO：11)
QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSS
>SC09-114VL蛋白(SEQ ID NO：12)
SYVLTQPPAVSGTPGQRVTISCSGSDSNIGRRSVNWYQQFPGTAPKLLIYSNDQRPSVVPDRFSGSKSGTSASLAISGLQSEDEAEYYCAAWDDSLKGAVFGGGTQLTVL
>CR6261VH蛋白(SEQ ID NO：9)
>CR6261VL蛋白(SEQ ID NO：10)
>SC08-057VH蛋白(SEQ ID NO：13)
EVQLVESGGGLVQPGGSLRLSCAASGFTDSVIFMSWVRQAPGKGLECVSIIYIDDSTYYADSVKGRFTISRHNSMGTVFLEMNSLRPDDTAVYYCATESGDFGDQTGPYHYYAMDV
>SC08-057VL蛋白(SEQ ID NO：14)
QSALTQPASVSGSPGQSITISCTGSSGDIGGYNAVSWYQHHPGKAPKLMIYEVTSRPSGVSDRFSASRSGDTASLTVSGLQAEDEAHYYCCSFADSNILI
>SC08-020VH蛋白(SEQ ID NO：17)
QVQLQQSGAEVKTPGASVKVSCKASGYTFTRFGVSWIRQAPGQGLEWIGWISAYNGDTYYAQKFQARVTMTTDTSTTTAYMEMRSLRSDDTAVYYCAREPPLFYSSWSLDN
>SC08-020VL蛋白(SEQ ID NO：18)
EIVXTQSPGTLSLSPGERATLSCRASQSVSMNYLAWFQQKPGQAPRLLIYGASRRATGIPDRISGSGSGTDFTLTISRLEPADFAVYYCQQYGTSPRT
SEQ ID NO：52：H1-mini2-簇1+5+6-GCN4t2
SEQ ID NO：53：H1-mini2-簇1+5+6-GCN4t3
SEQ ID NO：55：127H1
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：56：86B4
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTArGKEMNKIERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：57：74H9
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：58：6E12
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRNVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：59：55G7
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：60：115A1
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：61：71H2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：62：181H9
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：63：220C9
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：64：113E7
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：65：s74H9
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：66：s127H1
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：67：s86B4
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAIGKEMNKIERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：68：s55G7
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：69：s6E12
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKtDGRSLVPRGSPGHHHHHH
SEQ ID NO：70：s115A1
DTICIGYHAMNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：71：s71H2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：76：s181H9
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：77：s220C9
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：78：s113E7
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：72：s74H9-长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：73：s127H1-长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：74：s86B4-长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAIGKEMNKIERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：75：s55G7-长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：144：s6E12-长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：79：s115A长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：80：s71H2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSERMKQIEDKIE EIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：81：127H1-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：82：86B4-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAIGKEMNKIERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：83：74H9-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：84：6E12-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：85：55G7-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：86：115A1-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：87：71H2-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：88：181H9-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO： 89：220C9-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：90：113E7-t2
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：91：s127H1-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSERRMKQIEDKI EEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：92：s86B4-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAIGKEMNKIERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：93：s74H9-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：94：s6E12-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：95：s55G7-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：96：s115A1-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：97：s71H2-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：98：s181H9-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：99：s220C9-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：100：s113E7-t2
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：101：s127H1-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：102：s86B4-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAIGKEMNKIERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：103：s74H9-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：104：s6E12-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：105：s55G7-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：106：s115A1-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：107：s71H2-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：108：s181H9-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：109：s220C9-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：110：s113E7-t2长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：111：127H1-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：112：86B4-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAIGKEMNKIRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：113：74H9-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：114：6E12-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：115：55G7-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：116：115A1-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：117：71H2-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：118：181H9-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：119：220C9-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：120：113E7-t3
MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：121：s127H1-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：122：s86B4-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAIGKEMNKIRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：123：s74H9-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：124：s6E12-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：125：s55G7-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：126：s115A1-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：127：s71H2-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：128：s181H9-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：129：s220C9-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：130：s113E7-t3
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGRSLVPRGSPGHHHHHH
SEQ ID NO：131：s127H1-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEYNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：132：s86B4-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAIGKEMNKIRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：133：s74H9-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAFGKEMNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：134：s6E12-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNEPSNQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAFGKEVNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：135：s55G7-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTAIGKEMNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：136：s115A1-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGYTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQITAVGKEYNKIRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：137：s71H2-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSNQSQGLFGAIAGFKEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQLTAIGKEVNKSRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：138：s181H9-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：139：s220C9-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：140：s113E7-t3长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHRMKQIEDKIEEIESKQKIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：141：s181H9长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNVPSKQSQGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKNERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：142：s220C9长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSTQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTATGKEYNKLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：143：s113E7长
DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENGGGGKYVCSAKLRMVTGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQYTATGKEINKHERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQIEG
SEQ ID NO：149：smH1 Cali3964-55G7
MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDGGGGKYVCSTKLRLATGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQYTAIGKEMNHLERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGRSLVPRGSPGHHHHHH
SEQ ID NO：150：smH1 Cali3964-86B4
MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDGGGGKYVCSTKLRLATGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQFTAIGKEMNHIERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGRSLVPRGSPGHHHHHH
SEQ ID NO：151：smH1 Cali3964-127H1
MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDGGGGKYVCSTKLRLATGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQYTAIGKEYNHSERMKQIEDKIEEIESKQIWCYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGRSLVPRGSPGHHHHHH
SEQ ID NO：152：_smH1 Cali3964-55G7-t2
MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDGGGGKYVCSTKLRLATGLRNKPSNQSQGLFGAIAGYVEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQYTAIGKEMNHLERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGRSLVPRGSPGHHHHHH
SEQ ID NO：153：_smH1 Cali3964-86B4-t2
MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDGGGGKYVCSTKLRLATGLRNKPSNQSQGLFGAIAGYKEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQFTAIGKEMNHIERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGRSLVPRGSPGHHHHHH
SEQ ID NO：154：smH1 Cali3964-127Hl-t2
MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDGGGGKYVCSTKLRLATGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQYTAIGKEYNHSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGRSLVPRGSPGHHHHHH
SEQ ID NO：155：mH1 Cali3964-127H1-t2
MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDGGGGKYVCSTKLRLATGLRNKPSKQSQGLFGAIAGFTEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQYTAIGKEYNHSERRMKQIEDKIEEIESKIWCYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQILAIYSTVASSLVLVVSLGAISFWMCSNGSLQCRICI
SEQ ID NO：156：sH1-mini2-簇1+5+6-GCN4t2，不具有前导序列并且具有FLAG-折叠子-HIS
SEQ ID NO：157：H1 mini-HA GW1.5E2
SEQ ID NO：158 sH1 mini-HA GW1.5E2-FFH (#5145)
序列表
<110> 扬森疫苗与预防公司
<120> 流行性感冒病毒疫苗及其用途
<130> 0240 WO 00 ORD
<150> EP14176451.4
<151> 2014-07-10
<160> 158
<170> PatentIn版本3.5
<210> 1
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> H1 全长 (A/布里斯班/59/2007)
<400> 1
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Ser His Asn Gly Lys Leu Cys Leu Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Leu Leu Ile Ser Lys Glu Ser Trp Ser Tyr Ile
85 90 95
Val Glu Lys Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly His Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Val Thr Gly Val Ser Ala Ser Cys Ser His Asn Gly Glu Ser Ser Phe
145 150 155 160
Tyr Arg Asn Leu Leu Trp Leu Thr Gly Lys Asn Gly Leu Tyr Pro Asn
165 170 175
Leu Ser Lys Ser Tyr Ala Asn Asn Lys Glu Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Pro Asn Ile Gly Asp Gln Lys Ala Leu Tyr
195 200 205
His Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser Arg
210 215 220
Lys Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln Glu
225 230 235 240
Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Arg Tyr Ala Phe Ala
260 265 270
Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Asn Ser Asn Ala Pro Met
275 280 285
Asp Lys Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu
405 410 415
Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Ile
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asn Asp Glu Cys Met Glu Ser Val Lys
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 2
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> H1-mini2-簇1+5+6-GCN4
<400> 2
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Ile Pro Ser Ile Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ser Thr Ala
130 135 140
Thr Gly Lys Glu Gly Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 3
<211> 27
<212> PRT
<213> 人工序列
<220>
<223> 折叠子
<400> 3
Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys
1 5 10 15
Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
20 25
<210> 4
<211> 54
<212> PRT
<213> 人工序列
<220>
<223> FLAG-凝血酶-折叠子-HIS
<400> 4
Ser Gly Arg Asp Tyr Lys Asp Asp Asp Asp Lys Leu Val Pro Arg Gly
1 5 10 15
Ser Pro Gly Ser Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala
20 25 30
Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu Gly
35 40 45
His His His His His His
50
<210> 5
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 三聚结构域
<400> 5
Met Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Glu Ser Lys Gln
1 5 10 15
<210> 6
<211> 292
<212> PRT
<213> 人工序列
<220>
<223> 无前导序列并有FLAG-凝血酶-折叠子-HIS的H1-mini2-簇1+5+6-GCN4
<400> 6
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Ile Pro Ser Ile Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ser Thr Ala Thr
115 120 125
Gly Lys Glu Gly Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Ser Gly
225 230 235 240
Arg Asp Tyr Lys Asp Asp Asp Asp Lys Leu Val Pro Arg Gly Ser Pro
245 250 255
Gly Ser Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val
260 265 270
Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu Gly His His
275 280 285
His His His His
290
<210> 7
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 连接螺旋A的C-末端残基和螺旋CD的N-末端残基的H1 HA2氨基酸序列
<220>
<221> 尚未归类的特征
<222> (14)..(14)
<223> X=H 或 K
<220>
<221> 尚未归类的特征
<222> (17)..(17)
<223> X= K 或 R
<400> 7
Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Xaa Leu Glu
1 5 10 15
Xaa
<210> 8
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 连接螺旋A的C-末端残基和螺旋CD的N-末端残基的H1 HA2氨基酸序列
<220>
<221> 尚未归类的特征
<222> (1)..(1)
<223> X= M, E, K, V, R, T
<220>
<221> 尚未归类的特征
<222> (5)..(5)
<223> X= F, I, N, T, H, L, Y
<220>
<221> 尚未归类的特征
<222> (8)..(8)
<223> X= V, A, G, I, R, F, S
<220>
<221> 尚未归类的特征
<222> (12)..(12)
<223> X= F, I, N, S, T, Y, E, K, M, V
<220>
<221> 尚未归类的特征
<222> (14)..(14)
<223> X= F, I, N, S, T, Y, E, K, M, V
<220>
<221> 尚未归类的特征
<222> (14)..(14)
<223> X= H 或 K
<220>
<221> 尚未归类的特征
<222> (15)..(15)
<223> X= L, H, I, N, R
<220>
<221> 尚未归类的特征
<222> (17)..(17)
<223> X= K 或 R
<220>
<221> 尚未归类的特征
<222> (18)..(18)
<223> Xaa可以是任何天然存在的氨基酸
<400> 8
Xaa Asn Thr Gln Xaa Thr Ala Xaa Gly Lys Glu Xaa Asn Xaa Xaa Leu
1 5 10 15
Glu Xaa
<210> 9
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> CR6261 VH
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 10
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CR6261 VL 蛋白质
<400> 10
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asp
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80
Thr Gly Asp Glu Ala Asn Tyr Tyr Cys Ala Thr Trp Asp Arg Arg Pro
85 90 95
Thr Ala Tyr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 11
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> SC09-114 VH 蛋白质
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ser Ser Gly Gly Thr Ser Asn Asn Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Asp Trp Met
35 40 45
Gly Gly Ile Ser Pro Ile Phe Gly Ser Thr Ala Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Ser Ala Asp Ile Phe Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg His Gly Asn Tyr Tyr Tyr Tyr Ser Gly Met Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 12
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> SC09-114 VL 蛋白质
<400> 12
Ser Tyr Val Leu Thr Gln Pro Pro Ala Val Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Asp Ser Asn Ile Gly Arg Arg
20 25 30
Ser Val Asn Trp Tyr Gln Gln Phe Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asn Asp Gln Arg Pro Ser Val Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Lys Gly Ala Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu
100 105 110
<210> 13
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> SC08-057 VH 蛋白质
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Asp Ser Val Ile
20 25 30
Phe Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Cys Val
35 40 45
Ser Ile Ile Tyr Ile Asp Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg His Asn Ser Met Gly Thr Val Phe Leu
65 70 75 80
Glu Met Asn Ser Leu Arg Pro Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Glu Ser Gly Asp Phe Gly Asp Gln Thr Gly Pro Tyr His Tyr Tyr
100 105 110
Ala Met Asp Val
115
<210> 14
<211> 100
<212> PRT
<213> 人工序列
<220>
<223> SC08-057 VL 蛋白质
<400> 14
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Ser Ser Gly Asp Ile Gly Gly Tyr
20 25 30
Asn Ala Val Ser Trp Tyr Gln His His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Val Thr Ser Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Ala Ser Arg Ser Gly Asp Thr Ala Ser Leu Thr Val Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala His Tyr Tyr Cys Cys Ser Phe Ala Asp Ser
85 90 95
Asn Ile Leu Ile
100
<210> 15
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> His标签
<400> 15
His His His His His His
1 5
<210> 16
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> His标签
<400> 16
Met His His His His His His His
1 5
<210> 17
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> SC08-020 VH
<400> 17
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Thr Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Phe
20 25 30
Gly Val Ser Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asp Thr Tyr Tyr Ala Gln Lys Phe
50 55 60
Gln Ala Arg Val Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Met Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Pro Pro Leu Phe Tyr Ser Ser Trp Ser Leu Asp Asn
100 105 110
<210> 18
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> SC08-020 VL
<220>
<221> 尚未归类的特征
<222> (4)..(4)
<223> Xaa可以是任何天然存在的氨基酸
<400> 18
Glu Ile Val Xaa Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Met Asn
20 25 30
Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Ile Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Ala Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro
85 90 95
Arg Thr
<210> 19
<400> 19
000
<210> 20
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> GCN4 衍生序列
<400> 20
Arg Met Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Glu Ser Lys
1 5 10 15
<210> 21
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> GCN4 衍生序列
<400> 21
Arg Met Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Glu Ser Lys Gln
1 5 10 15
Lys
<210> 22
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> FLAG 标签
<400> 22
Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
<210> 23
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 凝血酶蛋白水解位点
<400> 23
Arg Ser Leu Val Pro Arg
1 5
<210> 24
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 因子X蛋白水解位点
<400> 24
Ile Glu Gly Arg
1
<210> 25
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> A/所罗门群岛/6/2003
<400> 25
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Leu Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Leu Leu Ile Ser Arg Glu Ser Trp Ser Tyr Ile
85 90 95
Val Glu Lys Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly His Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Thr Thr Gly Val Ser Ala Ser Cys Ser His Asn Gly Glu Ser Ser Phe
145 150 155 160
Tyr Lys Asn Leu Leu Trp Leu Thr Gly Lys Asn Gly Leu Tyr Pro Asn
165 170 175
Leu Ser Lys Ser Tyr Ala Asn Asn Lys Glu Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Pro Asn Ile Gly Asp Gln Arg Ala Leu Tyr
195 200 205
His Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser Arg
210 215 220
Lys Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln Glu
225 230 235 240
Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Arg Tyr Ala Phe Ala
260 265 270
Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Asn Ser Asn Ala Pro Met
275 280 285
Asp Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu
405 410 415
Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Ile
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asn Asp Glu Cys Met Glu Ser Val Lys
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 26
<211> 564
<212> PRT
<213> 人工序列
<220>
<223> A/新喀里多尼亚/20/1999
<400> 26
Lys Ala Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr Ala
1 5 10 15
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
20 25 30
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
35 40 45
Leu Glu Asp Ser His Asn Gly Lys Leu Cys Leu Leu Lys Gly Ile Ala
50 55 60
Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly Asn
65 70 75 80
Pro Glu Cys Glu Leu Leu Ile Ser Lys Glu Ser Trp Ser Tyr Ile Val
85 90 95
Glu Thr Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe Ala
100 105 110
Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu
115 120 125
Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr Val
130 135 140
Thr Gly Val Ser Ala Ser Cys Ser His Asn Gly Lys Ser Ser Phe Tyr
145 150 155 160
Arg Asn Leu Leu Trp Leu Thr Gly Lys Asn Gly Leu Tyr Pro Asn Leu
165 170 175
Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val Leu Trp
180 185 190
Gly Val His His Pro Pro Asn Ile Gly Asn Gln Arg Ala Leu Tyr His
195 200 205
Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser Arg Arg
210 215 220
Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln Glu Gly
225 230 235 240
Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile Ile
245 250 255
Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe Ala Leu
260 265 270
Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Pro Met Asp
275 280 285
Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser Ser
290 295 300
Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro Lys
305 310 315 320
Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn Ile
325 330 335
Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe Ile
340 345 350
Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His His
355 360 365
Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr Gln
370 375 380
Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu Lys
385 390 395 400
Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu Glu
405 410 415
Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu Asp
420 425 430
Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu Arg
435 440 445
Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys Val
450 455 460
Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys Phe
465 470 475 480
Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn
485 490 495
Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg
500 505 510
Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln Ile
515 520 525
Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser
530 535 540
Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln Cys
545 550 555 560
Arg Ile Cys Ile
<210> 27
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/加利福尼亚/07/2009
<400> 27
Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn
1 5 10 15
Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Lys His Asn Gly Lys Leu Cys Lys Leu Arg Gly Val
50 55 60
Ala Pro Leu His Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Ser Thr Ala Ser Ser Trp Ser Tyr Ile
85 90 95
Val Glu Thr Pro Ser Ser Asp Asn Gly Thr Cys Tyr Pro Gly Asp Phe
100 105 110
Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn His Asp
130 135 140
Ser Asn Lys Gly Val Thr Ala Ala Cys Pro His Ala Gly Ala Lys Ser
145 150 155 160
Phe Tyr Lys Asn Leu Ile Trp Leu Val Lys Lys Gly Asn Ser Tyr Pro
165 170 175
Lys Leu Ser Lys Ser Tyr Ile Asn Asp Lys Gly Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Ile His His Pro Ser Thr Ser Ala Asp Gln Gln Ser Leu
195 200 205
Tyr Gln Asn Ala Asp Ala Tyr Val Phe Val Gly Ser Ser Arg Tyr Ser
210 215 220
Lys Lys Phe Lys Pro Glu Ile Ala Ile Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Glu Gly Arg Met Asn Tyr Tyr Trp Thr Leu Val Glu Pro Gly Asp Lys
245 250 255
Ile Thr Phe Glu Ala Thr Gly Asn Leu Val Val Pro Arg Tyr Ala Phe
260 265 270
Ala Met Glu Arg Asn Ala Gly Ser Gly Ile Ile Ile Ser Asp Thr Pro
275 280 285
Val His Asp Cys Asn Thr Thr Cys Gln Thr Pro Lys Gly Ala Ile Asn
290 295 300
Thr Ser Leu Pro Phe Gln Asn Ile His Pro Ile Thr Ile Gly Lys Cys
305 310 315 320
Pro Lys Tyr Val Lys Ser Thr Lys Leu Arg Leu Ala Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Leu Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asp Glu Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn His
405 410 415
Leu Glu Lys Arg Ile Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Tyr His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Arg Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Thr Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ala Lys Leu
500 505 510
Asn Arg Glu Glu Ile Asp Gly Val Lys Leu Glu Ser Thr Arg Ile Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Val
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 28
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/猪/湖北/S1/2009
<400> 28
Met Glu Ala Lys Leu Phe Val Leu Phe Cys Ala Phe Thr Ala Leu Lys
1 5 10 15
Ala Asp Thr Phe Cys Val Gly Tyr His Ala Asn Tyr Ser Thr His Thr
20 25 30
Val Asp Thr Ile Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Ser His Asn Gly Lys Leu Cys Ser Leu Asn Gly Lys
50 55 60
Ile Pro Leu Gln Leu Gly Asn Cys Asn Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Lys Cys Asp Leu Leu Leu Thr Ala Asn Ser Ser Ser Tyr Ile
85 90 95
