CN111670045A - Ror1特异性抗原结合分子 - Google Patents

Ror1特异性抗原结合分子 Download PDF

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Publication number
CN111670045A
CN111670045A CN201880088475.7A CN201880088475A CN111670045A CN 111670045 A CN111670045 A CN 111670045A CN 201880088475 A CN201880088475 A CN 201880088475A CN 111670045 A CN111670045 A CN 111670045A
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seq
ser
gly
thr
binding molecule
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CN201880088475.7A
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Inventor
埃斯特尔·格蕾丝·麦克莱恩
保罗·理查德·特朗珀
詹妮弗·托姆
蒂莫西·哈里森
格雷厄姆·约翰·科顿
卡罗琳·巴莱勒
安德鲁·波特
玛丽娜·科瓦莱娃
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Almac Discovery Ltd
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Almac Discovery Ltd
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Publication of CN111670045A publication Critical patent/CN111670045A/zh
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Abstract

本发明涉及受体酪氨酸激酶样孤儿受体1(ROR1)特异性抗原结合分子以及相关融合蛋白和缀合物。在另一方面，本发明涉及经缀合免疫球蛋白样鲨鱼可变新型抗原受体(VNARs)。

Description

ROR1特异性抗原结合分子
发明领域
本发明涉及受体酪氨酸激酶样孤儿受体1(ROR1)特异性抗原结合分子以及相关融合蛋白和缀合物。在另一方面，本发明涉及经缀合免疫球蛋白样鲨鱼可变新型抗原受体(VNAR)。
背景技术
受体酪氨酸激酶样孤儿受体1(ROR1)是一种具有937个氨基酸的糖基化I型单次穿膜跨膜蛋白。细胞外区域由三个不同结构域组成，所述三个不同结构域组成N末端免疫球蛋白结构域(Ig)，继之以富含半胱氨酸的卷曲蛋白结构域(fz)，所述卷曲蛋白结构域转而连接于膜近端三环结构域(kr)。所述蛋白的细胞内区域含有假激酶结构域，继之以两个由富含脯氨酸的区域穿插的富含Ser/Thr的结构域，并且这个相同总体结构域构造在所述蛋白与其共有高序列同一性的密切相关的家族成员ROR2中是保守的。(Rebagay G等，FrontiersOncology，2012，2，Borcherding N等Protein Cell，2014，5，496-502)。
ROR1在胚胎发育期间表达，其中它主要在神经嵴细胞中以及在发育后期阶段在坏死区和指间区中表达。然而，在出生之后，它的表达被快速沉默，并且基本上不存在于正常成人组织中(Fukada PNAS，2012，Baskar等Clin.Cancer Res.，2008，14，396，Broome HE等，Leuk.Res.，2011，35，1390；Balakrishnan A等，Clin.Cancer.Res.2017，23，3061-3071)。
跨越广泛范围的实体肿瘤和血液恶性肿瘤，包括肺癌、乳腺癌、胰腺癌、卵巢癌、结肠癌、头颈部癌和前列腺癌、黑素瘤和肾细胞癌(Zhang S等Am J.Pathol.，2012，181，1903-1910)、乳腺癌(Zhang S等PLoS One 2012，7，e31127；Oxford Biotherapeutics专利申请WO2011054007)以及慢性淋巴细胞性白血病(CLL)和急性淋巴母细胞性白血病AML(FukudaT等，Proc Natl Acad Sci U S A.2008，105，3047-3052；Baskar S等，Clin Cancer Res.，2008，14，396-404；Daneshmanesh AH等，Int J Cancer.2008，123，1190-1195；Dave H等，PLOS ONE，2012，7，e52655)，已在mRNA水平与蛋白质水平两者上观察到ROR1表达。
另外，据报道ROR1表达增加与许多癌症适应症的不良临床结果相关联，所述癌症适应症包括乳腺癌(Chien HP等，Virchows Arch.，2016，468，589-595；Zhang)、卵巢癌(Zhang H等，Sci Rep.，2014，4：5811.doi：10.1038/srep05811)、结肠直肠癌(Zhou JK等，Oncotarget，2017，8，32864-32872)、肺腺癌(Zheng YZ等，Sci Rep.，2016，6，36447)和CLL(Cui B等，Blood，2016，128，2931-2940)。
与ROR1的表达样式以及和不良临床预后具有关联一致，已关于许多不同癌症适应症证明了ROR1在肿瘤发生和疾病进展中的功能性作用。ROR1在乳腺癌模型中促进上皮-间质转化和转移(Cui B等Cancer Res，2013，73，3649-3660)，并且在卵巢癌模型中促进球状体形成和肿瘤移入(Zhang S等，Proc Natl Acad Sci.，2014，11，17266-17271)。ROR1是肺腺癌中NKX2-1/TTF-1谱系存活因子致癌基因的转录物靶标，在肺腺癌中，ROR1维持EGFR信号传导以及阻遏促凋亡信号传导(Yamaguchi T等，Cancer Cell，2012，21，348-361；Ida L等，Cancer Science，2016，107，155-161)。还已显示ROR1作为支架用于维持胞膜窖结构和旁路信号传导机制，此举赋予对EGFR酪氨酸激酶抑制剂的抗性(Yamaguchi T等，NatCommun.，2016，7，10060)。通过ROR1-HER3复合物进行的信号传导调节Hippo-YAP路径，并且促进乳腺癌骨转移(Li C等，Nature Cell Biol.，19，1206-119)，并且所述蛋白可促进Met驱动的肿瘤发生(Gentile A等，Cancer Res.，2011，71，3132-3140)。同时，在CLL中，已报道ROR1应答于Wnt5a而与ROR2进行异寡聚以转导信号传导，并且使增殖和迁移增强(Yu J等，J.Clin.Invest.，2016，2，585-598)。
鉴于ROR1在癌症病变中的功能性作用以及在正常成人组织上普遍缺乏表达，这个癌胚蛋白是癌症疗法的一种具有吸引力的靶标。针对ROR1的抗体已描述于文献WO2021097313(4A5，kipps)、WO2014031174(UC961)、WO2016187220(Five Prime)、WO2010124188(2A2)、WO2012075158(R11、R12)、WO2011054007(Oxford Bio)、WO2011079902(Bioinvent)、WO2017127664、WO2017127664(NBE Therapeutics、SCRIPPS)、WO2016094847(Emergent)、WO2017127499中，并且人源化鼠抗ROR1抗体UC961已进入针对复发或难治性慢性淋巴细胞性白血病的临床试验。还已报道靶向ROR1的嵌合抗原受体T细胞(Hudecek M等，Clin.Cancer Res.，2013，19，3153-64)，并且用UC961以及用靶向ROR1的CAR-T细胞进行的临床前灵长类动物研究显示无明显毒性，此与所述蛋白在成人组织上普遍缺乏表达一致(Choi M等，Clinical Lymphoma，myeloma&leukemia，2015，S167；Berger C等，CancerImmunol.Res.，2015，3，206)。
单结构域结合分子可源于来自不同物种的一系列蛋白质。免疫球蛋白同种型新型抗原受体(IgNAR)是一种同二聚重链复合物，最初见于护士鲨(铰口鲨(Ginglymostomacirratum))以及其他鲨鱼和鳐鱼物种的血清中。IgNAR不含有轻链，并且不同于典型免疫球蛋白结构。每个分子由单一可变结构域(VNAR)和五个恒定结构域(CNAR)组成。文献中的命名法将IgNAR称为免疫球蛋白同种型新型抗原受体或免疫球蛋白同种型新抗原受体，并且所述术语是同义的。
存在被称为I、II和III的三种主要确定类型的鲨鱼IgNAR(Kovalena等，Exp OpinBiol Ther 2014 14(10)1527-1539)。这些类型已基于处于强烈选择压力下，因此很少被替代的非典型半胱氨酸残基的位置加以分类。
所有三种类型都具有在位置35和107处的使标准免疫球蛋白折叠稳定的经典免疫球蛋白典型半胱氨酸，以及在位置36处的不变色氨酸。不存在确定的CDR2本身，但更接近地类似于TCR HV2和HV4的序列变异区域已分别在框架2和3中确定。I型在框架2和框架4中具有种系编码的半胱氨酸残基，并且在CDR3内具有偶数个额外半胱氨酸。对针对溶菌酶加以分离并且与溶菌酶复合的I型IgNAR的晶体结构研究使得能够确定这些半胱氨酸残基的作用。框架2半胱氨酸与框架4半胱氨酸两者均与CDR3中的那些半胱氨酸形成二硫桥，从而形成紧密组装结构，在所述结构内，CDR3环被向下朝着HV2区域紧密固持。迄今为止，I型IgNAR仅已在护士鲨中鉴定-所有其他软骨鱼，包括同一目的成员，仅具有II型或这个类型的变化形式。
II型IgNAR定义为在CDR1和CDR3中具有形成分子内二硫键的半胱氨酸残基，所述二硫键将这两个区域紧密邻近固持，从而产生有助于结合口袋或沟槽的突出CDR3。I型序列相比于II型通常具有更长CDR3，分别具有平均21和15个残基。据信这是由于对I型CDR3中的两个或更多个半胱氨酸残基与它们的框架2和4对应物缔合具有强烈选择压力。对体细胞突变的积累的研究显示相比于I型，在II型的CDR1中存在更大数目的突变，而相比于II型，I型的HV2区域显示更大序列变异。这个迹象与这些区域在抗原结合位点内的所确定定位良好关联。被称为III型的第三IgNAR类型已在新生体中鉴定。IgNAR家族的这个成员由于D1和D2区域(其形成CDR3)与V基因的种系融合而在CDR3内缺乏多样性。几乎所有已知克隆都具有15个残基的CDR3长度，具有少许或不具有序列多样性。
VNAR的另一结构类型，被称为(IIb或IV)型，仅具有两个典型半胱氨酸残基(在框架1和框架3b区域中)。迄今为止，这个类型已主要见于角鲨中(Liu，J.L.等Mol.Immunol.2007.44(7)：第1775-1783页；Kovalenko O.V.等J Biol Chem.2013.288(24)：第17408-19页)，并且还从源于须鲨的半合成V-NAR文库分离(Streltsov，V.A.等(2004)Proc.Natl.Acad.Sci.U.S.A.101(34)：第12444-12449页)。
发明内容
本发明总体上涉及特异性抗原结合分子。在第一方面，提供了一种受体酪氨酸激酶样孤儿受体1(ROR1)特异性抗原结合分子，所述抗原结合分子包含由式(I)代表的氨基酸序列：
FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 (I)
其中
FW1是框架区
CDR1是CDR序列
FW2是框架区
HV2是高变序列
FW3a是框架区
HV4是高变序列
FW3b是框架区
CDR3是CDR序列
FW4是框架区。
框架区FW1在长度方面优选地是20至28个氨基酸，在长度方面更优选地是22至26个氨基酸，在长度方面还更优选地是23至25个氨基酸。在某些优选实施方案中，FW1在长度方面是26个氨基酸。在其他优选实施方案中，FW1在长度方面是25个氨基酸。在其他优选实施方案中，FW1在长度方面是24个氨基酸。
CDR区CDR1在长度方面优选地是7至11个氨基酸，在长度方面更优选地是8至10个氨基酸。在某些优选实施方案中，CDR1在长度方面是9个氨基酸。在其他优选实施方案中，CDR1在长度方面是8个氨基酸。
框架区FW2在长度方面优选地是6至14个氨基酸，在长度方面更优选地是8至12个氨基酸。在某些优选实施方案中，FW2在长度方面是12个氨基酸。在其他优选实施方案中，FW2在长度方面是10个氨基酸。在其他优选实施方案中，FW2在长度方面是9个氨基酸。在其他优选实施方案中，FW2在长度方面是8个氨基酸。
高变序列HV2在长度方面优选地是4至11个氨基酸，在长度方面更优选地是5至10个氨基酸。在某些优选实施方案中，HV2在长度方面是10个氨基酸。在某些优选实施方案中，HV2在长度方面是9个氨基酸。在其他优选实施方案中，HV2在长度方面是6个氨基酸。
框架区FW3a在长度方面优选地是6至10个氨基酸，在长度方面更优选地是7至9个氨基酸。在某些优选实施方案中，FW3a在长度方面是8个氨基酸。在某些优选实施方案中，FW3a在长度方面是7个氨基酸。
高变序列HV4在长度方面优选地是3至7个氨基酸，在长度方面更优选地是4至6个氨基酸。在某些优选实施方案中，HV4在长度方面是5个氨基酸。在其他优选实施方案中，HV4在长度方面是4个氨基酸。
框架区FW3b在长度方面优选地是17至24个氨基酸，在长度方面更优选地是18至23个氨基酸，在长度方面还更优选地是19至22个氨基酸。在某些优选实施方案中，FW3b在长度方面是21个氨基酸。在其他优选实施方案中，FW3b在长度方面是20个氨基酸。
CDR区CDR3在长度方面优选地是8至21个氨基酸，在长度方面更优选地是9至20个氨基酸，在长度方面还更优选地是10至19个氨基酸。在某些优选实施方案中，CDR3在长度方面是17个氨基酸。在其他优选实施方案中，CDR3在长度方面是14个氨基酸。在其他优选实施方案中，CDR3在长度方面是12个氨基酸。在其他优选实施方案中，CDR3在长度方面是10个氨基酸。
框架区FW4在长度方面优选地是7至14个氨基酸，在长度方面更优选地是8至13个氨基酸，在长度方面还更优选地是9至12个氨基酸。在某些优选实施方案中，FW4在长度方面是12个氨基酸。在其他优选实施方案中，FW4在长度方面是11个氨基酸。在其他优选实施方案中，FW4在长度方面是10个氨基酸。在其他优选实施方案中，FW4在长度方面是9个氨基酸。
优选地，ROR1特异性抗原结合分子不结合受体酪氨酸激酶样孤儿受体2(ROR2)。更优选地，ROR1特异性抗原结合分子结合人ROR1与鼠ROR1(mROR1)两者。还更优选地，ROR1特异性抗原结合分子结合去糖基化ROR1。
本发明的某些ROR1特异性抗原结合分子不结合选自以下的线性肽序列：
YMESLHMQGEIENQI(SEQ ID NO：34)
CQPWNSQYPHTHTFTALRFP(SEQ ID NO：35)
RSTIYGSRLRIRNLDTTDTGYFQ(SEQ ID NO：36)
QCVATNGKEVVSSTGVLFVKFGPPPTASPGYSDEYE(SEQ ID NO：37)
在ROR1特异性抗原结合分子的优选实施方案中：
FW1是具有20至28个氨基酸的框架区
CDR1是选自DTSYGLYS(SEQ ID NO：1)、GAKYGLAA(SEQ ID NO：2)、GAKYGLFA(SEQ IDNO：3)、GANYGLAA(SEQ ID NO：4)或GANYGLAS(SEQ ID NO：5)的CDR序列
FW2是具有6至14个氨基酸的框架区
HV2是选自TTDWERMSIG(SEQ ID NO：6)、SSNQERISIS(SEQ ID NO：7)或SSNKEQISIS(SEQ ID NO：8)的高变序列
FW3a是具有6至10个氨基酸的框架区
HV4是选自NKRAK(SEQ ID NO：9)、NKRTM(SEQ ID NO：10)、NKGAK(SEQ ID NO：11)或NKGTK(SEQ ID NO：12)的高变序列
FW3b是具有17至24个氨基酸的框架区
CDR3是选自QSGMAISTGSGHGYNWY(SEQ ID NO：13)、QSGMAIDIGSGHGYNWY(SEQ IDNO：14)、YPWAMWGQWY(SEQ ID NO：15)、VFMPQHWHPAAHWY(SEQ ID NO：16)、REARHPWLRQWY(SEQID NO：17)或YPWGAGAPWLVQWY(SEQ ID NO：18)的CDR序列
FW4是具有7至14个氨基酸的框架区
或与它们具有至少45％序列同一性的功能性变体。
在ROR1特异性抗原结合分子的其他优选实施方案中，FW1选自：ASVNQTPRTATKETGESLTINCVLT(SEQ ID NO：19)、AKVDQTPRTATKETGESLTINCVLT(SEQ ID NO：20)、TRVDQTPRTATKETGESLTINCVVT(SEQ ID NO：21)、TRVDQTPRTATKETGESLTINCVLT(SEQ IDNO：22)、ASVNQTPRTATKETGESLTINCVVT(SEQ ID NO：23)或TRVDQSPSSLSASVGDRVTITCVLT(SEQID NO：24)，FW2选自：TSWFRKNPG(SEQ ID NO：25)或TYWYRKNPG(SEQ ID NO：26)，FW3a选自：GRYVESV(SEQ ID NO：27)或GRYSESV(SEQ ID NO：28)，FW3b选自：SFSLRIKDLTVADSATYYCKA(SEQ ID NO：29)、SFTITISSLQPEDSATYYCRA(SEQ ID NO：30)或SFTLTISSLQPEDFATYYCKA(SEQID NO：31)，并且FW4选自DGAGTVLTVN(SEQ ID NO：32)或DGAGTKVEIK(SEQ ID NO：33)，或它们的具有至少45％的序列同一性的功能性变体。
以上所列的框架区、互补决定区和高变区的所有可能的组合和排列都明确涵盖在本文中。
关于本发明的分子提及的序列同一性可在单个CDR、HV或FW的水平上评判，或它可历经整个分子的长度加以评判。所描述的CDR、HV和FW序列还可为更长的或更短的，无论是通过在序列的N末端或C末端添加或缺失氨基酸，还是通过用某一序列进行氨基酸插入或缺失。
在ROR1特异性抗原结合分子的一优选实施方案中，FW1是ASVNQTPRTATKETGESLTINCVLT(SEQ ID NO：19)；CDR1是DTSYGLYS(SEQ ID NO：1)；FW2是TSWFRKNPG(SEQ ID NO：25)；HV2是TTDWERMSIG(SEQ ID NO：6)；FW3a是GRYVESV(SEQ ID NO：27)；HV4是NKRAK(SEQ ID NO：9)；FW3b是SFSLRIKDLTVADSATYYCKA(SEQ ID NO：29)；CDR3是QSGMAISTGSGHGYNWY(SEQ ID NO：13)；并且FW4是DGAGTVLTVN(SEQ ID NO：32)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是AKVDQTPRTATKETGESLTINCVLT(SEQ ID NO：20)；CDR1是DTSYGLYS(SEQ ID NO：1)；FW2是TSWFRKNPG(SEQ ID NO：25)；HV2是TTDWERMSIG(SEQ ID NO：6)；FW3a是GRYVESV(SEQ ID NO：27)；HV4是NKRAK(SEQ ID NO：9)；FW3b是SF SLRIKDLTVAD SATYYCKA(SEQ ID NO：29)；CDR3是QSGMAIDIGSGHGYNWY(SEQ ID NO：14)；并且FW4是DGAGTVLTVN(SEQ ID NO：32)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是TRVDQTPRTATKETGESLTINCVVT(SEQ ID NO：21)；CDR1是GAKYGLAA(SEQ ID NO：2)；FW2是TYWYRKNPG(SEQ ID NO：26)；HV2是SSNQERISIS(SEQ ID NO：7)；FW3a是GRYVESV(SEQ ID NO：27)；HV4是NKRTM(SEQ ID NO：10)；FW3b是SF SLRIKDLTVAD SATYYCKA(SEQ ID NO：29)；CDR3是YPWAMWGQWY(SEQ ID NO：15)；并且FW4是DGAGTVLTVN(SEQ ID NO：32)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是TRVDQTPRTATKETGESLTINCVVT(SEQ ID NO：21)；CDR1是GAKYGLFA(SEQ ID NO：3)；FW2是TYWYRKNPG(SEQ ID NO：26)；HV2是SSNQERISIS(SEQ ID NO：7)；FW3a是GRYVESV(SEQ ID NO：27)；HV4是NKRTM(SEQ ID NO：10)；FW3b是SF SLRIKDLTVAD SATYYCKA(SEQ ID NO：29)；CDR3是VFMPQHWHPAAHWY(SEQ ID NO：16)；并且FW4是DGAGTVLTVN(SEQ ID NO：32)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是TRVDQTPRTATKETGESLTINCVLT(SEQ ID NO：22)；CDR1是DTSYGLYS(SEQ ID NO：1)；FW2是TSWFRKNPG(SEQ ID NO：25)；HV2是TTDWERMSIG(SEQ ID NO：6)；FW3a是GRYVESV(SEQ ID NO：27)；HV4是NKGAK(SEQ ID NO：11)；FW3b是SF SLRIKDLTVAD SATYYCKA(SEQ ID NO：29)；CDR3是REARHPWLRQWY(SEQ ID NO：17)；并且FW4是DGAGTVLTVN(SEQ ID NO：32)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是ASVNQTPRTATKETGESLTINCVVT(SEQ ID NO：23)；CDR1是GANYGLAA(SEQ ID NO：4)；FW2是TYWYRKNPG(SEQ ID NO：26)；HV2是SSNQERISIS(SEQ ID NO：7)；FW3a是GRYVESV(SEQ ID NO：27)；HV4是NKRTM(SEQ ID NO：10)；FW3b是SFSLRIKDLTVADSATYYCKA(SEQ ID NO：29)；CDR3是YPWGAGAPWLVQWY(SEQ ID NO：18)；并且FW4是DGAGTVLTVN(SEQ ID NO：32)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是TRVDQSPSSLSASVGDRVTITCVLT(SEQ ID NO：24)；CDR1是GANYGLAS(SEQ ID NO：5)；FW2是TYWYRKNPG(SEQ ID NO：26)；HV2是SSNKEQISIS(SEQ ID NO：8)；FW3a是GRYSESV(SEQ ID NO：28)；HV4是NKGTK(SEQ ID NO：12)；FW3b是SFTLTISSLQPEDSATYYCRA(SEQ ID NO：30)；CDR3是YPWGAGAPWLVQWY(SEQ ID NO：18)；并且FW4是DGAGTKVEIK(SEQ ID NO：33)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是TRVDQSPSSLSASVGDRVTITCVLT(SEQ ID NO：24)；CDR1是GANYGLAS(SEQ ID NO：5)；FW2是TYWYRKNPG(SEQ ID NO：26)；HV2是SSNQERISIS(SEQ ID NO：7)；FW3a是GRYSESV(SEQ ID NO：28)；HV4是NKRTM(SEQ ID NO：10)；FW3b是SFTLTISSLQPEDSATYYCRA(SEQ ID NO：30)；CDR3是YPWGAGAPWLVQWY(SEQ ID NO：18)；并且FW4是DGAGTKVEIK(SEQ ID NO：33)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是TRVDQSPSSLSASVGDRVTITCVLT(SEQ ID NO：24)；CDR1是DTSYGLYS(SEQ ID NO：1)；FW2是TSWFRKNPG(SEQ ID NO：25)；HV2是TTDWERMSIG(SEQ ID NO：6)；FW3a是GRYVESV(SEQ ID NO：27)；HV4是NKGAK(SEQ ID NO：11)；FW3b是SFTLTISSLQPEDFATYYCKA(SEQ ID NO：31)；CDR3是REARHPWLRQWY(SEQ ID NO：17)；并且FW4是DGAGTKVEIK(SEQ ID NO：33)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是TRVDQSPSSLSASVGDRVTITCVLT(SEQ ID NO：24)；CDR1是DTSYGLYS(SEQ ID NO：1)；FW2是TYWYRKNPG(SEQ ID NO：26)；HV2是SSNKEQISIS(SEQ ID NO：8)；FW3a是GRYSESV(SEQ ID NO：28)；HV4是NKGTK(SEQ ID NO：12)；FW3b是SFTLTISSLQPEDSATYYCRA(SEQ ID NO：30)；CDR3是REARHPWLRQWY(SEQ ID NO：17)；并且FW4是DGAGTKVEIK(SEQ ID NO：33)；或它们的具有至少45％的序列同一性的功能性变体。
在ROR1特异性抗原结合分子的另一优选实施方案中，FW1是TRVDQSPSSLSASVGDRVTITCVLT(SEQ ID NO：24)；CDR1是DTSYGLYS(SEQ ID NO：1)；FW2是TYWYRKNPG(SEQ ID NO：26)；HV2是TTDWERMSIG(SEQ ID NO：6)；FW3a是GRYSESV(SEQ ID NO：28)；HV4是NKGAK(SEQ ID NO：11)；FW3b是SFTLTISSLQPEDSATYYCRA(SEQ ID NO：30)；CDR3是REARHPWLRQWY(SEQ ID NO：17)；并且FW4是DGAGTKVEIK(SEQ ID NO：33)；或它们的具有至少45％的序列同一性的功能性变体。
在其他优选实施方案中，ROR1特异性抗原结合分子包含选自以下的氨基酸序列：
Figure BDA0002615675830000131
Figure BDA0002615675830000132
Figure BDA0002615675830000141
Figure BDA0002615675830000142
或它们的具有至少45％的序列同一性的功能性变体。
本发明的ROR1特异性抗原结合分子可为人源化的。本发明的ROR1特异性抗原结合分子可为去免疫化的。本发明的人源化序列的实例包括但不限于：
Figure BDA0002615675830000143
D3人源化ADV1
Figure BDA0002615675830000151
D3人源化ADV2
Figure BDA0002615675830000152
D3人源化ADV3
Figure BDA0002615675830000153
B1人源化V5
Figure BDA0002615675830000154
B1人源化V7
Figure BDA0002615675830000155
D3人源化EL V1
Figure BDA0002615675830000156
Figure BDA0002615675830000161
D3人源化EL V2
Figure BDA0002615675830000162
D3人源化EL V3
Figure BDA0002615675830000163
D3人源化EL V4
Figure BDA0002615675830000164
Figure BDA0002615675830000165
知
D3人源化EL V5
Figure BDA0002615675830000166
本发明的ROR1特异性抗原结合分子还可缀合于可检测标记、染料、毒素、药物、前药、放射性核素或生物活性分子。
优选地，ROR1特异性抗原结合分子以约0.01至50nM，优选地以约0.1至30nM，甚至更优选地以约0.1至10nM的亲和常数与ROR1蛋白选择性相互作用。
此外，ROR1特异性抗原结合分子优选地能够介导对ROR1表达性肿瘤细胞的杀伤，或能够抑制癌细胞增殖。
ROR1特异性抗原结合分子在结合ROR1后还可能够被胞吞。在其他实施方案中，ROR1特异性抗原结合分子在结合ROR1后可不被胞吞。
在本发明的第二方面，提供了一种包含第一方面的特异性抗原结合分子的重组融合蛋白。优选地，在第二方面的重组融合蛋白中，特异性抗原结合分子融合于一种或多种生物活性蛋白。特异性抗原结合分子可通过一个或多个接头结构域融合于一种或多种生物活性蛋白。优选接头包括但不限于[G4S]x，其中x是1、2、3、4、5或6。特定优选接头是[G4S]3(SEQID NO：60)和[G4S]5(SEQ ID NO：61)。其他优选接头包括序列PGVQPSP(SEQ ID NO：62)、PGVQPSPGGGGS(SEQ ID NO：63)和PGVQPAPGGGGS(SEQ ID NO：64)。当重组融合蛋白于在糖基化样式方面不同的不同表达系统诸如CHO和昆虫以及不使所表达蛋白质糖基化的那些表达系统(例如大肠杆菌)中表达时，这些接头可为特别有用的。
还应了解本发明的融合蛋白可以任何顺序构建，即其中ROR1特异性抗原结合分子在N末端、C末端，或不在两个末端(例如在较长氨基酸序列的中间)。
优选生物活性蛋白包括但不限于免疫球蛋白、免疫球蛋白Fc区、免疫球蛋白Fab区、单链Fv(scFv)、微型双功能抗体、微型三功能抗体、微型四功能抗体、双特异性t细胞衔接物(BiTE)、内含肽、VNAR结构域、单结构域抗体(sdAb)、VH结构域或支架蛋白(亲和体、centyrin、经设计锚蛋白重复蛋白等)。一特别优选的生物活性蛋白是免疫球蛋白Fc区。其他优选融合蛋白包括VNAR-VNAR和VNAR-VNAR-VNAR。
本发明的融合蛋白的任何部分都可被工程改造来使得能够进行缀合。在一优选实例中，当使用免疫球蛋白Fc区时，它可被工程改造来包括半胱氨酸残基作为缀合位点。优选的所引入半胱氨酸残基包括但不限于S252C和S473C(Kabat编号)，其分别对应于EU编号下的S239C和S442C。
根据第二方面，提供了包含多个VNAR结构域的重组融合物。因此，本发明的重组融合物可为VNAR的二聚体、三聚体或更高级多聚体。在所述重组融合物中，每个VNAR的特异性可相同或不同。本发明的重组融合物包括但不限于双特异性或三特异性分子，其中每个VNAR结构域结合不同抗原，或结合单一抗原上的不同表位(双互补位结合剂)。如本文所用的术语“双互补位”意图涵盖结合给定抗原上的多个表位的分子。本文还涵盖结合给定抗原上的三个或更多个表位的分子，并且当使用术语“双互补位”时，应了解还涵盖关于三互补位或多互补位分子的潜在性。
此外，根据第二方面，提供了包括第一方面的ROR1特异性抗原结合分子和人源化VNAR结构域的重组融合物。人源化VNAR结构域可被称为soloMER，并且包括但不限于是以高亲和力结合人血清白蛋白的人源化VNAR的VNAR BA11(Kovalenko等，J.Biol.Chem.，2013JBC)。
双互补位和多价融合蛋白的实例包括但不限于：
Figure BDA0002615675830000191
其中：
B1是
Figure BDA0002615675830000192
Figure BDA0002615675830000193
2V是
Figure BDA0002615675830000194
Figure BDA0002615675830000195
P3A1是
Figure BDA0002615675830000196
Figure BDA0002615675830000201
D3是
Figure BDA0002615675830000202
Figure BDA0002615675830000203
BA11是
Figure BDA0002615675830000204
Figure BDA0002615675830000205
E9是
Figure BDA0002615675830000206
Figure BDA0002615675830000207
B1G2是
Figure BDA0002615675830000208
Figure BDA0002615675830000209
B1G1是
Figure BDA00026156758300002010
Figure BDA00026156758300002011
并且
其中未详细说明接头，(-)对应于接头-(G4S)5-
-(L2)-对应于接头-(G4S)3-
-(L3)-对应于接头-(G4S)7-
-(L4)-对应于接头Wobbe-G4S，其按顺序是PGVQPSPGGGGS(SEQ ID NO：63)
-(L5)-对应于接头Wobbe-G4S-GM，其按顺序是PGVQPAPGGGGS(SEQ ID NO：64)
Cys-对应于含有Cys的C末端标签-例如QACGAHHHHHHGAEFEQKLISEEDL(SEQ ID NO：67)
在某些实施方案中，本发明的特异性结合分子或重组融合物可在具有用以辅助纯化的N末端或C末端标签的情况下表达。实例包括但不限于His6和/或Myc。此外，N末端或C末端标签可被进一步工程改造来包括额外半胱氨酸残基以充当缀合点。因此，应了解，在本发明的所有方面提及特异性结合分子或重组融合物还意图涵盖具有多种N末端或C末端标签的所述分子，所述标签还可包括用于缀合的额外半胱氨酸。
在以下列出额外重组融合物。应了解，以下列出的并不是接头和VNAR或融合配偶体的每个组合。然而，所有所述组合都由本发明明确涵盖。
Figure BDA0002615675830000211
Figure BDA0002615675830000221
其中VNAR结构域之间的接头优选地是但不限于(G4S)5、(G4S)3、(G4S)7、PGVQPSPGGGGS(SEQ ID NO：63)(Wobbe-G4S)、PGVQPAPGGGGS(SEQ ID NO：64)(Wobbe-G4SGM)，并且其中不同接头的不同组合可组合在同一构建体内。
借此，额外C末端(或N末端)标签序列可或可不存在。
C末端标签包括但不限于含有用以有助于纯化的多组氨酸序列(诸如His6)的标签，含有用以使得能够进行检测的c-Myc序列(诸如EQKLISEEDL(SEQ ID NO：68))的标签，和/或含有用以使得能够使用硫醇反应性有效载荷和探针进行标记和生物缀合的半胱氨酸残基的标签，以及它们的组合。优选C末端标签包括但不限于：
QASGAHHHHHHGAEFEQKLISEEDL(SEQ ID NO：69)
QACGAHHHHHHGAEFEQKLISEEDL(SEQ ID NO：67)
QACKAHHHHHHGAEFEQKLISEEDL(SEQ ID NO：70)
AAAHHHHHHGAEFEQKLISEEDL(SEQ ID NO：71)
ACAHHHHHHGAEFEQKLISEEDL(SEQ ID NO：72)
QASGAHHHHHH(SEQ ID NO：73)
QACGAHHHHHH(SEQ ID NO：74)
QACKAHHHHHH(SEQ ID NO：75)
AAAHHHHHH(SEQ ID NO：76)
ACAHHHHHH(SEQ ID NO：77)
QASGA(SEQ ID NO：78)
QACGA(SEQ ID NO：79)
QACKA(SEQ ID NO：80)
ACA(SEQ ID NO：81)
SAPSA(SEQ ID NO：82)
其中：
·B1是
Figure BDA0002615675830000231
Figure BDA0002615675830000232
·2V是
Figure BDA0002615675830000233
Figure BDA0002615675830000234
·P3A1是
Figure BDA0002615675830000235
Figure BDA0002615675830000236
·D3是
Figure BDA0002615675830000237
Figure BDA0002615675830000241
·BA11是
Figure BDA0002615675830000242
Figure BDA0002615675830000243
·E9是
Figure BDA0002615675830000244
Figure BDA0002615675830000245
如上所陈述，VNAR和接头的所有组合都明确涵盖在本文中。
本文还涵盖VNAR的人源化衍生物。
此外，根据第二方面，提供了包括第一方面的ROR1特异性抗原结合分子和重组毒素的重组融合物。重组毒素的实例包括但不限于假单胞菌(Pseudomonas)外毒素PE38和白喉毒素。
此外，根据第二方面，提供了包括第一方面的ROR1特异性抗原结合分子和重组CD3结合蛋白的重组融合物。重组ROR1和CD3结合剂的实例包括但不限于：
B1 CD3
Figure BDA0002615675830000246
Figure BDA0002615675830000251
B1 CD3[G4S]3
Figure BDA0002615675830000252
P3A1 CD3
Figure BDA0002615675830000253
P3A1 CD3[G4S]3
Figure BDA0002615675830000254
Figure BDA0002615675830000261
P3A1 P3A1 CD3
Figure BDA0002615675830000262
P3A1 P3A1 CD3[G4S]3
Figure BDA0002615675830000263
Figure BDA0002615675830000271
P3A1-[PGVQPSPGGGGS]-B1-[G4S]-CD3
Figure BDA0002615675830000272
P3A1-[PGVQPSPGGGGS]-B1-[G4S]3-CD3
Figure BDA0002615675830000273
Figure BDA0002615675830000281
P3A1-[PGVQPAPGGGGS]-D3-[G4S]-CD3
Figure BDA0002615675830000282
P3A1-[PGVQPAPGGGGS]-D3-[G4S]3-CD3
Figure BDA0002615675830000283
Figure BDA0002615675830000291
P3A1-[G4S]5-D3-[G4S]-CD3
Figure BDA0002615675830000292
P3A1-[G4S]5-D3-[G4S]3-CD3
Figure BDA0002615675830000293
Figure BDA0002615675830000301
在本发明的第三方面，提供了一种ROR1特异性嵌合抗原受体(CAR)，所述嵌合抗原受体包含至少一个如由本发明的第一方面定义的ROR1特异性抗原结合分子，所述至少一个ROR1特异性抗原结合分子融合或缀合于至少一个跨膜区域和至少一个细胞内结构域。
本发明还提供了一种包含根据第三方面的嵌合抗原受体的细胞，所述细胞优选地是经工程改造T细胞。
在本发明的第四方面，提供了一种包含编码根据本发明的第一、第二或第三方面的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体的多核苷酸序列的核酸序列。
还提供了一种包含根据第四方面的核酸序列的载体和一种包含这种核酸的宿主细胞。
提供了一种用于制备第一、第二或第三方面的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体的方法，所述方法包括在各种条件下培养或维持包含以上所述的多核苷酸或载体的宿主细胞，以使所述宿主细胞产生所述特异性抗原结合分子、重组融合蛋白或嵌合抗原受体，任选地，所述方法还包括分离所述特异性抗原结合分子、重组融合蛋白或嵌合抗原受体。
在本发明的第五方面，提供了一种包含第一、第二或第三方面的特异性抗原结合分子、融合蛋白或嵌合抗原受体的药物组合物。药物组合物可含有多种药学上可接受的载体。本发明的药物组合物可用于通过本领域中已知的任何适合方法施用，包括但不限于静脉内、肌肉内、口服、腹膜内或经表面施用。在优选实施方案中，药物组合物可以液体、凝胶剂、粉剂、片剂、胶囊或泡沫剂形式制备。
第一、第二或第三方面的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体可用于疗法中。更特别地，第一、第二或第三方面的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体可用于治疗癌症。优选地，癌症是ROR1阳性癌症类型。更优选地，癌症选自包含以下的组：血液癌症，诸如淋巴瘤和白血病、慢性淋巴细胞性白血病(CLL)、套膜细胞淋巴瘤(MCL)、B细胞急性淋巴母细胞性白血病(B-ALL)、边缘区淋巴瘤(MZL)、非霍奇金淋巴瘤(non-Hodgkin lymphoma，NHL)、急性骨髓性白血病(AML)，以及实体肿瘤，包括神经母细胞瘤、肾癌、肺癌、结肠癌、卵巢癌、胰腺癌、乳腺癌、皮肤癌、子宫癌、前列腺癌、甲状腺癌、头颈部癌、膀胱癌、胃癌或肝癌。
本文还提供了第一、第二或第三方面的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体制造用于治疗有需要的患者的疾病的药剂的用途。
此外，根据本发明，提供了一种治疗需要治疗的患者的疾病的方法，所述方法包括向所述患者施用治疗有效剂量的第一、第二或第三方面的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体或第五方面的药物组合物。
优选地，癌症是ROR1阳性癌症类型。更优选地，癌症选自包含以下的组：血液癌症，诸如淋巴瘤和白血病、慢性淋巴细胞性白血病(CLL)、套膜细胞淋巴瘤(MCL)、B细胞急性淋巴母细胞性白血病(B-ALL)、边缘区淋巴瘤(MZL)、非霍奇金淋巴瘤(NHL)、急性骨髓性白血病(AML)，以及实体肿瘤，包括神经母细胞瘤、肾癌、肺癌、结肠癌、卵巢癌、胰腺癌、乳腺癌、皮肤癌、子宫癌、前列腺癌、甲状腺癌、头颈部癌、膀胱癌、胃癌或肝癌。
本文还提供了一种测定样品中靶标分析物的存在的方法，所述方法包括将第一方面的以可检测方式标记的特异性抗原结合分子或第二方面的重组融合蛋白添加至所述样品中，以及检测所述分子与所述靶标分析物的结合。
此外，本文提供了一种使受试者中的疾病部位成像的方法，所述方法包括向受试者施用第一方面的以可检测方式标记的特异性抗原结合分子或第二方面的以可检测方式标记的重组融合蛋白。
本文还提供了一种诊断受试者的疾病或医学状况的方法，所述方法包括施用第一方面的特异性抗原结合分子或第二方面的重组融合蛋白。
本文还涵盖一种与第一方面的ROR1特异性抗原结合分子竞争结合ROR1的抗体、抗体片段或抗原结合分子。当在抗原结合蛋白(例如中和抗原结合蛋白或中和抗体)的情形下使用时，术语“竞争”意指如通过某一测定所测定的在抗原结合蛋白之间的竞争，在所述测定中，所测试的抗原结合蛋白(例如抗体或其功能性片段)阻止或抑制本文定义的抗原结合分子(例如第一方面的特异性抗原结合分子)与共同抗原(例如在第一方面的特异性抗原结合分子的情况下的ROR1)的特异性结合。
本文还描述一种用于诊断罹患癌症或易患癌症的受试者，或用于提供所述受试者的疾患的预后的试剂盒，所述试剂盒包括用于检测存在于来自测试受试者的样品中的抗原的浓度的检测工具，其中所述检测工具包括第一方面的ROR1特异性抗原结合分子、第二方面的重组融合蛋白、第三方面的嵌合抗原受体或第四方面的核酸序列，各自任选地被衍生化，其中所述样品中存在抗原表明所述受试者罹患癌症。优选地，抗原包括ROR1蛋白，更优选地包括ROR1蛋白的细胞外结构域。更优选地，试剂盒用于鉴定样品中ROR1阳性细胞的存在或不存在，或测定样品中ROR1阳性细胞的浓度。试剂盒还可包括测定相对于其进行比较的阳性对照和/或阴性对照，和/或可被检测的标记。
本发明还提供了一种用于诊断罹患癌症或易患癌症的受试者，或用于提供所述受试者的疾患的预后的方法，所述方法包括检测存在于从受试者获得的样品中的抗原的浓度，其中所述检测使用各自任选地被衍生化的第一方面的ROR1特异性抗原结合分子、第二方面的重组融合蛋白、第三方面的嵌合抗原受体或第四方面的核酸序列实现，并且其中所述样品中存在抗原表明所述受试者罹患癌症。
本文还涵盖一种在体外或在患者中杀伤表达ROR1的细胞或抑制所述细胞的生长的方法，所述方法包括向所述细胞施用药学上有效量或药学上有效剂量的(i)第一方面的ROR1特异性抗原结合分子、第二方面的重组融合蛋白、第三方面的核酸序列、或根据第四方面的CAR或细胞，或(ii)第五方面的药物组合物。优选地，表达ROR1的细胞是癌细胞。更优选地，ROR1是人ROR1。
在本发明的第六方面，提供了一种包含由式(II)代表的氨基酸序列的特异性抗原结合分子：
X-FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4-Y (II)
其中
FW1是框架区
CDR1是CDR序列
FW2是框架区
HV2是高变序列
FW3a是框架区
HV4是高变序列
FW3b是框架区
CDR3是CDR序列
FW4是框架区
X和Y是任选氨基酸序列
其中所述特异性抗原结合分子缀合于第二部分。
在某些优选实施方案中，根据本发明的这个方面的特异性抗原结合分子可另外缀合于第三、第四或第五部分。还涵盖更多部分的缀合。在一些情况下，第三、第四或第五部分可缀合于第二部分。因此，应了解，根据本发明的这个方面的部分中的任一者可具有与其缀合的额外部分。对第二部分的如以下阐述的优选特征的描述在加以必要的变更下适用于第三、第四、第五或更高顺序部分。
优选地，X或Y单独地是不存在的，或选自包含以下的组：免疫球蛋白、免疫球蛋白Fc区、免疫球蛋白Fab区、单链Fv(scFv)、微型双功能抗体、微型三功能抗体、微型四功能抗体、双特异性t细胞衔接物(BiTE)、内含肽、VNAR结构域、单结构域抗体(sdAb)、VH结构域、支架蛋白(亲和体、centyrin、经设计锚蛋白重复蛋白等)、或毒素，包括但不限于假单胞菌外毒素PE38、白喉毒素。
优选地，缀合通过特异性抗原结合分子的氨基酸序列中的半胱氨酸残基来进行。半胱氨酸残基可在序列中的任何地方，包括在任选序列X或Y(如果存在)中。
缀合可通过并入在特异性抗原结合分子的氨基酸序列的N末端或C末端的硫醇、氨基氧基或肼基部分来进行。
优选地，第二部分选自包含以下的组：可检测标记、染料、毒素、药物、前药、放射性核素或生物活性分子。
更优选地，第二部分是至少一种选自包含以下的组的毒素：
·类美登素(maytansinoid)，
·澳瑞他汀(auristatin)，
·蒽环霉素(anthracyclin)，优选地是PNU衍生蒽环霉素
·卡奇霉素(calicheamicin)，
·鹅膏菌素(amanitin)衍生物，优选地是α-鹅膏菌素衍生物
·微管溶素(tubulysin)
·倍癌霉素(duocarmycin)
·放射性同位素，例如α发射放射性核素，诸如227Th或225Ac
·包含毒性有效载荷的脂质体，
·蛋白质毒素
·紫杉烷(taxane)
·吡咯并苯并二氮呯(pyrrolbenzodiazepine)
·吲哚啉并苯并二氮呯(indolinobenzodiazepine)假二聚体和/或
·剪接体抑制剂
·CDK11抑制剂
·吡啶并苯并二氮呯(Pyridinobenzodiazepine)
在根据这个方面的其他优选实施方案中，第二部分可来自包含以下的组：免疫球蛋白、免疫球蛋白Fc区、免疫球蛋白Fab区、单链Fv(scFv)、微型双功能抗体、微型三功能抗体、微型四功能抗体、双特异性t细胞衔接物(BiTE)、内含肽、VNAR结构域、单结构域抗体(sdAb)、VH结构域、支架蛋白(亲和体、centyrin、经设计锚蛋白重复蛋白等)、或毒素，包括但不限于假单胞菌外毒素PE38、白喉毒素。
在特别优选实施方案中，第二部分是VNAR结构域，所述VNAR结构域可与根据这个方面的特异性抗原结合分子相同或不同。因此，通过化学缀合连接的VNAR结构域的二聚体、三聚体或更高级多聚体明确涵盖在本文中。在所述实施方案中，每个单独的VNAR结构域可与其他VNAR结构域具有相同抗原特异性，或它们可为不同的。
根据这个方面，特异性抗原结合分子可包含例如如关于第一至第五方面所述的双互补位特异性抗原结合分子融合于其他生物活性分子(包括但不限于用于半衰期延长的分子，例如BA11)，接着进一步缀合于第二部分，包括但不限于细胞毒性有效载荷。
根据这个方面，特异性抗原结合分子可为受体酪氨酸激酶样孤儿受体1(ROR1)特异性抗原结合分子。这可为本发明的第一方面的ROR1特异性抗原结合分子。因此，以上关于第一、第二和第三方面所述的优选特征中的任一者在加以必要的变更下适用于第六方面。
第六方面的特异性抗原结合分子可用于疗法中。更特别地，第六方面的特异性抗原结合分子可用于治疗癌症。优选地，癌症是ROR1阳性癌症类型。更优选地，癌症选自包含以下的组：血液癌症，诸如淋巴瘤和白血病、慢性淋巴细胞性白血病(CLL)、套膜细胞淋巴瘤(MCL)、B细胞急性淋巴母细胞性白血病(B-ALL)、边缘区淋巴瘤(MZL)、非霍奇金淋巴瘤(NHL)、急性骨髓性白血病(AML)，以及实体肿瘤，包括神经母细胞瘤、肾癌、肺癌、结肠癌、卵巢癌、胰腺癌、乳腺癌、皮肤癌、子宫癌、前列腺癌、甲状腺癌、头颈部癌、膀胱癌、胃癌或肝癌。
本文还提供了第六方面的特异性抗原结合分子制造用于治疗有需要的患者的疾病的药剂的用途。
还提供了包含第六方面的特异性抗原结合分子的药物组合物。药物组合物可含有多种药学上可接受的载体。
此外，根据本发明，提供了一种治疗需要治疗的患者的疾病的方法，所述方法包括向所述患者施用治疗有效剂量的第六方面的特异性抗原结合分子或包含第六方面的特异性抗原结合分子的药物组合物。
优选地，癌症是ROR1阳性癌症类型。更优选地，癌症选自包含以下的组：血液癌症，诸如淋巴瘤和白血病、慢性淋巴细胞性白血病(CLL)、套膜细胞淋巴瘤(MCL)、B细胞急性淋巴母细胞性白血病(B-ALL)、边缘区淋巴瘤(MZL)、非霍奇金淋巴瘤(NHL)、急性骨髓性白血病(AML)，以及实体肿瘤，包括神经母细胞瘤、肾癌、肺癌、结肠癌、卵巢癌、胰腺癌、乳腺癌、皮肤癌、子宫癌、前列腺癌、甲状腺癌、头颈部癌、膀胱癌、胃癌或肝癌。
本文还提供了一种测定样品中靶标分析物的存在的方法，所述方法包括将第六方面的以可检测方式标记的特异性抗原结合分子添加至所述样品中，以及检测所述分子与所述靶标分析物的结合。
此外，本文提供了一种使受试者中的疾病部位成像的方法，所述方法包括向受试者施用第六方面的以可检测方式标记的特异性抗原结合分子。
本文还提供了一种诊断受试者的疾病或医学状况的方法，所述方法包括施用第六方面的特异性抗原结合分子。
此外，关于本发明的以上提及的方面中的任一者所述的特征中的任一者可在加以必要的变更下与本发明的其他方面组合。
附图说明
图1：展示VNAR结构域的抗ROR1噬菌体单克隆：在ELISA中与人或小鼠重组ROR1-Fc的结合。B1、P3A1和E7-特异性ROR1结合剂，H2-非特异性噬菌体。
图2：从使用人ROR1(B1和E7)和小鼠ROR1(P3A1和CPF7)筛选合成VNAR文库获得的ROR1结合序列。显示了不具有以及具有C末端His6Myc标签(His6 Myc序列用斜体表示)的序列。
图3：使用人ROR1对免疫化VNAR文库的产生：对三条白斑角鲨免疫前和免疫后血浆与鼠或人ROR1的结合的分析。
图4：由免疫化VNAR文库获得的抗ROR1噬菌体单克隆：在ELISA中与人或小鼠重组ROR1-Fc的结合。E9和D3-特异性ROR1结合剂，H1-展示在噬菌体上的非特异性VNAR结合剂。
图5：从使用小鼠ROR1筛选免疫化VNAR文库获得的ROR1结合序列E9和D3。显示了不具有以及具有C末端His6Myc标签(His6Myc序列用斜体表示)的序列。
图6：在室温下，在50mM NaCl、20mM NaP缓冲液(pH 6.0)中，无标签VNAR、VNAR6xHis和VNAR-His6-Myc的远紫外CD光谱。
图7：VNAR重定形式，A：单体VNAR，B：同二聚体，C：通过C末端分子间二硫键缀合的同二聚体，D：异二聚体，E：VNAR IgGFc融合物，F：IgG Fc-VNAR融合物，G：VNAR-(IgG Fc)-VNAR融合物。
图8：B1 C末端连接的同二聚体与hROR1的结合。根据ELISA，B1、B1 C末端硫醇(B1SH)和B1 C末端二硫醚二聚体(B1 S-S B1)与人ROR1的结合。
图9：根据流式细胞计量术，VNAR(His6Myc标签)分子与A549(ROR1高)肺癌细胞的细胞表面结合。在所有测试浓度下，B1和E7单体以及P3A1-P3A1二聚体都强烈结合A549细胞。CPF7和P3A1单体在50μg/ml下结合A549细胞。使用PE-抗Myc标签抗体(CST)检测VNAR结合，并且使用BD Biosciences FACSCalibur流式细胞仪加以分析。
图10：VNAR IgG Fc融合蛋白中使用的接头小鼠IgG和接头人IgG序列。经工程改造hIgG1 Fc融合蛋白在hIgG1 Fc序列中例如在位置S252C或S473C(Kabat编号)处并有经工程改造半胱氨酸取代以使得能够进行位点特异性标记。
图11：内含肽裂解试剂以及相应VNAR C末端衍生物。
图12：根据ELISA，VNAR与人ROR1、小鼠ROR1和大鼠ROR1以及人ROR2的结合。发现所有VNAR都与ROR1具有物种交叉反应性。VNAR克隆都不与人ROR2交叉反应。
图13：根据流式细胞计量术，VNAR与A549(ROR1高)相对于A427(ROR1低)肺癌细胞系的细胞表面结合。
图14：在4℃或37℃下持续2小时，VNAR与MDA-MB-231乳腺癌细胞的细胞表面结合。在37℃下的细胞表面信号丧失暗示ROR1内化。使用PE-抗Myc标签抗体(CST)检测VNAR结合，并且使用BD Biosciences FACS Calibur(B1)或ThermoFisher Attune NxT流式细胞仪加以分析。
图15：描绘VNAR-hFc分子与A549(ROR1高)相对于A427(ROR1低)肺癌细胞系的细胞表面结合的条形图。使用PE-抗人抗体(Jackson ImmunoResearch Labs/Stratech)和ThermoFisher Attune NxT流式细胞仪检测VNAR hFc结合。
图16：VNAR-Fc融合物的内化。在4℃或37℃下持续2小时，VNAR-Fc与MDA-MB-231乳腺癌细胞的细胞表面结合。在37℃下的细胞表面信号丧失暗示ROR1内化。
图17：VNAR与人ROR1的不依赖于糖基化的结合。A，对hROR1(泳道2)和去糖基化hROR1(泳道3)的SDS PAGE分析。分子量标记(泳道1)。B，根据ELISA，ROR1结合VNAR B1、P3A1-P3A1和D3-D3同等良好结合去糖基化hROR1。C，根据ELISA，B1 mFc同等良好结合糖基化hROR1和去糖基化hROR1。与展开hROR1(用28mM DTT、0.5％Sarkosyl还原)的结合显著降低，这与B1 VNAR结合一个或多个构象性表位一致。
图18.1：根据SEC，B1与ROR1 Ig结构域形成复合物。A，对具有以及不具有B1 his(分别是橙色和蓝色迹线)的人ROR1Ig结构域的叠加SEC分析(Superdex 200 Increase 10/300，GE Healthcare)。B，对峰级分的SDS PAGE分析。
图18.2：对ROR1特异性VNAR B1与非糖基化形式的ROR1 Ig结构域(IgHis)的结合的SEC分析。操作条件：20mM Hepes、150mM NaCl，pH 7.5。箭号指示被选择用于质谱测定法分析的峰。
图18.3：对在通过SEC分析非糖基化形式的ROR1 Ig结构域(IgHis)和ROR1特异性VNAR B1时形成的额外峰(图18.2)的质谱测定法分析。IgHis预期分子量：12,218.6Da；IgHis观察分子量：12,217.9Da。B1预期分子量：12,506.8Da；
B1观察分子量：12,506.0Da。这些数据显示已在B1与非糖基化IgHis之间形成复合物。
图18.4.如通过SEC/SDS-PAGE分析评估的VNAR结构域D3和P3A1与ROR1结构域的结合。
图19a：描绘VNAR与先前捕集/不捕集B1 His6Myc VNAR的hROR1的结合的SPR传感图。2V单体或二聚体在这些条件中的任一者下都不结合。
图19b：描绘i)ROR12A2 mAb，ii)基于UC961的mAb，iii)P3A1，iv)B1，v)D3和vi)E9与先前捕集/不捕集P3A1 His6Myc二聚体VNAR的hROR1的结合的代表性SPR传感图。除P3A1自身竞争(iii)以外，未观察到竞争结合hROR1。
图20：根据ELISA，B1和P3A1不结合所选线性ROR1肽。与人ROR1的结合作为阳性对照加以包括。
图21：根据ELISA，B1、P3A1、D3和D3-D3不结合所选线性ROR1肽。与人ROR1的结合作为阳性对照加以包括。
图22：竞争ELISA实验。
图23：竞争ELISA实验。
图24：B1、P3A1、D3单体和D3-D3二聚体与不同ROR1结构域的结合。
图25：BA11氨基氧基与苯甲醛荧光素缀合的示意图。
图26：BA11硫醇与顺丁烯二酰亚胺荧光素缀合的示意图。
图27：BA11 C末端半胱氨酸衍生物与顺丁烯二酰亚胺荧光素缀合的示意图。
图28：用于缀合的标记和有效载荷的实例。
图29：对B1 MMAE缀合物的分析。A，对B1 his myc衍生物和缀合物的SDS PAGE分析-泳道1，B1氨基氧基；2，B1肟MMAE；3，B1肟vc MMAE；4，B1 SH vc MMAE。B-F，B1 his myc衍生物和缀合物的电喷雾质谱-B，B1 SH(预期质量14908.9Da，观察质量14908.4Da)；C，B1 SHvc MMAE(预期质量16225.5Da，观察质量16225.5Da)；D，B1氨基氧基(预期质量14937.4Da，观察质量14936.5Da)；E，B1肟MMAE(预期质量16015.4Da，观察质量16016.7Da)；F，B1肟vcMMAE(预期质量16334.4Da，观察质量16334.2Da)。
图30：B1-hFc、P3A1-hFc和2V-hFc分子相对于MMAE缀合形式在A549(ROR1高)相对于A427(ROR1低)肺癌细胞系的情况下的细胞表面结合。使用PE-抗人抗体(JacksonImmunoResearch Labs/Stratech)和ThermoFisher Attune NxT流式细胞仪检测VNAR hFc结合。
图31：对VNAR hFc缀合物的分析。A和B，对VNAR hFc(S252C)蛋白和缀合物的SDSPAGE分析(分别采用4-12％和12％Bis Tris凝胶)。泳道1，未处理蛋白，2，再折叠蛋白，以及3，MMAE缀合物(采用/不采用DTT还原)。C和D，分别是在MMAE缀合之前和之后对去糖基化还原VNAR hFc(S252C)融合蛋白的质谱分析的实例。预期质量：未缀合，38,997.8Da，以及MMAE缀合物(DAR 2)，40,310.0Da。E和F，对VNAR hFc(S473C)蛋白缀合物的SDS PAGE分析。泳道3，MMAE缀合物，以及4，AF488缀合物(采用/不采用DTT还原)。G和H，分别是对去糖基化还原B1-hFc(S473C)MMAE缀合物和P3A1 hFc(S473C)MMAE缀合物的质谱分析。预期质量：B1缀合物，40,170.5Da，以及P3A1缀合物，40,308.5Da(DAR是2)[*对应于归因于源内裂解的MS伪迹]。I和J，分别是对去糖基化还原B1-hFc(S473C)AF488缀合物和P3A1 hFc(S473C)AF488缀合物的质谱分析。预期质量：B1缀合物，39,552.4Da，以及P3A1缀合物，39,690.4Da(DAR是2)。
图32：VNAR hFc PBD二聚体、鹅膏菌素和PNU缀合物的示意图。
图33：在一组不同人癌细胞系的情况下，用B1 mFc MMAE或2V mFc-MMAE分子处理(72小时)之后的细胞活力。Cell Titre Glo试剂(Promega)用于定量与培养中的代谢活性细胞的数目相关联的ATP。使用GraphPad Prism软件确定IC50值。
图34：在2种不同人癌细胞系(DU145和Jeko-1)的情况下，用VNAR hFc PBD缀合物处理(96小时)之后的细胞活力。Cell Titre Glo试剂(Promega)用于定量与培养中的代谢活性细胞的数目相关联的ATP。使用GraphPad Prism软件确定IC50值。通过使VNAR hIgG1Fc(S252C)融合物与MA PEG4 va PBD反应来产生VNAR hFc缀合物(参见图32)。
图35：在2种不同人癌细胞系(PA-1和Kasumi-2)的情况下，用VNAR hFc PBD、SG3199 PBD和PNU(PEG4 vc PAB DMAE PNU159682)缀合物处理(96小时)之后的细胞活力。Cell Titre Glo试剂(Promega)用于定量与培养中的代谢活性细胞的数目相关联的ATP。使用GraphPad Prism软件确定IC50值。借此，通过使VNAR hIgG1 Fc(S252C)融合物与M[APEG4 va PBD、MA PEG8 va PAB SG3199、MA PEG4 vc PAB DMAE PNU 159682反应来产生VNAR hFc缀合物(参见图32)。
图35b：在存在或不存在递增量的未缀合B1hFc或2VhFc下，用IC80浓度的B1hFc-SG3199、B1hFc-PNU或2VhFc非结合对照处理PA-1细胞和Kasumi-2细胞。使用Cell TiterGlo测定(Promega)评估细胞活力。在用蛋白质-药物缀合物分子处理之后对细胞活力的影响由递增量的竞争性未缀合B1hFc而非由2VhFc蛋白消除。
图36，B1-[(G4S)5]-D3 Alexa Fluor 488缀合物的QC数据。上部.对Alexa Fluor488 VNAR缀合物的SDS-PAGE分析。使用考马斯亮蓝(Coomassie Brilliant Blue)或UV进行显现。SDS-PAGE在还原性(+0.1M DTT)或非还原性(-0.1M DTT)条件下进行。下部.AlexaFluor 488 VNAR缀合物的去卷积质谱。观察质量(26286.8Da)与对于选择性标记的缀合物所预期的理论质量(29285.1Da)一致。
图37，P3A1-[(G4S)5]-BA11-[(G4S)5]-D3 Alexa Fluor 488缀合物的QC数据。上部.对Alexa Fluor 488VNAR缀合物的SDS-PAGE分析。使用考马斯亮蓝或UV进行显现。SDS-PAGE在还原性(+0.1M DTT)或非还原性(-0.1M DTT)条件下进行。下部.Alexa Fluor 488VNAR缀合物的去卷积质谱。观察质量(42273.81Da)与对于选择性标记的缀合物所预期的理论质量(42,279.1)一致。
图38，BA11-[PGVQPSPGGGGS]-B1 Alexa Fluor 488缀合物的QC数据。上部.对Alexa Fluor 488 VNAR缀合物的SDS-PAGE分析。使用考马斯亮蓝或UV进行显现。SDS-PAGE在还原性(+0.1M DTT)或非还原性(-0.1M DTT)条件下进行。下部.Alexa Fluor 488 VNAR缀合物的去卷积质谱。观察质量(27821.12Da)与对于选择性标记的缀合物所预期的理论质量(27,819.99Da)一致。
除提及的序列之外，还明确公开了以下序列。这些序列中的某些涉及本文所述的本发明的分子的实例：
Figure BDA0002615675830000441
Figure BDA0002615675830000451
Figure BDA0002615675830000461
Figure BDA0002615675830000471
具体实施方式
本发明总体上涉及特异性抗原结合分子。特别地，本发明提供了对受体酪氨酸激酶样孤儿受体1(ROR1)具有特异性的免疫球蛋白样鲨鱼可变新型抗原受体(VNAR)以及相关融合蛋白、嵌合抗原受体、缀合物和核酸，以及伴随的方法。ROR1特异性VNAR结构域在本文中描述为ROR1特异性抗原结合分子。
新型或新抗原受体(IgNAR)是一种见于软骨鱼的血清中的约160kDa同二聚蛋白质(Greenberg A.S.等，Nature，1995.374(6518)：第168-173页，Dooley，H.等，Mol.Immunol，2003.40(1)：第25-33页；Müller，M.R.等，mAbs，2012.4(6)：第673-685页)。每个分子由单一N末端可变结构域(VNAR)和五个恒定结构域(CNAR)组成。IgNAR结构域是免疫球蛋白超家族的成员。VNAR是与免疫球蛋白和T细胞受体可变结构域以及与细胞粘附分子具有结构类似性和一定序列类似性的紧密折叠结构域，并且由于类似于经典免疫球蛋白和T细胞受体的N可变末端结构域而被称为VNAR。VNAR与免疫球蛋白共有有限序列同源性，例如在VNAR与人轻链序列之间的25-30％类似性(Dooley，H.和Flajnik，M.F.，Eur.J.Immunol.，2005.35(3)：第936-945页)。
Kovaleva M.等Expert Opin.Biol.Ther.2014.14(10)：第1527-1539页以及Zielonka S.等mAbs 2015.7(1)：第15-25页提供对VNAR的结构表征和产生的概述，所述概述据此以引用的方式并入本文。
VNAR似乎不已从经典免疫球蛋白抗体祖先进化。VNAR的独特结构特征是等同于存在于常规免疫球蛋白可变结构域中的CDR2环的序列被截除，以及缺乏通常将允许与轻链结构域缔合的疏水性VH/VL界面残基，所述轻链结构域不存在于IgNAR结构中。此外，不同于经典免疫球蛋白，一些VNAR亚型在CDR区中包括额外半胱氨酸残基，除在N末端邻近于CDR 1和3的框架1和3区域中的半胱氨酸之间的典型免疫球蛋白超家族桥之外，还观察到所述额外半胱氨酸残基形成二硫桥。
迄今为止，存在被称为I、II和III的三种确定类型的鲨鱼IgNAR。这些类型已基于处于强烈选择压力下，因此很少被替代的非典型半胱氨酸残基的位置加以分类。
所有三种类型都具有在位置35和107(如Kabat，E.A.等Sequences of proteinsof immunological interest.第5版1991，Bethesda：US Dept.of Health and HumanServices，PHS，NIH中的编号)处的使标准免疫球蛋白折叠稳定的经典免疫球蛋白典型半胱氨酸，以及在位置36处的不变色氨酸。不存在确定的CDR2本身，但更接近地类似于TCR HV2和HV4的序列变异区域已分别在框架2和3中确定。I型在框架2和框架4中具有种系编码的半胱氨酸残基，并且在CDR3内具有偶数个额外半胱氨酸。对针对溶菌酶加以分离并且与溶菌酶复合的I型IgNAR的晶体结构研究使得能够确定这些半胱氨酸残基的作用。框架2半胱氨酸与框架4半胱氨酸两者均与CDR3中的那些半胱氨酸形成二硫桥，从而形成紧密组装结构，在所述结构内，CDR3环被向下朝着HV2区域紧密固持。迄今为止，I型IgNAR仅已在护士鲨中鉴定-所有其他软骨鱼，包括同一目的成员，仅具有II型或这个类型的变化形式。
II型IgNAR定义为在CDR1和CDR3中具有形成分子内二硫键的半胱氨酸残基，所述二硫键将这两个区域紧密邻近固持，从而产生有助于结合口袋或沟槽的突出CDR3(图2)。I型序列相比于II型通常具有更长CDR3，分别具有平均21和15个残基。据信这是由于对I型CDR3中的两个或更多个半胱氨酸残基与它们的框架2和4对应物缔合具有强烈选择压力。对体细胞突变的积累的研究显示相比于I型，在II型的CDR1中存在更大数目的突变，而相比于II型，I型的HV2区域显示更大序列变异。这个迹象与这些区域在抗原结合位点内的所确定定位良好关联。
被称为III型的第三IgNAR类型已在新生体中鉴定。IgNAR家族的这个成员由于D1和D2区域(其形成CDR3)与V基因的种系融合而在CDR3内缺乏多样性。几乎所有已知克隆都具有15个残基的CDR3长度，具有少许或不具有序列多样性。
VNAR的另一结构类型，被称为(IIb或IV)型，仅具有两个典型半胱氨酸残基(在框架1和框架3b区域中)。迄今为止，这个类型已主要见于角鲨中(Liu，J.L.等Mol.Immunol.2007.44(7)：第1775-1783页；Kovalenko O.V.等J Biol Chem.2013.288(24)：第17408-19页)，并且还从源于须鲨的半合成V-NAR文库分离(Streltsov，V.A.等(2004)Proc.Natl.Acad.Sci.U.S.A.101(34)：第12444-12449页)。
