申请/专利权人：上海博威生物医药有限公司

申请日：2019-04-01

公开（公告）日：2024-03-08

公开（公告）号：CN110343179B

主分类号：C07K16/28

分类号：C07K16/28

优先权：["20180402 CN 2018102844629"]

专利状态码：有效-授权

法律状态：2024.03.08#授权;2019.11.12#实质审查的生效;2019.10.18#公开

摘要：本发明涉及一种抗体，具体公开了一种结合淋巴细胞活化基因‑3LAG‑3的抗体，其具有显著改善的抑制LAG‑3与主要组织相容性MHCII类分子之结合的作用。本发明还涉及该抗体在疾病治疗中的用途。

主权项：1.一种结合淋巴细胞活化基因-3（LAG-3）的抗体，其中该抗体具有显著改善的抑制LAG-3与主要组织相容性MHCII类分子之结合的作用，所述抗体重链可变区和轻链可变区的组合如下：（1）氨基酸序列41和43；（2）氨基酸序列75和43；或（3）氨基酸序列77和43。

全文数据：结合淋巴细胞活化基因-3LAG-3的抗体及其用途技术领域本发明涉及抗体领域，同时涉及该抗的用途和制备方法。具体地，本发明涉及一种结合淋巴细胞活化基因-3LAG-3的抗体和其在疾病治疗中的用途。背景技术淋巴细胞活化基因-3lymphocyteactivationgene-3，即LAG-3，也称CD223，是免疫球蛋白超家族成员的一种膜蛋白。分子量为70KDa，定位于人12号染色体20p13.3。该膜蛋白含有四个胞外免疫球蛋白超家族结构域：一个V区和三个C2区。与CD4分子比较，它们在染色体的定位相似,而且两个分子含有部分共同氨基酸10N＝113565DE+DE10N＝213564ED+DE10N＝1c利用商购的稳定表达人LAG-3的细胞株LAG3NFATReporter-Jurkat的体外生物功能分析如实施例8所述。已知MV705-3变体克隆13365DD+DE，13565DE+DE和13564ED+DE和LAG-3的结合能力下降很多，因此仅测试了MV705-3单克隆抗体以及以下5个变体13380DE+DD；13381ED+DD；13386DD+ED；13563DE+ED和13616ED+ED。结果如表18所示，变体蛋白13380DE+DD和13381ED+DD具有和MV705-3单克隆抗体类似的体外激活T细胞的能力。表18MV705-3单克隆抗体和其5个变体的体外激活T细胞的能力受试样品EC50μgmlMV705-30.13±0.036n＝513380DE+DD0.05±0.03n＝213381ED+DD0.1±0.059n＝213386DD+ED30n＝113563DE+ED30n＝113616ED+ED30n＝1实施例1113381变体体内抑制肿瘤细胞生长的功效为了测试MV705-3单克隆抗体的13381变体在体内抑制肿瘤细胞生长的功效，使用了人源化的LAG-3Lymphocyte-activationgene3小鼠购自：南方模式生物科技股份有限公司，品系全名：B6.129-Lag3tmhLAG3Smoc；目录号NM-KI-00049。该小鼠通过同源重组方式，将小鼠內源Lag3基因胞外区序列全部替换为人源LAG3序列，从而使小鼠表达人源嵌合LAG3蛋白。给该小鼠接种鼠类MC38结肠癌细胞系制备肿瘤移植模型。上述人源化的LAG-3小鼠B6.129-Lag3tmhLAG3Smoc在第0天各自植入1×106个MC38细胞，在肿瘤长至均值为123mm3左右时开始分组给药，连续三周每周给药两次BIWx3，从给药开始连续三至四周观察测量肿瘤体积均值。动物分为四组n＝8：1PBS溶剂对照，BIWx3,ip；2mPD-1抗体BE0146，BioCell，1mgkg，BIWx3,ip；3MV705-3单克隆抗体13381变体，10mgkg,BIWx3,ip；4MV705-3单克隆抗体13381变体，10mgkg,和mPD-1抗体BE0146，BioCell，1mgkg,BIWx3，ip。结果如表19和图12所示，MV705-3单克隆抗体13381突变体单药就能够有效抑制肿瘤生长，平均肿瘤生长抑制率为35.11％；Ti或者Vi表示在某一特定时间点处理组或者对照组平均肿瘤体积；T0或V0表示分组后给药前处理组或者对照组平均肿瘤体积，而抗鼠PD-1单克隆抗体对肿瘤生长无抑制作用,MV705-3单克隆抗体13381变体在和抗鼠PD-1单克隆抗体联合用药对肿瘤生长抑制效果最强，平均肿瘤生长抑制率为46.07％。表19.LAG3人源化小鼠MC38荷瘤模型体内验证MV705-3单克隆抗体13381突变体肿瘤抑制效果。参考文献：1.TriebelF,JitsukawaS,BaixerasE,etal.LAG-3,anovellymphocyteactivationgenecloselyrelatedtoCD4[J].JExpMed,1990,1715:1393-1405.2.WorkmanCJ,DuggerKJ,ViganliDA,etal.Cuttingedge:molecularanalysisofthenegativeregulatoryfunctionoflymphocyteactivationgene-3[J].JImmunol,2002,16910:5392-5395.3.LiN,WorkmanCJ,MartinSM,etal.BiochemicalanalysisoftheregulatoryTcellproteinlymphocyteactivationgene-3LAG-3；CD223[J].JImmunol,2004,17311:6806-6812.4.LiN,WangY,ForbesK,etal.MetalloproteasesregulateTcellproliferationandeffectorfunctionviaLAG-3[J].EMBOJ,2007,262:494-504.5.WorkmanCJ,RiceDS,DuggerKJ,etal.PhenotypicanalysisofthemurineCD4-relatedglycoprotein,CD223LAG-3[J].EurJImmunol,2002,328:2255-2263.6.BlackburnSD,ShinH,HainingWN,etal.CoregulationofCD8+Tcellexhaustionbymultipleinhibitoryreceptorsduringchronicviralinfection[J].NatImmunol,2009,101:29-37.7.WorkmanCJ,VignaliDA.NegativeregulationofTcellhomeostasisbylymphocyteactivationgene-3CD223[J].JImmunol,2005,1742:688-695.8.WorkmanCJ,WangY,ElKasmiKC.LAG-3regulatesplasmacytoiddendriticcellhomeostasis[J].JImmunol,2009,1824:1885-1891.9.AnnunziatoF,ManettiR,TomasevicI,etal.ExpressionandreleaseofLAG-3-encodedproteinbyhumanCD4TcellsareassociatedwithIFN-gamaproduction[J].FASEBJ,1996,107:769-775.10.WorkmanCJ,CauleyLS,KimIJ,etal.Lymphocyteactivationgene-3CD223regulatesthesizeoftheexpandingTcellpopulationfollowingantigenactivationinvivo[J].JImmunol,2004,1729:5450-5455.11.Macon-LemaitreL,TriebelF.Thenegativeregulatoryfunctionofthelymphocyte-activationgene-3co-receptorCD223onhumanTcells[J].Immunol,2005,1152:170-178.12.HuangCT,WorkmanCJ,FliesD,etal.RoleofLAG-3inregulatoryTcells[J].Immun,2004,214:503-513.13.GandhiMK,LambleyE,DuraiswamyJ,etal.ExpressionofLAG-3bytumorinfiltratinglymphocytesiscoincidentwiththesuppressionoflatentmembraneantigenspecificCD8+TcellfunctioninHodgkin-lymphomapatients[J].Blood,2006,1087:2280-2289.14.AndreaeS,BiossonS,TriebelF,etal.MHCclassIIsignaltransductioninhumandendriticcellsinducedbyanaturalligand,theLAG-3proteinCD223[J].Blood,2003,1026:2130-2137.15.LiangB,WorkmanCJ,LeeJ,etal.RegulatoryTcellsinhibitdendriticcellsbylymphocyteactivationgene-3engagementofMHCclassII[J].JImmunol,2008,1809:5916-5926.16.BlackburnSD,ShinH,NicholasHainingW.CoregulationofCD8+Tcellexhaustionbymultipleinhibitoryreceptorsduringchronicviralinfection[J].NatImmunol,2009,101:29-37.17.KassuA,MarcusRA.ReceptorsduringChronicHIVInfectionFunctionbyMultipleCostimulatoryRegulationofVirus-SpecificCD4+TCell[J].JImmunol,2010,1855:3007-3018.18.KonnaiS,SuzukiS,ShiraiT.EnhancedexpressionofLAG-3onlymphocytesubpopulationsfrompersistentlylymphocytoticcattleinfectedwithbovineleukemiavirus[J].CompImmunolMicrobiolInfectDis,2013,361:63-69.序列表上海博威生物医药有限公司结合淋巴细胞活化基因-3（LAG-3）的抗体及其用途2019-04-0193SIPOSequenceListing1.016333DNA人工序列1agcgcccaatacgcaaaccgcctctccccgcgcgttggccgattcattaatgcagctggc60acgacaggtttcccgactggaaagcgggcagtgagcgcaacgcaattaatgtgagttagc120tcactcattaggcaccccaggctttacactttatgcttccggctcgtatgttgtgtggaa180ttgtgagcggataacaatttcacacaggaaacagctatgaccatgattacgccaagcttc240catgaaaattctatttcaaggagacagtcataatgaaatacctattgcctacggcagccg300ctggattgttattactcgcggcccagccggccatggcctagtgataacctggctccacac360tctggctgtcctgtggggtaccccctgactctgtgtccaggggccccctctcctggaccc420atgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccgg480ccagagatatgtgggtaatggagacgggtctgttgttgccccgggccacagctcaagacg540ctggaaagtattattgtcaccgtggcaacctgaccatgtcattccacctggagatcactg600ctcggccagtactatggcactggctgctgaggactggtggctggaaggtctcagctgtga660ctttggcttatctgatcttctgcctgtgttcccttgtgggcattcttcatcttcaaagag720ccctggtcctgaggaggaaaagaaagcgaatgactgaccccaccaggagattcttcaaag780tgacgcctcccccaggaagcgggccccagaaccagtacgggaacgtgctgtctctcccca840cacccacctcaggcctcggacgcgcccagcgttgggccgcaggcctggggggcactgccc900cgtcttatggaaacccgagcagcgacgtccaggcggatggagccttggggtcccggagcc960cgccgggagtgggcccagaagaagaggaaggggagggctatgaggaacctgacagtgagg1020aggactccgagttctatgagaacgactccaaccttgggcaggaccagctctcccaggatg1080gcagcggctacgagaaccctgaggatgagcccctgggtcctgaggatgaagactccttct1140ccaacgctgagtcttatgagaacgaggatgaagagctgacccagccggtcgccaggacaa1200tggacttcctgagccctcatgggtcagcctgggaccccagccgggaagcaacctccctgg1260ggtcccagtcctatgaggatatgagaggaatcctgtatgcagccccccagctccgctcca1320ttcggggccagcctggacccaatcatgaggaagatgcagactcttatgagaacatggata1380atcccgatgggccagacccagcctggggaggagggggccgcatgggcacctggagcacca1440ggtagtgataaaactcgagcggtggtggcggttctggtggtggtggtagcggtggcggtg1500gtagtggcggtggcggtgctagctagtgataatctgggccctggggctgcatcctcacct1560acagagatggcttcaacgtctccatcatgtataacctcactgttctgggtctggagcccc1620caactcccttgacagtgtacgctggagcaggttccagggtggggctgccctgccgcctgc1680ctgctggtgtggggacccggtctttcctcactgccaagtggactcctcctgggggaggcc1740ctgacctcctggtgactggagacaatggcgactttacccttcgactagaggatgtgagcc1800aggcccaggctgggacctacacctgccatatccatctgcaggaacagcagctcaatgcca1860ctgtcacattggcaatcatcacagtgactcccaaatcctttgggtcacctggatccctgg1920ggaagctgctttgtgaggtgactccagtatctggacaagaacgctttgtgtggagctctc1980tggacaccccatcccagaggagtttctcaggaccttggctggaggcacaggaggcccagc2040tcctttcccagccttggcaatgccagctgtaccagggggagaggcttcttggagcagcag2100tgtacttcacagagctgtctagcccaggtgcccaacgctctgggagagccccaggtgccc2160tcccagcaggccacctcgatatcgagggtcgtatggatcccaaatcttgtgacaaaactc2220acacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttcc2280ccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg2340tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggagg2400tgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtca2460gcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtct2520ccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagcccc2580gagagccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtca2640gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagca2700atgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctcct2760tcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttct2820catgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgt2880ctccgggtaaatagtgataagcggccgcaggcgcggaacaaaaactcatctcagaagagg2940atctgaatggggccgcacatcatcatcaccatcactagggtggcggctccggttccggtg3000attttgattatgaaaagatggcaaacgctaataagggggctatgaccgaaaatgccgatg3060aaaacgcgctacagtctgacgctaaaggcaaacttgattctgtcgctactgattacggtg3120ctgctatcgatggtttcattggtgacgtttccggccttgctaatggtaatggtgctactg3180gtgattttgctggctctaattcccaaatggctcaagtcggtgacggtgataattcacctt3240taatgaataatttccgtcaatatttaccttccctccctcaatcggttgaatgtcgccctt3300ttgtctttggcgctggtaaaccatatgaattttctattgattgtgacaaaataaacttat3360tccgtggtgtctttgcgtttcttttatatgttgccacctttatgtatgtattttctacgt3420ttgctaacatactgcgtaataaggagtcttaataagaattcactggccgtcgttttacaa3480cgtcgtgactgggaaaaccctggcgttacccaacttaatcgccttgcagcacatccccct3540ttcgccagctggcgtaatagcgaagaggcccgcaccgatcgcccttcccaacagttgcgc3600agcctgaatggcgaatggcgcctgatgcggtattttctccttacgcatctgtgcggtatt3660tcacaccgcatacgtcaaagcaaccatagtacgcgccctgtagcggcgcattaagcgcgg3720cgggtgtggtggttacgcgcagcgtgaccgctacacttgccagcgccctagcgcccgctc3780ctttcgctttcttcccttcctttctcgccacgttcgccggctttccccgtcaagctctaa3840atcgggggctccctttagggttccgatttagtgctttacggcacctcgaccccaaaaaac3900ttgatttgggtgatggttcacgtagtgggccatcgccctgatagacggtttttcgccctt3960tgacgttggagtccacgttctttaatagtggactcttgttccaaactggaacaacactca4020accctatctcgggctattcttttgatttataagggattttgccgatttcggcctattggt4080taaaaaatgagctgatttaacaaaaatttaacgcgaattttaacaaaatattaacgttta4140caattttatggtgcactctcagtacaatctgctctgatgccgcatagttaagccagcccc4200gacacccgccaacacccgctgacgcgccctgacgggcttgtctgctcccggcatccgctt4260acagacaagctgtgaccgtctccgggagctgcatgtgtcagaggttttcaccgtcatcac4320cgaaacgcgcgagacgaaagggcctcgtgatacgcctatttttataggttaatgtcatga4380taataatggtttcttagacgtcaggtggcacttttcggggaaatgtgcgcggaaccccta4440tttgtttatttttctaaatacattcaaatatgtatccgctcatgagacaataaccctgat4500aaatgcttcaataatattgaaaaaggaagagtatgagtattcaacatttccgtgtcgccc4560ttattcccttttttgcggcattttgccttcctgtttttgctcacccagaaacgctggtga4620aagtaaaagatgctgaagatcagttgggtgcacgagtgggttacatcgaactggatctca4680acagcggtaagatccttgagagttttcgccccgaagaacgttttccaatgatgagcactt4740ttaaagttctgctatgtggcgcggtattatcccgtattgacgccgggcaagagcaactcg4800gtcgccgcatacactattctcagaatgacttggttgagtactcaccagtcacagaaaagc4860atcttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgata4920acactgcggccaacttacttctgacaacgatcggaggaccgaaggagctaaccgcttttt4980tgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaag5040ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgca5100aactattaactggcgaactacttactctagcttcccggcaacaattaatagactggatgg5160aggcggataaagttgcaggaccacttctgcgctcggcccttccggctggctggtttattg5220ctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccag5280atggtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatg5340aacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaactgtcag5400accaagtttactcatatatactttagattgatttaaaacttcatttttaatttaaaagga5460tctaggtgaagatcctttttgataatctcatgaccaaaatcccttaacgtgagttttcgt5520tccactgagcgtcagaccccgtagaaaagatcaaaggatcttcttgagatcctttttttc5580tgcgcgtaatctgctgcttgcaaacaaaaaaaccaccgctaccagcggtggtttgtttgc5640cggatcaagagctaccaactctttttccgaaggtaactggcttcagcagagcgcagatac5700caaatactgtccttctagtgtagccgtagttaggccaccacttcaagaactctgtagcac5760cgcctacatacctcgctctgctaatcctgttaccagtggctgctgccagtggcgataagt5820cgtgtcttaccgggttggactcaagacgatagttaccggataaggcgcagcggtcgggct5880gaacggggggttcgtgcacacagcccagcttggagcgaacgacctacaccgaactgagat5940acctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggt6000atccggtaagcggcagggtcggaacaggagagcgcacgagggagcttccagggggaaacg6060cctggtatctttatagtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgt6120gatgctcgtcaggggggcggagcctatggaaaaacgccagcaacgcggcctttttacggt6180tcctggccttttgctggccttttgctcacatgttctttcctgcgttatcccctgattctg6240tggataaccgtattaccgcctttgagtgagctgataccgctcgccgcagccgaacgaccg6300agcgcagcgagtcagtgagcgaggaagcggaag63332747DNA人工序列2gaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactc60tcctgtgcagcctctggattcaccttcagtaattatgctatgcactgggtccgccaggct120ccaggcaaggggctggagtgggtggcagttatatcatatgatggaagcgataaatactac180gcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtat240ctgcaaatgaaaagcctgagagctgaggacacggctgtgtattactgtgcgagatcaatc300gggtttcttgagagcgatgcttttgatatctggggccaagggaccacggtcaccgtctcg360agcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggt420gctagcgacatcgtgctgacacagtctccatcctccctgtctgcatctgtaggagacaga480gtcaccatcacttgccaggcgagtcacggcatttccaactttttaaattggtatcagcag540aaaccaggaaaagcccctaagctcctcatctacgatgcatccactttggaaacaggggtc600ccatcaaggttcagtggaagtggatctgggacagattttagattcaccatcagcagcctg660cagcctgaagatattgcaacatattactgtcaacaatttgataatctcccgatcaccttc720ggccaagggacacgactggagattaaa7473249PRT人工序列3GluValGlnLeuValGluSerGlyGlyGlyValValGlnProGlyArg151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerAsnTyr202530AlaMetHisTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045AlaValIleSerTyrAspGlySerAspLysTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnSerLysAsnThrLeuTyr65707580LeuGlnMetLysSerLeuArgAlaGluAspThrAlaValTyrTyrCys859095AlaArgSerIleGlyPheLeuGluSerAspAlaPheAspIleTrpGly100105110GlnGlyThrThrValThrValSerSerGlyGlyGlyGlySerGlyGly115120125GlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerAspIle130135140ValLeuThrGlnSerProSerSerLeuSerAlaSerValGlyAspArg145150155160ValThrIleThrCysGlnAlaSerHisGlyIleSerAsnPheLeuAsn165170175TrpTyrGlnGlnLysProGlyLysAlaProLysLeuLeuIleTyrAsp180185190AlaSerThrLeuGluThrGlyValProSerArgPheSerGlySerGly195200205SerGlyThrAspPheArgPheThrIleSerSerLeuGlnProGluAsp210215220IleAlaThrTyrTyrCysGlnGlnPheAspAsnLeuProIleThrPhe225230235240GlyGlnGlyThrArgLeuGluIleLys2454756DNA人工序列4caggtccagttggtgcaatctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgacgacacggccgtgtattactgtgcgagagatgag300ggagctaactggggtgatgcttttgatatctggggccaagggaccatggtcaccgtctcg360agcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggt420gctagccagcttgtgctgactcaatcgccctcagcgtctgggacccccgggcagagggtc480accatctcttgttctggaagcagctccaacatcggaaataatgctgtaaactggtaccag540cagctcccaggaacggcccccaaaatcctcatctatagtaataatcagcggccctcaggg600gtccctgaccgattctctggctccaagtctggcgcctcagcctccctggccatcagtggg660ctccagtctgaggatgagtctgattattactgtgcagcatgggatgacagcctgaatgct720gtggtattcagcggagggaccgagctgaccgtccta7565252PRT人工序列5GlnValGlnLeuValGlnSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerAspAspThrAlaValTyrTyrCys859095AlaArgAspGluGlyAlaAsnTrpGlyAspAlaPheAspIleTrpGly100105110GlnGlyThrMetValThrValSerSerGlyGlyGlyGlySerGlyGly115120125GlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGlnLeu130135140ValLeuThrGlnSerProSerAlaSerGlyThrProGlyGlnArgVal145150155160ThrIleSerCysSerGlySerSerSerAsnIleGlyAsnAsnAlaVal165170175AsnTrpTyrGlnGlnLeuProGlyThrAlaProLysIleLeuIleTyr180185190SerAsnAsnGlnArgProSerGlyValProAspArgPheSerGlySer195200205LysSerGlyAlaSerAlaSerLeuAlaIleSerGlyLeuGlnSerGlu210215220AspGluSerAspTyrTyrCysAlaAlaTrpAspAspSerLeuAsnAla225230235240ValValPheSerGlyGlyThrGluLeuThrValLeu2452506756DNA人工序列6caggtacagcttcaggagtcgggcccaggactggtgaagccttcggagaccctgtccctc60acctgcactgtctctggtggctccatcagcagtggtggttactactggggctggatccgc120cagcccccagggaaggggctggagtggattgggagtatctattatagtgggagaacctac180tacaacccgtccctcaagagtcgagtcaccatatccgtagacacgtccaggaaccagttc240tccctgaaactgagctctctgaccgccgcagacacggctgtgtattactgtgcgagaact300ggggggggagcctacggttttgactactggggccagggaaccctggtcaccgtctcgagc360ggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggtgct420agccagcctgtgctgactcagccgcactctgtgtcggagtctccgggcaagacggtgacc480atctcctgcacccgcagcagtggcaacattgccagcaactatgtgcagtggtatcagaag540cgcccgggcagtccccccaccactgtgatctatgaggacaaccaaaggccctctggggtc600cctgatcgcttctccgcctccatcgacagctcctccaactctgcctccctcaccatctct660ggactgaggactgaggacgaggctgactactactgtcagtcttatgacactatcttgggt720tatgtcttcggaggaggcacccagctgaccgcccta7567252PRT人工序列7GlnValGlnLeuGlnGluSerGlyProGlyLeuValLysProSerGlu151015ThrLeuSerLeuThrCysThrValSerGlyGlySerIleSerSerGly202530GlyTyrTyrTrpGlyTrpIleArgGlnProProGlyLysGlyLeuGlu354045TrpIleGlySerIleTyrTyrSerGlyArgThrTyrTyrAsnProSer505560LeuLysSerArgValThrIleSerValAspThrSerArgAsnGlnPhe65707580SerLeuLysLeuSerSerLeuThrAlaAlaAspThrAlaValTyrTyr859095CysAlaArgThrGlyGlyGlyAlaTyrGlyPheAspTyrTrpGlyGln100105110GlyThrLeuValThrValSerSerGlyGlyGlyGlySerGlyGlyGly115120125GlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGlnProVal130135140LeuThrGlnProHisSerValSerGluSerProGlyLysThrValThr145150155160IleSerCysThrArgSerSerGlyAsnIleAlaSerAsnTyrValGln165170175TrpTyrGlnLysArgProGlySerProProThrThrValIleTyrGlu180185190AspAsnGlnArgProSerGlyValProAspArgPheSerAlaSerIle195200205AspSerSerSerAsnSerAlaSerLeuThrIleSerGlyLeuArgThr210215220GluAspGluAlaAspTyrTyrCysGlnSerTyrAspThrIleLeuGly225230235240TyrValPheGlyGlyGlyThrGlnLeuThrAlaLeu2452508759DNA人工序列8gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgacgacacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgatgatgcttttgatatctggggccaagggacaacggtc360accgtctcgagcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggc420ggtggcggtgctagccagcttgtgctgactcagtcgccctcagtgtccgtgtccccagga480cagacagccagcatcacctgctctggagataagttgggagataaatatgcttactggtat540cagcagaagccaggccaggcccctgtgctggtcatctattatgatagcgaccggccctca600