Ile Glu Thr Ser Lys Ser Lys Asn Gly Ala Cys Tyr Pro Gly Glu Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Lys Glu Gln Leu Ser Thr Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Ala Ile Ser Trp Pro Asp His Asp
130 135 140
Ala Thr Arg Gly Thr Thr Val Ala Cys Ser His Ser Gly Val Asn Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Ser Thr Val Lys Lys Gly Asn Ser Tyr Pro
165 170 175
Lys Leu Ser Lys Ser Tyr Thr Asn Asn Lys Gly Lys Glu Val Leu Val
180 185 190
Ile Trp Gly Val His His Pro Pro Thr Asp Ser Val Gln Gln Thr Leu
195 200 205
Tyr Gln Asn Lys His Thr Tyr Val Ser Val Gly Ser Ser Lys Tyr Tyr
210 215 220
Lys Arg Phe Thr Pro Glu Ile Val Ala Arg Pro Lys Val Arg Gly Gln
225 230 235 240
Ala Gly Arg Met Asn Tyr Tyr Trp Thr Leu Phe Asp Gln Gly Asp Thr
245 250 255
Ile Thr Phe Glu Ala Thr Gly Asn Leu Ile Ala Pro Trp His Ala Phe
260 265 270
Ala Leu Lys Lys Gly Ser Ser Ser Gly Ile Met Leu Ser Asp Ala Gln
275 280 285
Val His Asn Cys Thr Thr Lys Cys Gln Thr Pro His Gly Ala Leu Lys
290 295 300
Asn Asn Leu Pro Leu Gln Asn Val His Leu Phe Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Lys Ser Thr Gln Leu Arg Met Ala Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Arg Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Ile Ala Ile Asp Gly Ile Asn Asn Lys Ala Asn Ser Val Ile
385 390 395 400
Gly Lys Met Asn Ile Gln Leu Thr Ser Val Gly Lys Glu Phe Asn Ser
405 410 415
Leu Glu Lys Arg Lys Glu Asn Leu Asn Lys Thr Val Asp Asp Arg Phe
420 425 430
Leu Asp Val Trp Thr Phe Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Gln Arg Thr Leu Glu Phe His Asp Leu Asn Ile Lys Ser Leu Tyr Glu
450 455 460
Lys Val Lys Ser His Leu Arg Asn Asn Asp Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Arg Asp Asn Glu Cys Leu Glu Cys Val
485 490 495
Lys Asn Gly Thr Tyr Asn Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Phe
500 505 510
Asn Arg Glu Glu Ile Val Gly Val Lys Leu Glu Ser Met Gly Ile His
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Val Cys Ile
565
<210> 29
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/猪/哈塞吕内/IDT2617/2003
<400> 29
Met Glu Ala Lys Leu Phe Val Leu Phe Cys Ala Phe Thr Ala Leu Lys
1 5 10 15
Ala Asp Thr Ile Cys Val Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Ile Leu Glu Lys Asn Val Thr Val Thr His Ser Ile Asn
35 40 45
Leu Leu Glu Asn Asn His Asn Gly Lys Leu Cys Ser Leu Asn Gly Lys
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Asn Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Asp Leu Leu Leu Thr Val Asp Ser Trp Ser Tyr Ile
85 90 95
Ile Glu Thr Ser Asn Ser Lys Asn Gly Ala Cys Tyr Pro Gly Glu Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Thr Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Ala Thr Ser Trp Pro Asn His Asp
130 135 140
Thr Thr Arg Gly Thr Thr Ile Ser Cys Ser His Ser Gly Ala Asn Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Ile Val Lys Lys Gly Asn Ser Tyr Pro
165 170 175
Lys Leu Ser Lys Ser Tyr Thr Asn Asn Lys Gly Lys Glu Val Leu Val
180 185 190
Ile Trp Gly Val His His Pro Pro Thr Asp Ser Asp Gln Gln Thr Leu
195 200 205
Tyr Gln Asn Asn His Thr Tyr Val Ser Val Gly Ser Ser Lys Tyr Tyr
210 215 220
Gln Arg Phe Thr Pro Glu Ile Val Thr Arg Pro Lys Val Arg Gly Gln
225 230 235 240
Ala Gly Arg Met Asn Tyr Tyr Trp Thr Leu Leu Asp Gln Gly Asp Thr
245 250 255
Ile Thr Phe Glu Ala Thr Gly Asn Leu Ile Ala Pro Trp His Ala Phe
260 265 270
Ala Leu Asn Lys Gly Pro Ser Ser Gly Ile Met Ile Ser Asp Ala His
275 280 285
Val His Asn Cys Thr Thr Lys Cys Gln Thr Pro His Gly Ala Leu Lys
290 295 300
Ser Asn Leu Pro Phe Gln Asn Val His Pro Ser Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Lys Ser Thr Gln Leu Arg Met Ala Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Ile Ala Ile Asp Gly Ile Asn Asn Lys Val Asn Ser Ile Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ser Val Gly Lys Glu Phe Asn Asp
405 410 415
Leu Glu Lys Arg Ile Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Val Trp Thr Tyr Asn Ala Glu Leu Leu Ile Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Phe Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Arg Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asn Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val His
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 30
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> A/纽约/8/2006
<400> 30
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Leu Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Leu Leu Ile Ser Lys Glu Ser Trp Ser Tyr Ile
85 90 95
Val Glu Thr Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Val Thr Gly Val Ser Ala Ser Cys Ser His Asn Gly Lys Ser Ser Phe
145 150 155 160
Tyr Arg Asn Leu Leu Trp Leu Thr Gly Lys Asn Gly Leu Tyr Pro Asn
165 170 175
Leu Ser Lys Ser Tyr Ala Asn Asn Lys Glu Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Pro Asn Ile Gly Asp Gln Arg Ala Leu Tyr
195 200 205
His Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser Arg
210 215 220
Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln Glu
225 230 235 240
Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Arg Phe Ala Phe Ala
260 265 270
Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Pro Met
275 280 285
Asp Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu
405 410 415
Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asn Asp Glu Cys Met Glu Ser Val Lys
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Arg Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 31
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> A/所罗门群岛/3/2006
<400> 31
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Leu Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Leu Leu Ile Ser Arg Glu Ser Trp Ser Tyr Ile
85 90 95
Val Glu Lys Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly His Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Thr Thr Gly Val Ser Ala Ser Cys Ser His Asn Gly Glu Ser Ser Phe
145 150 155 160
Tyr Lys Asn Leu Leu Trp Leu Thr Gly Lys Asn Gly Leu Tyr Pro Asn
165 170 175
Leu Ser Lys Ser Tyr Ala Asn Asn Lys Glu Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Pro Asn Ile Gly Asp Gln Arg Ala Leu Tyr
195 200 205
His Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser Arg
210 215 220
Lys Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln Glu
225 230 235 240
Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Arg Tyr Ala Phe Ala
260 265 270
Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Asn Ser Asn Ala Pro Met
275 280 285
Asp Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu
405 410 415
Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Ile
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asn Asp Glu Cys Met Glu Ser Val Lys
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 32
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/纽约/146/2000
<400> 32
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Thr
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Phe Ser Lys Glu Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Pro Lys Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Asp Ser Ser Trp Pro Asn His Thr
130 135 140
Val Thr Lys Gly Val Thr Ala Ser Cys Ser His Asn Gly Lys Ser Ser
145 150 155 160
Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Leu Tyr Pro
165 170 175
Asn Leu Ser Lys Ser Tyr Val Asn Lys Lys Gly Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Met Gly Asp Gln Arg Ala Ile
195 200 205
Tyr His Lys Glu Asn Ala Tyr Val Ser Val Leu Ser Ser His Tyr Ser
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Glu Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Ile Ser Asn Ala Ser
275 280 285
Met Gly Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Val Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Ile Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Leu Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Asn Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Lys Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 33
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/纽约/653/1996
<400> 33
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Thr
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Phe Ser Lys Glu Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Val Thr Lys Gly Val Thr Ala Ser Cys Ser His Asn Gly Lys Ser Ser
145 150 155 160
Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Leu Tyr Pro
165 170 175
Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Gly Asp Gln Arg Ala Ile
195 200 205
Tyr His Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser
210 215 220
Arg Arg Phe Thr Pro Glu Ile Thr Lys Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Glu Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met Gly Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asp Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Thr Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 34
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> A/北京/262/1995
<400> 34
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Leu Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Ile Ser Lys Glu Ser Trp Ser Tyr Ile
85 90 95
Val Glu Thr Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Val Thr Gly Val Thr Ala Ser Cys Ser His Asn Gly Lys Ser Ser Phe
145 150 155 160
Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Leu Tyr Pro Asn
165 170 175
Leu Ser Asn Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Ser Asn Ile Arg Asp Gln Arg Ala Ile Tyr
195 200 205
His Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser Arg
210 215 220
Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Gly Gln Glu
225 230 235 240
Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe Ala
260 265 270
Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Pro Met
275 280 285
Asn Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Met Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu
405 410 415
Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 35
<211> 600
<212> PRT
<213> 人工序列
<220>
<223> A/德克萨斯/36/1991
<400> 35
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Lys Cys Glu Ser Leu Phe Ser Lys Glu Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Val Thr Lys Gly Val Thr Thr Ser Cys Ser His Asn Gly Lys Ser Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Lys Lys Asn Gly Leu Tyr Pro
165 170 175
Asn Val Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Gly Asp Gln Arg Ala Ile
195 200 205
Tyr His Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Glu Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met Asp Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Gly Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu Asp Ile Trp
485 490 495
Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu
500 505 510
Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser
515 520 525
Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe
530 535 540
Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn Gly Thr
545 550 555 560
Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg Gly Lys
565 570 575
Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala
580 585 590
Ile Tyr Ser Thr Val Ala Ser Ser
595 600
<210> 36
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/新加坡/6/1986
<400> 36
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Phe Thr Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Phe Ser Lys Lys Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Val Thr Lys Gly Val Thr Ala Ser Cys Ser His Lys Gly Arg Ser Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Lys Lys Asn Gly Ser Tyr Pro
165 170 175
Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Gly Asp Gln Arg Ala Ile
195 200 205
Tyr His Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Glu Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met Asp Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 37
<211> 506
<212> PRT
<213> 人工序列
<220>
<223> A/智利/1/1983
<400> 37
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Leu Ser Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Asn His Asn Gly Lys Leu Cys Lys Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Ser Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Phe Ser Lys Lys Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Ser Tyr Val Asn Asn Lys Glu Lys
115 120 125
Glu Val Leu Val Leu Trp Gly Val His His Pro Ser Asn Ile Glu Asp
130 135 140
Gln Lys Thr Ile Tyr Arg Lys Glu Asn Ala Tyr Val Ser Val Val Ser
145 150 155 160
Ser His Tyr Asn Arg Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys
165 170 175
Val Arg Asn Gln Glu Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu
180 185 190
Pro Gly Asp Thr Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro
195 200 205
Trp Tyr Ala Phe Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr
210 215 220
Ser Asn Ala Ser Met Asp Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln
225 230 235 240