然而，已显示从由VNAR序列形成的合成文库分离的特异性VNAR可以高亲和力结合其他蛋白质(Shao C.Y.等Mol Immunol.2007.44(4)：第656-65页；WO2014/173959)，并且IgNAR是适应性免疫系统的一部分，因为软骨鱼可用抗原免疫，并且获得结合所述抗原的应答性IgNAR(Dooley，H.等，Mol.Immunol，2003.40(1)：第25-33页；WO2003/014161)。已显示IgNAR具有用于使V样序列与D和J序列组合接合的机制，所述机制类似于免疫球蛋白和T细胞受体的机制(由Zielonka S.等mAbs 2015.7(1)：第15-25页概述)。
不同于其他天然免疫球蛋白中的可变结构域，VNAR结合表面来源于四个多样性区域：CDR1、HV2、HV4和CDR3(也参见Stanfield，R.L.等，Science，2004.305(5691)：第1770-1773页；Streltsov，V.A.等，Protein Sci.，2005.14(11)：第2901-2909页；Stanfield，R.L.等，J Mol.Biol.，2007.367(2)：第358-372页)，由间插框架序列以顺序：FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4接合。缺乏天然轻链配偶体和缺乏CDR2的组合使得VNAR成为脊椎动物界中最小的天然存在结合结构域。
IgNAR与见于骆驼科(骆驼、单峰驼和美洲驼，Hamers-Casterman，C.等Nature，1993.363，446-448；Wesolowski，J.等，Med Microbiol Immunol，2009.198(3)：第157-74页)中的仅有重链的免疫球蛋白(HCAb)共有一些附带特征。不同于IgNAR，HCAb明确地源于免疫球蛋白家族，并且与标准免疫球蛋白共有显著序列同源性。重要的是，VNAR的一个关键差别是分子尚未在它的进化中的任何点具有配偶轻链，这不同于经典免疫球蛋白或HCAb。Flajnik M.F.等PLoS Biol 2011.9(8)：e1001120以及Zielonka S.等mAbs 2015.7(1)：第15-25页已评论了VNAR与来自骆驼科动物的免疫球蛋白源性VHH单结合结构域之间的类似性和差异，以及它们的可能的和独特的进化起源。
尽管针对ROR1的抗体已在文献中报道，但人ROR1、小鼠ROR1和大鼠ROR1的细胞外结构域之间以及人ROR1和ROR2家族成员之间的高序列同一性意味着产生高亲和力hROR1特异性结合剂并非不重要。另外，抗体的大尺寸会损害它们穿透进入实体肿瘤中的能力，并且由于位阻因素而致使靶标蛋白质的区域不可及，此对于被观察到寡聚化或受体簇集的细胞表面蛋白质来说可为特别严重的。
因此，本领域中存在对与抗体具有不同功能性或物理性特征或性质的经改进抗ROR1结合蛋白剂以及对开发针对与ROR1表达相关的恶性肿瘤的治疗剂和诊断剂的需要。本发明提供了呈本文所述的ROR1特异性抗原结合分子形式的所述药剂。
已显示当前描述的ROR1特异性抗原结合分子会结合人ROR1与鼠ROR1两者。此外，本发明的ROR1特异性抗原结合分子结合ROR1的去糖基化形式，并且不结合与先前技术中所述的抗ROR1抗体相关的许多线性肽。因此，当前描述的ROR1特异性抗原结合分子被认为会结合ROR1序列中的新型表位。
已证明了本发明的ROR1特异性抗原结合分子与癌细胞系的结合以及内化。这确认了使用所述分子治疗癌症，尤其是表达ROR1的癌症的潜力。
描述了各种形式的ROR1特异性抗原结合分子，包括若干类型的融合蛋白。描述了包括免疫球蛋白Fc区的融合蛋白，以及同二聚体与异二聚体两者。蛋白质与Fc结构域的融合可使蛋白质溶解性和稳定性改进，显著地使血浆半衰期增加，并且使总体治疗有效性改进。
本发明者还已首次创建了缀合于多种部分和有效载荷的VNAR分子。因此，本发明还提供了以化学方式缀合的VNAR。更特别地，提供了呈若干经缀合形式的ROR1特异性抗原分子。
定义
本发明的抗原特异性结合分子包含源于VNAR分子的合成文库，或源于由使软骨鱼免疫获得的文库的氨基酸序列。术语VNAR、IgNAR和NAR也可互换使用。
氨基酸在本文中被表示为单字母代码或三字母代码或两者。
术语“亲和纯化”意指基于分子与化学或结合配偶体的特异性吸引或结合以形成组合或复合物来纯化所述分子，所述特异性吸引或结合允许所述分子在保持结合于配偶体部分或被吸引至配偶体部分的同时与杂质分离。
术语“互补决定区”或CDR(即CDR1和CDR3)是指VNAR结构域的其存在通常涉及于抗原结合中的氨基酸残基。每个VNAR通常具有标识为CDR1和CDR3的两个CDR区。另外，每个VNAR结构域包含来自“高变环”(HV)的也可涉及于抗原结合中的氨基酸。在一些情况下，互补决定区可包括来自CDR区与高变环两者的氨基酸。在其他情况下，抗原结合可仅涉及来自单一CDR或HV的残基。根据普遍接受的针对VNAR分子的命名法，CDR2区不存在。
“框架区”(FW)是除CDR残基以外的那些VNAR残基。每个VNAR通常具有标识为FW1、FW2、FW3a、FW3b和FW4的五个框架区。
VNAR中FW区、CDR区和HV区之间的边界不意图是固定的，因此，将预期在这些区域的长度和组成方面具有一定变化。这将由本领域技术人员所了解，特别是参考已在分析这些区域时所进行的工作。(Anderson等，PLoS ONE(2016)11(8)；Lui等，Mol Immun(2014)59，194-199；Zielonka等，Mar Biotechnol(2015).17，(4)386-392；Fennell等，J Mol Biol(2010)400.155-170；Kovalenko等，J Biol Chem(2013)288.17408-17419；Dooley等，(2006)PNAS 103(6).1846-1851)。尽管在本文中通过提及FW区、CDR区和HV区加以定义，但本发明的分子不限于这些严格定义。因此，符合本领域中理解为VNAR结构域的结构的变化形式明确涵盖在本文中。
“密码子集合”是指用于编码所需变异氨基酸的一组不同核苷酸三联体序列。可例如通过固相合成来合成一组寡核苷酸，包括代表由密码子集合提供的核苷酸三联体的所有可能组合，并且将编码所需氨基酸群组的序列。密码子标号的标准形式是IUB代码的形式，所述形式在本领域中是已知的并且在本文中加以描述。
密码子集合通常由3个斜体大写字母代表，例如NNK、NNS、XYZ、DVK等。因此，“非随机密码子集合”是指编码部分满足，优选地完全满足如本文所述的氨基酸选择准则的所选氨基酸的密码子集合。在某些位置处具有所选核苷酸“简并性”的寡核苷酸的合成在那个领域中是熟知的，例如TRIM方法(Knappek等；J.Mol.Biol.(1999)，296，57-86；Garrard和Henner，Gene(1993)，128，103)。具有某些密码子集合的所述寡核苷酸集合可使用商业核酸合成仪(可从例如Applied Biosystems，Foster City，CA获得)合成，或可商购获得(例如从Life Technologies，Rockville，MD)。具有特定密码子集合的一组合成寡核苷酸将通常包括具有不同序列的多种寡核苷酸，差异由所述密码子集合在总体序列内建立。根据本发明使用的寡核苷酸具有允许与VNAR核酸模板进行杂交的序列，并且当适宜时还可包括限制酶位点。
“细胞”、“细胞系”和“细胞培养物”可互换使用(除非上下文另外指示)，并且所述名称包括细胞或细胞系的所有子代。因此，举例来说，如“转化体”和“经转化细胞”的术语包括原代主题细胞以及由其获得的培养物而不考虑转移的次数。还应了解由于故意或无意突变，所以所有子代在DNA内含物方面可能不精确相同。包括具有与在最初转化细胞中筛选的功能或生物活性相同的功能或生物活性的突变子代。
“控制序列”在涉及表达时意指为在特定宿主生物体中表达可操作地连接的编码序列所必需的DNA序列。适于原核生物的控制序列例如包括启动子、任选地包括操纵子序列、核糖体结合位点等。真核细胞使用控制序列，诸如启动子、多腺苷酸化信号和增强子。
术语“外壳蛋白”意指其至少一部分存在于病毒粒子的表面上的蛋白质。从功能性观点来看，外壳蛋白是在于宿主细胞中进行的病毒组装过程期间与病毒粒子联合，并且保持与所组装病毒联合直至它感染另一宿主细胞的任何蛋白质。
特定测定中对化学实体的“检测限”是那个实体的可高于那个测定的背景水平被检测到的最小浓度。举例来说，在噬菌体ELISA中，对展示特定抗原结合片段的特定噬菌体的“检测限”是所述特定噬菌体产生的ELISA信号高于由不展示所述抗原结合片段的对照噬菌体产生的ELISA信号所处的噬菌体浓度。
“融合蛋白”和“融合多肽”是指具有两个共价连接在一起的部分的多肽，其中所述部分中的每一者是具有不同性质的多肽。性质可为生物性质，诸如体外或体内活性。性质还可为简单化学或物理性质，诸如与靶标抗原结合、催化某一反应等。两个部分可由单一肽键直接连接，或通过含有一个或多个氨基酸残基的肽接头连接。通常，两个部分和接头将彼此在阅读框中。优选地，多肽的两个部分从异源性或不同多肽获得。
术语“融合蛋白”在本文中一般来说意指一个或多个通过以下方式接合在一起的蛋白质：通过包括氢键或盐桥的化学手段；或通过蛋白质合成由肽键；或采用这两种方式。通常，融合蛋白将通过DNA重组技术制备，并且可在本文中称为重组融合蛋白。
“异源性DNA”是引入宿主细胞中的任何DNA。DNA可由多种来源获得，包括基因组DNA、cDNA、合成DNA以及这些DNA的融合或组合。DNA可包括来自与宿主或接受细胞相同的细胞或细胞类型的DNA，或来自不同细胞类型的DNA，例如来自同种异体或异种异体来源的DNA。DNA可任选地包括标记基因或选择基因，例如抗生素抗性基因、温度抗性基因等。
“高度多样性位置”是指位于轻链和重链的可变区中的氨基酸的位置，当比较已知和/或天然存在的抗体或抗原结合片段的氨基酸序列时，所述可变区在所述位置处表现有许多不同氨基酸。高度多样性位置通常在CDR或HV区中。
“同一性”描述两个或更多个多肽序列或两个或更多个多核苷酸序列之间的如通过比较序列所确定的关系。同一性还意指多肽或多核苷酸序列之间的序列相关程度(同源性)，视情况而定，如通过所述序列的串段之间的匹配所确定。尽管存在用以测量两个多肽或两个多核苷酸序列之间的同一性的许多方法，但通常用于确定同一性的方法被编码在计算机程序中。用以确定两个序列之间的同一性的优选计算机程序包括但不限于GCG程序包(Devereux等，Nucleic acids Research，12，387(1984))、BLASTP、BLASTN和FASTA(Atschul等，J.Molec.Biol.(1990)215，403)。
优选地，使用由HGMP(人类基因组图谱计划)提供的BLAST计算机程序(Atschul等，J.Mol.Biol.(1990)215，403-410)的缺省参数，在氨基酸水平上，蛋白质的氨基酸序列与本文公开的氨基酸序列具有至少45％同一性。
更优选地，在核酸或氨基酸水平上，蛋白质序列可与如本文所示的氨基酸序列具有至少45％、46％、47％、48％、49％、50％、55％、60％、65％、66％、67％、68％、69％、70％、75％、80％、85％、90％，并且还更优选地具有95％(还更优选地具有至少96％、97％、98％或99％)同一性。
蛋白质还可包含与本文公开的序列具有至少45％、46％、47％、48％、49％、50％、50％、55％、60％、65％、66％、67％、68％、69％、70％、75％、80％、85％、90％、95％、96％、97％、98％或99％同一性的序列，使用由HGMP提供的BLAST计算机程序的缺省参数对所述同一性进行确定。
“文库”是指多种VNAR或VNAR片段序列(例如本发明的多肽)，或编码这些序列的核酸，所述序列在根据本发明方法引入这些序列中的变异氨基酸的组合方面不同。
“连接”是在两个核酸片段之间形成磷酸二酯键的过程。对于两个片段的连接，片段的末端必须可彼此相容。在一些情况下，在核酸内切酶消化之后，末端将直接可相容。然而，可能必要的是首先使通常在核酸内切酶消化之后产生的交错末端转化成钝性末端以使得它们适合于连接。对于使末端钝化，在15℃下在适合缓冲液中用约10单位的DNA聚合酶I克列诺(Klenow)片段或T4 DNA聚合酶在四种三磷酸脱氧核糖核苷酸存在下处理DNA至少15分钟。DNA接着通过苯酚-氯仿提取和乙醇沉淀或通过二氧化硅纯化来纯化。将待连接在一起的DNA片段以约等摩尔量放置在溶液中。溶液还将含有ATP、连接酶缓冲液和连接酶，诸如在每0.5μg DNA约10单位下的T4 DNA连接酶。如果DNA将被连接至载体中，那么首先通过用一种或多种适当限制核酸内切酶消化来使所述载体线性化。线性化片段接着用细菌碱性磷酸酶或小牛肠磷酸酶处理以防止在连接步骤期间发生自连接。
“突变”是相对于参考核苷酸序列诸如野生型序列，一个或多个核苷酸的缺失、插入或取代。
“天然”或“天然存在的”VNAR是指从非合成来源，例如从离体获得的组织来源，或从板鳃亚纲(Elasmobranchii)的动物的血清鉴定的VNAR。这些VNAR可包括在任何类型的免疫应答(天然的或另外诱导的)中产生的VNAR。天然VNAR包括构成或编码这些抗体的氨基酸序列和核苷酸序列。如本文所用，天然VNAR不同于“合成VNAR”，合成VNAR涉及已例如通过在某一位置处用不同氨基酸进行一个氨基酸或超过一个氨基酸的替换、缺失或添加来从来源或模板序列变化的VNAR序列，所述不同氨基酸提供与来源抗体序列不同的抗体序列。
术语“核酸构建体”通常是指通过克隆获得或通过化学合成产生的任何长度的核酸，所述核酸可为DNA、cDNA或RNA诸如mRNA。DNA可为单链或双链。单链DNA可为编码有义链，或它可为非编码或反义链。对于治疗用途，核酸构建体优选地呈能够在待治疗的受试者中表达的形式。
“可操作地连接”在涉及核酸时意指核酸与另一核酸序列以功能性关系放置。举例来说，如果前序列或分泌前导物的DNA被表达为参与多肽的分泌的前蛋白质，那么所述DNA可操作地连接于所述多肽的DNA；如果启动子或增强子影响编码序列的转录，那么所述启动子或增强子可操作地连接于所述编码序列；或如果核糖体结合位点被定位以便有助于翻译，那么所述核糖体结合位点可操作地连接于编码序列。通常，“可操作地连接”意指所连接的DNA序列是邻接的，并且在分泌前导物的情况下，是邻接的并且处于阅读框中。然而，增强子不必是邻接的。连接通过在适宜限制位点处进行连接来实现。如果所述位点不存在，那么根据常规规范使用合成寡核苷酸衔接物或接头。
术语“蛋白质”一般来说意指多个由肽键接合在一起的氨基酸残基。它可与肽、寡肽、寡聚物或多肽互换使用，并且与肽、寡肽、寡聚物或多肽意思相同，并且包括糖蛋白及其衍生物。术语“蛋白质”还意图包括蛋白质的片段、类似物、变体和衍生物，其中所述片段、类似物、变体或衍生物基本上保留与参考蛋白质相同的生物活性或功能。蛋白质类似物和衍生物的实例包括肽核酸和DARPin(经设计锚蛋白重复蛋白(Designed Ankyrin RepeatProtein))。
视它所源于的原始蛋白质序列的长度而定，蛋白质的片段、类似物、变体或衍生物的长度可为至少25，优选地可为30或40，或多达50或100，或60至120个氨基酸。在一些情况下，90至120、100至110个氨基酸的长度可为适宜的。
蛋白质的片段、衍生物、变体或类似物可为(i)其中氨基酸残基中的一者或多者被保守或非保守氨基酸残基(优选地被保守氨基酸残基)取代，并且所述取代的氨基酸残基可为或可不为由遗传密码编码的氨基酸残基的片段、衍生物、变体或类似物，或(ii)其中氨基酸残基中的一者或多者包括取代基团的片段、衍生物、变体或类似物，或(iii)其中额外氨基酸融合于成熟多肽的片段、衍生物、变体或类似物，所述额外氨基酸诸如是用于纯化多肽的前导物或辅助序列。根据本文教义，所述片段、衍生物、变体和类似物被视为在本领域技术人员的见识范围内。
“寡核苷酸”是通过已知方法(诸如磷酸三酯、亚磷酸酯或亚磷酰胺化学，使用固相技术)以化学方式合成的长度较短的单链或双链多脱氧核苷酸。其他方法包括在已知基因的整个核酸序列，或互补于编码链的核酸的序列可用的条件下使用的聚合酶链式反应(PCR)。或者，如果靶标氨基酸序列是已知的，那么可使用每个氨基酸残基的已知和优选编码残基推断潜在核酸序列。寡核苷酸可在聚丙烯酰胺凝胶或分子尺寸分级柱上或通过沉淀来纯化。当DNA与非核酸杂质(其可为极性的、非极性的、离子性的等)分离时，DNA是“纯化的”。
如本文所用的“来源”或“模板”VNAR是指其抗原结合序列充当进行根据本文所述的准则的多样化所基于的模板序列的VNAR或VNAR抗原结合片段。在VNAR内，抗原结合序列通常优选地包括至少一个CDR，优选地包括框架区。
“转录调控元件”将含有以下组分中的一者或多者：增强子元件、启动子、操纵子序列、阻遏基因和转录终止序列。
“转化”意指细胞摄取DNA，并且变为“转化体”所凭借的过程。DNA摄取可为永久的或短暂的。“转化体”是已摄取并维持DNA的细胞，如由与所述DNA相关的表型(例如由所述DNA编码的蛋白质所赋予的抗生素抗性)的表达所证实。
起始或参考多肽(例如来源VNAR或其CDR)的“变体”或“突变体”，诸如融合蛋白(多肽)或异源性多肽(噬菌体异源性)，是(1)具有与所述起始或参考多肽的氨基酸序列不同的氨基酸序列，以及(2)通过天然或人工诱变来由所述起始或参考多肽获得的多肽。所述变体包括例如目标多肽的氨基酸序列内的残基缺失和/或插入和/或取代。举例来说，相对于来源VNAR或抗原结合片段，使用包含编码具有变异氨基酸(相对于在来源VNAR或抗原结合片段中的相应位置处所见的氨基酸)的序列的非随机密码子集合的寡核苷酸产生的本发明的融合多肽将是变异多肽。因此，变异CDR是指相对于起始或参考多肽序列(诸如来源VNAR或抗原结合片段的序列)，包含变异序列的CDR。在这个情形下，变异氨基酸是指与在起始或参考多肽序列(诸如来源VNAR或抗原结合片段的序列)中的相应位置处的氨基酸不同的氨基酸。可对缺失、插入和取代进行任何组合以获得最终变异或突变构建体，前提是最终构建体具有所需功能特征。氨基酸变化还可改变多肽的翻译后过程，诸如改变糖基化位点的数目或位置。
“野生型”或“参考”序列或“野生型”或“参考”蛋白质/多肽诸如外壳蛋白或来源VNAR的CDR的序列可为通过引入突变从其获得变异多肽的参考序列。一般来说，给定蛋白质的“野生型”序列是在自然界中最常见的序列。类似地，“野生型”基因序列是那个基因的在自然界中最通常得见的序列。突变可通过天然过程或通过人为手段引入“野生型”基因(以及因此它编码的蛋白质)中。所述过程的产物是原始“野生型”蛋白质或基因的“变异”或“突变”形式。
如本文所用的术语“嵌合抗原受体(CAR)”可指例如人工T细胞受体、嵌合T细胞受体或嵌合免疫受体，并且涵盖将人工特异性移植于特定免疫效应细胞上的经工程改造受体。CAR可用于将抗原特异性结合蛋白诸如单克隆抗体或VNAR的特异性赋予在T细胞上，由此允许产生许多特异性T细胞，例如用于过继性细胞疗法中。CAR可将细胞的特异性定向至例如肿瘤相关抗原。CAR可包含细胞内活化结构域、跨膜结构域、以及包含肿瘤相关抗原结合区的细胞外结构域。在特定方面，CAR包括源于单克隆抗体的单链可变片段(scFv)融合于CD3-ζ跨膜和内部结构域的融合物。在其他特定方面，CAR包括本文所述的VNAR结构域与CD3-ζ跨膜和内部结构域的融合物。其他CAR设计的特异性可源于受体的配体(例如肽)或源于样式识别受体诸如树突细胞相关C型凝集素(Dectin)。在特定实施方案中，可通过使用对B谱系分子CD 19具有特异性的CAR使T细胞的特异性重定向来靶向恶性B细胞。在某些情况下，可改变抗原识别结构域的间隔以降低活化诱导的细胞死亡。在某些情况下，CAR包含用于进行额外共刺激性信号传导的结构域，诸如CD3-ζ、FcR、CD27、CD28、CD 137、DAP 10和/或OX40。在一些情况下，分子可与CAR共表达，所述分子包括共刺激性分子、用于成像(例如用于正电子发射断层摄影术)的报告基因、在添加前药后条件性消除T细胞的基因产物、归巢受体、趋化因子、趋化因子受体、细胞因子和细胞因子受体。
如本文所用的术语“缀合”可指以化学方式连接两个或更多个化学部分的任何方法。通常，缀合将通过共价键来进行。在本发明的情形下，化学部分中的至少一者将是多肽，并且在一些情况下，缀合将涉及两个或更多个多肽，其中一者或多者可通过重组DNA技术产生。许多用于缀合多肽的系统在本领域中是已知的。举例来说，缀合可使用N-羟基-丁二酰亚胺通过存在于多肽分子中的赖氨酸残基实现，或使用顺丁烯二酰亚胺基苯甲酰基磺基丁二酰亚胺酯通过存在于多肽分子中的半胱氨酸残基实现。在一些实施方案中，缀合通过短效可降解键联发生，所述键联包括但不限于生理可裂解键联，包括酯、碳酸酯、氨基甲酸酯、硫酸酯、磷酸酯、酰基氧基烷基醚、缩醛和缩酮、腙、肟和二硫键联。在一些实施方案中，并入可由细胞内或细胞外酶诸如组织蛋白酶家族成员裂解，可在还原性条件或酸性pH下裂解的接头以使得所缀合部分能够从它与其缀合的多肽或蛋白质释放。
一特别优选缀合方法是使用基于内含肽的技术(US2006247417)。简要来说，将目标蛋白质表达为经工程改造内含肽结构域的N末端融合物(Muir 2006 Nature 442，517-518)。在蛋白质-内含肽结合处进行的后续N至S酰基迁移产生硫酯连接的中间体，所述中间体可用双氨基氧基剂或氨基硫醇化学裂解以分别产生所需蛋白质C末端氨基氧基或硫醇衍生物(图11)。这些C末端氨基氧基和硫醇衍生物可分别与醛/酮和顺丁烯二酰亚胺官能化部分以化学选择性方式反应以产生位点特异性C末端经修饰蛋白质(图25-图27)。
在另一优选缀合方法中，VNAR被直接表达来具有额外半胱氨酸，所述半胱氨酸在VNAR的C末端区域处或附近，或并入在短C末端标签序列内，从而使得能够与硫醇反应性有效载荷诸如顺丁烯二酰亚胺官能化部分缀合。
如本文提及的缀合还意图涵盖使用可赋予许多有用性质的接头部分。接头部分包括但不限于肽序列诸如多甘氨酸、gly-ser、val-cit或val-ala。在某些情况下，可选择接头部分以使它可在某些条件下例如通过使用酶、亲核/碱性试剂、还原剂、光照射、亲电子/酸性试剂、有机金属和金属试剂、或氧化试剂而裂解，或可特定地选择接头以抵抗在所述条件下的裂解。
多肽可缀合于多种功能性部分以实现许多目标。功能性部分的实例包括但不限于用以降低免疫原性和抗原性或用以改进溶解性的聚合物诸如聚乙二醇。其他非限制性实例包括使多肽缀合于治疗剂或细胞毒性剂。
术语“可检测标记”在本文中用于指明实体可通过分光、光化学、生物化学、免疫化学、电学、光学、化学或其他手段显现或另外检测。可选择可检测标记以使它产生可被测量，并且其强度与所结合实体的量成比例的信号。广泛多种用于标记和/或检测蛋白质和肽的系统在本领域中是已知的。标记可为直接可检测的(即它不需要任何其他反应或操作来达成可检测，例如荧光团是直接可检测的)，或它可为间接可检测的(即它通过与可检测的另一实体的反应或结合而可检测，例如半抗原在与包含报告体诸如荧光团的适当抗体反应之后可通过免疫染色检测)。适合可检测剂包括但不限于放射性核素、荧光团、化学发光剂、微粒、酶、比色标记、磁性标记、半抗原、分子信标和适体信标。
本文涵盖在体外或在患者中杀伤表达ROR1的细胞或抑制所述细胞的生长的方法。一般来说，如本文在细胞的情形下所用的术语“杀伤”意指导致细胞死亡。这可通过许多机制诸如坏死或其他细胞损伤或诱导凋亡来实现。当在本文中使用时，短语“抑制生长”或“抑制增殖”意图涵盖阻止细胞发育，更特别地涵盖阻止细胞分裂。
通过参考以下实施例，将进一步理解本发明。
实施例
实施例1-特异性抗ROR1 VNAR序列的产生
来自合成文库的特异性VNAR序列
采用两个选择活动来筛选VNAR合成结构域文库(WO2014173959)中的特异性ROR1结合剂。第一活动利用人ROR1抗原，并且第二活动使用小鼠ROR1抗原。两种重组ROR1蛋白均根据制造商说明书(Thermo Scientific磺基-NHS-LC-生物素方案，目录号21327)加以生物素化以辅助抗原递呈和选择过程。在使用固定在链霉亲和素包被珠粒上的这些生物素化ROR1抗原进行3轮选择之后，分离了VNAR结构域。在选择后以及在筛选单个克隆之后，发现70％的展示VNAR结构域的单克隆噬菌体(针对人ROR1蛋白加以选择)对人ROR1和小鼠ROR1而非密切相关的ROR2蛋白具有特异性(来自这个选择的先导克隆被称为B1-40％和E7-30％，图1))。类似地，45％的用小鼠ROR1选择的单克隆噬菌体对人ROR1和小鼠ROR1而非ROR2具有特异性(来自这个选择的先导克隆被称为P3A1，图1)。从小鼠ROR1筛选获得的另一特异性克隆是CPF7，其作为出自200个筛选克隆中的单一序列存在。
从用人ROR1进行筛选获得的序列是B1和E7，并且从用小鼠ROR1进行筛选获得的序列是P3A1和CPF7。(图2)
来自免疫化文库的特异性VNAR序列
文库构建。
三条白斑角鲨用重组人ROR1蛋白的细胞外结构域加以免疫，并且通过分析免疫后血清来监测靶标特异性IgNAR免疫应答，如MüllerM.R.等Generation and Isolation ofTarget-Specific Single-Domain Antibodies from Shark Immune Repertoires，HumanaPress 2012中所述。从动物获取免疫前和免疫后血清样品，并且在ELISA中测试抗原结合。在所有动物中，在16周之后，观察到对人ROR1具有特异性的IgNAR效价增加(图3)。还观察到免疫后血清对小鼠ROR1的特异性，从而指示在经免疫动物中存在物种交叉反应性ROR1特异性IgNAR结合剂(图3)。
使用特异性PCR引物从角鲨血液扩增VNAR谱系(IgNAR的结合位点)，并且克隆至含有噬菌体M13基因的同框外壳蛋白pIII的噬菌体展示载体中，如Müller M.R.等Generationand Isolation of Target-Specific Single-Domain Antibodies from Shark ImmuneRepertoires，Humana Press 2012中所述。计算文库大小，并且显示于表1中：
表1：
鱼编号 文库 大小(独特转化体)
154 ELSI 5 6x107
156 ELSI 6 1.7x107
161 ELSI 7 2x107
筛选免疫化文库中的抗原特异性VNAR序列。
重组小鼠ROR1蛋白用于筛选免疫化文库(ELSI 5-7)。遵循与用于筛选合成文库的方案类似的方案，在使用固定在链霉亲和素包被珠粒上的生物素化ROR1抗原进行3轮选择之后，分离了VNAR结构域。在选择过程之后，45％的展示VNAR结构域的单克隆噬菌体(根据来自3个文库的组合输出)对人ROR1和小鼠ROR1具有特异性。发现三分之一的ROR1特异性VNAR具有序列D3(图4和图5)，并且其余三分之二具有序列E9(图4和图5)。
从用小鼠ROR1进行筛选获得的序列是E9和D3。(图5)
所有先导抗ROR1 VNAR蛋白都在TG1大肠杆菌或HEK293哺乳动物细胞中表达，并且分别从周质部分或细胞上清液加以IMAC纯化。
方法
血清ELISA中的IgNAR滴定
使用以下方案进行ELISA：
1.用100μl/孔的含1mg/ml人ROR1-Fc或小鼠ROR1-Fc的PBS或PBS包被ELISA板。在4℃下孵育过夜。
2.用PBST将板洗涤3次。
3.通过添加200μl/孔2％(w/v)M-PBS来对板进行封闭，并且在37℃下孵育1小时。
4.用PBST将板洗涤3次。
5.在PBS中从至少1∶10直至1∶1000连续稀释角鲨血清，并且添加100μl/孔。在室温下孵育1小时。
6.用PBST将板洗涤3次。
7.添加100μl/孔的以杂交瘤组织培养上清液形式于PBST中稀释的初级抗体(小鼠单克隆抗IgNAR抗体GA8)。
8.用PBST将板洗涤3次。
9.添加100μl/孔的于PBS中稀释的适合二级抗小鼠IgG HRP缀合物。孵育1小时。
10.用PBST将板洗涤2次，随后用PBS将板洗涤2次。
11.将100μl/孔的TMB底物添加至板中，并且孵育直至出现信号/发生饱和。通过添加100μl/孔的0.18M H2SO4来终止显色。
12.用微量滴定板读取器在450nm下进行读取。
文库筛选
1.为挽救文库噬菌体以进行选择，使来自文库甘油储备物的培养物在37℃和250rpm下，在2xTY、2％葡萄糖、100μg/ml氨苄青霉素中生长至OD600 0.5。
2.将细胞用109 M13K07辅助噬菌体(NEB)超感染，接着在25℃和250rpm下在2xTY、100μg/ml氨苄青霉素、50μg/ml卡那霉素中孵育过夜。
3.从细菌培养物对噬菌体进行两次PEG沉淀(20％PEG/2.5M NaCl)，并且将所得噬菌体集结块再混悬于1ml PBS中。
4.在室温下，在20rpm下旋转下，将200μl的用2％(w/v)MPBS预封闭的DynabeadsM-280链霉亲和素(Invitrogen#11205D)用400nM生物素化小鼠ROR1包被1小时。
5.文库噬菌体通过在室温下在旋转下与Dynabeads一起孵育1小时来去选择，接着添加至抗原包被的珠粒中。
6.用PBST洗涤珠粒5-10次，并且用PBS洗涤珠粒5-10次，通过在400μl 100mM TEA中旋转8分钟来洗脱，并且通过添加200μl 1M Tris-HCl(pH7.5)来中和。
7.将大肠杆菌TG1细胞(10ml)在37℃下用300μl的所洗脱噬菌体感染30分钟，并且在37℃下在含有2％(w/v)葡萄糖和100μg/ml氨苄青霉素的TYE琼脂板上生长过夜。
8.再进行三轮选择，并且通过单克隆噬菌体和周质提取物ELISA针对人ROR1或小鼠ROR1筛选具有抗原特异性结合的输出物。使用HRP缀合的抗M13抗体(GE Healthcare，27942101)检测噬菌体结合剂，并且使用HRP缀合的抗c-Myc抗体(Roche，118 141 50 001)检测周质蛋白。
VNAR在大肠杆菌中的表达
1.在具有磷酸盐、1％葡萄糖、100ug/ml氨苄青霉素的TB培养基中1∶50稀释过夜培养物，并且在37℃下在剧烈振荡(250rpm)下孵育一整天。
2.通过在20℃下在3,000x g下离心20分钟来集结细胞。
3.将细胞再混悬于相同体积的具有磷酸盐、100ug/ml氨苄青霉素的TB培养基(无葡萄糖)中。
4.添加IPTG直至1mM IPTG的最终浓度，并且在16℃下在250rpm下振荡下孵育过夜(16小时)。
5.通过在6,000x g下离心30分钟来收集细胞(集结块可在此时冷冻在-20℃下)。
6.将集结块再混悬于10％培养体积的冰冷TES中，并且在冰上温和振荡15分钟。
7.添加相等体积的冰冷5mM MgSO4(以达成MgSO4的2.5mM最终浓度)，并且再继续在冰上温和振荡15分钟。
8.通过在4℃下在15,000x g下离心30分钟来集结混悬液，并且小心地将含有经释放周质蛋白的上清液倾析至洁净falcon中。
9.将10x PBS(pH 7.4)[1xPBS的最终浓度]添加至周质制备提取物中，随后进行IMAC孵育。
VNAR在HEK293中的表达
于水(经无菌过滤)中的10μg DNA用于10ml培养物。
在50ml生物反应管中使用10ml细胞(约106/ml)(于新鲜培养基中的处于指数生长中的细胞)
将OptiMEM培养基添加至DNA中以达到500μl的总体积。
将25μl PEI(在水中配制的1mg/ml储备物)添加至单独500μl OptiMEM培养基中。
在室温下孵育DNA和PEI直至15分钟。
向每500μl的含DNA的培养基中混合500μl的含PEI的培养基。
在室温下孵育20-30分钟，从而有助于复合物形成。
将1ml混合物添加至细胞中，并且在37℃、5％CO2、140rpm振荡下孵育。
次日，通过将250μl 20％(w/v)胰蛋白胨添加至10ml细胞中以获得0.5％胰蛋白胨的最终浓度来对细胞进行喂养
持续3-5天使细胞进行表达。
将细胞进行旋转，并且评估上清液中的分泌蛋白以确定生产能力。
将10x PBS(pH 7.4)[1xPBS的最终浓度]添加至周质制备提取物中，随后进行IMAC孵育。
这个方案可根据需要按比例扩大或缩小以进行蛋白质生产。
蛋白质表达(按比例扩大)
ROR1结合VNAR蛋白以许多不同形式在若干不同表达系统中良好表达。添加包括His和His6Myc的标准C末端标签以辅助蛋白质纯化、处理和蛋白质分析不影响ROR1 VNAR与靶标ROR1的结合(表2)。
表2：关于具有不同C末端标签的VNAR与人ROR1和ROR2的结合的SPR数据
Figure BDA0002615675830000681
此外，VNARC末端标签不影响VNAR结构，如通过圆二色性所测量(图6-VNAR的CD光谱)(Glasgow University，UK)。
VNAR还在遗传融合于小鼠和人IgG Fc序列的情况下以及以与经工程改造内含肽的N末端融合物形式表达，从而使得能够位点特异性缀合于标记和药物。使用的表达系统包括大肠杆菌(周质和细胞质表达)、HEK 293和CHO(Evitria Fc融合蛋白)。
实施例2-VNAR重定形式
同二聚体
通过使用标准的基于GlySer的接头进行遗传融合，ROR1结合VNAR被成功地重定形式成为同二聚体(图7B)。根据SPR和ELISA，显示同二聚体对重组hROR1具有增加的亲和力，并且根据流式细胞计量术，显示同二聚体与ROR1阳性癌细胞系上的细胞表面ROR1的结合增加(图9)。流式细胞计量术实验更详细地描述于实施例4中。
此外，通过化学缀合成功地产生了ROR1结合VNAR同二聚体。将VNAR表达为内含肽融合蛋白，并且用半胱胺裂解以产生C末端硫醇衍生物，所述硫醇衍生物接着通过C末端分子间二硫醚形成来自缔合成同二聚体(图7C)。根据ELISA，这些二硫连接的同二聚体显示对重组hROR1的结合亲和力增加(图8)。内含肽融合蛋白的产生更详细地在实施例8中讨论。
异二聚体
ROR1结合VNAR异二聚体通过用标准GlySer接头或者用PGVQPSPGGGGS(SEQ ID NO：63)或PGVQPAPGGGGS(SEQ ID NO：64)接头进行遗传融合来产生(图7D)，并且显示与重组ROR1和ROR1阳性细胞的高亲和力特异性结合。异二聚VNAR蛋白还可通过化学缀合产生。
结合表征实验的结果表列于表3和表4(参见实施例3)以及表18、19、20(参见实施例10)中。
VNAR Fc融合蛋白
蛋白质与Fc结构域的融合可使蛋白质溶解性和稳定性改进，显著地使血浆半衰期增加，并且使总体治疗有效性改进。通过标准GlySer接头使ROR1结合VNAR遗传融合于小鼠IgG2a Fc(mFc)的N末端以及人IgG1(hFc)的N末端与C末端两者(图7E、图7F、图7G)。
Fc序列的实例
小鼠IgG2a Fc(mFc)
Figure BDA0002615675830000691
Figure BDA0002615675830000701
人IgG1 Fc(hFc)
Figure BDA0002615675830000702
VNAR Fc融合蛋白在CHO K1细胞中表达为分泌蛋白，并且使用MabSelectTM SuReTM(Evitria，Switzerland)从培养基纯化。纯化蛋白通过SEC(AdvanceBio，Agilent)、SDSPAGE和质谱测定法分析以确认序列和蛋白质完整性。根据SPR，所得VNAR Fc融合蛋白结合重组人ROR1(表6)，以及以高亲和力结合ROR1阳性细胞(图15)，并且显示所得VNAR Fc融合蛋白会内化至ROR1阳性细胞中。还使ROR1结合VNAR遗传融合于在hIgG1 Fc序列中例如在位置S252C或S473C(Kabat编号)处并有经工程改造半胱氨酸取代的经工程改造hIgG1 Fc融合蛋白以使得能够进行位点特异性标记(图10)。
用于表达VNAR内含肽融合蛋白的典型方法
对于以内含肽融合物形式表达，使编码VNAR的DNA关于大肠杆菌表达加以优化(GeneArt，Thermo)，并且克隆至pTXB1载体(NEB)及其衍生物的NdeI/SapI位点中。这导致编码目标VNAR蛋白的基因融合于经工程改造内含肽结构域，所述内含肽结构域转而融合于几丁质结合结构域(CBD)以使得能够在几丁质管柱上纯化。pTXB1载体衍生物编码呈融合蛋白形式的替代性内含肽。
使经转化大肠杆菌细胞在1L摇瓶中生长直至OD600＝约0.6，4℃冷激2小时，接着用0.5mM IPTG在18℃下过夜诱导蛋白质表达。通过在溶解缓冲液(50mM磷酸钠(pH 7.4)、0.5M NaCl、15％甘油、0.5mM EDTA、0.1％Sarkosyl、1mM AEBSF)中进行声波处理来使细胞溶解，并且离心以移除细胞碎片。通过在几丁质珠粒(NEB，S6651)上固定来从澄清细胞溶解产物纯化VNAR内含肽融合蛋白。依次用溶解缓冲液和裂解缓冲液(50mM磷酸钠(pH 6.9)、200mM NaCl)充分洗涤珠粒，并且通过在400mM二氧基胺或O，O’-1，3-丙二基双羟胺或100mM半胱氨酸或半胱胺中进行过夜化学裂解来使VNAR从珠粒释放以产生VNAR的相应C末端氨基氧基、C末端半胱氨酸或C末端硫醇衍生物(图11)。
经裂解VNAR上清液接着通过SEC(Superdex75 26/60 GE healthcare)和/或IMAC(HisTrap HP，GE Healthcare)来进一步纯化。使用根据氨基酸序列预测的理论消光系数，由在280nm下的吸光度确定浓度。所有蛋白质都通过还原性和非还原性SDS PAGE分析和质谱测定法来表征。所需二硫键的形成通过质谱测定方法确认。
实施例3-抗ROR1 VNAR表征-
根据SPR和ELISA的与ROR1和ROR2的结合
ROR1 VNAR结合剂的物种交叉反应性
连同阳性对照抗体2A2和抗ROR2特异性抗体对照一起分析可溶性VNAR蛋白克隆(B1、P3A1和D3)与人ROR1、小鼠ROR1和大鼠ROR1的物种交叉反应性。2A2是一种抗人ROR1特异性小鼠单克隆抗体(BioLegend目录号2357802)，并且抗ROR2抗体是一种来自R&DSystems(目录号MAB2064)的商业单克隆小鼠抗体。
观察到VNAR B1是一种针对小鼠ROR1与人ROR1两者的极强结合剂。所有VNAR都与源于人、小鼠和大鼠来源的ROR1具有物种交叉反应性(表3和表4)。VNAR克隆都不与人ROR2交叉反应(表3)。
测定与人ROR1、人ROR2、小鼠ROR1或大鼠ROR1的结合动力学
使用Pioneer表面等离子体共振(SPR)仪器(SensiQ/Pall ForteBio)测定结合动力学。使用胺偶联，将ROR1-hFc或ROR2-hFc融合蛋白(细胞外结构域)于pH 5乙酸钠缓冲液中固定至COOH2芯片。在各种浓度下测试VNAR和VNAR-Fc分子，并且使用QDat软件(SensiQ/Pall ForteBio)确定Ka(M-1s-1)、Kd(s-1)和KD(nM)值。ROR1 2A2 mAb(Biolegend)和ROR2mAb(R&D Systems)作为与ROR1和ROR2结合的阳性/阴性对照加以包括。2V是一种源于原初VNAR文库的对照VNAR序列，因此代表这个蛋白质类别，但不具有已知靶标。
表3：关于VNAR分子与人ROR1(hROR1)和人ROR2(hROR2)的结合的SPR数据。表达了C末端His6或His6Myc标签化VNAR。
Figure BDA0002615675830000721
表4-关于与小鼠ROR1(mROR1)和大鼠ROR1(rROR1)的结合的SPR数据
Figure BDA0002615675830000731
已开发了以单体和多聚形式(同二聚形式与异二聚形式两者)以高亲和力结合人ROR1 ECD，显示不与密切相关的家族成员人ROR2结合，并且以高亲和力与ROR1的小鼠和大鼠直系同源物交叉反应的VNAR蛋白。以二聚体形式将P3A1和D3蛋白重定形式使对人ROR1的结合亲和力显著增加，其中观察到解离速率常数显著降低。
还通过ELISA评估以化学方式缀合的B1同二聚体与hROR1的结合。为产生这个分子，通过用半胱胺化学裂解相应B1-内含肽融合蛋白前体产生了具有独特C末端硫醇官能基的B1衍生物。分子间二硫键形成用于共价连接两个蛋白质的C末端以产生非天然但具有确定拓扑结构的同二聚体(B1-S-S-B1，图7C)。借助于ELISA，将B1-S-S-B1与hROR1的结合与B1单体进行比较。
简要来说，ELISA方法如下。将孔用100ng抗原包被，并且在室温下在覆盖的情况下孵育2小时。将板每孔用400ul PBST(PBS+0.05％吐温20(Tween 20)(v/v))洗涤3次，接着用含4％脱脂奶粉(w/v)的PBST在37℃下封闭1小时。如前所述将板洗涤，外加在单独PBS中进行额外洗涤。将结合蛋白在4％奶PBST中稀释，并且在4℃下孵育过夜。用PBST将板洗涤3次，用PBS将板洗涤3次，并且使用于4％奶PBST中的适当二级检测抗体在室温下持续1小时检测结合。使用的二级抗体包括：
抗c-Myc抗体，HRP(Invitrogen#R951-25)
兔抗人IgG H和L抗体，HRP(Abcam#ab6759)
兔抗小鼠IgG H和L抗体，HRP(Abcam#ab97046)
小鼠抗多His抗体，HRP(Sigma#A7058)
用PBST将板洗涤3次。添加100μLTMB底物(Thermo#34029)，并且使反应在室温下进行10分钟。添加100μL 2M H2SO4以淬灭反应。将板短暂离心，随后在CLARIOstar板读取器(BMG Labtech)上在450nm下读取吸光度。尽管B1单体和C末端硫醇衍生物强烈结合人ROR1，但观察到以化学方式连接的B1-S-S-B1二聚体在人ROR1结合方面的增加(图8)。
实施例4-抗ROR1 VNAR表征-根据流式细胞计量术的细胞结合和内化
细胞表面结合
通过与0.1％EDTA/PBS溶液一起在37℃下孵育约10分钟或直至细胞易于脱离，使贴壁人癌细胞从组织培养烧瓶脱离。在15ml管中将细胞再混悬于5ml冰冷PBS/2％FCS中，并且在4℃下在1500rpm下离心5分钟。移除上清液，并且将细胞集结块再混悬于1-2mlPBS/2％FCS中。使用Z1 Coulter粒子计数器(Beckman Coulter)进行细胞计数，并且每个测试样品等分5x 10^5个细胞。使细胞与100μl VNAR(His6Myc标签化)、VNAR-Fc分子或ROR1 mAb和IgG对照一起在冰上孵育1小时。过量VNAR、VNAR-Fc或mAb通过添加5ml冰冷PBS/2％FCS移除，随后在4℃下在1500rpm下离心5分钟。移除上清液，并且通过将细胞集结块再混悬于1ml冰冷PBS/2％FCS中，以及再添加4ml冰冷PBS/2％FCS来进行第二洗涤。样品再次在4℃下在1500rpm下离心5分钟。移除上清液，并且通过将管在薄纸上吸干来移除过量液体。适当二级抗体用于检测结合的VNAR(His6Myc)、VNAR-hFc、VNAR-mFc或ROR1 mAb(分别使用PE-抗Myc标签抗体(CST)、PE-抗人抗体(JIR labs/Stratech)和PE-抗小鼠抗体(JIR/Stratech))。使细胞与所选二级抗体一起在冰上孵育30分钟。如早先所述洗涤细胞以移除过量抗体。将细胞集结块再混悬于0.5ml冰冷PBS/2％FCS中，并且在黑暗中留置在冰上，随后在FACSCalibur(BD Biosciences)或Attune NxT(ThermoFisher)流式细胞仪上分析。
VNAR与一组癌细胞系的结合
图9显示关于抗ROR1 VNAR与ROR1高A549肺腺癌细胞的结合的代表性流式细胞计量术直方图。
图13显示根据流式细胞计量术，在固定浓度的蛋白质下，不同VNAR与ROR1高A549肺腺癌细胞和ROR1低肺癌细胞系A427的结合。
表5显示关于VNAR蛋白与多种ROR1高和ROR1低癌细胞系的结合的流式细胞计量术数据的概述。
表5：在人癌细胞系的情况下，VNAR细胞表面结合的相对分级，通过流式细胞计量术所确定。‘+’的数目对应于结合强度。‘-’指示无结合。‘/’未在这个细胞系的情况下测定。
Figure BDA0002615675830000751
Figure BDA0002615675830000761
相较于其中对于测试的大多数ROR1结合VNAR，观察到少许染色乃至无染色的ROR1低癌细胞系，观察到VNAR与ROR1表达性癌细胞系的稳健结合。
P3A1的细胞表面染色-P3A1不与B1或D3-D3蛋白一样强力，此可能反映在这些结合剂的表位方面的差异，以及在细胞情形下，ROR1的细胞外结构域的一些区域相比于其他区域潜在地更加可及以达成结合。
在37℃相对于4℃下孵育之后的细胞表面染色。
简要来说，使5x10^5个MDA-MB-231细胞与VNAR、VNAR-Fc、ROR1 2A2 mAb或IgG1对照一起在冰上孵育1小时。通过添加5ml冰冷PBS/2％FCS，随后在4℃下在1500rpm下离心5分钟来将细胞洗涤两次。在最终离心步骤之后，移除过量上清液，并且将管在薄纸上吸干。将每个细胞集结块再混悬于200μl PBS/2％FCS中，并且在冰上或在37℃下放置2小时。使用PE缀合的抗Myc标签抗体(CST)、PE缀合的抗人抗体(JIR/Stratech)或PE缀合的抗小鼠抗体(JIR/Stratech)检测结合的VNAR(His6Myc标签化)、VNAR-hFc、VNAR-mFc或ROR1 2A2 mAb。相对于在冰上孵育的样品，在37℃下的信号丧失指示ROR1内化。
观察到相对于4℃，在37℃下孵育之后，呈单体形式以及呈包含相同或不同VNAR结合模块的多聚体形式的抗ROR1 VNAR构建体的细胞表面结合均降低(图14)，此与蛋白质的通过ROR1达成的结合和内化一致。
实施例5-对抗ROR1 VNAR-Fc融合蛋白的表征-
根据SPR的与ROR1和ROR2的结合以及细胞表面结合和内化
ROR1结合VNAR在通过标准GlySer接头融合于小鼠IgG2a Fc(mFc)的N末端以及人IgG1(hFc)的N末端和C末端的情况下表达。还产生了人IgG1 Fc的融合物，借此，Fc区中的Ser252(Kabat编号)被Cys替换(图10)。
根据SPR的与ROR1和ROR2的结合
使用以上概述的程序，通过SPR来测定VNAR-Fc融合物与人ROR1、小鼠ROR1和大鼠ROR1以及人ROR2的结合。
表6-关于VNAR-Fc融合物与人ROR1和人ROR2的结合的SPR数据
Figure BDA0002615675830000771
如表6中所示，抗ROR1 VNAR-Fc蛋白以高亲和力结合人ROR1，其中未观察到与人ROR2的结合。还观察到与小鼠和大鼠ROR1 ECD的强烈结合。相对于相应VNAR单体，作为VNAR-Fc融合物，被观察到关于ROR1结合的KD表观值显著降低。这与在SPR实验中这些VNAR-Fc融合物以二价方式结合ROR1芯片表面一致。N末端VNARFc融合物与C末端VNAR Fc融合物两者均以高亲和力结合人ROR1，但不结合人ROR2。
VNAR与癌细胞系的结合
使用先前概述的方法，通过流式细胞计量术测量VNAR-Fc融合物与一组癌细胞系的表面的结合。图15显示根据流式细胞计量术，在固定浓度的蛋白质下，不同VNAR-Fc融合物与ROR1高A549肺腺癌细胞和ROR1低肺癌细胞系A427的结合。
表7概述关于VNAR-Fc蛋白与多种ROR1高癌细胞系的结合数据。
表7：在ROR1高人癌细胞系的情况下，VNAR hFc分子细胞表面结合的相对分级。‘+’的数目指示结合的强度。‘-’指示无结合。‘/’指示结合尚未被测定。使用PE-抗人抗体(Jackson Immune Research/Stratech)和ThermoFisher Attune NxT流式细胞仪检测hFc分子。
Figure BDA0002615675830000781
相较于其中对于测试的大多数ROR1结合VNAR，检测到少许染色乃至无染色的ROR1低癌细胞系，观察到VNAR与ROR1表达性癌细胞系的稳健结合。
平均细胞表面染色的差异可指示当蛋白质在细胞表面上表达时，ROR1的不同区域相比于其他区域可能更加可及。对于靶向癌细胞上ROR1的较不可及区域，与将在空间上受阻的大型抗体相对比，将有利的是使用小型蛋白质结合剂诸如VNAR。
在37℃相对于4℃下孵育之后的细胞表面染色。
使用先前所述的方法，通过流式细胞计量术来测定在37℃或4℃下孵育之后，VNAR-Fc融合物与MDA-MB-231细胞的结合。对于测试的B1-hFc、P3A1-hFc、D3-hFc和D3D3-hFc蛋白，相对于4℃，在37℃下孵育之后，存在细胞表面染色的丧失(图16)，这与这些VNAR-hFc融合蛋白的结合和内化一致。
在37℃相对于4℃下孵育之后根据免疫荧光的内化。
人IgG1 Fc和小鼠IgG2a Fc融合蛋白的细胞定位可使用靶向这些结构域的经荧光标记二级抗体，通过免疫荧光来检测。免疫荧光方法用于检测VNAR-Fc的通过癌细胞上的ROR1达成的内化。
将黑色透明底部96孔板(Greiner)用100μg/ml胶原I(Sigma)包被以辅助细胞附着。将细胞于完全生长培养基(Gibco)中接种至经包被96孔板中，并且在5％CO2、37℃下孵育24小时。在次日，移除培养基并用无血清培养基(Gibco)替换，并且留置过夜。在次日早晨，移除培养基，并且用各种浓度的VNAR-Fc、ROR1 2A2 mAb或IgG1阴性对照(两者均来自BioLegend)处理细胞。将板在冰上孵育1小时。移除处理剂，并且用每孔100μl的PBS/2％FCS替换。将一个板保持在冰上，并且将另一板在37℃、5％CO2下放置2小时。在这个2小时孵育之后，移除PBS/2％FCS溶液，并且在冰上用含4％多聚甲醛的冰冷PBS固定细胞20分钟。移除PFA溶液，并且用在PBS/2％FCS中配制的0.05％皂素(Sigma)替换，在室温下持续15分钟。这个步骤使细胞膜具有可渗透性。使用用以检测VNAR-hFc融合蛋白的AF488-抗人抗体(1∶250；ThermoFisher)以及用以检测VNAR-mFc融合分子和ROR1 2A2 mAb的AF488-抗小鼠抗体(1∶500；CST)进行二级抗体染色。所有二级抗体工作储备物都在0.05％皂素/PBS/2％FCS中配制。将板在4℃下在黑暗中孵育过夜。在次日，移除二级AF488缀合抗体，并且使用0.05％皂素/PBS/2％FCS洗涤细胞3次。添加Lamp-1抗体(1∶200；CST)或EEA1抗体(1∶50；SantaCruz)以分别检测溶酶体和早期内体区室。在室温下在黑暗中将板孵育2小时。接着移除Lamp-1和EEA1抗体，并且用0.05％皂素/PBS/2％FCS洗涤细胞3次。接着添加AF647-抗兔抗体(1∶1000；CST)以检测Lamp1和EEA1抗体结合。再在室温下在黑暗中持续2小时进行孵育，随后移除AF647二级抗体，并且用0.05％皂素/PBS/2％FCS洗涤细胞3次。使用含10μMHoechst试剂(Sigma)的0.05％皂素/PBS/2％FCS，在室温下在黑暗中对细胞核染色20分钟。最后，移除这个溶液，并且用PBS替换。将板在4℃下在黑暗中储存，随后使用GE HealthcareInCell 2000仪器进行成像。
在MDA-MB-231乳腺癌细胞的情况下，在37℃下孵育2小时之后，观察到B1 hFc和B1mFc的内化。VNAR-Fc-ROR1复合物在内化之后似乎与Lamp-1和EEA1染色重叠，此暗示通过早期内体和溶酶体区室达成ROR1细胞迁移。当在冰上孵育样品2小时时，ROR1-VNAR-Fc染色突出地保持在细胞表面处。在与2V Fc蛋白(非结合阴性对照VNAR)一起孵育之后，未观察到细胞表面结合或内化。B1-hFc和B1-mFc未由ROR1低肺癌细胞系A427内化。
实施例6-人源化以及进一步工程改造
使用两种不同策略产生了两种先导ROR1结合VNAR的许多人源化序列衍生物。
基于人种系Vκ1序列DPK-9设计了人源化序列。举例来说，在P3A1 V1中，使VNAR的框架区1、3和4突变以与DPK-9的框架区一致。
第二策略涉及将ROR1结合VNAR的结合环移植于先前人源化的VNAR框架上(Kovalenko等JBC 2013 288(24)17408-17419；WO2013/167883)。对于第一构建体(G1)，仅移植了CDR1和CDR3环。第二构建体(G2)移植了CDR与HV环两者。
使用方法的组合设计人源化D3序列。
人源化/移植化VNAR序列的实例：
Figure BDA0002615675830000811
D3人源化ADV1
Figure BDA0002615675830000821
D3人源化ADV2
Figure BDA0002615675830000822
D3人源化ADV3
Figure BDA0002615675830000823
B1人源化V5
Figure BDA0002615675830000824
B1人源化V7
Figure BDA0002615675830000825
编码人源化构建体的DNA关于在大肠杆菌中表达加以密码子优化，并且由GeneArt(Thermo)合成。P3A1序列被设计成采用连接VNAR结构域的[G4S]5接头的二聚体。所有人源化序列都在具有以下C末端His6myc标签的情况下产生：
QASGAHHHHHHGAEFEQKLISEEDLG(SEQ ID NO：97)
将编码这些蛋白质的DNA亚克隆至内含肽表达载体中，在大肠杆菌中表达并纯化，如先前在“用于表达VNAR内含肽融合蛋白的典型方法”章节中所述。
如下创建了D3的其他人源化形式：
D3人源化EL V1
Figure BDA0002615675830000831
D3人源化EL V2
Figure BDA0002615675830000832
D3人源化EL V3
Figure BDA0002615675830000833
D3人源化EL V4
Figure BDA0002615675830000834
D3人源化EL V5
Figure BDA0002615675830000835
Figure BDA0002615675830000841
根据SPR，人源化ROR1结合VNAR变体显示与人ROR1的高亲和力结合，并且显示改进的热稳定性。使用固定于芯片表面的人ROR1 ECD-Fc，如先前所述进行SPR。热稳定性测定使用Applied Biosystems StepOne实时PCR系统以及蛋白质Thermal ShiftTM染料试剂盒(Thermo)。设置测定混合物，以使蛋白质处于在20μL中20μM的最终浓度下。5μL ThermalShiftTM缓冲液与2.5uL 8x Thermal ShiftTM染料并行添加。使用StepOne软件来操作测定，并且使用蛋白质Thermal ShiftTM软件分析数据。所有数据都来自一阶导数分析。
表8-人源化VNAR变体的热稳定性和hROR1结合数据
Figure BDA0002615675830000842
将B1的HV和/或CDR环移植于人源化VNAR框架上以及用来自人DPK-9序列的区域取代P3A1序列产生了具有稳定性，并且分别以纳体积摩尔浓度和皮体积摩尔浓度亲和力维持hROR1结合的实质上经工程改造蛋白质。类似方法产生了D3的维持与野生型(WT)VNAR类似的结合特征的人源化变体。
实施例7-表位定位
蛋白质与去糖基化人ROR1的结合
ELISA用于将VNAR与糖基化人ROR1蛋白的结合和VNAR与去糖基化人ROR1蛋白的结合进行比较。为产生去糖基化人ROR1，使0.2mg/ml蛋白质与每2μg ROR1蛋白1U PNGaseF(Roche)一起在室温下孵育过夜。在不添加PNGaseF下并行制备对照糖基化人ROR1。在PNGaseF处理时，SDS PAGE分析显示移动，这与ROR1去糖基化一致(图17A)。
这些ROR1蛋白用于包被ELISA板，并且进行ELISA，如先前在“抗ROR1 VNAR表征”章节中所述。根据ELISA，VNAR(B1、P3A1-P3A1、D3-D3、B1 mFc)同等良好结合糖基化ROR1蛋白与去糖基化ROR1蛋白两者(图17B和图17C)，从而指示ROR1结合不依赖于ROR1糖基化。
B1与展开hROR1(用28mM DTT、0.5％Sarkosyl还原)的结合显著降低，这与B1 VNAR结合一个或多个构象性表位一致(图17C)。
根据SEC的B1与ROR1 Ig结构域的结合
根据SEC，B1 VNAR与ROR1 Ig结构域形成复合物(图18.1)。将1∶1 VNAR∶ROR1结构域或ROR1结构域配对在冰上孵育30分钟，接着在Superdex 200 increase 10/300管柱(GEHealthcare)上采用PBS进行操作，并且通过SDS-PAGE分析级分。在这些条件下，B1与ROR1Ig结构域形成复合物。
VNAR B1与非糖基化ROR1 Ig结构域的结合
为评估糖基化在VNAR B1与ROR1的结合中的涉及，通过在大肠杆菌中表达以产生蛋白质的非糖基化形式来产生ROR1 Ig结构域。
接着使这个非糖基化ROR1 Ig结构域与过量VNAR B1(比率1∶2)一起在冰上孵育30分钟，并且使用分析型尺寸排阻柱(S75 increase 10/300 GL分析型SEC柱)，通过尺寸排阻色谱法(SEC)加以评估。采用20mM Hepes、150mM NaCl(pH 7.5)进行色谱法。
SEC分析显示在以对应于比单独ROR1 Ig或B1具有更高分子量的物质的体积洗脱时，形成了新峰(图18.2)。对这个较早洗脱峰的MS分析显示它对应于ROR1 Ig与B1之间的复合物(图18.3)。
进一步结构域定位
为确定单个VNAR所结合的特定ROR1结构域，以Fc融合蛋白形式表达人ROR1细胞外结构域(ECD)和子结构域和结构域配对。接着使用分析型SEC评估复合物形成。
特别地，创建了以下ROR1结构域融合物：
·Ig-Fc
·Ig-Fz-Fc
·Fz-Kr-Fc
·Fz-Fc
·Kr-Fc
对于(D3)和(P3A1)的SEC分析/SDS-PAGE的结果显示于图18.4中。这些数据显示D3结合ROR1 Ig结构域，而P3A1结合单独Fz或Fz-Kr界面。
表位划分实验
使用SPR完成了结合竞争研究。通过胺偶联，将人ROR1(hROR1)固定于COOH2芯片的流动通道1和3(FC1和FC3)。FC2用作参考通道。所选VNAR例如B1、P3A1二聚体；或ROR1 2A2mAb(BioLegend)接着被捕集至FC1上的hROR1。接着评估测试分析物与i)先前捕集了VNAR或ROR12A2 mAb的hROR1，或ii)在不存在结合的VNAR或mAb下的hROR1的结合。在每种测试分析物之后，使用pH 2甘氨酸使hROR1芯片表面再生。在测试下一分析物之前，VNAR或ROR12A2mAb被再次捕集至FC1中的hROR1，以此类推。使用QDat软件确定结合动力学。对于非竞争性分子，结合动力学和传感图概况是类似的/不受hROR1捕集/未捕集结合剂的影响。对于竞争性分子，传感图概况和结合动力学显著改变。
图19显示关于VNAR与先前不与以及与B1一起孵育的人ROR1的结合的代表性传感图和结合动力学。结果显示B1和P3A1 VNAR不彼此竞争，也不与ROR1 mAb 2A2竞争结合hROR1。当B1 VNAR被捕集至芯片表面上的hROR1时，B1的进一步结合受到显著阻碍，然而，P3A1单体、P3A1二聚体或ROR1 2A2 mAb与hROR1的结合概况在不存在以及存在预捕集的B1下是相同的(图19)。关于这些分子在存在或不存在捕集的B1 VNAR下与hROR1的结合所获得的动力学参数确认它们不与B1竞争(例外之处是B1，如所预期，所述B1与自身竞争)。
表9-通过对在hROR1先前捕集/不捕集B1 VNAR的情况下的VNAR或ROR1 2A2 mAb的SPR分析获得的结合动力学数据。数据显示B1结合不与P3A1或2A2竞争。VNAR在具有C末端His6Myc标签的情况下表达。
Figure BDA0002615675830000871
Figure BDA0002615675830000881
以类似方式评估在预捕集以及不预捕集P3A1衍生物的情况下，VNAR、2A2 mAb或基于UC-961的mAb与hROR1的结合。结果概述于(图19b和表9b)中，所述图19b和表9b显示P3A1确实与B1、D3或E9或mAb 2A2或基于UC-961(由Kipps/Oncternal创建，重链：SEQ ID NO：98；轻链：SEQ ID NO：99)的mAb竞争。表9c进一步概述VNAR之间的结合竞争研究的根据SPR的研究结果。
表9b-通过对在hROR1先前捕集/不捕集P3A1His6Myc二聚体VNAR的情况下的VNAR序列、基于UC961的mAb或ROR1 2A2 mAb的SPR分析获得的结合动力学数据。数据显示除P3A1自身竞争以外，未观察到P3A1与其他ROR1结合剂之间竞争结合hROR1。
Figure BDA0002615675830000882
表9c：使用SPR测定分子之间竞争结合hROR1所获得的结果的概述。P3A1不与任何其他序列竞争。B1、D3和E9展现结合竞争，从而表明这些序列结合hROR1的重叠表位。
Figure BDA0002615675830000883
Figure BDA0002615675830000891
使用抗ROR1肽对抗ROR1 VNAR进行表位定位
ELISA分析用于确定先导抗ROR1 VNAR结构域B1、P3A1和D3是否结合于ROR1上的相同或重叠表位(在此处定义为四种ECD肽)。对与固定于ELISA板上的肽(于PBS和DMSO中)的直接结合的初始分析指示VNAR都不结合所述肽中的任一者，但确实结合作为同一ELISA的一部分而包括的固定化ECD hROR1-Fc蛋白对照(图20和图21)。为进一步对此进行探询，设计了竞争测定，其中使VNAR与递增浓度的四种测试肽(或人ROR1 ECD-Fc)一起在溶液中孵育，并且接着观察对与固定在ELISA板上的ROR1-Fc的残余结合的评估。在VNAR与用作阳性对照的人ROR1 ECD-Fc之间，竞争是明显的。然而，在肽存在下，没有明显的降低信号，从而明确指示未发生VNAR与这些特定ECD肽的结合(图22和图23)。
此外，B1、P3A1和D3 VNAR不结合跨越hROR1的整个ECD的任何重叠线性15聚体肽。它们也不结合先前在含有SDS的缓冲液中在还原性条件下加以声波处理的hROR1，所述还原性条件是通常使蛋白质变性的条件(肽扫描数据未显示)。总之，这指示B1、P3A1和D3 VNAR结合人ROR1 ECD蛋白上的一个或多个独特构象性表位。
VNAR与ECD肽的直接结合
合成以下肽，并且溶解于PBS(pH 7.4)中：
肽1-YMESLHMQGEIENQI(SEQ ID NO：34)
肽2-RSTIYGSRLRINLDTTDTGYFQ(SEQ ID NO：38)
肽3-CQPWNSQYPHTHTFTALRFP(SEQ ID NO：35)
肽4-QCVATNGKEVVSSTGVLFVKFGPPPTASPGYSDEYE(SEQ ID NO：37)
肽5-RSTIYGSRLRIRNLDTTDTGYFQ(SEQ ID NO：36)
从ELSS 1分离的克隆B1和P3A1以单体形式评估，并且来自免疫化文库的D3以单体与同二聚体两种形式评估。
B1与P3A1两种均显示结合ROR1，其中没有与五种肽中的任一者的明显结合。HSA作为非特异性对照加以包括(图20)。
然而，因为肽2不溶于PBS中，所以用溶解于25％DMSO中的肽重复直接结合ELISA。D3和呈蛋白质二聚体形式的D3-D3被包括在这些数据集中，并且同样未观察到与肽的结合(图21)。
方法
直接肽结合ELISA
1.用处于PBS中的10或50nM huROR1-Fc或处于PBS或25％DMSO中的10μM肽包被96孔板。在4℃下孵育过夜
2.用PBS洗涤2次
3.在室温下用200μl/孔的4％MPBS封闭1小时。
4.用PBS洗涤2次
5.添加在1μg/ml(67nM)下的B1或P3A1；在10μg/ml(670nM)下的D3和D3-D3，并且以横穿板的方式添加1∶3连续稀释液。在室温下孵育1小时。
6.用PBST洗涤3次
7.使板与100ul抗his-HRP抗体(SIGMA，于PBST中1∶1000稀释)一起在室温下孵育1小时
8.用PBST洗涤2次，并且用PBS洗涤2次
9.添加100μl/孔的TMB底物。用1M H2SO4终止反应
VNAR和ROR1肽的竞争测定
如方法中所述用在PBS中复原的所有四种肽进行竞争测定。在这些测定中，未观察到由VNAR B1或P3A1对以典型结合ELISA形式固定的四种肽中的任一者的结合(图22)。因此，不存在证据表明这些肽代表ROR1上由B1或P3A1识别的表位。
遵循图21中使用的条件(由于肽2不溶于PBS中)，所有竞争测定都用溶解于25％DMSO中的肽重复。对于测定，还在这些数据集中包括D3和D3-D3二聚体。这些结果确认VNAR结构域B1、P3A1和D3识别与由测试的4种肽代表的那些表位不同的一个表位(或多个表位)。
方法
竞争ELISA
1.用处于PBS中的50nM huROR1-Fc(对于P3A1)；10nM huROR1-Fc(对于B1、D3和D3-D3二聚体)包被96孔板。在4℃下孵育过夜
2.用PBS洗涤2次
3.在室温下用200μl/孔4％MPBS封闭1小时
4.用PBS洗涤2次
5.在室温下预孵育30分钟
·B1＝15nM
在1μM的起始浓度下外加肽(于PBS或25％DMSO中)(接着以横穿板的方式外加1∶3连续稀释液)
或在100nM的起始浓度下外加huROR1-Fc(接着以横穿板的方式外加1∶3连续稀释液)
·P3A1＝670nM
在50μM的起始浓度下外加肽(于PBS或25％DMSO中)(接着以横穿板的方式外加1∶3连续稀释液)
或在起始浓度1μM下外加huROR1-Fc(接着以横穿板的方式外加1∶3连续稀释液)
·D3＝67nM
在500nM的起始浓度下外加肽或huROR1-Fc(于PBS或25％DMSO中)(接着以横穿板的方式外加1∶3连续稀释液)
·D3-D3＝0.67nM
在500nM的起始浓度下外加肽或huROR1-Fc(于PBS或25％DMSO中)(接着以横穿板的方式外加1∶3连续稀释液)
6.添加100μl/孔的预孵育样品。在室温下孵育1小时
7.用PBST洗涤3次
8.使板与100μl/孔的抗His-HRP抗体(于PBST中1∶1000稀释)一起孵育。在室温下孵育1小时
9.用PBST洗涤2次，并且用PBS洗涤2次
10.添加100μl/孔的TMB底物。用50μl/孔1M H2SO4终止反应
使用重组ROR1结构域对抗ROR1 VNAR进行表位定位
ROR1 ECD由三个不同蛋白结构域：Ig样结构域、卷曲蛋白结构域和三环结构域组成。为确定由这些VNAR中的每一者识别的表位是否在整个ROR1蛋白的特定子结构域内，进行了以下ELISA分析。
VNAR与ROR1结构域的直接结合
通过直接结合ELISA评估抗ROR1 VNAR B1、P3A1和D3与人ROR1的三个细胞外结构域(Ig样结构域、卷曲蛋白结构域和三环结构域)的结合。B1和P3A1以单体形式评估，并且D3以单体与同二聚体(D3-D3)两种形式评估。还向测定中并入2A2抗ROR1抗体作为阳性对照。
B1和2A2识别Ig样结构域，然而，相较于它们对整个细胞外huROR1的结合，与Ig样结构域的这个结合要微弱得多。P3A1识别卷曲蛋白结构域，但相比于与完整ROR1蛋白的结合，同样是更微弱的(图24和表10)。D3和D3-D3同二聚体结合全长ROR1 ECD，但未观察到与单个ROR1 ECD子结构域的结合(图24和表10)。
所有结果都概述于表10中。
表10：
B1 P3A1 D3 2A2
rhROR1-Fc +++ +++ +++ +++
Ig样结构域 + - - +
卷曲蛋白结构域 - + - -
三环结构域 - - - -
方法
与ROR1结构域的直接结合ELISA
1.用处于PBS中的1μg/ml的huROR1-Fc或huROR1结构域包被96孔板。在4℃下孵育过夜。
2.用PBS洗涤2次
3.在室温下用200μl/孔的4％MPBS封闭1小时。
4.用PBS洗涤2次
5.在起始浓度10μg/ml(对于VNAR)和1∶150稀释度(对于mAb)下添加D3、D3-D3二聚体或2A2 mAb。以横穿板的方式制备3倍连续稀释液。在室温下孵育1小时。
6.用PBST洗涤3次
7.使板与100μl的抗c-myc-HRP抗体(于PBST中1∶1000稀释)一起在室温下孵育1小时。
8.用PBST洗涤2次，并且用PBS洗涤2次
9.添加100μl/孔的TMB底物。用1M H2SO4终止反应。
实施例8-VNAR缀合化学
对BA11进行标记作为位点特异性VNAR缀合的概念验证
当前，不存在用于使标记和药物以位点特异性方式缀合于VNAR的方法，因此，有需要建立所述缀合方法。VNAR BA11是E06的一种人源化变体，其以高亲和力结合人血清白蛋白(Kovalenko等，J.Biol.Chem.，2013 JBC)，并且具有作为半衰期延长技术的应用。BA11作为模型VNAR用于确定是否可在不损害VNAR结构域的结合活性下以良好产量产生位点特异性缀合的VNAR。VNAR的C末端在CDR1和CDR3以及HV2和HV4区域的远端，所述区域是VNAR的通常用于结合它的靶标的区域。
因此，基于内含肽的技术(US2006247417)用于评估有效载荷通过不同化学过程与VNAR的C末端的位点特异性缀合。简要来说，将目标蛋白质表达为经工程改造内含肽结构域的N末端融合物(Muir TW 2006 Nature 442，517-518)。在蛋白质-内含肽结合处进行的后续N至S酰基迁移产生硫酯连接的中间体，所述中间体可用双氨基氧基剂或氨基硫醇化学裂解以分别产生所需蛋白质C末端氨基氧基或硫醇衍生物(图11)。这些C末端氨基氧基和硫醇衍生物可分别与醛/酮和顺丁烯二酰亚胺官能化部分以化学选择性方式反应以产生位点特异性C末端经修饰蛋白质(图25-图27)。使用这个方法，通过肟和硫醚形成化学，以良好产量产生了BA11荧光素缀合物，并且这些缀合物维持与人血清白蛋白的结合。
初始，从在大肠杆菌中进行胞质表达开始，如先前所述以≥10mg/L的典型产量产生了固定在几丁质珠粒上的BA11内含肽-CBD融合蛋白。接着在水性缓冲条件下用不同小分子剂裂解这个前体融合蛋白以产生在它的C末端具有独特化学反应性官能基的BA11。
BA11-氨基氧基的产生(图11)
在含400mM二氧基胺(NH2-O-(CH2)2-O-NH2)的裂解缓冲液(pH 6.9)中使固定化BA11内含肽-CBD融合蛋白裂解过夜，从而导致约75％裂解。
排放含有BA11氨基氧基的裂解上清液，并且在Superdex75 26/60(GEHealthcare)上采用20mM磷酸钠(pH 6.9)、200mM NaCl加以纯化。这以＞2mg/L大肠杆菌的产量产生了可溶性衍生化折叠蛋白。所有蛋白质都通过还原性和非还原性SDS PAGE分析和质谱测定法来表征。所需二硫键的形成通过质谱方法确认。
BA11-肟-荧光素的产生(图25)
在室温下使纯化BA11氨基氧基与3摩尔当量苯甲醛-peg-荧光素在具有10％乙腈和10mM苯胺催化剂的pH 5.5缓冲液中混合过夜。SDS PAGE和质谱测定法显示≥98％反应，并且缀合物如上通过SEC加以纯化，并且通过还原性和非还原性SDS PAGE分析和质谱测定法来确认。
BA11 C末端硫醇衍生物的产生(图11)
在含100mM半胱胺(Sigma)的具有2mM TCEP的裂解缓冲液中使固定在几丁质珠粒上的BA11内含肽-CBD融合蛋白裂解过夜，以产生VNAR的相应C末端硫醇衍生物。排放含有BA11硫醇的裂解上清液，用2mM TCEP处理以使所引入C末端硫醇基团上的任何半胱胺加合物还原，并且在Superdex75 26/60(GE Healthcare)上采用20mM磷酸钠(pH 6.9)、200mMNaCl纯化蛋白质。对于BA11 SH，获得了约1.6mg/L大肠杆菌的产量。所有蛋白质都通过还原性和非还原性SDS PAGE分析和质谱测定法来表征。所需二硫键和游离C末端硫醇的形成通过质谱方法确认。
BA11-C末端硫醇-顺丁烯二酰亚胺-peg-荧光素的产生(图26)
在室温下使所产生的具有C末端硫醇的BA11(BA11 SH)与4摩尔当量顺丁烯二酰亚胺-peg-荧光素在具有最终0.3％DMF的pH 6.9缓冲液中混合0.5-1小时。SDS PAGE和质谱测定法显示≥98％反应。缀合物如上通过SEC加以纯化，并且通过还原性和非还原性SDSPAGE分析和质谱测定法来确认。
BA11 C末端半胱氨酸衍生物的产生(图11)
在含100mM半胱氨酸的具有2mM TCEP的裂解缓冲液中使固定在几丁质珠粒上的BA11内含肽-CBD融合蛋白裂解过夜，以产生VNAR的相应C末端半胱氨酸衍生物。排放含有BA11 Cys的裂解上清液，用2mM TCEP处理以使所引入C末端硫醇基团上的任何半胱氨酸加合物还原，并且在Superdex75 26/60(GE Healthcare)上采用20mM磷酸钠(pH 6.9)、200mMNaCl纯化蛋白质。对于BA11-cys，获得了约＞3mg/L大肠杆菌的产量。所有蛋白质都通过还原性和非还原性SDS PAGE分析和质谱测定法来表征。所需二硫键和游离C末端半胱氨酸硫醇的形成通过质谱方法确认。
BA11-C末端半胱氨酸-顺丁烯二酰亚胺-peg-荧光素的产生(图27)
在室温下使所产生的具有C末端半胱氨酸的BA11(BA11 cys)与4摩尔当量顺丁烯二酰亚胺-peg-荧光素在具有最终0.3％DMF的pH 6.9缓冲液中混合0.5-1小时。SDS PAGE和质谱测定法显示BA11 cys反应60-80％，反应较低是由于形成大量BA11 cys二聚体。缀合物如上通过SEC加以纯化，并且通过还原性和非还原性SDS PAGE分析和质谱测定法来确认。
BA11以及相应C末端衍生物和缀合物与血清白蛋白的结合通过SPR来测定。
对半衰期延长VNAR(BA11)或荧光素缀合的BA11与人、小鼠、大鼠和食蟹猴血清白蛋白的结合动力学的测定
使用SPR测定结合动力学。使用如下优化缓冲条件通过胺偶联将血清白蛋白或阴性对照蛋白固定于COOH2芯片：-人血清白蛋白(HSA)和小鼠血清白蛋白(MSA)于pH 5乙酸钠缓冲液中加以固定。大鼠血清白蛋白(RSA)和食蟹猴血清白蛋白(CSA)于pH 4.5乙酸钠缓冲液中加以固定，并且阴性对照鸡卵溶菌酶(HEL)蛋白于pH 5.5乙酸钠缓冲液中加以固定。
在各种浓度下测试分析物(BA11、BA11-荧光素或2V阴性对照结合剂)，并且使用QDat软件(SensiQ/Pall ForteBio)确定Ka(M-1s-1)、Kd(s-1)和KD(nM)值。对于每个分析物测试实验，与阴性对照蛋白(HEL)并行测定与所选血清白蛋白的结合。
表11.关于BA11 C末端衍生物以及具有不同缀合化学组成的后续荧光素缀合物与血清白蛋白的结合的SPR数据(KD nM)的概述。Fl，荧光素；cys，半胱氨酸；mal，顺丁烯二酰亚胺；SH，硫醇；2V，非结合VNAR阴性对照。
Figure BDA0002615675830000981
在pH 7.4与pH 5.5两者下，所有BA11衍生物和缀合物都显示与不同血清白蛋白的高亲和力结合。因此，描述的方法提供维持蛋白质的结合活性的用于对VNAR进行位点特异性修饰和缀合的稳健高产量途径。
ROR1结合VNAR-AF488和MMAE缀合物
以C末端内含肽融合蛋白形式表达ROR1结合VNAR使得能够产生具有独特C末端氨基氧基和C末端硫醇基团的ROR1结合VNAR。这转而使得能够分别通过肟形成缀合化学和顺丁烯二酰亚胺化学来以位点特异性方式在C末端缀合于荧光标记和细胞毒性有效载荷。使用的标记和有效载荷的实例显示于图28中。
如上所述产生固定在几丁质珠粒上的ROR1结合VNAR内含肽CBD融合蛋白。
VNAR-ox-vcMMAE和VNAR-ox-MMAE的产生
在室温下用处于裂解缓冲液(pH 6.9)中的400mM O，O’-1，3-丙二基双羟胺(NH2-O-(CH2)3-O-NH2)使固定化VNAR内含肽融合蛋白裂解过夜。所得含有C末端氨基氧基的VNAR(VNAR氨基氧基)通过IMAC或SEC纯化，并且在室温下与3摩尔当量的苯甲醛PEG2 vc PABMMAE或苯甲醛PEG4 MMAE在具有最终10mM苯胺催化剂的10％乙腈中反应过夜。缀合物通过IMAC或SEC纯化，加以无菌过滤，并且所需物质的形成和最终纯度通过还原性和非还原性SDSPAGE分析和质谱测定法来确认(图29)。
VNAR-S-mal-vcMMAE的产生
在室温下用处于具有2mM TCEP的裂解缓冲液(pH 6.9)中的100mM半胱胺使固定化VNAR内含肽融合蛋白裂解。所得含有C末端硫醇基团的VNAR(VNAR SH)通过IMAC或SEC纯化，并且与4摩尔当量的MC vc PAB MMAE或malAF488反应。缀合物通过IMAC或SEC纯化，并加以无菌过滤，并且所需物质的形成和最终纯度通过还原性和非还原性SDS PAGE分析和质谱测定法来确认(图29)。
对抗ROR1 VNAR-MMAE缀合物的表征-根据SPR的与ROR1和ROR2的结合以及根据流式细胞计量术的细胞表面结合
根据SPR的VNAR缀合物与ROR1和ROR2的结合
使用以上所述的程序，通过SPR来测定VNAR-MMAE缀合物和VNAR-荧光素缀合物结合人ROR1 ECD的能力。
如表12中所示，通过使苯甲醛有效载荷与C末端氨基氧基VNAR进行肟连接；通过使顺丁烯二酰亚胺官能化有效载荷与C末端硫醇VNAR进行硫醚连接以及通过使顺丁烯二酰亚胺官能化有效载荷与C末端半胱氨酸VNAR进行硫醚连接所制备的VNAR缀合物全都维持对人ROR1的高亲和力，但不结合人ROR2。缀合物使用酶可裂解接头(Val-Cit)或非可裂解接头制备，并且显示类似的与人ROR1的结合。
表12：关于VNAR以及相应荧光素和MMAE缀合物与人ROR1和ROR2的结合的SPR数据。VNAR在具有C末端His6Myc标签的情况下表达。
Figure BDA0002615675830001001
VNAR缀合物与癌细胞系的结合
使用以上所述的方法，通过流式细胞计量术来测定B1和P3A1MMAE缀合物与癌细胞系的结合。根据流式细胞计量术，在固定浓度的蛋白质下，B1和P3A1缀合物维持与ROR1高A549肺腺癌细胞的结合，并且不结合ROR1低肺癌细胞系A427。
VNAR mFc融合蛋白缀合物
通过从对抗体链间二硫醚进行部分还原和标记(Methods in Molecular Biology第1045卷第9章；Sun等，Bioconj Chem 2005)加以改编的方案；，用mal AF488和mc vc PABMMAE标记B1 mIgG2a Fc和非结合2V mIgG2a Fc融合蛋白。简要来说，在37℃下用2.75摩尔当量新鲜TCEP部分地还原在1mg/ml下处于添加有1mM EDTA的PBS+100mM L-Arg中的VNARmIgG2a Fc蛋白2小时。添加针对游离蛋白质硫醇的1.1摩尔当量顺丁烯二酰亚胺标记，在冰上孵育45分钟，并且添加L-半胱氨酸以终止反应。对反应进行透析以移除未反应标记/药物，加以无菌过滤，并且通过SDS PAGE来分析。对于B1-mFc-AF488，典型DAR是4.4，并且对于2V-mFc-AF488，典型DAR是3.9。
VNAR hFc融合蛋白药物缀合物
用于产生ADC的另一方法是在抗体的轻链和重链上的位置处进行半胱氨酸取代或添加的工程改造，并且这些半胱氨酸为位点特异性标记提供反应性硫醇基团(Junutula2008 Nature Biotechnology 26，925-932，Jeffrey 2013，Sutherland 2016)。
使抗ROR1 VNAR遗传融合于在hIgG1 Fc序列中含有半胱氨酸取代S252C或S473C(Kabat编号)的经工程改造hIgG1 Fc结构域。这使得能够用荧光标记(AF488)和细胞毒性药物(MC vc PAB MMAE、MC vc PAB NHC6 α-鹅膏菌素、MA PEG4 va PBD、MA PEG8 vaPABSG3199、MA PEG4 vc PAB DMAE PNU 159682)的顺丁烯二酰亚胺衍生物进行位点特异性标记(图32)。
VNAR-hFc-药物缀合物的产生
一种用以标记VNAR Fc S252C或VNAR Fc S473的部分还原、再折叠和标记方法从文献(Junutula等，2008 Nat Biotech，Jeffrey等，2013 Bioconj Chem)改编。简要来说，在具有1mM EDTA的PBS+100mM L-精氨酸(pH 7.4)中制备1mg/ml VNAR hFc溶液。添加20摩尔当量TCEP，并且在4℃下孵育至少48小时。添加30摩尔当量DHAA，将pH调整至6.5，并且在室温下孵育1小时。对再折叠的VNAR Fc S252C或S473C进行充分透析或进行缓冲液交换以进入PBS+50mM L-精氨酸中，并且通过UV来定量，随后视标记/药物而定，在室温下持续1小时直至过夜来与4摩尔当量顺丁烯二酰亚胺标记/药物溶液反应。缀合物直接进行透析/缓冲液交换，或通过SEC或IEX来进一步纯化，随后进行透析/缓冲液交换。
这个方法用于产生B1、P3A1和2V Fc融合蛋白的MMAE缀合物，借此，相应hIgG1 Fc(S252C或S473C)衍生物用并有酶可裂解(组织蛋白酶B)接头的顺丁烯二酰亚胺官能化MMAE有效载荷标记。
对最终缀合物的SDS-PAGE和质谱测定法分析确定标记已以定量方式进行以产生高度纯净的同质VNAR-hFc-MMAE缀合物，具有是2的药物与抗体比率(DAR)(图31显示与VNAR-hFc(S252C)的缀合)。类似程序用于产生经半胱氨酸工程改造的VNAR-hFc融合蛋白(Levena Biopharma，San Diego)的PBD二聚体、α-鹅膏菌素和PNU缀合物。借此，使VNAR(B1、P3A1、2V)hIgG1 Fc(S252C)融合物与MC vc PAB NHC6 α-鹅膏菌素、MA PEG4 va PBD、MAPEG8 va PAB SG3199、MA PEG4 vc PAB DMAE PNU 159682反应(图32)。
VNAR-hFc-MMAE缀合物与hROR1和癌细胞系的结合
使用以上所述的程序，通过SPR来测定VNAR-hFc缀合物结合人ROR1 ECD的能力。
表13：关于VNAR人Fc(hFc)和MMAE缀合形式与人ROR1和人ROR2的结合的SPR数据
Figure BDA0002615675830001021
B1和P3A1 VNAR-hIgG Fc(S252C)-vcMMAE缀合物显示与ROR1的高亲和力结合，但不结合人ROR2。2V是一种非结合VNAR，并且相应2V-hFc药物缀合物作为非结合对照而产生。
使用以上所述的方法，通过流式细胞计量术来测定B1和P3A1hFc-vcMMAE缀合物与ROR1高A549肺腺癌细胞系和ROR1低A427肺癌细胞系的结合。
图30显示B1和P3A1 hFc-vcMMAE缀合物强烈结合ROR1高癌细胞而非ROR1低癌细胞。然而，2V-hFc-vcMMAE缀合物不结合任一细胞系。
针对用抗ROR1 VNAR药物缀合物处理的癌细胞的体外细胞活力测定
将细胞接种至白色透明底部96孔板(Costar)中，并且在37℃、5％CO2下孵育24小时。在次日，以x10工作储备物创建每种测试剂的稀释系列。剂量响应X10储备物是：10000、5000、1000、500、100、50、10、5、1、0.5nM。使用多通道吸移器将10μL的X10储备溶液添加至细胞板(每孔90μl)中。这导致向孔中进行1∶10稀释，并且剂量响应在1000nM(第1列)至0.05nM(第10列)的范围内。将10μl媒介物对照(PBS)添加至对照孔(第11和12列)中。将板在37℃、5％CO2下孵育72-96小时。根据制造商说明书使用Promega Cell Titre Glo试剂来评估细胞活力。简要来说，从孵育器移除测定板，并且使其平衡至室温，随后将100μl的室温CellTitre Glo试剂添加至每个100μl测定孔中。将板放置在板振荡器上，在600rpm下持续2分钟。使板在室温下再静置10分钟，随后使用Clariostar板读取器(BMG)测量发光读数。通过计算未处理(仅媒介物)对照孔的平均值，以及确定每个经处理孔相对于对照的％来分析数据。接着将对照数据％相对于Log[处理]浓度绘图，并且在GraphPad Prism软件中使用非线性回归拟合来获得IC50值。
细胞系
DU145前列腺癌细胞：EMEM，10％hiFCS
JeKo-1套膜细胞淋巴瘤细胞：RPMI 1640，20％hiFCS
Kasumi-2 B细胞前体白血病细胞：RPMI 1640，10％hiFCS
PA-1卵巢癌细胞：EMEM，10％hiFCS
PA-1 ROR1剔除细胞：EMEM，10％hiFCS
A549细胞：DMEM，10％hiFCS
MDA-MB-231细胞：DMEM，10％hiFCS
图33显示关于由B1-mFc-vcMMAE和2V-mFc-vcMMAE缀合物对ROR1阳性癌细胞系A549(肺腺癌)、MDA-MB-231(乳腺癌)、DU145(前列腺癌)、Kasumi-2(ALL细胞)和Jeko1(MCL细胞)达成的细胞杀伤的剂量响应曲线以及相应IC50值。B1-mFc-vcMMAE缀合物显示对ROR1阳性癌细胞的强力细胞杀伤，并且遍及细胞系中的每一者，显示比相应2V-mFc-vcMMAE缀合物优越的效能。
表14：关于由B1-mFc-MMAE和2V-mFc-MMAE在每种细胞系的情况下达成的细胞杀伤的IC50值。
Figure BDA0002615675830001041
图34显示关于A)由B1-hFc-PBD、D3-hFc-PBD和2V-hFc-PBD缀合物对ROR1阳性DU145前列腺癌细胞，以及B)由B1-hFc-PBD、P3A1-hFc-PBD、D3-hFc-PBD和2V-hFc-PBD缀合物对ROR1阳性Jeko1 MCL细胞达成的细胞杀伤的剂量响应曲线以及相应IC50值。
表15：对VNAR hFc-PBD分子在DU145和Jeko-1癌细胞系的情况下在96小时时确定的IC50值(nM)。
Figure BDA0002615675830001051
靶向ROR1的VNAR-PBD缀合物显示对两种癌细胞系的强力杀伤，并且相对于2V-hFc-PBD缀合物，显示增加的效能，其中2V-hFc缀合物的IC50值是B1-hFc缀合物的IC50值的至少49倍高。
图35显示关于由B1-hFc-PNU、2V-hFc-PNU缀合物(PEG4-vc PAB DMAE PNU159682)、P3A1-hFc-PBD、D3-hFc-PBD和2V-hFc-PBD缀合物以及B1-hFc SG3199 PBD和2V-hFc SG3199 PBD缀合物对ROR1阳性PA-1卵巢癌细胞(A、C、E)和Kasumi-2 B细胞前体白血病细胞(B、D、F)达成的细胞杀伤的剂量响应曲线以及相应IC50值。
表16：关于由VNAR-hFc缀合物对PA-1和Kasumi-2癌细胞达成的细胞杀伤的计算IC50值(nM)。PA-1 ROR1 ko是其中ROR1表达已被剔除的PA-1癌细胞系。
Figure BDA0002615675830001052
Figure BDA0002615675830001061
靶向ROR1的VNAR缀合物显示对PA-1与Kasumi-2两种癌细胞系的强力杀伤，并且相对于相应2V-hFc缀合物，显示增加的效能，其中相应2V-hFc缀合物对照的IC50值是许多靶向ROR1的缀合物的IC50值的＞100倍高。此外，B1hFc-SG3199和B1hFc-PNU的细胞杀伤作用是ROR-1依赖性的-在PA-1和Kasumi-2细胞系的情况下进行的竞争实验(图35b)。B1hFc以剂量依赖性方式抑制由B1hFc-SG3199和B1hFc-PNU达成的细胞杀伤，2VhFc不抑制由这些药物缀合物分子达成的细胞杀伤(图35b)。
实施例10
ROR1 VNAR双特异性剂
ROR1结合VNAR的双特异性靶标组合包括例如
用于半衰期延长的HSA；ROR1和血清白蛋白的双特异性啮合
RTK例如EGFR、Her3；双特异性靶向细胞的表面上的EGFR与ROR1两者或HER3与ROR1两者。
已在本文中讨论和例示的VNAR BA11是HSA结合VNAR的一实例。讨论了包含HSA结合VNAR(诸如BA11)和另一特异性结合分子的双特异性分子。
在CHO细胞(Evitria)中表达通过2种不同长度G4S接头使N末端ROR1 VNAR与C末端抗CD3 scFv(克隆OKT3)组合的ROR1 x CD3双特异性序列，并且依次通过IMAC(HisTrapExcel，GE Healthcare)和SEC(Superdex 200 26/60，GE Healthcare)来纯化。类似地，还在CHO(Evitria)中表达使N末端双互补位ROR1 VNAR与C末端抗CD3 scFv组合的双互补位ROR1x CD3双特异性序列。
CD3 BiTE样方法；用作ROR1 VNAR双特异性剂的CD3结合序列的实例
抗CD3 scFv克隆OKT3(WO 2014028776，Zyngenia)及其定向和人源化衍生物
VH-[G4S]3-VL
Figure BDA0002615675830001071
人源化抗CD3 scFv UCHT1(Amett等PNAS 2004 101(46)16268-16273)及其衍生物
VL-[G4S]3-VH
Figure BDA0002615675830001072
表17-对ROR1xCD3构建体的表征
Figure BDA0002615675830001073
Figure BDA0002615675830001081
双互补位VNAR分子
使用(G4S)5接头设计和克隆了若干双互补位VNAR构建体。
使用SPR(如先前所述)或使用生物层干涉测量术(K2 Octet仪器/Pall ForteBio)测定结合动力学。对于BLI实验，使用胺偶联，将ROR1-hFc、ROR2-hFc融合蛋白(细胞外结构域)和HSA于pH 5乙酸钠缓冲液中固定至AR2G传感器。在各种浓度下测试VNAR和VNAR-Fc分子，并且使用Octet数据分析HT软件(Pall ForteBio)确定Ka(M-1s-1)、Kd(s-1)和KD(nM)值。2V是一种源于原初VNAR文库的对照VNAR序列，因此代表这个蛋白质类别，但不具有已知靶标。
还采用饱和水平的HSA(200nM)，在基线、缔合和解离的条件下，进行关于hROR1结合的结合动力学研究。
Figure BDA0002615675830001091
Figure BDA0002615675830001101
Figure BDA0002615675830001111
Figure BDA0002615675830001121
本文提及的双互补位VNAR构建体还已成功地与顺丁烯二酰亚胺Alexa488荧光团偶联，从而显示所述构建体适于与其他部分缀合。这个概念验证工作显示双互补位分子与其他有效载荷的缀合将是可能的。
在采用IMAC洗脱缓冲液(通常是50mM NaPi(pH 6.9)、150mM NaCl、50mM L-精氨酸、250mM咪唑，同时添加2mM TCEP以从被并入来进行缀合的Cys移除任何封盖)对VNAR进行Ni2+IMAC纯化之后，用Alexa Fluor 488 C5顺丁烯二酰亚胺(Thermo Fisher Scientific，U.K.)对VNAR进行选择性标记。将约4摩尔当量的Alexa Fluor 488染料添加至VNAR溶液(典型蛋白质浓度是2-30μM)中，并且在室温下在温和搅拌下在黑暗中孵育反应混合物1小时。通过LC-MS(ESI)监测反应以确保无未反应VNAR剩余在溶液中。为移除未反应染料，用50mMNaPi(pH 6.9)、150mM NaCl、50mM L-精氨酸稀释反应混合物以达到50mM咪唑浓度，并且使用HisTrap Excel柱在
Figure BDA0002615675830001131
Pure系统(两者均来自GE Healthcare，U.K.)上进行Ni2+IMAC。将蛋白质洗脱于50mM NaPi(pH 6.9)、150mM NaCl、50mM L-精氨酸、250mM咪唑中。汇合含有Alexa488 VNAR缀合物的洗脱级分，并且在4℃下储存直至需要。通过SEC或透析使蛋白质进行缓冲液交换以进入PBS(pH 7.4)或PBS(pH 7.4)、50mM L-Arg中。参见图36至图38。
实施例11-ROR1 CAR-T方法
可产生基于本申请中所述的ROR1特异性抗原结合分子的嵌合抗原受体(CAR)。此外，还可产生表达这种CAR的经工程改造T细胞，所述经工程改造T细胞可接着用于例如过继性细胞疗法中。
简要来说，可产生编码ROR1特异性CAR的核酸构建体。ROR1特异性CAR可包括细胞内活化结构域、跨膜结构域、以及包含本文所述的ROR1特异性抗原结合分子的细胞外结构域。核酸构建体可接着并入病毒载体诸如逆转录病毒载体(例如慢病毒载体)中。
T细胞可从需要治疗的患者分离，所述T细胞可接着例如通过逆转录病毒转染或使用诸如CRISPR-CAS-9的方法进行基因编辑来被修饰以表达编码CAR的核酸构建体。
可接着将经工程改造T细胞再输注至患者中以治疗疾患，诸如治疗癌症。
序列表
<110> 阿尔麦克探索有限公司(Almac Discovery Limited)
<120> ROR1特异性抗原结合分子
<130> P114734WO
<150> GB1721802.5
<151> 2017-12-22
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Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
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Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Ala Met Trp Gly Gln Trp Tyr Asp
85 90 95
Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 42
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 42
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Lys Tyr Gly Leu Phe
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Val Phe Met Pro Gln His Trp His Pro Ala Ala
85 90 95
His Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 43
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 43
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 44
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 44
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 45
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 45
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 46
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105
<210> 47
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 47
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105
<210> 48
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 48
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105
<210> 49
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 49
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105
<210> 50
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 50
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 51
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 51
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 52
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 52
Ala Ser Val Asn Gln Ser Pro Ser Ser Ala Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Leu Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Leu Glu Val Lys
100 105 110
<210> 53
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 53
Ala Ser Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105
<210> 54
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 54
Ala Ser Val Asp Gln Ser Pro Ser Ser Ala Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Leu Thr Ile Thr Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Leu Glu Val Lys
100 105
<210> 55
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 55
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 56
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 56
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 57
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 57
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Phe Ser Gly Ser Gly Ser Lys Arg Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 58
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 58
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Tyr Gln Gln Lys Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 59
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 59
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Tyr Gln Gln Lys Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Phe Ser Gly Ser Gly Ser Lys Arg Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 60
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 60
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 61
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 61
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 62
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 62
Pro Gly Val Gln Pro Ser Pro
1 5
<210> 63
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 63
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser
1 5 10
<210> 64
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 64
Pro Gly Val Gln Pro Ala Pro Gly Gly Gly Gly Ser
1 5 10
<210> 65
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 65
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 66
<211> 103
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 66
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys
100
<210> 67
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 67
Gln Ala Cys Gly Ala His His His His His His Gly Ala Glu Phe Glu
1 5 10 15
Gln Lys Leu Ile Ser Glu Glu Asp Leu
20 25
<210> 68
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 68
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
1 5 10
<210> 69
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 69
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
1 5 10 15
Gln Lys Leu Ile Ser Glu Glu Asp Leu
20 25
<210> 70
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 70
Gln Ala Cys Lys Ala His His His His His His Gly Ala Glu Phe Glu
1 5 10 15
Gln Lys Leu Ile Ser Glu Glu Asp Leu
20 25
<210> 71
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 71
Ala Ala Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys
1 5 10 15
Leu Ile Ser Glu Glu Asp Leu
20
<210> 72
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 72
Ala Cys Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys
1 5 10 15
Leu Ile Ser Glu Glu Asp Leu
20
<210> 73
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 73
Gln Ala Ser Gly Ala His His His His His His
1 5 10
<210> 74
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 74
Gln Ala Cys Gly Ala His His His His His His
1 5 10
<210> 75
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 75
Gln Ala Cys Lys Ala His His His His His His
1 5 10
<210> 76
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 76
Ala Ala Ala His His His His His His
1 5
<210> 77
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 77
Ala Cys Ala His His His His His His
1 5
<210> 78
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 78
Gln Ala Ser Gly Ala
1 5
<210> 79
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 79
Gln Ala Cys Gly Ala
1 5
<210> 80
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 80
Gln Ala Cys Lys Ala
1 5
<210> 81
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 81
Ala Cys Ala
1
<210> 82
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 82
Ser Ala Pro Ser Ala
1 5
<210> 83
<211> 361
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 83
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro
115 120 125
Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr
130 135 140
Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu
145 150 155 160
Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln
165 170 175
Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr
180 185 190
Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr
195 200 205
Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly
210 215 220
Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
225 230 235 240
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro
245 250 255
Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg
260 265 270
Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly
275 280 285
Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly
290 295 300
Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu
305 310 315 320
Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln
325 330 335
Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu
340 345 350
Leu Lys Ser His His His His His His
355 360
<210> 84
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 84
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu
115 120 125
Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met
130 135 140
Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp
145 150 155 160
Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
165 170 175
Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala
180 185 190
Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
195 200 205
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr
210 215 220
Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
225 230 235 240
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser
260 265 270
Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser
275 280 285
Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp
290 295 300
Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser
305 310 315 320
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
325 330 335
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro
340 345 350
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His
355 360 365
His His His
370
<210> 85
<211> 359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 85
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
115 120 125
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr
130 135 140
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
145 150 155 160
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
165 170 175
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
180 185 190
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
195 200 205
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
210 215 220
Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile
245 250 255
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
260 265 270
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser
275 280 285
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro
290 295 300
Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
305 310 315 320
Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
325 330 335
Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
340 345 350
Ser His His His His His His
355
<210> 86
<211> 369
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 86
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln
115 120 125
Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys
145 150 155 160
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser
165 170 175
Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu
180 185 190
Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu
195 200 205
Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp
210 215 220
His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
260 265 270
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
275 280 285
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
290 295 300
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser
305 310 315 320
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
325 330 335
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
340 345 350
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His His His
355 360 365
His
<210> 87
<211> 491
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 87
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly
225 230 235 240
Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala
245 250 255
Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr
260 265 270
Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly
275 280 285
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr
290 295 300
Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser
305 310 315 320
Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala
325 330 335
Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr
340 345 350
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln
370 375 380
Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr
385 390 395 400
Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys
405 410 415
Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala
420 425 430
Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr
435 440 445
Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr
450 455 460
Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys
465 470 475 480
Leu Glu Leu Lys Ser His His His His His His
485 490
<210> 88
<211> 501
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 88
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
245 250 255
Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val
260 265 270
Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met
275 280 285
His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr
290 295 300
Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp
305 310 315 320
Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
325 330 335
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
340 345 350
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr
355 360 365
Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser
385 390 395 400
Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser
405 410 415
Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys
420 425 430
Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg
435 440 445
Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser
450 455 460
Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser
465 470 475 480
Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His
485 490 495
His His His His His
500
<210> 89
<211> 480
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 89
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr
130 135 140
Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly
195 200 205
Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val
210 215 220
Leu Thr Val Asn Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser
225 230 235 240
Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys
245 250 255
Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln
260 265 270
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg
275 280 285
Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr
290 295 300
Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr
305 310 315 320
Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His
325 330 335
Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
340 345 350
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
355 360 365
Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu
370 375 380
Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn
385 390 395 400
Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp
405 410 415
Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly
420 425 430
Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp
435 440 445
Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe
450 455 460
Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His His His His
465 470 475 480
<210> 90
<211> 490
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 90
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr
130 135 140
Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly
195 200 205
Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val
210 215 220
Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
225 230 235 240
Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg
245 250 255
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe
260 265 270
Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
275 280 285
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn
290 295 300
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser
305 310 315 320
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
325 330 335
Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp
340 345 350
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
355 360 365
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser
370 375 380
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
385 390 395 400
Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
405 410 415
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser
420 425 430
Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
435 440 445
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
450 455 460
Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
465 470 475 480
Glu Leu Lys Ser His His His His His His
485 490
<210> 91
<211> 483
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 91
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ala Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met
195 200 205
Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser Asp Ile Lys Leu
225 230 235 240
Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met
245 250 255
Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp
260 265 270
Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
275 280 285
Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala
290 295 300
Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
305 310 315 320
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr
325 330 335
Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
340 345 350
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
355 360 365
Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser
370 375 380
Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser
385 390 395 400
Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp
405 410 415
Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser
420 425 430
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
435 440 445
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro
450 455 460
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His
465 470 475 480
His His His
<210> 92
<211> 493
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 92
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ala Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met
195 200 205
Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu
245 250 255
Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly
260 265 270
Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly
275 280 285
Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr
290 295 300
Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys
305 310 315 320
Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp
325 330 335
Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu
340 345 350
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly
355 360 365
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu
370 375 380
Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr
385 390 395 400
Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln
405 410 415
Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys
420 425 430
Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr
435 440 445
Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr
450 455 460
Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly
465 470 475 480
Thr Lys Leu Glu Leu Lys Ser His His His His His His
485 490
<210> 93
<211> 496
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 93
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
210 215 220
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser
245 250 255
Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys
260 265 270
Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln
275 280 285
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg
290 295 300
Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr
305 310 315 320
Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr
325 330 335
Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His
340 345 350
Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
370 375 380
Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu
385 390 395 400
Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn
405 410 415
Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp
420 425 430
Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly
435 440 445
Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp
450 455 460
Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe
465 470 475 480
Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His His His His
485 490 495
<210> 94
<211> 506
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 94
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
210 215 220
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg
260 265 270
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe
275 280 285
Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
290 295 300
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn
305 310 315 320
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser
325 330 335
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
340 345 350
Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp
355 360 365
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser
385 390 395 400
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
405 410 415
Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
420 425 430
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser
435 440 445
Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
450 455 460
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
485 490 495
Glu Leu Lys Ser His His His His His His
500 505
<210> 95
<211> 233
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 95
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
20 25 30
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
35 40 45
Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