Gly Ala Ile Asn Ser Ser Leu Pro Phe Gln Asn Val His Pro Val Thr
245 250 255
Ile Gly Glu Cys Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val
260 265 270
Thr Gly Leu Arg Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly
275 280 285
Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly
290 295 300
Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala
305 310 315 320
Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val
325 330 335
Asn Ser Ile Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys
340 345 350
Glu Phe Asn Lys Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val
355 360 365
Asp Asp Gly Phe Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val
370 375 380
Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys
385 390 395 400
Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu
405 410 415
Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys
420 425 430
Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu
435 440 445
Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser
450 455 460
Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser
465 470 475 480
Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser
485 490 495
Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
500 505
<210> 38
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/贝勒/11515/1982
<400> 38
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Leu Ser Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Ser Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Phe Ser Lys Lys Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Lys His Ser
130 135 140
Val Thr Arg Gly Val Thr Ala Ser Cys Ser His Lys Gly Lys Ser Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Ser Tyr Pro
165 170 175
Asn Leu Ser Lys Ser Tyr Val Asn Asp Lys Glu Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Glu Asp Gln Lys Thr Ile
195 200 205
Tyr Arg Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Glu Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Val Ser
275 280 285
Met Asp Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 39
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> A/巴西/11/1978
<400> 39
Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Leu Ser Ala Thr Asp Ala
1 5 10 15
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
20 25 30
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
35 40 45
Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile Ala
50 55 60
Pro Leu Gln Leu Gly Lys Cys Ser Ile Ala Gly Trp Ile Leu Gly Asn
65 70 75 80
Pro Glu Cys Glu Ser Leu Phe Ser Lys Lys Ser Trp Ser Tyr Ile Ala
85 90 95
Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe Ala
100 105 110
Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu
115 120 125
Arg Phe Glu Ile Phe Pro Lys Glu Arg Ser Trp Pro Lys His Asn Ile
130 135 140
Thr Arg Gly Val Thr Ala Ser Cys Ser His Lys Gly Lys Ser Ser Phe
145 150 155 160
Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Ser Tyr Pro Asn
165 170 175
Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Ser Asn Ile Glu Asp Gln Lys Thr Ile Tyr
195 200 205
Arg Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn Arg
210 215 220
Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Gly Gln Glu
225 230 235 240
Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe Ala
260 265 270
Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser Met
275 280 285
Asp Glu Cys Asp Thr Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu
405 410 415
Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Leu
465 470 475 480
Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn
485 490 495
Gly Ser Leu Gln Cys Arg Ile Cys Ile
500 505
<210> 40
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/USSR/90/1977
<400> 40
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Leu Ser Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Phe Ser Lys Lys Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Arg Ser Trp Pro Lys His Asn
130 135 140
Val Thr Arg Gly Val Thr Ala Ser Cys Ser His Lys Gly Lys Ser Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Ser Tyr Pro
165 170 175
Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Glu Asp Gln Lys Thr Ile
195 200 205
Tyr Arg Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Gly Gln
225 230 235 240
Ala Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp His Ala Phe
260 265 270
Ala Leu Asn Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met Asp Glu Cys Asp Thr Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 41
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/新泽西/8/1976
<400> 41
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Phe Thr Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Ser Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Phe Ser Lys Lys Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Val Thr Lys Gly Val Thr Ala Ser Cys Ser His Lys Gly Arg Ser Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Lys Lys Asn Gly Ser Tyr Pro
165 170 175
Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Gly Asp Gln Arg Ala Ile
195 200 205
Tyr His Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Glu Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met Asp Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 42
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> A/丹佛/1957
<400> 42
Met Lys Ala Lys Leu Leu Ile Leu Leu Cys Ala Leu Ser Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Lys
50 55 60
Ala Pro Leu Gln Leu Gly Asn Cys Asn Ile Ala Gly Trp Val Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Leu Ser Asn Arg Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Asp Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Arg Ser Trp Pro Asn His Thr
130 135 140
Thr Arg Gly Val Thr Ala Ala Cys Pro His Ala Arg Lys Ser Ser Phe
145 150 155 160
Tyr Lys Asn Leu Val Trp Leu Thr Glu Ala Asn Gly Ser Tyr Pro Asn
165 170 175
Leu Ser Arg Ser Tyr Val Asn Asn Gln Glu Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Ser Asn Ile Glu Glu Gln Arg Ala Leu Tyr
195 200 205
Arg Lys Asp Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn Arg
210 215 220
Arg Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln Ser
225 230 235 240
Gly Arg Met Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Thr Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe Ala
260 265 270
Leu Ser Arg Gly Pro Gly Ser Gly Ile Ile Thr Ser Asn Ala Pro Leu
275 280 285
Asp Glu Cys Asp Thr Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Phe Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Val Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Met Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu
405 410 415
Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Met
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Asn Gln Leu Arg Asn Asn Ala Lys Glu Leu Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu Ser Val Lys
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Arg
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 43
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/奥尔巴尼/4835/1948
<400> 43
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Leu Ser Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Phe Ser Lys Lys Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Arg Ser Trp Pro Lys His Asn
130 135 140
Ile Thr Arg Gly Val Thr Ala Ala Cys Ser His Lys Gly Lys Ser Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Ser Tyr Pro
165 170 175
Asn Leu Asn Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Glu Asp Gln Lys Thr Leu
195 200 205
Tyr Arg Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Gly Gln
225 230 235 240
Ala Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp His Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met Asp Glu Cys Asp Thr Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 44
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/蒙默斯堡/1/1947
<400> 44
Met Lys Ala Lys Leu Leu Ile Leu Leu Cys Ala Leu Thr Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Leu Ser Lys Arg Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Ala Cys Tyr Pro Gly Asp Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Arg Ser Trp Pro Lys His Asn
130 135 140
Ile Thr Arg Gly Val Thr Ala Ala Cys Ser His Ala Gly Lys Ser Ser
145 150 155 160
Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Thr Asp Gly Ser Tyr Pro
165 170 175
Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Glu Asp Gln Lys Thr Leu
195 200 205
Tyr Arg Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Gly Gln
225 230 235 240
Ala Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Asp Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met Asp Glu Cys Asp Thr Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Lys Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Trp Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Asn Gln Leu Arg Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 45
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/卡梅隆/1946
<400> 45
Met Lys Ala Lys Leu Leu Ile Leu Leu Cys Ala Leu Ser Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Leu Ser Lys Arg Ser Trp Ser Tyr Ile
85 90 95
Ala Glu Thr Pro Asn Ser Glu Asn Gly Ala Cys Tyr Pro Gly Asp Phe
100 105 110
Ala Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Gly Arg Ser Trp Pro Glu His Asn
130 135 140
Ile Asp Ile Gly Val Thr Ala Ala Cys Ser His Ala Gly Lys Ser Ser
145 150 155 160
Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Lys Asp Gly Ser Tyr Pro
165 170 175
Asn Leu Asn Lys Ser Tyr Val Asn Lys Lys Glu Lys Glu Val Leu Ile
180 185 190
Leu Trp Gly Val His His Pro Pro Asn Ile Glu Asn Gln Lys Thr Leu
195 200 205
Tyr Arg Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Gly Gln
225 230 235 240
Ala Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Asn Arg Gly Ile Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met Asp Glu Cys Asp Thr Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Ile His Pro Phe Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Asp Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys
405 410 415
Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Asn Gln Leu Arg Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Phe Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 46
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/维斯/1943
<400> 46
Met Lys Ala Arg Leu Leu Val Leu Leu Cys Ala Leu Ala Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Ile Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Leu Ser Glu Arg Ser Trp Ser Tyr Ile
85 90 95
Val Glu Ile Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Asp Phe
100 105 110
Thr Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Lys His Asn
130 135 140
Thr Ala Arg Gly Val Thr Ala Ala Cys Ser His Ala Gly Lys Ser Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Asp Gly Ser Tyr Pro
165 170 175
Asn Leu Lys Asn Ser Tyr Val Asn Lys Lys Gly Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Ser Ile Lys Glu Gln Gln Thr Leu
195 200 205
Tyr Gln Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Ala Gly Arg Met Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met His Glu Cys Asp Thr Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Asn
405 410 415
Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Ile Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Arg Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val
485 490 495
Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile Met Lys Ala Arg Leu Leu Val Leu Leu Cys
565 1 5 10
Ala Leu Ala Ala Thr Asp Ala Asp Thr Ile Cys Ile Gly Tyr His Ala
15 20 25
Asn Asn Ser Thr Asp Thr Val Asp Thr Ile Leu Glu Lys Asn Val Thr
30 35 40
Val Thr His Ser Val Asn Leu Leu Glu Asp Ser His Asn Gly Lys Leu
45 50 55
Cys Arg Leu Lys Gly Ile Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile
60 65 70 75
Ala Gly Trp Ile Leu Gly Asn Pro Glu Cys Glu Ser Leu Leu Ser Glu
80 85 90
Arg Ser Trp Ser Tyr Ile Val Glu Ile Pro Asn Ser Glu Asn Gly Thr
95 100 105
Cys Tyr Pro Gly Asp Phe Thr Asp Tyr Glu Glu Leu Arg Glu Gln Leu
110 115 120
Ser Ser Val Ser Ser Phe Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser
125 130 135
Ser Trp Pro Lys His Asn Thr Ala Arg Gly Val Thr Ala Ala Cys Ser
140 145 150 155
His Ala Gly Lys Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu
160 165 170
Lys Asp Gly Ser Tyr Pro Asn Leu Lys Asn Ser Tyr Val Asn Lys Lys
175 180 185
Gly Lys Glu Val Leu Val Leu Trp Gly Val His His Pro Ser Ser Ile
190 195 200
Lys Glu Gln Gln Thr Leu Tyr Gln Lys Glu Asn Ala Tyr Val Ser Val
205 210 215
Val Ser Ser Asn Tyr Asn Arg Arg Phe Thr Pro Glu Ile Ala Glu Arg
220 225 230 235
Pro Lys Val Arg Asp Gln Ala Gly Arg Met Asn Tyr Tyr Trp Thr Leu
240 245 250
Leu Glu Pro Gly Asp Thr Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile
255 260 265
Ala Pro Trp Tyr Ala Phe Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile
270 275 280
Ile Thr Ser Asn Ala Ser Met His Glu Cys Asp Thr Lys Cys Gln Thr
285 290 295
Pro Gln Gly Ala Ile Asn Ser Ser Leu Pro Phe Gln Asn Ile His Pro
300 305 310 315
Val Thr Ile Gly Glu Cys Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg
320 325 330
Met Val Thr Gly Leu Arg Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu
335 340 345
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Ile
350 355 360
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
365 370 375
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
380 385 390 395
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val
400 405 410
Gly Lys Glu Phe Asn Asn Leu Glu Lys Arg Met Glu Asn Leu Asn Lys
415 420 425
Lys Val Asp Asp Gly Phe Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu
430 435 440
Leu Ile Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
445 450 455
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Arg Asn Asn Ala
460 465 470 475
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asn
480 485 490
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
495 500 505
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
510 515 520
Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala
525 530 535
Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp Met
540 545 550 555
Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
560 565
<210> 47
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> A/爱荷华/1943
<400> 47
Met Lys Ala Arg Leu Leu Val Leu Leu Cys Ala Leu Ala Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Leu Ser Glu Arg Ser Trp Ser Tyr Ile
85 90 95
Val Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Asp Phe
100 105 110
Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Ser Lys Glu Ser Ser Trp Pro Lys His Thr
130 135 140
Thr Gly Gly Val Thr Ala Ala Cys Ser His Ala Gly Lys Ser Ser Phe
145 150 155 160
Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Asp Gly Ser Tyr Pro Asn
165 170 175
Leu Asn Asn Ser Tyr Val Asn Lys Lys Gly Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Ser Asn Ile Lys Asp Gln Gln Thr Leu Tyr
195 200 205
Gln Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn Arg
210 215 220
Arg Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Gly Gln Ala
225 230 235 240
Gly Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Lys Pro Gly Asp Thr Ile
245 250 255
Met Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe Ala
260 265 270
Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser Met
275 280 285
His Glu Cys Asp Thr Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Phe Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Asn Leu
405 410 415
Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Asn Gln Leu Arg Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Ala Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 48
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> A/贝拉米/1942
<400> 48
Met Lys Ala Arg Leu Leu Val Leu Leu Cys Ala Ile Ala Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Ile Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly
65 70 75 80
Asn Pro Glu Cys Glu Ser Leu Leu Ser Glu Arg Ser Trp Ser Tyr Ile
85 90 95
Val Glu Thr Pro Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Asp Phe
100 105 110
Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Thr Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Thr Ser Trp Pro Lys His Asn
130 135 140
Thr Thr Lys Gly Val Thr Ala Ala Cys Ser His Ala Gly Lys Cys Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Asp Gly Ser Tyr Pro
165 170 175
Asn Leu Asn Asn Ser Tyr Val Asn Lys Lys Gly Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Ser Asn Ile Lys Asp Gln Gln Thr Leu
195 200 205
Tyr Gln Lys Glu Asn Ala Tyr Val Ser Val Val Ser Ser Asn Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Gly Gln
225 230 235 240
Ala Gly Arg Met Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser
275 280 285
Met His Glu Cys Asn Thr Lys Cys Gln Thr Pro Gln Met Ile Asp Gly
290 295 300
Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala
305 310 315 320
Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val
325 330 335
Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys
340 345 350
Glu Phe Asn Asn Leu Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val
355 360 365
Asp Asp Gly Phe Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val
370 375 380
Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys
385 390 395 400
Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Arg Asn Asn Ala Lys Glu
405 410 415
Ile Gly Asn Gly Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
420 425 430
Trp Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
435 440 445
<210> 49
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> A/波多黎各/8/1934
<400> 49
Met Lys Ala Asn Leu Leu Val Leu Leu Cys Ala Leu Ala Ala Ala Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Leu Leu Gly
65 70 75 80
Asn Pro Glu Cys Asp Pro Leu Leu Pro Val Arg Ser Trp Ser Tyr Ile
85 90 95
Val Glu Thr Pro Asn Ser Glu Asn Gly Ile Cys Tyr Pro Gly Asp Phe
100 105 110
Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Asn
130 135 140
Thr Asn Gly Val Thr Ala Ala Cys Ser His Glu Gly Lys Ser Ser Phe
145 150 155 160
Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys Glu Gly Ser Tyr Pro Lys
165 170 175
Leu Lys Asn Ser Tyr Val Asn Lys Lys Gly Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Ile His His Pro Pro Asn Ser Lys Glu Gln Gln Asn Leu Tyr
195 200 205
Gln Asn Glu Asn Ala Tyr Val Ser Val Val Thr Ser Asn Tyr Asn Arg
210 215 220
Arg Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Asp Gln Ala
225 230 235 240
Gly Arg Met Asn Tyr Tyr Trp Thr Leu Leu Lys Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Met Tyr Ala Phe Ala
260 265 270
Leu Arg Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser Met
275 280 285
His Glu Cys Asn Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn Ser
290 295 300
Ser Leu Pro Tyr Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Ile Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu
405 410 415
Glu Lys Arg Met Glu Asn Leu Asn Asn Lys Val Asp Asp Gly Phe Leu
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu Ser Val Arg
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Lys Val Asp Gly Val Lys Leu Glu Ser Met Gly Ile Tyr Gln
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 50
<211> 565
<212> PRT
<213> 人工序列
<220>
<223> A/WSN/1933
<400> 50
Met Lys Ala Lys Leu Leu Val Leu Leu Tyr Ala Phe Val Ala Thr Asp
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Ile Phe Glu Lys Asn Val Ala Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Arg His Asn Gly Lys Leu Cys Lys Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Thr Gly Trp Leu Leu Gly
65 70 75 80
Asn Pro Glu Cys Asp Ser Leu Leu Pro Ala Arg Ser Trp Ser Tyr Ile
85 90 95
Val Glu Thr Pro Asn Ser Glu Asn Gly Ala Cys Tyr Pro Gly Asp Phe
100 105 110
Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Leu
115 120 125
Glu Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr
130 135 140
Phe Asn Gly Val Thr Val Ser Cys Ser His Arg Gly Lys Ser Ser Phe
145 150 155 160
Tyr Arg Asn Leu Leu Trp Leu Thr Lys Lys Gly Asp Ser Tyr Pro Lys
165 170 175
Leu Thr Asn Ser Tyr Val Asn Asn Lys Gly Lys Glu Val Leu Val Leu
180 185 190
Trp Gly Val His His Pro Ser Ser Ser Asp Glu Gln Gln Ser Leu Tyr
195 200 205
Ser Asn Gly Asn Ala Tyr Val Ser Val Ala Ser Ser Asn Tyr Asn Arg
210 215 220
Arg Phe Thr Pro Glu Ile Ala Ala Arg Pro Lys Val Lys Asp Gln His
225 230 235 240
Gly Arg Met Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile
245 250 255
Ile Phe Glu Ala Thr Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe Ala
260 265 270
Leu Ser Arg Gly Phe Glu Ser Gly Ile Ile Thr Ser Asn Ala Ser Met
275 280 285
His Glu Cys Asn Thr Lys Cys Gln Thr Pro Gln Gly Ser Ile Asn Ser
290 295 300
Asn Leu Pro Phe Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys Pro
305 310 315 320
Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg Asn
325 330 335
Ile Pro Ser Ile Gln Tyr Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
340 345 350
Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr His
355 360 365
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr
370 375 380
Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu
385 390 395 400
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Asn Leu
405 410 415
Glu Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu
420 425 430
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
435 440 445
Arg Thr Leu Asp Phe His Asp Leu Asn Val Lys Asn Leu Tyr Glu Lys
450 455 460
Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
465 470 475 480
Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu Ser Val Arg
485 490 495
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn
500 505 510
Arg Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln
515 520 525
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
530 535 540
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
545 550 555 560
Cys Arg Ile Cys Ile
565
<210> 51
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> A/南卡罗来纳/1/1918
<400> 51
Met Glu Ala Arg Leu Leu Val Leu Leu Cys Ala Phe Ala Ala Thr Asn
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Ser His Asn Gly Lys Leu Cys Lys Leu Lys Gly Ile
50 55 60
Ala Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Leu Leu Gly
65 70 75 80
Asn Pro Glu Cys Asp Leu Leu Leu Thr Ala Ser Ser Trp Ser Tyr Ile
85 90 95
Val Glu Thr Ser Asn Ser Glu Asn Gly Thr Cys Tyr Pro Gly Asp Phe
100 105 110
Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe
115 120 125
Glu Lys Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn His Glu
130 135 140
Thr Thr Lys Gly Val Thr Ala Ala Cys Ser Tyr Ala Gly Ala Ser Ser
145 150 155 160
Phe Tyr Arg Asn Leu Leu Trp Leu Thr Lys Lys Gly Ser Ser Tyr Pro
165 170 175
Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys Gly Lys Glu Val Leu Val
180 185 190
Leu Trp Gly Val His His Pro Pro Thr Gly Thr Asp Gln Gln Ser Leu
195 200 205
Tyr Gln Asn Ala Asp Ala Tyr Val Ser Val Gly Ser Ser Lys Tyr Asn
210 215 220
Arg Arg Phe Thr Pro Glu Ile Ala Ala Arg Pro Lys Val Arg Asp Gln
225 230 235 240
Ala Gly Arg Met Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr
245 250 255
Ile Thr Phe Glu Ala Thr Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe
260 265 270
Ala Leu Asn Arg Gly Ser Gly Ser Gly Ile Ile Thr Ser Asp Ala Pro
275 280 285
Val His Asp Cys Asn Thr Lys Cys Gln Thr Pro His Gly Ala Ile Asn
290 295 300
Ser Ser Leu Pro Phe Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys
305 310 315 320
Pro Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Ala Thr Gly Leu Arg
325 330 335
Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr
355 360 365
His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser
370 375 380
Thr Gln Asn Ala Ile Asp Gly Ile Thr Asn Lys Val Asn Ser Val Ile
385 390 395 400
Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Asn
405 410 415
Leu Glu Arg Arg Ile Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe
420 425 430
Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn
435 440 445
Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Arg Asn Leu Tyr Glu
450 455 460
Lys Val Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly
465 470 475 480
Cys Phe Glu Phe Tyr His Lys Cys Asp Asp Ala Cys Met Glu Ser Val
485 490 495
Arg Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu
500 505 510
Asn Arg Glu Glu Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr
515 520 525
Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
530 535 540
Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu
545 550 555 560
Gln Cys Arg Ile Cys Ile
565
<210> 52
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> H1-mini2-簇1+5+6-GCN4t2
<400> 52
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Ile Pro Ser Ile Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ser Thr Ala
130 135 140
Thr Gly Lys Glu Gly Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 53
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> H1-mini2-簇1+5+6-GCN4t3
<400> 53
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Ile Pro Ser Ile Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ser Thr Ala
130 135 140
Thr Gly Lys Glu Gly Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 54
<400> 54
000
<210> 55
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 127H1
<400> 55
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Tyr Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 56
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 86B4
<400> 56
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn Lys Ile Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 57
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 74H9