50 55 60
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
65 70 75 80
Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
85 90 95
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
100 105 110
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
115 120 125
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
130 135 140
Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro
145 150 155 160
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
165 170 175
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
180 185 190
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
195 200 205
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
210 215 220
Lys Ser Phe Ser Arg Thr Pro Gly Lys
225 230
<210> 96
<211> 232
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 96
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 97
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 97
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
1 5 10 15
Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly
20 25
<210> 98
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 98
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ala Phe Thr Ala Tyr
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ser Phe Asp Pro Tyr Asp Gly Gly Ser Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val
65 70 75 80
Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Tyr Tyr Phe Asp Tyr Trp Gly His Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 99
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 99
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Thr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser
65 70 75 80
Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln His Asp Glu Ser Pro Tyr
85 90 95
Thr Phe Gly Glu Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 100
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 100
Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile
130 135 140
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
145 150 155 160
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser
165 170 175
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro
180 185 190
Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
195 200 205
Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
210 215 220
Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
225 230 235 240
Ser
<210> 101
<211> 245
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 101
Met Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu
1 5 10 15
Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn
20 25 30
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu
35 40 45
Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu
65 70 75 80
Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro
85 90 95
Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln
115 120 125
Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Met Lys Ile Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val
145 150 155 160
Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro
165 170 175
Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr
180 185 190
Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser
195 200 205
Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr
210 215 220
Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr
225 230 235 240
Leu Thr Val Phe Ser
245
<210> 102
<211> 105
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 102
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Lys Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Ala Met Trp Gly Gln Trp Tyr Asp
85 90 95
Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 103
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 103
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Lys Tyr Gly Leu Phe
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Val Phe Met Pro Gln His Trp His Pro Ala Ala
85 90 95
His Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 104
<211> 130
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 104
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Lys Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Ala Met Trp Gly Gln Trp Tyr Asp
85 90 95
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His
100 105 110
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
115 120 125
Asp Leu
130
<210> 105
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 105
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Lys Tyr Gly Leu Phe
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Val Phe Met Pro Gln His Trp His Pro Ala Ala
85 90 95
His Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 106
<211> 132
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 106
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala
100 105 110
His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser
115 120 125
Glu Glu Asp Leu
130
<210> 107
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 107
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 108
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 108
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 109
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 109
Ala Lys Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Asp Ile Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 110
<211> 248
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala
20 25 30
Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile
35 40 45
Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val
50 55 60
Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val
65 70 75 80
Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp
85 90 95
Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln
100 105 110
Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp
115 120 125
Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val
130 135 140
Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr
145 150 155 160
Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu
165 170 175
Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr
180 185 190
Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr
195 200 205
Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr
210 215 220
Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys
225 230 235 240
Ser Phe Ser Arg Thr Pro Gly Lys
245
<210> 111
<211> 247
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 111
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
20 25 30
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
35 40 45
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
50 55 60
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
65 70 75 80
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
85 90 95
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
100 105 110
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
115 120 125
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
130 135 140
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
145 150 155 160
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
165 170 175
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
180 185 190
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
195 200 205
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
210 215 220
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
225 230 235 240
Leu Ser Leu Ser Pro Gly Lys
245
<210> 112
<211> 247
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 112
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
20 25 30
Glu Leu Leu Gly Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys
35 40 45
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
50 55 60
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
65 70 75 80
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
85 90 95
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
100 105 110
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
115 120 125
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
130 135 140
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
145 150 155 160
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
165 170 175
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
180 185 190
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
195 200 205
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
210 215 220
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
225 230 235 240
Leu Ser Leu Ser Pro Gly Lys
245
<210> 113
<211> 247
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 113
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
20 25 30
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
35 40 45
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
50 55 60
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
65 70 75 80
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
85 90 95
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
100 105 110
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
115 120 125
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
130 135 140
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
145 150 155 160
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
165 170 175
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
180 185 190
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
195 200 205
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
210 215 220
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
225 230 235 240
Leu Cys Leu Ser Pro Gly Lys
245
<210> 114
<211> 252
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 114
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250
<210> 115
<211> 253
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 115
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val
100 105 110
Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro
115 120 125
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
130 135 140
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
145 150 155 160
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
165 170 175
Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys
180 185 190
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu
195 200 205
Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val
210 215 220
Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His His His Gly
225 230 235 240
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 116
<211> 253
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 116
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr
130 135 140
Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly
195 200 205
Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val
210 215 220
Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His His His Gly
225 230 235 240
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 117
<211> 256
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 117
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
115 120 125
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
130 135 140
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
145 150 155 160
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
165 170 175
Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu
180 185 190
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
195 200 205
Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His
225 230 235 240
His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250 255
<210> 118
<211> 256
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 118
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met
195 200 205
Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His
225 230 235 240
His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250 255
<210> 119
<211> 258
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 119
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val
100 105 110
Gln Pro Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
115 120 125
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
130 135 140
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
145 150 155 160
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
165 170 175
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
180 185 190
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
195 200 205
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
210 215 220
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His
225 230 235 240
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
245 250 255
Asp Leu
<210> 120
<211> 368
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 120
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val
100 105 110
Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro
115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
130 135 140
Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys
145 150 155 160
Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr
165 170 175
Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser
180 185 190
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser
195 200 205
Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
210 215 220
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
225 230 235 240
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
245 250 255
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
260 265 270
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
275 280 285
Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu
290 295 300
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
305 310 315 320
Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala
325 330 335
Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His
340 345 350
His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
355 360 365
<210> 121
<211> 368
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 121
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Pro Gly Val Gln Pro Ser Pro Gly Gly
100 105 110
Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu
115 120 125
Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr
130 135 140
Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn
145 150 155 160
Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys
165 170 175
Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp
180 185 190
Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro
195 200 205
Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
210 215 220
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
225 230 235 240
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
245 250 255
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
260 265 270
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
275 280 285
Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu
290 295 300
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
305 310 315 320
Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala
325 330 335
Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His
340 345 350
His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
355 360 365
<210> 122
<211> 368
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 122
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser
115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu
165 170 175
Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu
180 185 190
Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn
195 200 205
Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Pro Gly
210 215 220
Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr
225 230 235 240
Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys
245 250 255
Val Val Thr Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg
260 265 270
Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg
275 280 285
Tyr Val Glu Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile
290 295 300
Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr
305 310 315 320
Pro Trp Gly Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala
325 330 335
Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His
340 345 350
His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
355 360 365
<210> 123
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 123
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
115 120 125
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
130 135 140
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
145 150 155 160
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
165 170 175
Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu
180 185 190
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
195 200 205
Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro Ser Pro Gly Gly
225 230 235 240
Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser
245 250 255
Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr
260 265 270
Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn
275 280 285
Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys
290 295 300
Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
305 310 315 320
Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly
325 330 335
Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Cys Lys Ala His
340 345 350
His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu
355 360 365
Glu Asp Leu
370
<210> 124
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 124
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
115 120 125
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
130 135 140
Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp
145 150 155 160
Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser
165 170 175
Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu
180 185 190
Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg
195 200 205
Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val
210 215 220
Glu Ile Lys Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr
225 230 235 240
Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser
245 250 255
Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser
260 265 270
Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met
275 280 285
Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser
290 295 300
Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr
305 310 315 320
Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr
325 330 335
Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His
340 345 350
His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu
355 360 365
Glu Asp Leu
370
<210> 125
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 125
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser
115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu
165 170 175
Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu
180 185 190
Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn
195 200 205
Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Pro Gly
210 215 220
Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr
225 230 235 240
Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys
245 250 255
Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg
260 265 270
Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg
275 280 285
Tyr Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile
290 295 300
Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln
305 310 315 320
Ser Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr
325 330 335
Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His
340 345 350
His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu
355 360 365
Glu Asp Leu
370
<210> 126
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 126
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met
195 200 205
Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro Ser Pro Gly Gly
225 230 235 240
Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser
245 250 255
Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr
260 265 270
Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn
275 280 285
Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys
290 295 300
Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
305 310 315 320
Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly
325 330 335
Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Cys Lys Ala His
340 345 350
His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu
355 360 365
Glu Asp Leu
370
<210> 127
<211> 373
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 127
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val
100 105 110
Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro
115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
130 135 140
Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys
145 150 155 160
Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr
165 170 175
Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser
180 185 190
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser
195 200 205
Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
210 215 220
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn
225 230 235 240
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
245 250 255
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
260 265 270
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
275 280 285
Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu
290 295 300
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
305 310 315 320
Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn
325 330 335
Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys
340 345 350
Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile
355 360 365
Ser Glu Glu Asp Leu
370
<210> 128
<211> 373
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 128
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Pro Gly Val Gln Pro Ser Pro Gly Gly
100 105 110
Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu
115 120 125
Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr
130 135 140
Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn
145 150 155 160
Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys
165 170 175
Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp
180 185 190
Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro
195 200 205
Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
210 215 220
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn
225 230 235 240
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
245 250 255
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
260 265 270
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
275 280 285
Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu
290 295 300
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
305 310 315 320
Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn
325 330 335
Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys
340 345 350
Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile
355 360 365
Ser Glu Glu Asp Leu
370
<210> 129
<211> 373
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 129
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
115 120 125
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
130 135 140
Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp
145 150 155 160
Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser
165 170 175
Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu
180 185 190
Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg
195 200 205
Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val
210 215 220
Glu Ile Lys Pro Gly Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Ala
225 230 235 240
Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser
245 250 255
Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala Ala
260 265 270
Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg Ile
275 280 285
Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met Ser
290 295 300
Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr
305 310 315 320
Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val Gln
325 330 335
Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys
340 345 350
Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile
355 360 365
Ser Glu Glu Asp Leu
370
<210> 130
<211> 256
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 130
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Pro Gly Val Gln Pro Ala Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
115 120 125
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
130 135 140
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
145 150 155 160
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
165 170 175
Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu
180 185 190
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
195 200 205
Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His
225 230 235 240
His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250 255
<210> 131
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 131
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Pro Gly Val Gln Pro Ala Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
115 120 125
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
130 135 140
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
145 150 155 160
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
165 170 175
Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu
180 185 190
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
195 200 205
Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro Ala Pro Gly Gly
225 230 235 240
Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser
245 250 255
Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr
260 265 270
Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn
275 280 285
Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys
290 295 300
Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
305 310 315 320
Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly
325 330 335
Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Cys Lys Ala His
340 345 350
His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu
355 360 365
Glu Asp Leu
370
<210> 132
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 132
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Pro Gly Val Gln Pro Ala Pro Gly Gly Gly Gly Ser Thr Arg Val Asp
115 120 125
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
130 135 140
Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp
145 150 155 160
Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser
165 170 175
Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu
180 185 190
Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg
195 200 205
Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val
210 215 220
Glu Ile Lys Pro Gly Val Gln Pro Ala Pro Gly Gly Gly Gly Ser Thr
225 230 235 240
Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser
245 250 255
Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser
260 265 270
Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met
275 280 285
Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser
290 295 300
Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr
305 310 315 320
Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr
325 330 335
Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His
340 345 350
His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu
355 360 365
Glu Asp Leu
370
<210> 133
<211> 256
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 133
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ala Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met
195 200 205
Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His
225 230 235 240
His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250 255
<210> 134
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 134
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ala Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser
115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu
165 170 175
Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu
180 185 190
Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn
195 200 205
Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Pro Gly
210 215 220
Val Gln Pro Ala Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr
225 230 235 240
Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys
245 250 255
Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg
260 265 270
Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg
275 280 285
Tyr Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile
290 295 300
Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln
305 310 315 320
Ser Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr
325 330 335
Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Lys Ala His
340 345 350
His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu
355 360 365
Glu Asp Leu
370
<210> 135
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 135
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ala Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met
195 200 205
Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro Ala Pro Gly Gly
225 230 235 240
Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser
245 250 255
Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr
260 265 270
Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn
275 280 285
Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys
290 295 300
Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
305 310 315 320
Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly
325 330 335
Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Cys Lys Ala His
340 345 350
His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu
355 360 365
Glu Asp Leu
370
<210> 136
<211> 366
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 136
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser
115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu
165 170 175
Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu
180 185 190
Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn
195 200 205
Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Pro Gly
210 215 220
Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr
225 230 235 240
Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys
245 250 255
Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg
260 265 270
Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg
275 280 285
Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile
290 295 300
Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg
305 310 315 320
Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr
325 330 335
Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His His His
340 345 350
Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
355 360 365
<210> 137
<211> 366
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 137
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Pro Gly Val Gln Pro Ser Pro Gly Gly
100 105 110
Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu
115 120 125
Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr
130 135 140
Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp
145 150 155 160
Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys
165 170 175
Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp
180 185 190
Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu
195 200 205
Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly
210 215 220
Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr
225 230 235 240
Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys
245 250 255
Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg
260 265 270
Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg
275 280 285
Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile
290 295 300
Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg
305 310 315 320
Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr
325 330 335
Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His His His
340 345 350
Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
355 360 365
<210> 138
<211> 251
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 138
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Leu Ala
195 200 205
Ile Ser Thr Arg Ser Tyr Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr
210 215 220
Val Asn Gln Ala Cys Lys Ala His His His His His His Gly Ala Glu
225 230 235 240
Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 139
<211> 366
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 139
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser
115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu
165 170 175
Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu
180 185 190
Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn
195 200 205
Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Pro Gly
210 215 220
Val Gln Pro Ser Pro Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr
225 230 235 240
Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys
245 250 255
Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg
260 265 270
Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg
275 280 285
Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile
290 295 300
Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln
305 310 315 320
Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp Tyr Asp Gly Ala Gly Thr
325 330 335
Val Leu Thr Val Asn Gln Ala Cys Lys Ala His His His His His His
340 345 350
Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
355 360 365
<210> 140
<211> 250
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 140
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Pro Gly Val Gln Pro Ser Pro Gly Gly
100 105 110
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
115 120 125
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn
130 135 140
Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
145 150 155 160
Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn
165 170 175
Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
180 185 190
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala
195 200 205
Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val
210 215 220
Asn Gln Ala Cys Gly Ala His His His His His His Gly Ala Glu Phe
225 230 235 240
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 141
<211> 250
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 141
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Pro Gly Val Gln Pro Ala Pro Gly Gly
100 105 110
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
115 120 125
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn
130 135 140
Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
145 150 155 160
Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn
165 170 175
Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
180 185 190
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala
195 200 205
Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val
210 215 220
Asn Gln Ala Cys Gly Ala His His His His His His Gly Ala Glu Phe
225 230 235 240
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 142
<211> 250
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 142
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Pro Gly Val Gln Pro Ser Pro Gly Gly
100 105 110
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
115 120 125
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn
130 135 140
Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
145 150 155 160
Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn
165 170 175
Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
180 185 190
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala
195 200 205
Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val
210 215 220
Asn Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe
225 230 235 240
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 143
<211> 250
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 143
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Pro Gly Val Gln Pro Ala Pro Gly Gly
100 105 110
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
115 120 125
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn
130 135 140
Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
145 150 155 160
Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn
165 170 175
Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
180 185 190
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala
195 200 205
Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val
210 215 220
Asn Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe
225 230 235 240
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 144
<211> 271
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 144
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala
130 135 140
Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp
145 150 155 160
Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly
165 170 175
Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser
180 185 190
Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr
195 200 205
Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala
210 215 220
Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly
225 230 235 240
Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His His
245 250 255
His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265 270
<210> 145
<211> 269
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 145
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu
210 215 220
Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His His His Gly
245 250 255
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265
<210> 146
<211> 269
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 146
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
210 215 220
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His His His Gly
245 250 255
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265
<210> 147
<211> 271
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 147
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Val Thr Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys
165 170 175
Asn Pro Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro
210 215 220
Trp Gly Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly
225 230 235 240
Thr Val Leu Thr Val Asn Gln Ala Cys Gly Ala His His His His His
245 250 255
His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265 270
<210> 148
<211> 271
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 148
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala
130 135 140
Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp
145 150 155 160
Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly
165 170 175
Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser
180 185 190
Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr
195 200 205
Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala
210 215 220
Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly
225 230 235 240
Thr Val Leu Thr Val Asn Gln Ala Cys Gly Ala His His His His His
245 250 255
His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265 270
<210> 149
<211> 269
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 149
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu
210 215 220
Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gln Ala Cys Gly Ala His His His His His His Gly
245 250 255
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265
<210> 150
<211> 269
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 150
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
210 215 220
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gln Ala Cys Gly Ala His His His His His His Gly
245 250 255
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265
<210> 151
<211> 394
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 151
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu
130 135 140
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp
145 150 155 160
Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly
165 170 175
Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser
180 185 190
Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln
195 200 205
Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile
210 215 220
Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala
260 265 270
Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp
275 280 285
Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly
290 295 300
Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser
305 310 315 320
Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr
325 330 335
Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His
340 345 350
Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val
355 360 365
Asn Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe
370 375 380
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
385 390
<210> 152
<211> 399
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 152
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu
130 135 140
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp
145 150 155 160
Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly
165 170 175
Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser
180 185 190
Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln
195 200 205
Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile
210 215 220
Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala
260 265 270
Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp
275 280 285
Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly
290 295 300
Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser
305 310 315 320
Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr
325 330 335
Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala
340 345 350
Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly
355 360 365
Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His His
370 375 380
His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
385 390 395
<210> 153
<211> 399
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 153
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys
165 170 175
Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr
180 185 190
Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser
210 215 220
Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
260 265 270
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
275 280 285
Val Thr Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys
290 295 300
Asn Pro Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr
305 310 315 320
Val Glu Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys
325 330 335
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro
340 345 350
Trp Gly Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly
355 360 365
Thr Val Leu Thr Val Asn Gln Ala Cys Gly Ala His His His His His
370 375 380
His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
385 390 395
<210> 154
<211> 399
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 154
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys
165 170 175
Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr
180 185 190
Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser
210 215 220
Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
260 265 270
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
275 280 285
Val Thr Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys
290 295 300
Asn Pro Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr
305 310 315 320
Val Glu Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys
325 330 335
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro
340 345 350
Trp Gly Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly
355 360 365
Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His His
370 375 380
His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
385 390 395
<210> 155
<211> 397
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 155
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys
165 170 175
Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr
180 185 190
Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser
210 215 220
Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro
260 265 270
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
275 280 285
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
290 295 300
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
305 310 315 320
Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys
325 330 335
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu
340 345 350
Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val
355 360 365
Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His His His Gly
370 375 380
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
385 390 395
<210> 156
<211> 397
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 156
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
165 170 175
Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn
180 185 190
Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr
210 215 220
Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
260 265 270
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
275 280 285
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
290 295 300
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
305 310 315 320
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
325 330 335
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
340 345 350
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
355 360 365
Leu Thr Val Asn Gln Ala Cys Gly Ala His His His His His His Gly
370 375 380
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
385 390 395
<210> 157
<211> 397
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 157
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
165 170 175
Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn
180 185 190
Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr
210 215 220
Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
260 265 270
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
275 280 285
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
290 295 300
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
305 310 315 320
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
325 330 335
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
340 345 350
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
355 360 365
Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His His His Gly
370 375 380
Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
385 390 395
<210> 158
<211> 266
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 158
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn
145 150 155 160
Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
165 170 175
Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala
210 215 220
Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val
225 230 235 240
Asn Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe
245 250 255
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265
<210> 159
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 159
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
210 215 220
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His His His
245 250 255
<210> 160
<211> 246
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 160
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn
145 150 155 160
Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
165 170 175
Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala
210 215 220
Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val
225 230 235 240
Asn Ser Ala Pro Ser Ala
245
<210> 161
<211> 260
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 161
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
165 170 175
Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn
180 185 190
Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr
210 215 220
Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Cys Gly Ala
225 230 235 240
His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser
245 250 255
Glu Glu Asp Leu
260
<210> 162
<211> 260
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 162
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
165 170 175
Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn
180 185 190
Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr
210 215 220
Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Ser Gly Ala
225 230 235 240
His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser
245 250 255
Glu Glu Asp Leu
260
<210> 163
<211> 260
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 163
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
130 135 140
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
145 150 155 160
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
165 170 175
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
180 185 190
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
195 200 205
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
210 215 220
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala
225 230 235 240
His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser
245 250 255
Glu Glu Asp Leu
260
<210> 164
<211> 402
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 164
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
260 265 270
Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
275 280 285
Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro
290 295 300
Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys
305 310 315 320
Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly
325 330 335
Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser
340 345 350
Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp
355 360 365
Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Ser Gly Ala His His
370 375 380
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
385 390 395 400
Asp Leu
<210> 165
<211> 402
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 165
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
260 265 270
Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
275 280 285
Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro
290 295 300
Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys
305 310 315 320
Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly
325 330 335
Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser
340 345 350
Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp
355 360 365
Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Cys Gly Ala His His
370 375 380
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
385 390 395 400
Asp Leu
<210> 166
<211> 402
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 166
Ala Lys Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Asp Ile Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys
165 170 175
Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr
180 185 190
Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser
210 215 220
Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Lys Val Asp Gln Thr Pro
260 265 270
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
275 280 285
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
290 295 300
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
305 310 315 320
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
325 330 335
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
340 345 350
Gly Met Ala Ile Asp Ile Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
355 360 365
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His
370 375 380
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
385 390 395 400
Asp Leu
<210> 167
<211> 402
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 167
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys
165 170 175
Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr
180 185 190
Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser
210 215 220
Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
260 265 270
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
275 280 285
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
290 295 300
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
305 310 315 320
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
325 330 335
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
340 345 350
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
355 360 365
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His
370 375 380
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
385 390 395 400
Asp Leu
<210> 168
<211> 392
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 168
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
165 170 175
Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn
180 185 190
Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr
210 215 220
Gly Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys
260 265 270
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
275 280 285
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
290 295 300
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
305 310 315 320
Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
325 330 335
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
340 345 350
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln
355 360 365
Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln
370 375 380
Lys Leu Ile Ser Glu Glu Asp Leu
385 390
<210> 169
<211> 262
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 169
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
130 135 140
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
145 150 155 160
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
165 170 175
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
180 185 190
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
195 200 205
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
210 215 220
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser
225 230 235 240
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
245 250 255
Ile Ser Glu Glu Asp Leu
260
<210> 170
<211> 249
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 170
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Ser Pro Ser
100 105 110
Thr Pro Pro Thr Pro Ser Pro Thr Pro Pro Ala Thr Arg Val Asp Gln
115 120 125
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
130 135 140
Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr
145 150 155 160
Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly
165 170 175
Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr
180 185 190
Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala
195 200 205
Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu
210 215 220
Ile Lys Ala Cys Ala His His His His His His Gly Ala Glu Phe Glu
225 230 235 240
Gln Lys Leu Ile Ser Glu Glu Asp Leu
245
<210> 171
<211> 251
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 171
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Ser Pro Ser Thr Pro Pro Thr Pro Ser
100 105 110
Pro Thr Pro Pro Ala Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr
115 120 125
Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala
130 135 140
Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser
145 150 155 160
Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val
165 170 175
Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val
180 185 190
Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly
195 200 205
Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr
210 215 220
Val Asn Gln Ala Cys Gly Ala His His His His His His Gly Ala Glu
225 230 235 240
Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 172
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 172
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Ala Glu Ala Ala Ala Lys Glu Ala Ala
100 105 110
Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Leu Glu Ala
115 120 125
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
130 135 140
Ala Ala Ala Lys Ala Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr
145 150 155 160
Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala
165 170 175
Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser
180 185 190
Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val
195 200 205
Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val
210 215 220
Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly
225 230 235 240
Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr
245 250 255
Val Asn Gln Ala Cys Gly Ala His His His His His His Gly Ala Glu
260 265 270
Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
275 280
<210> 173
<211> 264
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 173
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Ser Pro Ser Thr Pro Pro Thr Pro Ser
100 105 110
Pro Thr Pro Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser Pro Thr Pro
115 120 125
Pro Ala Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr
130 135 140
Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly
145 150 155 160
Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln
165 170 175
Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg
180 185 190
Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser
195 200 205
Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp
210 215 220
Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln
225 230 235 240
Ala Cys Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln
245 250 255
Lys Leu Ile Ser Glu Glu Asp Leu
260
<210> 174
<211> 249
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 174
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Ser Pro Ser
100 105 110
Thr Pro Pro Thr Pro Ser Pro Thr Pro Pro Ala Thr Arg Val Asp Gln
115 120 125
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
130 135 140
Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr Ser Thr Tyr Trp Tyr
145 150 155 160
Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly
165 170 175
Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr
180 185 190
Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala
195 200 205
Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala Gly Thr Lys Val Glu
210 215 220
Ile Lys Ala Cys Ala His His His His His His Gly Ala Glu Phe Glu
225 230 235 240
Gln Lys Leu Ile Ser Glu Glu Asp Leu
245
<210> 175
<211> 251
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 175
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Ser Pro Ser Thr Pro Pro Thr Pro Ser
100 105 110
Pro Thr Pro Pro Ala Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr
115 120 125
Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala
130 135 140
Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser
145 150 155 160
Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val
165 170 175
Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val
180 185 190
Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly
195 200 205
Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr
210 215 220
Val Asn Gln Ala Cys Gly Ala His His His His His His Gly Ala Glu
225 230 235 240
Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 176
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 176
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Ala Glu Ala Ala Ala Lys Glu Ala Ala
100 105 110
Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Leu Glu Ala
115 120 125
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
130 135 140
Ala Ala Ala Lys Ala Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr
145 150 155 160
Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala
165 170 175
Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser
180 185 190
Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val
195 200 205
Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val
210 215 220
Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly
225 230 235 240
Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr
245 250 255
Val Asn Gln Ala Cys Gly Ala His His His His His His Gly Ala Glu
260 265 270
Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
275 280
<210> 177
<211> 264
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 177
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Ser Pro Ser Thr Pro Pro Thr Pro Ser
100 105 110
Pro Thr Pro Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser Pro Thr Pro
115 120 125
Pro Ala Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr
130 135 140
Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly
145 150 155 160
Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln
165 170 175
Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg
180 185 190
Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser
195 200 205
Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp
210 215 220
Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln
225 230 235 240
Ala Cys Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln
245 250 255
Lys Leu Ile Ser Glu Glu Asp Leu
260
<210> 178
<211> 256
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 178
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr
115 120 125
Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys
130 135 140
Val Val Thr Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg
145 150 155 160
Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg
165 170 175
Tyr Val Glu Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile
180 185 190
Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr
195 200 205
Pro Trp Gly Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His His His
225 230 235 240
His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250 255
<210> 179
<211> 276
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 179
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser
130 135 140
Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu
145 150 155 160
Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala Ala Thr
165 170 175
Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg Ile Ser
180 185 190
Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met Ser Phe
195 200 205
Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr
210 215 220
Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val Gln Trp
225 230 235 240
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala
245 250 255
His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser
260 265 270
Glu Glu Asp Leu
275
<210> 180
<211> 252
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 180
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala
115 120 125
Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly
130 135 140
Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly
145 150 155 160
Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser
165 170 175
Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr
180 185 190
Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala
195 200 205
Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu
210 215 220
Thr Val Asn Gln Ala Cys Gly Ala His His His His His His Gly Ala
225 230 235 240
Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
245 250
<210> 181
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 181
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 182
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 182
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 183
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 183
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser
100 105 110
Gly Ala His His His His His His
115 120
<210> 184
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 184
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser
100 105 110
Gly Ala
<210> 185
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 185
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys
100 105 110
Gly Ala His His His His His His
115 120
<210> 186
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 186
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys
100 105 110
Lys Ala His His His His His His
115 120
<210> 187
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 187
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Ser Ala Pro
100 105 110
Ser Ala
<210> 188
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 188
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Ser Pro Ser
100 105 110
Thr Pro Pro Thr Pro Ser Pro Thr Pro Pro Ala
115 120
<210> 189
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 189
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 190
<211> 132
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 190
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala
100 105 110
His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser
115 120 125
Glu Glu Asp Leu
130
<210> 191
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 191
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala
100 105 110
His His His His His His His
115
<210> 192
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 192
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105
<210> 193
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 193
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 194
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 194
Ala Lys Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Asp Ile Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 195
<211> 130
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 195
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Lys Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Ala Met Trp Gly Gln Trp Tyr Asp
85 90 95
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His
100 105 110
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
115 120 125
Asp Leu
130
<210> 196
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 196
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Lys Tyr Gly Leu Phe
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Val Phe Met Pro Gln His Trp His Pro Ala Ala
85 90 95
His Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 197
<211> 103
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 197
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Pro Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Met Ser Thr Asn Ile Trp Thr Gly Asp Gly Ala
85 90 95
Gly Thr Lys Val Glu Ile Lys
100
<210> 198
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 198
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 199
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 199
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 200
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 200
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 201
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 201
Ala Ser Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 202
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 202
Ala Ser Val Asp Gln Ser Pro Ser Ser Ala Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Leu Thr Ile Thr Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Leu Glu Val Lys Gln Ala Ser
100 105 110
Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln Lys Leu
115 120 125
Ile Ser Glu Glu Asp Leu
130
<210> 203
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 203
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 204
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 204
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 205
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 205
Ala Ser Val Asn Gln Ser Pro Ser Ser Ala Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Leu Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Leu Glu Val Lys
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 206
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 206
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 207
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 207
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 208
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 208
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Phe Ser Gly Ser Gly Ser Lys Arg Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 209
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 209
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Tyr Gln Gln Lys Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 210
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 210
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Tyr Gln Gln Lys Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Phe Ser Gly Ser Gly Ser Lys Arg Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gln Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu
115 120 125
Gln Lys Leu Ile Ser Glu Glu Asp Leu
130 135
<210> 211
<211> 264
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 211
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln
225 230 235 240
Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln
245 250 255
Lys Leu Ile Ser Glu Glu Asp Leu
260
<210> 212
<211> 250
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 212
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gln
225 230 235 240
Ala Ser Gly Ala His His His His His His
245 250
<210> 213
<211> 244
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 213
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Ser
225 230 235 240
Ala Pro Ser Ala
<210> 214
<211> 274
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 214
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His
245 250 255
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
260 265 270
Asp Leu
<210> 215
<211> 260
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 215
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Ser Gly Ala His His
245 250 255
His His His His
260
<210> 216
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 216
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Lys Tyr Gly Leu Phe
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Val Phe Met Pro Gln His Trp His Pro Ala Ala
85 90 95
His Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala
130 135 140
Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr Gly
145 150 155 160
Ala Lys Tyr Gly Leu Phe Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly
165 170 175
Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser
180 185 190
Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr
195 200 205
Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Val Phe Met Pro Gln
210 215 220
His Trp His Pro Ala Ala His Trp Tyr Asp Gly Ala Gly Thr Val Leu
225 230 235 240
Thr Val Asn Gln Ala Ser Gly Ala His His His His His His Gly Ala
245 250 255
Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265
<210> 217
<211> 254
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 217
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Gly Ala
245 250
<210> 218
<211> 260
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 218
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Val Leu Thr Val Asn Gln Ala Cys Gly Ala His His
245 250 255
His His His His
260
<210> 219
<211> 264
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 219
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
195 200 205
Asp Phe Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln
225 230 235 240
Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln
245 250 255
Lys Leu Ile Ser Glu Glu Asp Leu
260
<210> 220
<211> 264
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 220
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser
165 170 175
Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn
180 185 190
Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln
225 230 235 240
Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln
245 250 255
Lys Leu Ile Ser Glu Glu Asp Leu
260
<210> 221
<211> 264
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 221
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gln
225 230 235 240
Ala Ser Gly Ala His His His His His His Gly Ala Glu Phe Glu Gln
245 250 255
Lys Leu Ile Ser Glu Glu Asp Leu
260
<210> 222
<211> 274
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 222
Ala Ser Val Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Ser Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Ser Gly Ala His His
245 250 255
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
260 265 270
Asp Leu
<210> 223
<211> 274
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 223
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Ser Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Lys Val Glu Ile Lys Gln Ala Ser Gly Ala His His
245 250 255
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
260 265 270
Asp Leu
<210> 224
<211> 274
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 224
Ala Ser Val Asn Gln Ser Pro Ser Ser Ala Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Leu Thr Ile Thr Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Lys Leu Glu Val Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Ser Pro
130 135 140
Ser Ser Ala Ser Ala Ser Val Gly Asp Arg Leu Thr Ile Thr Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Ser Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Lys Leu Glu Val Lys Gln Ala Ser Gly Ala His His
245 250 255
His His His His Gly Ala Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu
260 265 270
Asp Leu
<210> 225
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 225
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu
130 135 140
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Gly
145 150 155 160
Ala Asn Tyr Gly Leu Ala Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly
165 170 175
Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser
180 185 190
Val Asn Lys Arg Thr Met Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln
195 200 205
Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala
210 215 220
Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Gln Ala Ser Gly Ala His His His His His His Gly Ala
245 250 255
Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265
<210> 226
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 226
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Thr Arg Val Asp Gln Ser Pro Ser Ser Leu
130 135 140
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Val Leu Thr Gly
145 150 155 160
Ala Asn Tyr Gly Leu Ala Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly
165 170 175
Ser Ser Asn Lys Glu Gln Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser
180 185 190
Val Asn Lys Gly Thr Lys Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln
195 200 205
Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala
210 215 220
Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Gln Ala Ser Gly Ala His His His His His His Gly Ala
245 250 255
Glu Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
260 265
<210> 227
<211> 357
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 227
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Arg Gly
115 120 125
Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu
130 135 140
Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val
145 150 155 160
Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val
165 170 175
Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val
180 185 190
Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser
195 200 205
Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met
210 215 220
Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala
225 230 235 240
Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro
245 250 255
Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln
260 265 270
Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr
275 280 285
Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr
290 295 300
Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu
305 310 315 320
Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser
325 330 335
Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser
340 345 350
Arg Thr Pro Gly Lys
355
<210> 228
<211> 355
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 228
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Arg Gly Pro Thr
115 120 125
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
130 135 140
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
145 150 155 160
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu
165 170 175
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
180 185 190
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu
195 200 205
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
210 215 220
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
225 230 235 240
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
245 250 255
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
260 265 270
Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
275 280 285
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
290 295 300
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
305 310 315 320
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
325 330 335
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
340 345 350
Pro Gly Lys
355
<210> 229
<211> 356
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 229
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser
115 120 125
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
130 135 140
Gly Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
145 150 155 160
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
165 170 175
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
180 185 190
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
195 200 205
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
210 215 220
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
225 230 235 240
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
245 250 255
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
260 265 270
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
275 280 285
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
290 295 300
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
305 310 315 320
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
325 330 335
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
340 345 350
Ser Pro Gly Lys
355
<210> 230
<211> 356
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 230
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Lys Glu Gln
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Gly Thr Lys
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser
115 120 125
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
130 135 140
Gly Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
145 150 155 160
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
165 170 175
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
180 185 190
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
195 200 205
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
210 215 220
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
225 230 235 240
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
245 250 255
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
260 265 270
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
275 280 285
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
290 295 300
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
305 310 315 320
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
325 330 335
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
340 345 350
Ser Pro Gly Lys
355
<210> 231
<211> 356
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 231
Thr Arg Val Asp Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Val Leu Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ser Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Ser Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Arg Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Lys Val Glu Ile Lys Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser
115 120 125
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
130 135 140
Gly Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
145 150 155 160
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
165 170 175
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
180 185 190
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
195 200 205
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
210 215 220
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
225 230 235 240
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
245 250 255
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
260 265 270
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
275 280 285
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
290 295 300
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
305 310 315 320
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
325 330 335
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
340 345 350
Ser Pro Gly Lys
355
<210> 232
<211> 356
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 232
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser
115 120 125
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
130 135 140
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
145 150 155 160
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
165 170 175
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
180 185 190
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
195 200 205
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
210 215 220
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
225 230 235 240
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
245 250 255
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
260 265 270
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
275 280 285
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
290 295 300
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
305 310 315 320
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
325 330 335
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Cys Leu
340 345 350
Ser Pro Gly Lys
355
<210> 233
<211> 354
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 233
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
130 135 140
Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
145 150 155 160
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
165 170 175
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
180 185 190
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
195 200 205
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
210 215 220
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
225 230 235 240
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
245 250 255
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
260 265 270
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
275 280 285
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
290 295 300
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
305 310 315 320
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
325 330 335
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
340 345 350
Gly Lys
<210> 234
<211> 359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 234
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Arg Val Asp
245 250 255
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
260 265 270
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
275 280 285
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
290 295 300
Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys Ser Phe Ser Leu
305 310 315 320
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
325 330 335
Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp Tyr Asp Gly Ala
340 345 350
Gly Thr Val Leu Thr Val Asn
355
<210> 235
<211> 354
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 235
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
130 135 140
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
145 150 155 160
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
165 170 175
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
180 185 190
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
195 200 205
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
210 215 220
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
225 230 235 240
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
245 250 255
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
260 265 270
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
275 280 285
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
290 295 300
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
305 310 315 320
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
325 330 335
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Cys Leu Ser Pro
340 345 350
Gly Lys
<210> 236
<211> 359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 236
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys
355
<210> 237
<211> 364
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 237
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn
245 250 255
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
260 265 270
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
275 280 285
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
290 295 300
Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu
305 310 315 320
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
325 330 335
Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn
340 345 350
Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
355 360
<210> 238
<211> 496
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 238
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro
130 135 140
Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val
145 150 155 160
Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys
165 170 175
Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr
180 185 190
Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys
195 200 205
Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser
210 215 220
Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp
225 230 235 240
Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr
260 265 270
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Cys
275 280 285
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
290 295 300
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
305 310 315 320
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
325 330 335
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
340 345 350
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
355 360 365
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
370 375 380
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
385 390 395 400
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
405 410 415
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
420 425 430
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
435 440 445
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
450 455 460
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
465 470 475 480
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
485 490 495
<210> 239
<211> 501
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 239
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Val Asn
245 250 255
Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile
260 265 270
Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp
275 280 285
Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly
290 295 300
Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu
305 310 315 320
Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys
325 330 335
Ala Gln Ser Gly Met Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn
340 345 350
Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr
385 390 395 400
Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr
405 410 415
Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr
420 425 430
Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val
435 440 445
Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val
450 455 460
Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile
465 470 475 480
Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr
485 490 495
Val Leu Thr Val Asn
500
<210> 240
<211> 359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 240
Ala Lys Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Asp Ile Gly Ser Gly
85 90 95
His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys
355
<210> 241
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 241
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
130 135 140
Pro Cys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
145 150 155 160
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
165 170 175
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
180 185 190
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
195 200 205
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
210 215 220
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
225 230 235 240
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
245 250 255
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
260 265 270
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
275 280 285
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
290 295 300
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
305 310 315 320
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
325 330 335
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
340 345 350
Gly
<210> 242
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 242
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
130 135 140
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
145 150 155 160
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
165 170 175
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
180 185 190
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
195 200 205
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
210 215 220
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
225 230 235 240
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
245 250 255
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
260 265 270
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
275 280 285
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
290 295 300
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
305 310 315 320
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
325 330 335
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Cys Leu Ser Pro
340 345 350
Gly
<210> 243
<211> 376
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 243
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Ile Ser Ser Glu Leu Asn Lys Asp Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Thr Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Leu Ser Phe Arg Ser
65 70 75 80
Thr Ile Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Glu Val Val Ser
100 105 110
Ser Thr Gly Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser
115 120 125
Pro Gly Tyr Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met
145 150 155 160
Glu Ser Leu His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu
195 200 205
Thr Ser Ser Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu
210 215 220
Ile Leu Glu Asn Val Leu Cys Gln Thr Glu Tyr Ile Phe Ala Arg Ser
225 230 235 240
Asn Pro Met Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu
245 250 255
Pro Gln Pro Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Ile
260 265 270
Pro Met Ala Asp Pro Ile Asn Lys Asn His Lys Cys Tyr Asn Ser Thr
275 280 285
Gly Val Asp Tyr Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln
290 295 300
Cys Gln Pro Trp Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala
305 310 315 320
Leu Arg Phe Pro Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro
325 330 335
Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe
340 345 350
Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Lys
355 360 365
Glu Lys Asn Lys Met Glu Phe Cys
370 375
<210> 244
<211> 616
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 244
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Ile Ser Ser Glu Leu Asn Lys Asp Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Thr Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Leu Ser Phe Arg Ser
65 70 75 80
Thr Ile Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Glu Val Val Ser
100 105 110
Ser Thr Gly Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser
115 120 125
Pro Gly Tyr Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met
145 150 155 160
Glu Ser Leu His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu
195 200 205
Thr Ser Ser Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu
210 215 220
Ile Leu Glu Asn Val Leu Cys Gln Thr Glu Tyr Ile Phe Ala Arg Ser
225 230 235 240
Asn Pro Met Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu
245 250 255
Pro Gln Pro Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Ile
260 265 270
Pro Met Ala Asp Pro Ile Asn Lys Asn His Lys Cys Tyr Asn Ser Thr
275 280 285
Gly Val Asp Tyr Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln
290 295 300
Cys Gln Pro Trp Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala
305 310 315 320
Leu Arg Phe Pro Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro
325 330 335
Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe
340 345 350
Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Lys
355 360 365
Glu Lys Asn Lys Met Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
385 390 395 400
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
405 410 415
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
420 425 430
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
435 440 445
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
450 455 460
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
465 470 475 480
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
485 490 495
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
500 505 510
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
515 520 525
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
530 535 540
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
545 550 555 560
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
565 570 575
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
580 585 590
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
595 600 605
Ser Leu Ser Leu Ser Pro Gly Lys
610 615
<210> 245
<211> 363
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 245
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Ile Ser Ser Glu Leu Asn Lys Asp Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Thr Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Leu Ser Phe Arg Ser
65 70 75 80
Thr Ile Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Glu Val Val Ser
100 105 110
Ser Thr Gly Val Leu Phe Val Lys Phe Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
130 135 140
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
145 150 155 160
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
165 170 175
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
180 185 190
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
195 200 205
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
210 215 220
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
225 230 235 240
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
245 250 255
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
260 265 270
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
275 280 285
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
290 295 300
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
305 310 315 320
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
325 330 335
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
340 345 350
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
355 360
<210> 246
<211> 377
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 246
Glu Glu Asp Gly Phe Cys Gln Pro Tyr Arg Gly Ile Ala Cys Ala Arg
1 5 10 15
Phe Ile Gly Asn Arg Thr Val Tyr Met Glu Ser Leu His Met Gln Gly
20 25 30
Glu Ile Glu Asn Gln Ile Thr Ala Ala Phe Thr Met Ile Gly Thr Ser
35 40 45
Ser His Leu Ser Asp Lys Cys Ser Gln Phe Ala Ile Pro Ser Leu Cys
50 55 60
His Tyr Ala Phe Pro Tyr Cys Asp Glu Thr Ser Ser Val Pro Lys Pro
65 70 75 80
Arg Asp Leu Cys Arg Asp Glu Cys Glu Ile Leu Glu Asn Val Leu Cys
85 90 95
Gln Thr Glu Tyr Ile Phe Ala Arg Ser Asn Pro Met Ile Leu Met Arg
100 105 110
Leu Lys Leu Pro Asn Cys Glu Asp Leu Pro Gln Pro Glu Ser Pro Glu
115 120 125
Ala Ala Asn Cys Ile Arg Ile Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
145 150 155 160
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
165 170 175
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
180 185 190
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
195 200 205
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
210 215 220
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
225 230 235 240
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
245 250 255
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
260 265 270
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
275 280 285
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
290 295 300
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
305 310 315 320
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
325 330 335
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
340 345 350
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
355 360 365
Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375
<210> 247
<211> 322
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 247
Lys Cys Tyr Asn Ser Thr Gly Val Asp Tyr Arg Gly Thr Val Ser Val
1 5 10 15
Thr Lys Ser Gly Arg Gln Cys Gln Pro Trp Asn Ser Gln Tyr Pro His
20 25 30
Thr His Thr Phe Thr Ala Leu Arg Phe Pro Glu Leu Asn Gly Gly His
35 40 45
Ser Tyr Cys Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe
50 55 60
Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys
65 70 75 80
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
85 90 95
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
100 105 110
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
115 120 125
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
130 135 140
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
145 150 155 160
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
165 170 175
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
180 185 190
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
195 200 205
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
210 215 220
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
225 230 235 240
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
245 250 255
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
260 265 270
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
275 280 285
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
290 295 300
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
305 310 315 320
Gly Lys
<210> 248
<211> 512
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 248
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Ile Ser Ser Glu Leu Asn Lys Asp Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Thr Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Leu Ser Phe Arg Ser
65 70 75 80
Thr Ile Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Glu Val Val Ser
100 105 110
Ser Thr Gly Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser
115 120 125
Pro Gly Tyr Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met
145 150 155 160
Glu Ser Leu His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu
195 200 205
Thr Ser Ser Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu
210 215 220
Ile Leu Glu Asn Val Leu Cys Gln Thr Glu Tyr Ile Phe Ala Arg Ser
225 230 235 240
Asn Pro Met Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu
245 250 255
Pro Gln Pro Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Gly
260 265 270
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr
275 280 285
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
290 295 300
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
305 310 315 320
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
325 330 335
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
340 345 350
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
355 360 365
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
370 375 380
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
385 390 395 400
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
405 410 415
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
420 425 430
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
435 440 445
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
450 455 460
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
465 470 475 480
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
485 490 495
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
500 505 510
<210> 249
<211> 469
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 249
Glu Glu Asp Gly Phe Cys Gln Pro Tyr Arg Gly Ile Ala Cys Ala Arg
1 5 10 15
Phe Ile Gly Asn Arg Thr Val Tyr Met Glu Ser Leu His Met Gln Gly
20 25 30
Glu Ile Glu Asn Gln Ile Thr Ala Ala Phe Thr Met Ile Gly Thr Ser
35 40 45
Ser His Leu Ser Asp Lys Cys Ser Gln Phe Ala Ile Pro Ser Leu Cys
50 55 60
His Tyr Ala Phe Pro Tyr Cys Asp Glu Thr Ser Ser Val Pro Lys Pro
65 70 75 80
Arg Asp Leu Cys Arg Asp Glu Cys Glu Ile Leu Glu Asn Val Leu Cys
85 90 95
Gln Thr Glu Tyr Ile Phe Ala Arg Ser Asn Pro Met Ile Leu Met Arg
100 105 110
Leu Lys Leu Pro Asn Cys Glu Asp Leu Pro Gln Pro Glu Ser Pro Glu
115 120 125
Ala Ala Asn Cys Ile Arg Ile Gly Ile Pro Met Ala Asp Pro Ile Asn
130 135 140
Lys Asn His Lys Cys Tyr Asn Ser Thr Gly Val Asp Tyr Arg Gly Thr
145 150 155 160
Val Ser Val Thr Lys Ser Gly Arg Gln Cys Gln Pro Trp Asn Ser Gln
165 170 175
Tyr Pro His Thr His Thr Phe Thr Ala Leu Arg Phe Pro Glu Leu Asn
180 185 190
Gly Gly His Ser Tyr Cys Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro
195 200 205
Trp Cys Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Cys Asp Ile
210 215 220
Pro Ala Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 250
<211> 611
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 250
Glu Val Glu Val Leu Asp Pro Asn Asp Pro Leu Gly Pro Leu Asp Gly
1 5 10 15
Gln Asp Gly Pro Ile Pro Thr Leu Lys Gly Tyr Phe Leu Asn Phe Leu
20 25 30
Glu Pro Val Asn Asn Ile Thr Ile Val Gln Gly Gln Thr Ala Ile Leu
35 40 45
His Cys Lys Val Ala Gly Asn Pro Pro Pro Asn Val Arg Trp Leu Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Ile Ile Ile Arg Lys
65 70 75 80
Thr Glu Tyr Gly Ser Arg Leu Arg Ile Gln Asp Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Tyr Gln Cys Val Ala Thr Asn Gly Met Lys Thr Ile Thr
100 105 110
Ala Thr Gly Val Leu Phe Val Arg Leu Gly Pro Thr His Ser Pro Asn
115 120 125
His Asn Phe Gln Asp Asp Tyr His Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Ile Tyr Val
145 150 155 160
Asp Ser Leu Gln Met Gln Gly Glu Ile Glu Asn Arg Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Thr His Leu Ser Asp Gln Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Phe Cys His Phe Val Phe Pro Leu Cys Asp Ala
195 200 205
Arg Ser Arg Thr Pro Lys Pro Arg Glu Leu Cys Arg Asp Glu Cys Glu
210 215 220
Val Leu Glu Ser Asp Leu Cys Arg Gln Glu Tyr Thr Ile Ala Arg Ser
225 230 235 240
Asn Pro Leu Ile Leu Met Arg Leu Gln Leu Pro Lys Cys Glu Ala Leu
245 250 255
Pro Met Pro Glu Ser Pro Asp Ala Ala Asn Cys Met Arg Ile Gly Ile
260 265 270
Pro Ala Glu Arg Leu Gly Arg Tyr His Gln Cys Tyr Asn Gly Ser Gly
275 280 285
Met Asp Tyr Arg Gly Thr Ala Ser Thr Thr Lys Ser Gly His Gln Cys
290 295 300
Gln Pro Trp Ala Leu Gln His Pro His Ser His His Leu Ser Ser Thr
305 310 315 320
Asp Phe Pro Glu Leu Gly Gly Gly His Ala Tyr Cys Arg Asn Pro Gly
325 330 335
Gly Gln Met Glu Gly Pro Trp Cys Phe Thr Gln Asn Lys Asn Val Arg
340 345 350
Met Glu Leu Cys Asp Val Pro Ser Cys Ser Pro Arg Asp Ser Ser Lys
355 360 365
Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
385 390 395 400
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
405 410 415
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
420 425 430
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
435 440 445
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
450 455 460
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
465 470 475 480
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
485 490 495
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
500 505 510
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
515 520 525
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
530 535 540
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
545 550 555 560
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
565 570 575
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
580 585 590
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
595 600 605
Pro Gly Lys
610
<210> 251
<211> 616
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 251
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Thr Ser Ser Glu Ile Asp Lys Gly Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Ser Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Ile Ser Phe Arg Ala
65 70 75 80
Thr Asn Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Lys Val Val Ser
100 105 110
Thr Thr Gly Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser
115 120 125
Pro Gly Ser Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met
145 150 155 160
Glu Ser Leu His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu
195 200 205
Thr Ser Ser Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu
210 215 220
Val Leu Glu Asn Val Leu Cys Gln Thr Glu Tyr Ile Phe Ala Arg Ser
225 230 235 240
Asn Pro Met Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu
245 250 255
Pro Gln Pro Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Ile
260 265 270
Pro Met Ala Asp Pro Ile Asn Lys Asn His Lys Cys Tyr Asn Ser Thr
275 280 285
Gly Val Asp Tyr Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln
290 295 300
Cys Gln Pro Trp Asn Ser Gln Tyr Pro His Thr His Ser Phe Thr Ala
305 310 315 320
Leu Arg Phe Pro Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro
325 330 335
Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe
340 345 350
Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Lys
355 360 365
Glu Lys Asn Lys Met Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
385 390 395 400
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
405 410 415
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
420 425 430
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
435 440 445
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
450 455 460
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
465 470 475 480
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
485 490 495
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
500 505 510
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
515 520 525
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
530 535 540
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
545 550 555 560
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
565 570 575
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
580 585 590
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
595 600 605
Ser Leu Ser Leu Ser Pro Gly Lys
610 615
<210> 252
<211> 615
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 252
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Thr Ser Ser Glu Ile Asp Lys Asp Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Asn Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Ile Ser Phe Arg Ala
65 70 75 80
Thr Asn Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Ser Gly Lys Lys Val Val Ser
100 105 110
Thr Thr Gly Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser
115 120 125
Pro Gly Ser Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met
145 150 155 160
Glu Ser Leu His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu
195 200 205
Thr Ser Ser Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu
210 215 220
Val Leu Glu Asn Val Leu Cys His Thr Glu Tyr Ile Phe Ala Arg Ser
225 230 235 240
Asn Pro Met Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu
245 250 255
Pro Gln Pro Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Ile
260 265 270
Pro Met Ala Asp Pro Ile Asn Lys Asn His Lys Cys Tyr Asn Ser Thr
275 280 285
Gly Val Asp Tyr Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln
290 295 300
Cys Gln Pro Trp Asn Ser Gln Tyr Pro His Thr His Ser Phe Thr Ala
305 310 315 320
Leu Arg Phe Pro Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro
325 330 335
Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe
340 345 350
Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Lys
355 360 365
Glu Lys Asn Lys Met Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
385 390 395 400
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
405 410 415
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
420 425 430
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
435 440 445
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
450 455 460
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
465 470 475 480
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
485 490 495
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
500 505 510
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
515 520 525
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
530 535 540
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
545 550 555 560
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
565 570 575
Ser Lys Leu Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
580 585 590
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
595 600 605
Leu Ser Leu Ser Pro Gly Lys
610 615
<210> 253
<211> 382
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 253
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Ile Ser Ser Glu Leu Asn Lys Asp Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Thr Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Leu Ser Phe Arg Ser
65 70 75 80
Thr Ile Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Glu Val Val Ser
100 105 110
Ser Thr Gly Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser
115 120 125
Pro Gly Tyr Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met
145 150 155 160
Glu Ser Leu His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu
195 200 205
Thr Ser Ser Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu
210 215 220
Ile Leu Glu Asn Val Leu Cys Gln Thr Glu Tyr Ile Phe Ala Arg Ser
225 230 235 240
Asn Pro Met Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu
245 250 255
Pro Gln Pro Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Ile
260 265 270
Pro Met Ala Asp Pro Ile Asn Lys Asn His Lys Cys Tyr Asn Ser Thr
275 280 285
Gly Val Asp Tyr Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln
290 295 300
Cys Gln Pro Trp Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala
305 310 315 320
Leu Arg Phe Pro Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro
325 330 335
Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe
340 345 350
Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Lys
355 360 365
Glu Lys Asn Lys Met Glu His His His His His His His His
370 375 380
<210> 254
<211> 380
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 254
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Ile Ser Ser Glu Leu Asn Lys Asp Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Thr Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Leu Ser Phe Arg Ser
65 70 75 80
Thr Ile Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Glu Val Val Ser
100 105 110
Ser Thr Gly Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser
115 120 125
Pro Gly Tyr Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met
145 150 155 160
Glu Ser Leu His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu
195 200 205
Thr Ser Ser Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu
210 215 220
Ile Leu Glu Asn Val Leu Cys Gln Thr Glu Tyr Ile Phe Ala Arg Ser
225 230 235 240
Asn Pro Met Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu
245 250 255
Pro Gln Pro Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Ile
260 265 270
Pro Met Ala Asp Pro Ile Asn Lys Asn His Lys Cys Tyr Asn Ser Thr
275 280 285
Gly Val Asp Tyr Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln
290 295 300
Cys Gln Pro Trp Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala
305 310 315 320
Leu Arg Phe Pro Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro
325 330 335
Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe
340 345 350
Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Lys
355 360 365
Glu Lys Asn Lys Met Glu His His His His His His
370 375 380
<210> 255
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 255
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Ile Ser Ser Glu Leu Asn Lys Asp Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Thr Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Leu Ser Phe Arg Ser
65 70 75 80
Thr Ile Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Glu Val Val Ser
100 105 110
Ser Thr Gly Val Leu Phe Val Lys Phe His His His His His
115 120 125
<210> 256
<211> 382
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 256
Gln Glu Thr Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser
1 5 10 15
Trp Asn Thr Ser Ser Glu Ile Asp Lys Gly Ser Tyr Leu Thr Leu Asp
20 25 30
Glu Pro Met Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu
35 40 45
His Cys Lys Val Ser Gly Asn Pro Pro Pro Ser Ile Arg Trp Phe Lys
50 55 60
Asn Asp Ala Pro Val Val Gln Glu Pro Arg Arg Ile Ser Phe Arg Ala
65 70 75 80
Thr Asn Tyr Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp
85 90 95
Thr Gly Tyr Phe Gln Cys Val Ala Thr Asn Gly Lys Lys Val Val Ser
100 105 110
Thr Thr Gly Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser
115 120 125
Pro Gly Ser Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr
130 135 140
Arg Gly Ile Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met
145 150 155 160
Glu Ser Leu His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala
165 170 175
Phe Thr Met Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln
180 185 190
Phe Ala Ile Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu
195 200 205
Thr Ser Ser Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu
210 215 220
Val Leu Glu Asn Val Leu Cys Gln Thr Glu Tyr Ile Phe Ala Arg Ser
225 230 235 240
Asn Pro Met Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu
245 250 255
Pro Gln Pro Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Ile
260 265 270
Pro Met Ala Asp Pro Ile Asn Lys Asn His Lys Cys Tyr Asn Ser Thr
275 280 285
Gly Val Asp Tyr Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln
290 295 300
Cys Gln Pro Trp Asn Ser Gln Tyr Pro His Thr His Ser Phe Thr Ala
305 310 315 320
Leu Arg Phe Pro Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro
325 330 335
Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe
340 345 350
Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Lys
355 360 365
Glu Lys Asn Lys Met Glu His His His His His His His His
370 375 380
<210> 257
<211> 361
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 257
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro
115 120 125
Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr
130 135 140
Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu
145 150 155 160
Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln
165 170 175
Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr
180 185 190
Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr
195 200 205
Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly
210 215 220
Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
225 230 235 240
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro
245 250 255
Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg
260 265 270
Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly
275 280 285
Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly
290 295 300
Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu
305 310 315 320
Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln
325 330 335
Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu
340 345 350
Leu Lys Ser His His His His His His
355 360
<210> 258
<211> 371
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 258
Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Val Thr Gly Ala Asn Tyr Gly Leu Ala
20 25 30
Ala Thr Tyr Trp Tyr Arg Lys Asn Pro Gly Ser Ser Asn Gln Glu Arg
35 40 45
Ile Ser Ile Ser Gly Arg Tyr Val Glu Ser Val Asn Lys Arg Thr Met
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly Ala Gly Ala Pro Trp Leu Val
85 90 95
Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu
115 120 125
Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met
130 135 140
Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp
145 150 155 160
Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
165 170 175
Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala
180 185 190
Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
195 200 205
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr
210 215 220
Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
225 230 235 240
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser
260 265 270
Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser
275 280 285
Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp
290 295 300
Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser
305 310 315 320
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
325 330 335
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro
340 345 350
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His
355 360 365
His His His
370
<210> 259
<211> 359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 259
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
115 120 125
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr
130 135 140
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
145 150 155 160
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
165 170 175
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
180 185 190
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
195 200 205
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
210 215 220
Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile
245 250 255
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
260 265 270
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser
275 280 285
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro
290 295 300
Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
305 310 315 320
Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
325 330 335
Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
340 345 350
Ser His His His His His His
355
<210> 260
<211> 369
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 260
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln
115 120 125
Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys
145 150 155 160
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser
165 170 175
Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu
180 185 190
Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu
195 200 205
Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp
210 215 220
His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
260 265 270
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
275 280 285
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
290 295 300
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser
305 310 315 320
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
325 330 335
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
340 345 350
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His His His
355 360 365
His
<210> 261
<211> 491
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 261
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly
225 230 235 240
Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala
245 250 255
Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr
260 265 270
Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly
275 280 285
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr
290 295 300
Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser
305 310 315 320
Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala
325 330 335
Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr
340 345 350
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln
370 375 380
Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr
385 390 395 400
Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys
405 410 415
Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala
420 425 430
Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr
435 440 445
Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr
450 455 460
Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys
465 470 475 480
Leu Glu Leu Lys Ser His His His His His His
485 490
<210> 262
<211> 501
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 262
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Gly Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp
210 215 220
Leu Arg Gln Trp Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
245 250 255
Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val
260 265 270
Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met
275 280 285
His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr
290 295 300
Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp
305 310 315 320
Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
325 330 335
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
340 345 350
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr
355 360 365
Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser
385 390 395 400
Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser
405 410 415
Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys
420 425 430
Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg
435 440 445
Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser
450 455 460
Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser
465 470 475 480
Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His
485 490 495
His His His His His
500
<210> 263
<211> 359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 263
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