<400> 57
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Phe Gly Lys Glu Met Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 58
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 6E12
<400> 58
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala
130 135 140
Phe Gly Lys Glu Val Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 59
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 55G7
<400> 59
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 60
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 115A1
<400> 60
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala
130 135 140
Val Gly Lys Glu Tyr Asn Lys Ile Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 61
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 71H2
<400> 61
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala
130 135 140
Ile Gly Lys Glu Val Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 62
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 181H9
<400> 62
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Val Gly Lys Glu Phe Asn Lys Asn Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 63
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 220C9
<400> 63
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Thr Gly Lys Glu Tyr Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 64
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 113E7
<400> 64
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Thr Gly Lys Glu Ile Asn Lys His Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 65
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s74H9
<400> 65
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Phe
115 120 125
Gly Lys Glu Met Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 66
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s127H1
<400> 66
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Tyr Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 67
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s86B4
<400> 67
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Ile Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 68
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s55G7
<400> 68
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 69
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s6E12
<400> 69
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Phe
115 120 125
Gly Lys Glu Val Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 70
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s115A1
<400> 70
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala Val
115 120 125
Gly Lys Glu Tyr Asn Lys Ile Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 71
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s71H2
<400> 71
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Ile
115 120 125
Gly Lys Glu Val Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 72
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s74H9-长
<400> 72
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Phe
115 120 125
Gly Lys Glu Met Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 73
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s127H1-长
<400> 73
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Tyr Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 74
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s86B4-长
<400> 74
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Ile Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 75
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s55G7-长
<400> 75
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 76
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s181H9
<400> 76
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val
115 120 125
Gly Lys Glu Phe Asn Lys Asn Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 77
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s220C9
<400> 77
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Thr
115 120 125
Gly Lys Glu Tyr Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 78
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s113E7
<400> 78
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Thr
115 120 125
Gly Lys Glu Ile Asn Lys His Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 79
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s115A长
<400> 79
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala Val
115 120 125
Gly Lys Glu Tyr Asn Lys Ile Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 80
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s71H2长
<400> 80
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Ile
115 120 125
Gly Lys Glu Val Asn Lys Ser Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 81
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 127H1-t2
<400> 81
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Tyr Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 82
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 86B4-t2
<400> 82
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn Lys Ile Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 83
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 74H9-t2
<400> 83
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Phe Gly Lys Glu Met Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 84
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 6E12-t2
<400> 84
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala
130 135 140
Phe Gly Lys Glu Val Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 85
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 55G7-t2
<400> 85
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 86
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 115A1-t2
<400> 86
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala
130 135 140
Val Gly Lys Glu Tyr Asn Lys Ile Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 87
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 71H2-t2
<400> 87
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala
130 135 140
Ile Gly Lys Glu Val Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 88
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 181H9-t2
<400> 88
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Val Gly Lys Glu Phe Asn Lys Asn Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 89
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 220C9-t2
<400> 89
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Thr Gly Lys Glu Tyr Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 90
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 113E7-t2
<400> 90
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Thr Gly Lys Glu Ile Asn Lys His Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 91
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s127H1-t2
<400> 91
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Tyr Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 92
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s86B4-t2
<400> 92
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Ile Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 93
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s74H9-t2
<400> 93
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Phe
115 120 125
Gly Lys Glu Met Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 94
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s6E12-t2
<400> 94
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Phe
115 120 125
Gly Lys Glu Val Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 95
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s55G7-t2
<400> 95
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 96
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s115A1-t2
<400> 96
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala Val
115 120 125
Gly Lys Glu Tyr Asn Lys Ile Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 97
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s71H2-t2
<400> 97
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Ile
115 120 125
Gly Lys Glu Val Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 98
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s181H9-t2
<400> 98
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val
115 120 125
Gly Lys Glu Phe Asn Lys Asn Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 99
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s220C9-t2
<400> 99
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Thr
115 120 125
Gly Lys Glu Tyr Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 100
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s113E7-t2
<400> 100
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Thr
115 120 125
Gly Lys Glu Ile Asn Lys His Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 101
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s127H1-t2长
<400> 101
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Tyr Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 102
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s86B4-t2长
<400> 102
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Ile Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 103
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s74H9-t2长
<400> 103
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Phe
115 120 125
Gly Lys Glu Met Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 104
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s6E12-t2长
<400> 104
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Phe
115 120 125
Gly Lys Glu Val Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 105
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s55G7-t2长
<400> 105
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 106
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s115A1-t2长
<400> 106
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala Val
115 120 125
Gly Lys Glu Tyr Asn Lys Ile Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 107
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s71H2-t2长
<400> 107
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Ile
115 120 125
Gly Lys Glu Val Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 108
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s181H9-t2长
<400> 108
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val
115 120 125
Gly Lys Glu Phe Asn Lys Asn Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 109
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s220C9-t2长
<400> 109
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Thr
115 120 125
Gly Lys Glu Tyr Asn Lys Leu Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 110
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s113E7-t2长
<400> 110
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Thr
115 120 125
Gly Lys Glu Ile Asn Lys His Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 111
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 127H1-t3
<400> 111
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Tyr Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 112
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 86B4-t3
<400> 112
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn Lys Ile Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 113
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 74H9-t3
<400> 113
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Phe Gly Lys Glu Met Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 114
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 6E12-t3
<400> 114
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala
130 135 140
Phe Gly Lys Glu Val Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 115
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 55G7-t3
<400> 115
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 116
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 115A1-t3
<400> 116
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala
130 135 140
Val Gly Lys Glu Tyr Asn Lys Ile Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 117
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 71H2-t3
<400> 117
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala
130 135 140
Ile Gly Lys Glu Val Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 118
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 181H9-t3
<400> 118
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Val Gly Lys Glu Phe Asn Lys Asn Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 119
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 220C9-t3
<400> 119
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Thr Gly Lys Glu Tyr Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 120
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 113E7-t3
<400> 120