115 120 125
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr
130 135 140
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
145 150 155 160
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
165 170 175
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
180 185 190
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
195 200 205
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
210 215 220
Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile
245 250 255
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
260 265 270
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser
275 280 285
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro
290 295 300
Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
305 310 315 320
Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
325 330 335
Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
340 345 350
Ser His His His His His His
355
<210> 264
<211> 369
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 264
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Gln Ser Leu Ala Ile Ser Thr Arg Ser Tyr Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln
115 120 125
Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys
145 150 155 160
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser
165 170 175
Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu
180 185 190
Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu
195 200 205
Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp
210 215 220
His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
260 265 270
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
275 280 285
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
290 295 300
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser
305 310 315 320
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
325 330 335
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
340 345 350
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His His His
355 360 365
His
<210> 265
<211> 480
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 265
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr
130 135 140
Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly
195 200 205
Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val
210 215 220
Leu Thr Val Asn Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser
225 230 235 240
Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys
245 250 255
Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln
260 265 270
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg
275 280 285
Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr
290 295 300
Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr
305 310 315 320
Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His
325 330 335
Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
340 345 350
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
355 360 365
Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu
370 375 380
Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn
385 390 395 400
Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp
405 410 415
Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly
420 425 430
Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp
435 440 445
Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe
450 455 460
Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His His His His
465 470 475 480
<210> 266
<211> 490
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 266
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ser Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Val Thr
130 135 140
Gly Ala Asn Tyr Gly Leu Ala Ala Thr Tyr Trp Tyr Arg Lys Asn Pro
145 150 155 160
Gly Ser Ser Asn Gln Glu Arg Ile Ser Ile Ser Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Thr Met Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Tyr Pro Trp Gly
195 200 205
Ala Gly Ala Pro Trp Leu Val Gln Trp Tyr Asp Gly Ala Gly Thr Val
210 215 220
Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
225 230 235 240
Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg
245 250 255
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe
260 265 270
Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
275 280 285
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn
290 295 300
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser
305 310 315 320
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
325 330 335
Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp
340 345 350
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
355 360 365
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser
370 375 380
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
385 390 395 400
Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
405 410 415
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser
420 425 430
Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
435 440 445
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
450 455 460
Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
465 470 475 480
Glu Leu Lys Ser His His His His His His
485 490
<210> 267
<211> 483
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 267
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ala Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met
195 200 205
Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser Asp Ile Lys Leu
225 230 235 240
Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met
245 250 255
Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp
260 265 270
Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
275 280 285
Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala
290 295 300
Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
305 310 315 320
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr
325 330 335
Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
340 345 350
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
355 360 365
Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser
370 375 380
Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser
385 390 395 400
Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp
405 410 415
Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser
420 425 430
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
435 440 445
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro
450 455 460
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His
465 470 475 480
His His His
<210> 268
<211> 493
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 268
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Pro Gly Val Gln Pro
100 105 110
Ala Pro Gly Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr
115 120 125
Ala Thr Lys Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr
130 135 140
Asp Thr Ser Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro
145 150 155 160
Gly Thr Thr Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu
165 170 175
Ser Val Asn Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu
180 185 190
Thr Val Ala Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met
195 200 205
Ala Ile Ser Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala
210 215 220
Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu
245 250 255
Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly
260 265 270
Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly
275 280 285
Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr
290 295 300
Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys
305 310 315 320
Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp
325 330 335
Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu
340 345 350
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly
355 360 365
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu
370 375 380
Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr
385 390 395 400
Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln
405 410 415
Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys
420 425 430
Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr
435 440 445
Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr
450 455 460
Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly
465 470 475 480
Thr Lys Leu Glu Leu Lys Ser His His His His His His
485 490
<210> 269
<211> 496
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 269
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
210 215 220
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser
245 250 255
Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys
260 265 270
Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln
275 280 285
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg
290 295 300
Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr
305 310 315 320
Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr
325 330 335
Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His
340 345 350
Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
370 375 380
Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu
385 390 395 400
Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn
405 410 415
Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp
420 425 430
Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly
435 440 445
Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp
450 455 460
Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe
465 470 475 480
Gly Ala Gly Thr Lys Leu Glu Leu Lys Ser His His His His His His
485 490 495
<210> 270
<211> 506
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列
<400> 270
Thr Arg Val Asp Gln Thr Pro Arg Thr Ala Thr Lys Glu Thr Gly Glu
1 5 10 15
Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser Tyr Gly Leu Tyr
20 25 30
Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr Asp Trp Glu Arg
35 40 45
Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn Lys Gly Ala Lys
50 55 60
Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala Asp Ser Ala Thr
65 70 75 80
Tyr Tyr Cys Lys Ala Arg Glu Ala Arg His Pro Trp Leu Arg Gln Trp
85 90 95
Tyr Asp Gly Ala Gly Thr Val Leu Thr Val Asn Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ser Val Asn Gln Thr Pro Arg Thr Ala Thr Lys
130 135 140
Glu Thr Gly Glu Ser Leu Thr Ile Asn Cys Val Leu Thr Asp Thr Ser
145 150 155 160
Tyr Gly Leu Tyr Ser Thr Ser Trp Phe Arg Lys Asn Pro Gly Thr Thr
165 170 175
Asp Trp Glu Arg Met Ser Ile Gly Gly Arg Tyr Val Glu Ser Val Asn
180 185 190
Lys Arg Ala Lys Ser Phe Ser Leu Arg Ile Lys Asp Leu Thr Val Ala
195 200 205
Asp Ser Ala Thr Tyr Tyr Cys Lys Ala Gln Ser Gly Met Ala Ile Ser
210 215 220
Thr Gly Ser Gly His Gly Tyr Asn Trp Tyr Asp Gly Ala Gly Thr Val
225 230 235 240
Leu Thr Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg
260 265 270
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe
275 280 285
Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
290 295 300
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn
305 310 315 320
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser
325 330 335
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
340 345 350
Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp
355 360 365
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser
385 390 395 400
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
405 410 415
Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
420 425 430
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser
435 440 445
Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
450 455 460
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
485 490 495
Glu Leu Lys Ser His His His His His His
500 505

Claims (66)

1.一种受体酪氨酸激酶样孤儿受体1(ROR1)特异性抗原结合分子，所述抗原结合分子包含由式(I)代表的氨基酸序列：
FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 (I)
其中
FW1是框架区
CDR1是CDR序列
FW2是框架区
HV2是高变序列
FW3a是框架区
HV4是高变序列
FW3b是框架区
CDR3是CDR序列
FW4是框架区
或所述抗原结合分子的功能性变体。
2.如权利要求1所述的ROR1特异性抗原结合分子，其中所述ROR1特异性抗原结合分子不结合受体酪氨酸激酶样孤儿受体2(ROR2)。
3.如权利要求1或权利要求2所述的ROR1特异性抗原结合分子，其中所述ROR1特异性抗原结合分子结合人ROR1与鼠ROR1(mROR1)两者。
4.如权利要求1至3中任一项所述的ROR1特异性抗原结合分子，其中所述ROR1特异性抗原结合分子结合去糖基化ROR1。
5.如权利要求1至4中任一项所述的ROR1特异性抗原结合分子，其中所述ROR1特异性抗原结合分子不结合选自以下的线性肽序列：
YMESLHMQGEIENQI(SEQ ID NO：34)
CQPWNSQYPHTHTFTALRFP(SEQ ID NO：35)
RSTIYGSRLRIRNLDTTDTGYFQ(SEQ ID NO：36)
QCVATNGKEVVSSTGVLFVKFGPPPTASPGYSDEYE(SEQ ID NO：37)
6.如权利要求1至5中任一项所述的ROR1特异性抗原结合分子，其中
FW1是具有20至28个氨基酸的框架区
CDR1是选自DTSYGLYS(SEQ ID NO：1)、GAKYGLAA(SEQ ID NO：2)、GAKYGLFA(SEQ ID NO：3)、GANYGLAA(SEQ ID NO：4)或GANYGLAS(SEQ ID NO：5)的CDR序列
FW2是具有6至14个氨基酸的框架区
HV2是选自TTDWERMSIG(SEQ ID NO：6)、SSNQERISIS(SEQ ID NO：7)或SSNKEQISIS(SEQID NO：8)的高变序列
FW3a是具有6至10个氨基酸的框架区
HV4是选自NKRAK(SEQ ID NO：9)、NKRTM(SEQ ID NO：10)、NKGAK(SEQ ID NO：11)或NKGTK(SEQ ID NO：12)的高变序列
FW3b是具有17至24个氨基酸的框架区
CDR3是选自QSGMAISTGSGHGYNWY(SEQ ID NO：13)、QSGMAIDIGSGHGYNWY(SEQ ID NO：14)、YPWAMWGQWY(SEQ ID NO：15)、VFMPQHWHPAAHWY(SEQ ID NO：16)、REARHPWLRQWY(SEQ IDNO：17)或YPWGAGAPWLVQWY(SEQ ID NO：18)的CDR序列
FW4是具有7至14个氨基酸的框架区
或它们的与它们具有至少45％序列同一性的功能性变体。
7.如权利要求6所述的ROR1特异性抗原结合分子，其中FW1选自：ASVNQTPRTATKETGESLTINCVLT(SEQ ID NO：19)、AKVDQTPRTATKETGESLTINCVLT(SEQ ID NO：20)、TRVDQTPRTATKETGESLTINCVVT(SEQ ID NO：21)、TRVDQTPRTATKETGESLTINCVLT(SEQ IDNO：22)、ASVNQTPRTATKETGESLTINCVVT(SEQ ID NO：23)或TRVDQSPSSLSASVGDRVTITCVLT(SEQID NO：24)，FW2选自：TSWFRKNPG(SEQ ID NO：25)或TYWYRKNPG(SEQ ID NO：26)；FW3a选自：GRYVESV(SEQ ID NO：27)或GRYSESV(SEQ ID NO：28)，FW3b选自：SFSLRIKDLTVADSATYYCKA(SEQ ID NO：29)、SFTLTISSLQPEDSATYYCRA(SEQ ID NO：30)或SFTLTISSLQPEDFATYYCKA(SEQID NO：31)，并且FW4选自：DGAGTVLTVN(SEQ ID NO：32)或DGAGTKVEIK(SEQ ID NO：33)；或它们的具有至少45％的序列同一性的功能性变体。
8.如权利要求1至7中任一项所述的ROR1特异性抗原结合分子，其中所述ROR1特异性抗原结合分子包含选自以下的氨基酸序列：
ASVNQTPRTATKETGESLTINCVLTDTSYGLYSTSWFRKNPGTTDWERMSIGGRYVESVNKRAKSFSLRIKDLTVADSATYYCKAQSGM[AISTGSGHGYNWYDGAGTVLTVN(SEQ ID NO：39)；
AKVDQTPRTATKETGESLTINCVLTDTSYGLYSTSWFRKNPGTTDWERMSIGGRYVESVNKRAKSFSLRIKDLTVADSATYYCKAQSGM[AIDIGSGHGYNWYDGAGTVLTVN(SEQ ID NO：40)；
TRVDQTPRTATKETGESLTINCVVTGAKYGLAATYWYRKNPGSSNQERISISGRYVESVNKRTMSFSLRIKDLTVADSATYYCKAYPWAMWGQWYDGAGTVLTVN(SEQ ID NO：41)；
TRVDQTPRTATKETGESLTINCVVTGAKYGLFATYWYRKNPGSSNQERISISGRYVESVNKRTMSFSLRIKDLTVADSATYYCKAVFMPQHWHPAAHWYDGAGTVLTVN(SEQ ID NO：42)；
TRVDQTPRTATKETGESLTINCVLTDTSYGLYSTSWFRKNPGTTDWERMSIGGRYVESVNKGAKSFSLRIKDLTVADSATYYCKAREARHPWLRQWYDGAGTVLTVN(SEQ ID NO：43)；
ASVNQTPRTATKETGESLTINCVVTGANYGLAATYWYRKNPGSSNQERISISGRYVESVNKRTMSFSLRIKDLTVADSATYYCKAYPWGAGAPWLVQWYDGAGTVLTVN(SEQ ID NO：44)；
TRVDQSPSSLSASVGDRVTITCVLTGANYGLASTYWYRKNPGSSNKEQISISGRYSESVNKGTKSFTLTISSLQPEDSATYYCRAYPWGAGAPWLVQWYDGAGTKVEIK(SEQ ID NO：45)；
TRVDQSPSSLSASVGDRVTITCVLTGANYGLASTYWYRKNPGSSNQERISISGRYSESVNKRTMSFTLTISSLQPEDSATYYCRAYPWGAGAPWLVQWYDGAGTKVEIK(SEQ ID NO：46)；
TRVDQSPSSLSASVGDRVTITCVLTDTSYGLYSTSWFRKNPGTTDWERMSIGGRYVESVNKGAKSFTLTISSLQPEDFATYYCKAREARHPWLRQWYDGAGTKVEIK(SEQ ID NO：47)；
TRVDQSPSSLSASVGDRVTITCVLTDTSYGLYSTYWYRKNPGSSNKEQISISGRYSESVNKGTKSFTLTISSLQPEDSATYYCRAREARHPWLRQWYDGAGTKVEIK(SEQ ID NO：48)；
TRVDQSPSSLSASVGDRVTITCVLTDTSYGLYSTYWYRKNPGTTDWERMSIGGRYSESVNKGAKSFTLTISSLQPEDSATYYCRAREARHPWLRQWYDGAGTKVEIK(SEQ ID NO：49)；或它们的具有至少45％的序列同一性的功能性变体。
9.如权利要求1至8中任一项所述的ROR1特异性抗原结合分子，其中所述ROR1特异性抗原结合分子是人源化的。
10.如权利要求1至8中任一项所述的ROR1特异性抗原结合分子，其中所述ROR1特异性抗原结合分子是去免疫化的。
11.如权利要求1至10中任一项所述的ROR1特异性抗原结合分子，其中所述双特异性抗原结合分子缀合于可检测标记、染料、毒素、药物、前药、放射性核素或生物活性分子。
12.如权利要求1至11中任一项所述的ROR1特异性抗原结合分子，其中所述特异性抗原结合分子以约0.01至50nM，优选地以约0.1至30nM，甚至更优选地以约0.1至10nM的亲和常数与ROR1蛋白选择性相互作用。
13.如权利要求1至12中任一项所述的ROR1特异性抗原结合分子，其中所述特异性抗原结合分子能够介导对ROR1表达性肿瘤细胞的杀伤。
14.如权利要求1至12中任一项所述的ROR1特异性抗原结合分子，其中所述特异性抗原结合分子能够抑制癌细胞增殖。
15.如权利要求1至12中任一项所述的ROR1特异性抗原结合分子，其中所述特异性抗原结合分子在结合ROR1后能够被胞吞。
16.一种重组融合蛋白，所述重组融合蛋白包含如权利要求1至15中任一项中所要求保护的特异性抗原结合分子。
17.如权利要求16中所要求保护的重组融合蛋白，其中所述特异性抗原结合分子融合于一种或多种生物活性蛋白。
18.如权利要求17中所要求保护的重组融合蛋白，其中所述特异性抗原结合分子通过一个或多个接头结构域融合于一种或多种生物活性蛋白。
19.如权利要求17或18中所要求保护的重组融合蛋白，其中至少一种生物活性蛋白是免疫球蛋白、免疫球蛋白Fc区、免疫球蛋白Fab区、单链Fv(scFv)、微型双功能抗体、微型三功能抗体、微型四功能抗体、双特异性t细胞衔接物(BiTE)、内含肽、VNAR结构域、单结构域抗体(sdAb)、VH结构域或支架蛋白。
20.如权利要求19中所要求保护的重组融合蛋白，其中至少一种生物活性蛋白是免疫球蛋白Fc区。
21.一种ROR1特异性嵌合抗原受体(CAR)，所述嵌合抗原受体包含至少一个如权利要求1至10中任一项中所定义的ROR1特异性抗原结合分子，其融合或缀合于至少一个跨膜区域和至少一个细胞内结构域。
22.一种细胞，所述细胞包含根据权利要求21所述的嵌合抗原受体，所述细胞优选地是经工程改造T细胞。
23.一种核酸序列，所述核酸序列包含编码根据权利要求1至21中任一项所述的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体的多核苷酸序列。
24.一种载体，所述载体包含如权利要求23中所要求保护的核酸序列，任选地，所述载体还包含一条或多条调控序列。
25.一种宿主细胞，所述宿主细胞包含如权利要求24中所要求保护的载体。
26.一种用于制备特异性抗原结合分子、重组融合蛋白或嵌合抗原受体的方法，所述方法包括在各种条件下培养或维持包含如权利要求23所述的多核苷酸的宿主细胞，以使所述宿主细胞产生所述结合分子，任选地，所述方法还包括分离所述结合分子。
27.一种药物组合物，所述药物组合物包含如权利要求1至21中任一项所述的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体。
28.如权利要求1至21中任一项所述的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体，所述特异性抗原结合分子、重组融合蛋白或嵌合抗原受体用于疗法中。
29.如权利要求1至21中任一项所述的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体，所述特异性抗原结合分子、重组融合蛋白或嵌合抗原受体用于治疗癌症。
30.如权利要求29所述的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体，其中所述癌症是ROR1阳性癌症类型。
31.如权利要求29所述的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体，其中所述癌症选自包含以下的组：血液癌症，诸如淋巴瘤和白血病、慢性淋巴细胞性白血病(CLL)、套膜细胞淋巴瘤(MCL)、B细胞急性淋巴母细胞性白血病(B-ALL)、边缘区淋巴瘤(MZL)、非霍奇金淋巴瘤(NHL)、急性骨髓性白血病(AML)，以及实体肿瘤，包括神经母细胞瘤、肾癌、肺癌、结肠癌、卵巢癌、胰腺癌、乳腺癌、皮肤癌、子宫癌、前列腺癌、甲状腺癌、头颈部癌、膀胱癌、胃癌或肝癌。
32.如权利要求1至21中任一项所述的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体制造用于治疗有需要的患者的疾病的药剂的用途。
33.一种治疗需要治疗的患者的疾病的方法，所述方法包括向所述患者施用治疗有效剂量的如权利要求1至21中任一项所述的特异性抗原结合分子、重组融合蛋白或嵌合抗原受体或如权利要求27所述的药物组合物。
34.如权利要求33所述的方法，其中所述疾病是癌症。
35.如权利要求34所述的方法，其中所述癌症是ROR1阳性癌症类型。
36.如权利要求34所述的方法，其中所述癌症选自包含以下的组：血液癌症，诸如淋巴瘤和白血病、慢性淋巴细胞性白血病(CLL)、套膜细胞淋巴瘤(MCL)、B细胞急性淋巴母细胞性白血病(B-ALL)、边缘区淋巴瘤(MZL)、非霍奇金淋巴瘤(NHL)、急性骨髓性白血病(AML)，以及实体肿瘤，包括神经母细胞瘤、肾癌、肺癌、结肠癌、卵巢癌、胰腺癌、乳腺癌、皮肤癌、子宫癌、前列腺癌、甲状腺癌、头颈部癌、膀胱癌、胃癌或肝癌。
37.一种测定样品中靶标分析物的存在的方法，所述方法包括将如权利要求1至15中任一项所述的以可检测方式标记的特异性抗原结合分子或如权利要求16至20所述的重组融合蛋白添加至所述样品中，以及检测所述分子与所述靶标分析物的结合。
38.一种使受试者中的疾病部位成像的方法，所述方法包括向受试者施用如权利要求1至15中任一项中所要求保护的以可检测方式标记的特异性抗原结合分子或如权利要求16至20中任一项所述的以可检测方式标记的重组融合蛋白。
39.一种诊断受试者的疾病或医学状况的方法，所述方法包括施用如权利要求1至15中任一项中所要求保护的特异性抗原结合分子或如权利要求16至20所述的重组融合蛋白。
40.一种抗体、抗体片段或抗原结合分子，所述抗体、抗体片段或抗原结合分子与如权利要求1至15中任一项所述的ROR1特异性抗原结合分子竞争结合ROR1。
41.一种用于诊断罹患癌症或易患癌症的受试者，或用于提供所述受试者的疾患的预后的试剂盒，所述试剂盒包括用于检测存在于来自测试受试者的样品中的抗原的浓度的检测工具，其中所述检测工具包括如权利要求1至15中任一项中所定义的ROR1特异性抗原结合分子、如权利要求16至20中任一项中所定义的重组融合蛋白、如权利要求21中所定义的CAR、或如权利要求23中所定义的核酸，各自任选地被衍生化，其中所述样品中存在抗原表明所述受试者罹患癌症。
42.根据权利要求41所述的试剂盒，其中所述抗原包括ROR1蛋白，更优选地包括所述ROR1蛋白的细胞外结构域。
43.根据权利要求41所述的试剂盒，其中所述试剂盒用于鉴定所述样品中ROR1阳性细胞的存在或不存在，或测定所述样品中所述ROR1阳性细胞的浓度。
44.根据权利要求41所述的试剂盒，其中所述试剂盒包括测定相对于其进行比较的阳性对照和/或阴性对照。
45.根据权利要求41所述的试剂盒，其中所述试剂盒还包括可被检测的标记。
46.一种用于诊断罹患癌症或易患癌症的受试者，或用于提供所述受试者的疾患的预后的方法，所述方法包括检测存在于从受试者获得的样品中的抗原的浓度，其中所述检测使用各自任选地被衍生化的如权利要求1至15中任一项中所定义的ROR1特异性抗原结合分子、如权利要求16至20中任一项中所定义的重组融合蛋白、如权利要求21中所定义的CAR、或如权利要求23中所定义的核酸序列实现，并且其中所述样品中存在抗原表明所述受试者罹患癌症。
47.一种在体外或在患者中杀伤表达ROR1的细胞或抑制所述细胞的生长的方法，所述方法包括向所述细胞施用药学上有效量或药学上有效剂量的(i)如权利要求1至15中任一项中所定义的ROR1特异性抗原结合分子、如权利要求16至20中任一项中所定义的重组融合蛋白、如权利要求23中所定义的核酸、或根据权利要求21或23所述的CAR或细胞，或(ii)根据权利要求27所述的药物组合物。
48.如权利要求47所述的方法，其中表达ROR1的所述细胞是癌细胞。
49.根据权利要求47或48所述的方法，其中所述ROR1是人ROR1。
50.一种包含由式(II)代表的氨基酸序列的特异性抗原结合分子：
X-FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4-Y (II)
其中
FW1是框架区
CDR1是CDR序列
FW2是框架区
HV2是高变序列
FW3a是框架区
HV4是高变序列
FW3b是框架区
CDR3是CDR序列
FW4是框架区
X和Y是任选氨基酸序列
其中所述特异性抗原结合分子缀合于第二部分。
51.如权利要求50所述的特异性抗原结合分子，其中X或Y单独地是不存在的，或选自包含以下的组：免疫球蛋白、免疫球蛋白Fc区、免疫球蛋白Fab区、单链Fv(scFv)、微型双功能抗体、微型三功能抗体、微型四功能抗体、双特异性t细胞衔接物(BiTE)、内含肽、VNAR结构域、单结构域抗体(sdAb)、VH结构域或支架蛋白。
52.如权利要求50或权利要求51所述的特异性抗原结合分子，其中所述缀合通过所述特异性抗原结合分子的氨基酸序列中的半胱氨酸残基来进行。
53.如权利要求50或权利要求51所述的特异性抗原结合分子，其中所述缀合通过并入在所述特异性抗原结合分子的氨基酸序列的N末端或C末端的硫醇、氨基氧基或肼基部分来进行。
54.如权利要求50至53中任一项所述的特异性抗原结合分子，其中所述第二部分选自包含以下的组：免疫球蛋白、免疫球蛋白Fc区、免疫球蛋白Fab区、单链Fv(scFv)、微型双功能抗体、微型三功能抗体、微型四功能抗体、双特异性t细胞衔接物(BiTE)、内含肽、VNAR结构域、单结构域抗体(sdAb)、VH结构域或支架蛋白。
55.如权利要求50至53中任一项所述的特异性抗原结合分子，其中所述第二部分选自包含以下的组：可检测标记、染料、毒素、药物、前药、放射性核素或生物活性分子。
56.根据权利要求50至53或55中任一项所述的特异性抗原结合分子，其中所述第二部分是至少一种选自包含以下的组的毒素：
·类美登素，
·澳瑞他汀，
·蒽环霉素，优选地是PNU衍生蒽环霉素
·鹅膏菌素衍生物，优选地是α-鹅膏菌素衍生物
·卡奇霉素，
·微管溶素
·倍癌霉素
·放射性同位素-诸如α发射放射性核素，诸如227Th或225Ac标记
·包含毒性有效载荷的脂质体，
·蛋白质毒素
·紫杉烷
·吡咯并苯并二氮呯和/或
·吲哚啉并苯并二氮呯假二聚体和/或
·剪接体抑制剂
·CDK11抑制剂
·吡啶并苯并二氮呯
57.根据权利要求50至56中任一项所述的特异性抗原结合分子，其中所述特异性抗原结合分子是受体酪氨酸激酶样孤儿受体1(ROR1)特异性抗原结合分子。
58.根据权利要求57所述的特异性抗原结合分子，其中所述ROR1特异性抗原结合分子不结合受体酪氨酸激酶样孤儿受体2(ROR2)。
59.根据权利要求57或58所述的特异性抗原结合分子，其中所述ROR1特异性抗原结合分子结合人ROR1与鼠ROR1(mROR1)两者。
60.根据权利要求57至59中任一项所述的特异性抗原结合分子，其中所述ROR1特异性抗原结合分子结合去糖基化ROR1。
61.根据权利要求57至60中任一项所述的特异性抗原结合分子，其中所述ROR1特异性抗原结合分子不结合选自以下的线性肽序列：
YMESLHMQGEIENQI(SEQ ID NO：34)
CQPWNSQYPHTHTFTALRFP(SEQ ID NO：35)
RSTIYGSRLRIRNLDTTDTGYFQ(SEQ ID NO：36)
QCVATNGKEVVSSTGVLFVKFGPPPTASPGYSDEYE(SEQ ID NO：37)
62.根据权利要求57至61中任一项所述的特异性抗原结合分子，其中：
FW1是具有20至28个氨基酸的框架区
CDR1是选自DTSYGLYS(SEQ ID NO：1)、GAKYGLAA(SEQ ID NO：2)、GAKYGLFA(SEQ ID NO：3)、GANYGLAA(SEQ ID NO：4)或GANYGLAS(SEQ ID NO：5)的CDR序列
FW2是具有6至14个氨基酸的框架区
HV2是选自TTDWERMSIG(SEQ ID NO：6)、SSNQERISIS(SEQ ID NO：7)或SSNKEQISIS(SEQID NO：8)的高变序列
FW3a是具有6至10个氨基酸的框架区
HV4是选自NKRAK(SEQ ID NO：9)、NKRTM(SEQ ID NO：10)、NKGAK(SEQ ID NO：11)或NKGTK(SEQ ID NO：12)的高变序列
FW3b是具有17至24个氨基酸的框架区
CDR3是选自QSGMAISTGSGHGYNWY(SEQ ID NO：13)、QSGMAIDIGSGHGYNWY(SEQ ID NO：14)、YPWAMWGQWY(SEQ ID NO：15)、VFMPQHWHPAAHWY(SEQ ID NO：16)、REARHPWLRQWY(SEQ IDNO：17)或YPWGAGAPWLVQWY(SEQ ID NO：18)的CDR序列
FW4是具有7至14个氨基酸的框架区
或它们的与它们具有至少45％序列同一性的功能性变体。
63.根据权利要求57至62中任一项所述的特异性抗原结合分子，其中FW1选自ASVNQTPRTATKETGESLTINCVLT(SEQ ID NO：19)、AKVDQTPRTATKETGESLTINCVLT(SEQ ID NO：20)、TRVDQTPRTATKETGESLTINCVVT(SEQ ID NO：21)、TRVDQTPRTATKETGESLTINCVLT(SEQ IDNO：22)、ASVNQTPRTATKETGESLTINCVVT(SEQ ID NO：23)或TRVDQSPSSLSASVGDRVTITCVLT(SEQID NO：24)，FW2选自TSWFRKNPG(SEQ ID NO：25)或TYWYRKNPG(SEQ ID NO：26)，FW3a选自GRYVESV(SEQ ID NO：27)或GRYSESV(SEQ ID NO：28)，FW3b选自SFSLRIKDLTVADSATYYCKA(SEQ ID NO：29)、SFTLTISSLQPEDSATYYCRA(SEQ ID NO：30)或SFTLTISSLQPEDFATYYCKA(SEQID NO：31)，并且FW4选自DGAGTVLTVN(SEQ ID NO：32)或DGAGTKVEIK(SEQ ID NO：33)，或它们的具有至少45％的序列同一性的功能性变体。
64.根据权利要求57至62中任一项所述的特异性抗原结合分子，其中所述ROR1特异性抗原结合分子包含选自以下的氨基酸序列：
ASVNQTPRTATKETGESLTINCVLTDTSYGLYSTSWFRKNPGTTDWERMSIGGRYVESVNKRAKSFSLRIKDLTVADSATYYCKAQSGM[AISTGSGHGYNWYDGAGTVLTVN(SEQ ID NO：39)；
AKVDQTPRTATKETGESLTINCVLTDTSYGLYSTSWFRKNPGTTDWERMSIGGRYVESVNKRAKSFSLRIKDLTVADSATYYCKAQSGM[AIDIGSGHGYNWYDGAGTVLTVN(SEQ ID NO：40)；
TRVDQTPRTATKETGESLTINCVVTGAKYGLAATYWYRKNPGS SNQERISISGRYVESVNKRTMSFSLRIKDLTVADSATYYCKAYPWAMWGQWYDGAGTVLTVN(SEQ ID NO：41)；
TRVDQTPRTATKETGESLTINCVVTGAKYGLFATYWYRKNPGS SNQERISISGRYVESVNKRTMSFSLRIKDLTVADSATYYCKAVFMPQHWHPAAHWYDGAGTVLTVN(SEQ ID NO：42)；
TRVDQTPRTATKETGESLTINCVLTDTSYGLYSTSWFRKNPGTTDWERMSIGGRYVESVNKGAKSFSLRIKDLTVADSATYYCKAREARHPWLRQWYDGAGTVLTVN(SEQ ID NO：43)；
ASVNQTPRTATKETGESLTINCVVTGANYGLAATYWYRKNPGS SNQERISISGRYVESVNKRTMSFSLRIKDLTVADSATYYCKAYPWGAGAPWLVQWYDGAGTVLTVN(SEQ ID NO：44)；
TRVDQSPSSLSASVGDRVTITCVLTGANYGLASTYWYRKNPGSSNKEQISISGRYSESVNKGTKSFTLTISSLQPEDSATYYCRAYPWGAGAPWLVQWYDGAGTKVEIK(SEQ ID NO：45)；
TRVDQSPSSLSASVGDRVTITCVLTGANYGLASTYWYRKNPGSSNQERISISGRYSESVNKRTMSFTLTISSLQPEDSATYYCRAYPWGAGAPWLVQWYDGAGTKVEIK(SEQ ID NO：46)；
TRVDQSPSSLSASVGDRVTITCVLTDTSYGLYSTSWFRKNPGTTDWERMSIGGRYVESVNKGAKSFTLTISSLQPEDFATYYCKAREARHPWLRQWYDGAGTKVEIK(SEQ ID NO：47)；
TRVDQSPSSLSASVGDRVTITCVLTDTSYGLYSTYWYRKNPGSSNKEQISISGRYSESVNKGTKSFTLTISSLQPEDSATYYCRAREARHPWLRQWYDGAGTKVEIK(SEQ ID NO：48)；
TRVDQSPSSLSASVGDRVTITCVLTDTSYGLYSTYWYRKNPGTTDWERMSIGGRYSESVNKGAKSFTLTISSLQPEDSATYYCRAREARHPWLRQWYDGAGTKVEIK(SEQ ID NO：49)；或它们的具有至少45％的序列同一性的功能性变体。
65.根据权利要求57至64中任一项所述的特异性抗原结合分子，其中所述ROR1特异性抗原结合分子是人源化的。
66.根据权利要求57至64中任一项所述的特异性抗原结合分子，其中所述ROR1特异性抗原结合分子是去免疫化的。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112074534A (zh) * 2017-12-22 2020-12-11 阿尔麦克探索有限公司 双特异性抗原结合分子
WO2024008112A1 (en) * 2022-07-06 2024-01-11 Nona Biosciences (Suzhou) Co., Ltd. Anti-ror1 antibodies

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201710836D0 (en) 2017-07-05 2017-08-16 Ucl Business Plc ROR1 Car T-Cells
GB201710835D0 (en) 2017-07-05 2017-08-16 Ucl Business Plc ROR1 Antibodies
GB201710838D0 (en) 2017-07-05 2017-08-16 Ucl Business Plc Bispecific antibodies
WO2020018964A1 (en) 2018-07-20 2020-01-23 Fred Hutchinson Cancer Research Center Compositions and methods for controlled expression of antigen-specific receptors
US20220323598A1 (en) * 2018-08-01 2022-10-13 National University Corporation Tokai National Higher Education And Research System Anti-ror1 monoclonal antibody, functional fragment thereof, gene, drug delivery composition, and pharmaceutical composition
EP3636284A1 (en) * 2018-10-11 2020-04-15 NBE Therapeutics AG Binding protein-toxin conjugates comprising anthracyclines, and use thereof in immune-oncological applications
CN113474357A (zh) * 2018-12-21 2021-10-01 非营利性组织佛兰芒综合大学生物技术研究所 具有毒素和支架蛋白的融合蛋白
JP2022523740A (ja) * 2019-02-01 2022-04-26 ベロスビオ・インコーポレイテッド Ｒｏｒ１抗体イムノコンジュゲートによる癌の治療
GB201908886D0 (en) 2019-06-20 2019-08-07 Almac Discovery Ltd Anthracycline derivatives
GB202020152D0 (en) * 2020-12-18 2021-02-03 Elasmogen Ltd Fast-track humanisation of specific binding molecules
GB202020154D0 (en) 2020-12-18 2021-02-03 Almac Discovery Ltd ROR1-specific variant antigen binding molecules
KR20230150858A (ko) * 2021-02-27 2023-10-31 엘루미넥스 바이오사이언시스 (쑤저우) 리미티드 Il-6 수용체 및 혈관신생 인자를 표적화하는 항체 융합 단백질
AU2022376953A1 (en) 2021-10-28 2024-05-02 Lyell Immunopharma, Inc. Methods for culturing cells expressing ror1-binding protein
CN114044823B (zh) * 2021-11-05 2022-07-05 深圳市人民医院 靶向钙粘蛋白17的纳米抗体及其应用
CN116333117B (zh) * 2021-12-16 2024-04-26 徕特康(苏州)生物制药有限公司 抗表皮生长因子受体抗体及其制备方法和用途
CN116333118B (zh) * 2021-12-16 2024-04-19 徕特康(苏州)生物制药有限公司 抗表皮生长因子受体抗体及其制备方法和用途
WO2023247729A1 (en) * 2022-06-22 2023-12-28 Almac Discovery Limited Ror1/egfr bi-specific antigen binding molecules
GB202209196D0 (en) * 2022-06-22 2022-08-10 Almac Discovery Ltd Bi-specific antigen binding molecules
WO2024064958A1 (en) 2022-09-23 2024-03-28 Lyell Immunopharma, Inc. Methods for culturing nr4a-deficient cells
WO2024064952A1 (en) 2022-09-23 2024-03-28 Lyell Immunopharma, Inc. Methods for culturing nr4a-deficient cells overexpressing c-jun
WO2024077174A1 (en) 2022-10-05 2024-04-11 Lyell Immunopharma, Inc. Methods for culturing nr4a-deficient cells

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011130613A1 (en) * 2010-04-15 2011-10-20 Seattle Genetics, Inc. Targeted pyrrolobenzodiazapine conjugates
WO2014011518A1 (en) * 2012-07-09 2014-01-16 Genentech, Inc. Immunoconjugates comprising anti-cd22 antibodies
WO2015107075A1 (en) * 2014-01-14 2015-07-23 Cellectis Chimeric antigen receptor using antigen recognition domains derived from cartilaginous fish
CN105246504A (zh) * 2013-03-15 2016-01-13 纪念斯隆-凯特琳癌症中心 用于免疫疗法的组合物和方法
CN105531370A (zh) * 2013-04-23 2016-04-27 阿伯丁大学理事会 治疗靶向特异性vnar结构域与icosl的分离
WO2017156479A1 (en) * 2016-03-11 2017-09-14 Bluebird Bio, Inc. Ror1 chimeric antigen receptors

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002319544B2 (en) 2001-08-10 2008-07-10 Aberdeen University Antigen binding domains from fish
JP4637838B2 (ja) 2003-08-05 2011-02-23 アルマック サイエンシズ （スコットランド） リミテッド ライゲーション法
CN101321784A (zh) * 2005-10-11 2008-12-10 埃博灵克斯股份有限公司 针对egfr和igf－ir的纳米抗体tm和多肽
US9316646B2 (en) 2009-04-23 2016-04-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-human ROR1 antibodies
US20120282177A1 (en) 2009-11-02 2012-11-08 Christian Rohlff ROR1 as Therapeutic and Diagnostic Target
WO2011079902A2 (en) 2009-12-18 2011-07-07 Biolnvent International Ab Biological materials and uses thereof
CA2818992C (en) 2010-12-01 2021-05-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric rabbit/human ror1 antibodies
US9217040B2 (en) 2011-01-14 2015-12-22 The Regents Of The University Of California Therapeutic antibodies against ROR-1 protein and methods for use of same
AU2013221672B2 (en) * 2012-02-13 2017-11-09 Seattle Children's Hospital D/B/A Seattle Children's Research Institute Bispecific chimeric antigen receptors and therapeutic uses thereof
AU2013257848A1 (en) 2012-05-07 2014-11-27 The University Court Of The University Of Aberdeen Single domain binding molecule
WO2014028776A1 (en) 2012-08-15 2014-02-20 Zyngenia, Inc. Monovalent and multivalent multispecific complexes and uses thereof
EP2888283B1 (en) 2012-08-24 2018-09-19 The Regents of The University of California Antibodies and vaccines for use in treating ror1 cancers and inhibiting metastasis
US10479990B2 (en) * 2014-06-26 2019-11-19 Ossianix, Inc. Semi-synthetic nurse shark VNAR libraries for making and using selective binding compounds
CA2956482A1 (en) * 2014-07-31 2016-02-04 Cellectis Ror1 specific multi-chain chimeric antigen receptor
WO2016055593A1 (en) * 2014-10-09 2016-04-14 Engmab Ag Bispecific antibodies against cd3epsilon and ror1 for use in the treatment of ovarian cancer
BR112017012125A2 (pt) 2014-12-12 2018-01-23 Saint Gobain Performance Plastics Corp selador de tubo ir e métodos de selagem de um tubo
JP7163028B2 (ja) * 2015-05-13 2022-10-31 アブリンクス エン．ヴェー． Ｃｄ３反応性に基づくｔ細胞リクルートポリペプチド
US20180147271A1 (en) * 2015-05-18 2018-05-31 Bluebird Bio, Inc. Anti-ror1 chimeric antigen receptors
JP2018524284A (ja) 2015-05-18 2018-08-30 ユーリカ セラピューティックス， インコーポレイテッド 抗ｒｏｒ１抗体
EP3405496B1 (en) 2016-01-20 2023-10-25 University of Florida Research Foundation, Incorporated Ror1 antibody compositions and related methods
KR20180100238A (ko) 2016-01-22 2018-09-07 얀센 바이오테크 인코포레이티드 항-ror1 항체, ror1 × cd3 이중특이성 항체, 및 이를 사용하는 방법
WO2017133175A1 (en) * 2016-02-04 2017-08-10 Nanjing Legend Biotech Co., Ltd. Engineered mammalian cells for cancer therapy
WO2017142928A1 (en) * 2016-02-17 2017-08-24 Macrogenics, Inc. Ror1-binding molecules, and methods of use thereof
WO2017196847A1 (en) * 2016-05-10 2017-11-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Variable new antigen receptor (vnar) antibodies and antibody conjugates targeting tumor and viral antigens
EP3630183A4 (en) * 2017-05-23 2021-03-03 Dragonfly Therapeutics, Inc. PROTEIN THAT BINDING NKG2D, CD16 AND ROR1 OR ROR2
GB201721802D0 (en) * 2017-12-22 2018-02-07 Almac Discovery Ltd Ror1-specific antigen binding molecules

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011130613A1 (en) * 2010-04-15 2011-10-20 Seattle Genetics, Inc. Targeted pyrrolobenzodiazapine conjugates
WO2014011518A1 (en) * 2012-07-09 2014-01-16 Genentech, Inc. Immunoconjugates comprising anti-cd22 antibodies
CN105246504A (zh) * 2013-03-15 2016-01-13 纪念斯隆-凯特琳癌症中心 用于免疫疗法的组合物和方法
CN105531370A (zh) * 2013-04-23 2016-04-27 阿伯丁大学理事会 治疗靶向特异性vnar结构域与icosl的分离
WO2015107075A1 (en) * 2014-01-14 2015-07-23 Cellectis Chimeric antigen receptor using antigen recognition domains derived from cartilaginous fish
WO2017156479A1 (en) * 2016-03-11 2017-09-14 Bluebird Bio, Inc. Ror1 chimeric antigen receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
马天明;张娜;郑维萍;陈黎;唐俐;苏新良;: "乳腺癌相关抗原ROR1 H-2Kd限制性CTL表位预测及初步鉴定", 重庆医科大学学报, no. 02, pages 66 - 69 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112074534A (zh) * 2017-12-22 2020-12-11 阿尔麦克探索有限公司 双特异性抗原结合分子
WO2024008112A1 (en) * 2022-07-06 2024-01-11 Nona Biosciences (Suzhou) Co., Ltd. Anti-ror1 antibodies

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