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Thr Gly Lys Glu Ile Asn Lys His Arg Met Lys Gln Ile Glu Asp Lys
145 150 155 160
Ile Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 121
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s127H1-t3
<400> 121
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Tyr Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 122
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s86B4-t3
<400> 122
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Ile Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 123
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s74H9-t3
<400> 123
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Phe
115 120 125
Gly Lys Glu Met Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 124
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s6E12-t3
<400> 124
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Phe
115 120 125
Gly Lys Glu Val Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 125
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s55G7-t3
<400> 125
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 126
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s115A1-t3
<400> 126
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala Val
115 120 125
Gly Lys Glu Tyr Asn Lys Ile Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 127
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s71H2-t3
<400> 127
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Ile
115 120 125
Gly Lys Glu Val Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 128
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s181H9-t3
<400> 128
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val
115 120 125
Gly Lys Glu Phe Asn Lys Asn Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 129
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s220C9-t3
<400> 129
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Thr
115 120 125
Gly Lys Glu Tyr Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 130
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> s113E7-t3
<400> 130
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Thr
115 120 125
Gly Lys Glu Ile Asn Lys His Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Arg Ser Leu
225 230 235 240
Val Pro Arg Gly Ser Pro Gly His His His His His His
245 250
<210> 131
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s127H1-t3长
<400> 131
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Tyr Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 132
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s86B4-t3长
<400> 132
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Ile Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 133
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s74H9-t3长
<400> 133
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Phe
115 120 125
Gly Lys Glu Met Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 134
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s6E12-t3长
<400> 134
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Phe
115 120 125
Gly Lys Glu Val Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 135
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s55G7-t3长
<400> 135
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Ile
115 120 125
Gly Lys Glu Met Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 136
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s115A1-t3长
<400> 136
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala Val
115 120 125
Gly Lys Glu Tyr Asn Lys Ile Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 137
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s71H2-t3长
<400> 137
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Ile
115 120 125
Gly Lys Glu Val Asn Lys Ser Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 138
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s181H9-t3长
<400> 138
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val
115 120 125
Gly Lys Glu Phe Asn Lys Asn Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 139
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s220C9-t3长
<400> 139
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Thr
115 120 125
Gly Lys Glu Tyr Asn Lys Leu Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 140
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s113E7-t3长
<400> 140
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Thr
115 120 125
Gly Lys Glu Ile Asn Lys His Arg Met Lys Gln Ile Glu Asp Lys Ile
130 135 140
Glu Glu Ile Glu Ser Lys Gln Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 141
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s181H9长
<400> 141
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Val Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val
115 120 125
Gly Lys Glu Phe Asn Lys Asn Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 142
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s220C9长
<400> 142
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Thr Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Thr
115 120 125
Gly Lys Glu Tyr Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 143
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s113E7长
<400> 143
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala Thr
115 120 125
Gly Lys Glu Ile Asn Lys His Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 144
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> s6E12-长
<400> 144
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Glu Pro Ser Asn Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Leu Thr Ala Phe
115 120 125
Gly Lys Glu Val Asn Lys Leu Glu Arg Met Lys Gln Ile Glu Asp Lys
130 135 140
Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 145
<211> 292
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<220>
<221> 尚未归类的特征
<222> (56)..(56)
<223> X1= E, I, K, V, A, 或 T
<220>
<221> 尚未归类的特征
<222> (59)..(59)
<223> X2= I, K, R, T, F, N, S, 或 Y
<220>
<221> 尚未归类的特征
<222> (71)..(71)
<223> X3= I, D, F, V, Y, A, I, N, S, T
<220>
<221> 尚未归类的特征
<222> (72)..(72)
<223> X4= I, K, R, T, E, G, V
<220>
<221> 尚未归类的特征
<222> (121)..(121)
<223> X5= M, E, K, V, R, T
<220>
<221> 尚未归类的特征
<222> (125)..(125)
<223> X6= F, I, N, S, T, Y, H, L
<220>
<221> 尚未归类的特征
<222> (128)..(128)
<223> X7= A, G, I, R, T, V, F, S
<220>
<221> 尚未归类的特征
<222> (132)..(132)
<223> X8= F, I, N, S, T, Y, G, E, K, M, V
<220>
<221> 尚未归类的特征
<222> (135)..(135)
<223> X9= H, I, L, N, R, S
<400> 145
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Xaa Pro Ser Xaa Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Xaa Xaa Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Xaa Asn Thr Gln Xaa Thr Ala Xaa
115 120 125
Gly Lys Glu Xaa Asn Lys Xaa Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Ser Gly
225 230 235 240
Arg Asp Tyr Lys Asp Asp Asp Asp Lys Leu Val Pro Arg Gly Ser Pro
245 250 255
Gly Ser Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val
260 265 270
Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu Gly His His
275 280 285
His His His His
290
<210> 146
<211> 237
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<220>
<221> 尚未归类的特征
<222> (56)..(56)
<223> X1= E, I, K, V, A, 或 T
<220>
<221> 尚未归类的特征
<222> (59)..(59)
<223> X2= I, K, R, T, F, N, S, 或 Y
<220>
<221> 尚未归类的特征
<222> (71)..(71)
<223> X3= I, D, F, V, Y, A, I, N, S, T
<220>
<221> 尚未归类的特征
<222> (72)..(72)
<223> X4= I, K, R, T, E, G, V
<220>
<221> 尚未归类的特征
<222> (121)..(121)
<223> X5= M, E, K, V, R, T
<220>
<221> 尚未归类的特征
<222> (125)..(125)
<223> X6= F, I, N, S, T, Y, H, L
<220>
<221> 尚未归类的特征
<222> (128)..(128)
<223> X7= A, G, I, R, T, V, F, S
<220>
<221> 尚未归类的特征
<222> (132)..(132)
<223> X8= F, I, N, S, T, Y, G, E, K, M, V
<220>
<221> 尚未归类的特征
<222> (135)..(135)
<223> X9= H, I, L, N, R, S
<400> 146
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Xaa Pro Ser Xaa Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Xaa Xaa Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Xaa Asn Thr Gln Xaa Thr Ala Xaa
115 120 125
Gly Lys Glu Xaa Asn Lys Xaa Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly
225 230 235
<210> 147
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<220>
<221> 尚未归类的特征
<222> (56)..(56)
<223> X1= E, I, K, V, A, 或 T
<220>
<221> 尚未归类的特征
<222> (59)..(59)
<223> X2= I, K, R, T, F, N, S, 或 Y
<220>
<221> 尚未归类的特征
<222> (71)..(71)
<223> X3= I, D, F, V, Y, A, I, N, S, T
<220>
<221> 尚未归类的特征
<222> (72)..(72)
<223> X4= I, K, R, T, E, G, V
<220>
<221> 尚未归类的特征
<222> (121)..(121)
<223> X5= M, E, K, V, R, T
<220>
<221> 尚未归类的特征
<222> (125)..(125)
<223> X6= F, I, N, S, T, Y, H, L
<220>
<221> 尚未归类的特征
<222> (128)..(128)
<223> X7= A, G, I, R, T, V, F, S
<220>
<221> 尚未归类的特征
<222> (132)..(132)
<223> X8= F, I, N, S, T, Y, G, E, K, M, V
<220>
<221> 尚未归类的特征
<222> (135)..(135)
<223> X9= H, I, L, N, R, S
<400> 147
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Xaa Pro Ser Xaa Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Xaa Xaa Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Xaa Asn Thr Gln Xaa Thr Ala Xaa
115 120 125
Gly Lys Glu Xaa Asn Lys Xaa Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Glu Gly
245 250
<210> 148
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<220>
<221> 尚未归类的特征
<222> (56)..(56)
<223> X1= E, I, K, V, A, 或 T
<220>
<221> 尚未归类的特征
<222> (58)..(58)
<223> X2= I, K, R, T, F, N, S, 或 Y
<220>
<221> 尚未归类的特征
<222> (59)..(59)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (71)..(71)
<223> X3= I, D, F, V, Y, A, I, N, S, T
<220>
<221> 尚未归类的特征
<222> (72)..(72)
<223> X4= I, K, R, T, E, G, V
<220>
<221> 尚未归类的特征
<222> (121)..(121)
<223> X5= M, E, K, V, R, T
<220>
<221> 尚未归类的特征
<222> (125)..(125)
<223> X6= F, I, N, S, T, Y, H, L
<220>
<221> 尚未归类的特征
<222> (128)..(128)
<223> X7= A, G, I, R, T, V, F, S
<220>
<221> 尚未归类的特征
<222> (132)..(132)
<223> X8= F, I, N, S, T, Y, G, E, K, M, V
<220>
<221> 尚未归类的特征
<222> (135)..(135)
<223> X9= H, I, L, N, R, S
<400> 148
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Xaa Pro Ser Xaa Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Xaa Xaa Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Xaa Asn Thr Gln Xaa Thr Ala Xaa
115 120 125
Gly Lys Glu Xaa Asn Lys Xaa Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys Leu
225 230 235 240
Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala
245 250 255
Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp Met
260 265 270
Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
275 280
<210> 149
<211> 270
<212> PRT
<213> 人工序列
<220>
<223> smH1 Cali3964-55G7
<400> 149
Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn
1 5 10 15
Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Gly Gly Gly Gly Lys Tyr Val Cys Ser Thr Lys Leu
50 55 60
Arg Leu Ala Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Leu Lys Ser Thr Gln Asn Ala Ile Asp Glu Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn His Leu Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Tyr His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp
210 215 220
Asn Thr Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ala Lys Leu Asn Arg Glu Glu Ile Asp Gly Arg Ser
245 250 255
Leu Val Pro Arg Gly Ser Pro Gly His His His His His His
260 265 270
<210> 150
<211> 270
<212> PRT
<213> 人工序列
<220>
<223> smH1 Cali3964-86B4
<400> 150
Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn
1 5 10 15
Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Gly Gly Gly Gly Lys Tyr Val Cys Ser Thr Lys Leu
50 55 60
Arg Leu Ala Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Leu Lys Ser Thr Gln Asn Ala Ile Asp Glu Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn His Ile Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Tyr His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp
210 215 220
Asn Thr Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ala Lys Leu Asn Arg Glu Glu Ile Asp Gly Arg Ser
245 250 255
Leu Val Pro Arg Gly Ser Pro Gly His His His His His His
260 265 270
<210> 151
<211> 270
<212> PRT
<213> 人工序列
<220>
<223> smH1 Cali3964-127H1
<400> 151
Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn
1 5 10 15
Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Gly Gly Gly Gly Lys Tyr Val Cys Ser Thr Lys Leu
50 55 60
Arg Leu Ala Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Leu Lys Ser Thr Gln Asn Ala Ile Asp Glu Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Tyr Asn His Ser Glu Arg Met Lys Gln Ile Glu Asp
145 150 155 160
Lys Ile Glu Glu Ile Glu Ser Lys Gln Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Tyr His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp
210 215 220
Asn Thr Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ala Lys Leu Asn Arg Glu Glu Ile Asp Gly Arg Ser
245 250 255
Leu Val Pro Arg Gly Ser Pro Gly His His His His His His
260 265 270
<210> 152
<211> 270
<212> PRT
<213> 人工序列
<220>
<223> smH1 Cali3964-55G7-t2
<400> 152
Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn
1 5 10 15
Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Gly Gly Gly Gly Lys Tyr Val Cys Ser Thr Lys Leu
50 55 60
Arg Leu Ala Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Val Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Leu Lys Ser Thr Gln Asn Ala Ile Asp Glu Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn His Leu Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Tyr His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp
210 215 220
Asn Thr Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ala Lys Leu Asn Arg Glu Glu Ile Asp Gly Arg Ser
245 250 255
Leu Val Pro Arg Gly Ser Pro Gly His His His His His His
260 265 270
<210> 153
<211> 270
<212> PRT
<213> 人工序列
<220>
<223> smH1 Cali3964-86B4-t2
<400> 153
Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn
1 5 10 15
Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Gly Gly Gly Gly Lys Tyr Val Cys Ser Thr Lys Leu
50 55 60
Arg Leu Ala Thr Gly Leu Arg Asn Lys Pro Ser Asn Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Leu Lys Ser Thr Gln Asn Ala Ile Asp Glu Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala
130 135 140
Ile Gly Lys Glu Met Asn His Ile Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Tyr His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp
210 215 220
Asn Thr Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ala Lys Leu Asn Arg Glu Glu Ile Asp Gly Arg Ser
245 250 255
Leu Val Pro Arg Gly Ser Pro Gly His His His His His His
260 265 270
<210> 154
<211> 270
<212> PRT
<213> 人工序列
<220>
<223> smH1 Cali3964-127H1-t2
<400> 154
Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn
1 5 10 15
Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Gly Gly Gly Gly Lys Tyr Val Cys Ser Thr Lys Leu
50 55 60
Arg Leu Ala Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Leu Lys Ser Thr Gln Asn Ala Ile Asp Glu Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Tyr Asn His Ser Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Tyr His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp
210 215 220
Asn Thr Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ala Lys Leu Asn Arg Glu Glu Ile Asp Gly Arg Ser
245 250 255
Leu Val Pro Arg Gly Ser Pro Gly His His His His His His
260 265 270
<210> 155
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> mH1 Cali3964-127H1-t2
<400> 155
Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn
1 5 10 15
Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asp Gly Gly Gly Gly Lys Tyr Val Cys Ser Thr Lys Leu
50 55 60
Arg Leu Ala Thr Gly Leu Arg Asn Lys Pro Ser Lys Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Phe Thr Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Leu Lys Ser Thr Gln Asn Ala Ile Asp Glu Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Tyr Thr Ala
130 135 140
Ile Gly Lys Glu Tyr Asn His Ser Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Tyr His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp
210 215 220
Asn Thr Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ala Lys Leu Asn Arg Glu Glu Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Thr Arg Ile Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Val Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 156
<211> 286
<212> PRT
<213> 人工序列
<220>
<223> 无前导序列并有FLAG-折叠子-HIS的 sH1-mini2-簇1+5+6-GCN4t2
<400> 156
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Ile Pro Ser Ile Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ser Thr Ala Thr
115 120 125
Gly Lys Glu Gly Asn Lys Ser Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Ser Gly
225 230 235 240
Arg Asp Tyr Lys Asp Asp Asp Asp Lys Pro Gly Ser Gly Tyr Ile Pro
245 250 255
Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp
260 265 270
Val Leu Leu Ser Thr Phe Leu Gly His His His His His His
275 280 285
<210> 157
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> H1 mini-HA GW1.5E2
<400> 157
Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr
1 5 10 15
Ala Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr
20 25 30
Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn
35 40 45
Leu Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu
50 55 60
Arg Met Val Thr Gly Leu Arg Asn Lys Pro Ser Ile Gln Ser Gln Gly
65 70 75 80
Leu Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met
85 90 95
Val Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly
100 105 110
Tyr Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr
115 120 125
Asn Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala
130 135 140
Thr Gly Lys Glu Thr Asn Lys Arg Glu Arg Arg Met Lys Gln Ile Glu
145 150 155 160
Asp Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu
165 170 175
Leu Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser
180 185 190
Asn Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn
195 200 205
Ala Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn
210 215 220
Asp Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys
225 230 235 240
Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Lys
245 250 255
Leu Glu Ser Met Gly Val Tyr Gln Ile Leu Ala Ile Tyr Ser Thr Val
260 265 270
Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Trp
275 280 285
Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
290 295 300
<210> 158
<211> 286
<212> PRT
<213> 人工序列
<220>
<223> mini-HA GW1.5E2-FFH (#5145)
<400> 158
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asn Gly Gly Gly Gly Lys Tyr Val Cys Ser Ala Lys Leu Arg
35 40 45
Met Val Thr Gly Leu Arg Asn Lys Pro Ser Ile Gln Ser Gln Gly Leu
50 55 60
Phe Gly Ala Ile Ala Gly Tyr Lys Glu Gly Gly Trp Thr Gly Met Val
65 70 75 80
Asp Gly Trp Tyr Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr
85 90 95
Ala Ala Asp Gln Lys Ser Thr Gln Asn Ala Ile Asn Gly Ile Thr Asn
100 105 110
Lys Val Asn Ser Val Ile Glu Lys Met Asn Thr Gln Ile Thr Ala Thr
115 120 125
Gly Lys Glu Thr Asn Lys Arg Glu Arg Arg Met Lys Gln Ile Glu Asp
130 135 140
Lys Ile Glu Glu Ile Glu Ser Lys Ile Trp Cys Tyr Asn Ala Glu Leu
145 150 155 160
Leu Val Leu Leu Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn
165 170 175
Val Lys Asn Leu Tyr Glu Lys Val Lys Ser Gln Leu Lys Asn Asn Ala
180 185 190
Lys Glu Ile Gly Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asn Asp
195 200 205
Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr
210 215 220
Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile Asp Gly Val Ser Gly
225 230 235 240
Arg Asp Tyr Lys Asp Asp Asp Asp Lys Pro Gly Ser Gly Tyr Ile Pro
245 250 255
Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp
260 265 270
Val Leu Leu Ser Thr Phe Leu Gly His His His His His His
275 280 285

Claims (15)

1.一种流行性感冒血球凝集素主干域多肽，包括：
(a)一种流行性感冒血球凝集素HA1域，该HA1域包含HA1N-末端主干区段，该HA1N-末端主干区段通过具有0-50个氨基酸残基的连接序列共价连接至HA1C-末端主干区段，所述HA1C-末端区段被连接到(b)一种流行性感冒血球凝集素HA2域，其中该HA1域和HA2域来源于包括H1亚型的HA的甲型流行性感冒病毒亚型；
(c)其中该多肽不包括在HA1和HA2域之间的接合处的蛋白酶切割位点；
(d)其中所述HA1N-末端区段包含HA1的氨基酸1-x，优选地是HA1的氨基酸p-x，并且其中该HA1C-末端主干区段包含HA1的氨基酸y-C-末端氨基酸，其中x＝SEQ ID NO:1的位置52(或在另一个流行性感冒病毒株的血球凝集素中的等价位置)上的氨基酸，p＝SEQ ID NO:1的位置18(或在另一个流行性感冒病毒的血球凝集素中的等价位置)上的氨基酸并且y＝SEQ ID NO:1的位置320(或在另一个血球凝集素中的等价位置)上的氨基酸；
(e)其中包括氨基酸残基402-418的区域包含氨基酸序列X1NTQX2TAX3GKEX4N(H/K)X5E(K/R)(SEQ ID NO:8)，
其中：
X1是选自下组的氨基酸，该组由以下各项组成：M、E、K、V、R以及T，
X2是选自下组的氨基酸，该组由以下各项组成：F、I、N、T、H、L以及Y，优选I、L或Y，
X3是选自下组的氨基酸，该组由以下各项组成：V、A、G、I、R、F以及S，优选A、I或F，
X4是选自下组的氨基酸，该组由以下各项组成：F、I、N、S、T、Y、E、K、M、以及V，优选I、Y、M或V，
X5是选自下组的氨基酸，该组由以下各项组成：L、H、I、N、R，优选I；
(f)其中位置337上的氨基酸残基(HA1域)选自下组，该组由以下各项组成：I、E、K、V、A、以及T，
位置340上的氨基酸残基(HA1域)选自下组，该组由以下各项组成：I、K、R、T、F、N、S以及Y，
位置352上的氨基酸残基(HA2域)选自下组，该组由以下各项组成：D、V、Y、A、I、N、S、以及T，并且
位置353上的氨基酸残基(HA2域)选自下组，该组由以下各项组成：K、R、T、E、G、以及V；并且
(g)其中该多肽进一步包含位置324上的氨基酸和位置436上的氨基酸之间的二硫桥；并且
(h)其中氨基酸序列RMKQIEDKIEEIESK(SEQ ID NO:20)已经引入位置419-433处，或其中序列RMKQIEDKIEEIESKQK(SEQ ID NO:21)已经引入位置417-433处。
2.根据权利要求1所述的多肽，其中该HA2域已被截短。
3.根据权利要求1或2所述的多肽，其中从位置519到C末端氨基酸的HA2域的C-末端部分已被缺失。
4.根据权利要求1或2所述的多肽，其中从位置530到C末端氨基酸的HA2域的C-末端部分已被缺失。
5.根据权利要求3或4所述的多肽，其中该HA2域的C-末端部分已被氨基酸序列GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID NO:3)替代，任选通过接头连接。
6.根据以上权利要求中任一项所述的多肽，其中该HA1C-末端主干区段的C-末端氨基酸残基是除了精氨酸(R)或赖氨酸(K)的任何氨基酸，优选地是谷氨酰胺(Q)。
7.根据以上权利要求中任一项所述的多肽，其中该多肽在该HA1域和/或该HA2域中包含一或多个其他突变。
8.根据以上权利要求中任一项所述的多肽，其中该多肽选择性结合抗体CR6261和/或CR9114。
9.根据以上权利要求中任一项所述的多肽，其中该多肽不结合抗体CR8020和/或CR8057。
10.核酸分子，该核酸分子编码如权利要求1至9中任一项所述的多肽。
11.载体，该载体包括如权利要求10所述的核酸分子。
12.组合物，该组合物包括如权利要求1至9中任一项所述的多肽，和/或根据权利要求10所述的核酸分子。
13.根据权利要求1-9中任一项所述的多肽、根据权利要求10所述的核酸分子、和/或根据权利要求11所述的载体，用作一种药物。
14.根据权利要求1-9中任一项所述的多肽、根据权利要求10所述的核酸分子、和/或根据权利要求11所述的载体，用于在诱导针对流行性感冒病毒的免疫应答中使用。
15.根据权利要求1-9中任一项所述的多肽、根据权利要求10所述的核酸分子、和/或根据权利要求11所述的载体，用作一种疫苗。
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Families Citing this family (13)

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JP2012521786A (ja) 2009-03-30 2012-09-20 モウント シナイ スクール オフ メディシネ インフルエンザウイルスワクチン及びその使用
AU2012343981B2 (en) 2011-11-28 2017-09-07 Janssen Vaccines & Prevention B.V. Influenza virus vaccines and uses thereof
WO2014099931A1 (en) 2012-12-18 2014-06-26 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
WO2014159960A1 (en) 2013-03-14 2014-10-02 Icahn School Of Medicine At Mount Sinai Antibodies against influenza virus hemagglutinin and uses thereof
CN105452270B (zh) 2013-05-30 2020-12-01 扬森疫苗与预防公司 流行性感冒病毒疫苗及其用途
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EA038400B1 (ru) 2014-07-10 2021-08-23 Янссен Вэксинс Энд Превеншн Б.В. Полипептид стеблевого домена гемагглютинина вируса гриппа и его применение
EP3247389A4 (en) 2015-01-23 2019-10-30 Icahn School of Medicine at Mount Sinai INFLUENZAVIRUSSCHUTZIMPFPLÄNE
WO2017218624A1 (en) 2016-06-15 2017-12-21 Icahn School Of Medicine At Mount Sinai Influenza virus hemagglutinin proteins and uses thereof
CA3058652A1 (en) 2017-04-07 2018-10-11 Icahn School Of Medicine At Mount Sinai Anti-influenza b virus neuraminidase antibodies and uses thereof
PE20210651A1 (es) 2018-01-23 2021-03-26 Janssen Vaccines And Prevention B V Vacunas contra virus de la gripe y usos de las mismas
CA3152957A1 (en) 2019-09-05 2021-03-11 Janssen Vaccines & Prevention B.V. Influenza virus vaccines and uses thereof
WO2023198815A1 (en) 2022-04-14 2023-10-19 Janssen Vaccines & Prevention B.V. Sequential administration of adenoviruses

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013079473A1 (en) * 2011-11-28 2013-06-06 Crucell Holland B.V. Influenza virus vaccines and uses thereof

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5057540A (en) 1987-05-29 1991-10-15 Cambridge Biotech Corporation Saponin adjuvant
NZ230747A (en) 1988-09-30 1992-05-26 Bror Morein Immunomodulating matrix comprising a complex of at least one lipid and at least one saponin; certain glycosylated triterpenoid saponins derived from quillaja saponaria molina
CA2017507C (en) 1989-05-25 1996-11-12 Gary Van Nest Adjuvant formulation comprising a submicron oil droplet emulsion
AUPM873294A0 (en) 1994-10-12 1994-11-03 Csl Limited Saponin preparations and use thereof in iscoms
SE0202110D0 (sv) 2002-07-05 2002-07-05 Isconova Ab Iscom preparation and use thereof
SE0301998D0 (sv) 2003-07-07 2003-07-07 Isconova Ab Quil A fraction with low toxicity and use thereof
MX2009002174A (es) 2006-09-07 2009-03-12 Crucell Holland Bv Moleculas de union humanas capaces de neutralizar el virus de la influenza h5n1 y usos de las mismas.
JP2012521786A (ja) 2009-03-30 2012-09-20 モウント シナイ スクール オフ メディシネ インフルエンザウイルスワクチン及びその使用
ES2934102T3 (es) 2009-05-11 2023-02-16 Janssen Vaccines & Prevention Bv Moléculas de unión humanas que pueden neutralizar el virus de la gripe H3N2 y usos de las mismas
EP3900740A1 (en) 2010-03-30 2021-10-27 Icahn School of Medicine at Mount Sinai Influenza virus vaccines and uses thereof
CA2838999C (en) 2011-07-14 2021-02-16 Crucell Holland B.V. Human binding molecules capable of neutralizing influenza a viruses of phylogenetic group 1 and phylogenetic group 2 and influenza b viruses
CN105452270B (zh) * 2013-05-30 2020-12-01 扬森疫苗与预防公司 流行性感冒病毒疫苗及其用途
JP7094103B2 (ja) 2014-07-10 2022-07-01 ヤンセン ファッシンズ アンド プリベンション ベーフェー インフルエンザウイルスワクチンおよびその使用
EA038400B1 (ru) 2014-07-10 2021-08-23 Янссен Вэксинс Энд Превеншн Б.В. Полипептид стеблевого домена гемагглютинина вируса гриппа и его применение

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013079473A1 (en) * 2011-11-28 2013-06-06 Crucell Holland B.V. Influenza virus vaccines and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GAYATHRI BOMMAKANTI: "Design of an HA2-based Escherichia coli expressed influenza immunogen that protects mice from pathogenic challenge", 《PNAS》 *
VAMSEE V. A. MALLAJOSYULA: "Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection", 《PNAS》 *

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