gggatccctgagcgattctctggctccaactctgggaacacggccaccctgaccatcagc660agggtcgaagccggggatgaggccgactattactgtcaggtgtgggatagtagtagtgat720caagtggtattcggcggaggcacccagctgaccgtcctc7599253PRT人工序列9GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerAspAspThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProAspAspAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSerGlyGlyGlyGly115120125SerGlyGlyGlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAla130135140SerGlnLeuValLeuThrGlnSerProSerValSerValSerProGly145150155160GlnThrAlaSerIleThrCysSerGlyAspLysLeuGlyAspLysTyr165170175AlaTyrTrpTyrGlnGlnLysProGlyGlnAlaProValLeuValIle180185190TyrTyrAspSerAspArgProSerGlyIleProGluArgPheSerGly195200205SerAsnSerGlyAsnThrAlaThrLeuThrIleSerArgValGluAla210215220GlyAspGluAlaAspTyrTyrCysGlnValTrpAspSerSerSerAsp225230235240GlnValValPheGlyGlyGlyThrGlnLeuThrValLeu24525010756DNA人工序列10gaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactc60tcctgtgcagcgtctggattcaccttcagtagctttggcatacactgggtccgccaggct120ccaggcaaggggctggagtgggtggcagttatatggtacgatggaagtaataaatactat180gcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctctat240ctgcaaatgaacagcctgagagccgaggacacggctgtgtattactgtgcgaaggatttt300gggggtggtgactggggtatggacgtctggggccaagggaccacggtcaccgtctcgagc360ggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggtgct420agccagtctgtgctgactcagccgccctcagtgtctggggccccagggcagagggtcacc480atctcctgcactgggagcagctccaacatcggggcaggtgatgatgtacattggtaccag540cagcttccaggaacagcccccaaactcctcatctatactaacaacaatcggccctcaggg600gtccctgaccgattctctggctccaagtctggcacctcagcctccctggccatcagtgag660ctccagtctgaggatgaggctgattattattgtgcagcatgggatgacagcctgaatggt720ccggtgttcggcggaggaacccagctgaccgccctc75611252PRT人工序列11GluValGlnLeuValGluSerGlyGlyGlyValValGlnProGlyArg151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerSerPhe202530GlyIleHisTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045AlaValIleTrpTyrAspGlySerAsnLysTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnSerLysAsnThrLeuTyr65707580LeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValTyrTyrCys859095AlaLysAspPheGlyGlyGlyAspTrpGlyMetAspValTrpGlyGln100105110GlyThrThrValThrValSerSerGlyGlyGlyGlySerGlyGlyGly115120125GlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGlnSerVal130135140LeuThrGlnProProSerValSerGlyAlaProGlyGlnArgValThr145150155160IleSerCysThrGlySerSerSerAsnIleGlyAlaGlyAspAspVal165170175HisTrpTyrGlnGlnLeuProGlyThrAlaProLysLeuLeuIleTyr180185190ThrAsnAsnAsnArgProSerGlyValProAspArgPheSerGlySer195200205LysSerGlyThrSerAlaSerLeuAlaIleSerGluLeuGlnSerGlu210215220AspGluAlaAspTyrTyrCysAlaAlaTrpAspAspSerLeuAsnGly225230235240ProValPheGlyGlyGlyThrGlnLeuThrAlaLeu24525012747DNA人工序列12gaggtgcagctgttgcagtctgggggaggcttggtacagcctggagggtccctgagactc60tcctgtgcagcctctggattcaccttcagtagttatgaaatgaactgggtccgccaggct120ccagggaaggggctggagtgggtttcatacattagtagtagtggtagtaccatatactac180gcagactctgtgaagggccgattcaccatctccagagacaacgccaagaactcactgtat240ctgcaaatgaacagcctgagagccgaggacacggctgtgtattactgtgcgagagttgga300ctccttgatgcttttgatatctggggccaagggaccatggtcaccgtctcgagcggtggt360ggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggtgctagccag420tctgtcttgacgcagccgccctcagtgtctgcggccccaggacagaaggtcaccatctcc480tgctctggaagcagctccaacattgggaataattatgtatcctggtaccagctgatccca540gaaaaagcccccagactcctcatttatgacgatgataagcgaccctccgggattcctgac600cgattctctggctcccagtctggcacgtcagccaccctgggcatcaccggactccagact660ggggacgaggccgattatttctgcggaacatgggataacagcctgagtggtgcggtattc720ggcggaggaacccagctgatcatttta74713249PRT人工序列13GluValGlnLeuLeuGlnSerGlyGlyGlyLeuValGlnProGlyGly151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerSerTyr202530GluMetAsnTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045SerTyrIleSerSerSerGlySerThrIleTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnAlaLysAsnSerLeuTyr65707580LeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValTyrTyrCys859095AlaArgValGlyLeuLeuAspAlaPheAspIleTrpGlyGlnGlyThr100105110MetValThrValSerSerGlyGlyGlyGlySerGlyGlyGlyGlySer115120125GlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGlnSerValLeuThr130135140GlnProProSerValSerAlaAlaProGlyGlnLysValThrIleSer145150155160CysSerGlySerSerSerAsnIleGlyAsnAsnTyrValSerTrpTyr165170175GlnLeuIleProGluLysAlaProArgLeuLeuIleTyrAspAspAsp180185190LysArgProSerGlyIleProAspArgPheSerGlySerGlnSerGly195200205ThrSerAlaThrLeuGlyIleThrGlyLeuGlnThrGlyAspGluAla210215220AspTyrPheCysGlyThrTrpAspAsnSerLeuSerGlyAlaValPhe225230235240GlyGlyGlyThrGlnLeuIleIleLeu24514750DNA人工序列14gaggtgcatctggtagagtctgggggaggcgtggtccagcctgggaggtccctgagactc60tcctgtgcagcctctggattcaccttcagtaactatgctatgcactgggtccgccaggct120ccaggcaaggggctggagtgggtggcagttatatcatatgatggaaacaatcaatactac180gcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtat240ctgcaaatgaacagcctgagagctgaggacacggctgtgttttactgtgcgagatcaatc300ggattccttgagagcgatgcttttgatatctggggccaagggacaacggtcaccgtctcg360agcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggt420gctagcgaaatagtgttgatgcagtctccaggcaccctgtctttgtctccaggggaaaga480gccaccctctcctgcagggccagtcaaagttttagtgacgggtccttagcctggtaccag540cagaaacctggccagcctcccagactcgtcatctatgatgcatcgaagcgggccactggc600atccctgacaggttcagtggcagtaggtctgggacagagttcactctcaccatcagcagc660ctgcagtctgaagattttgcagtttattcctgtcagcagtattataactggcctcccacc720ttcggccaagggacacgactggagattaaa75015250PRT人工序列15GluValHisLeuValGluSerGlyGlyGlyValValGlnProGlyArg151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerAsnTyr202530AlaMetHisTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045AlaValIleSerTyrAspGlyAsnAsnGlnTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnSerLysAsnThrLeuTyr65707580LeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValPheTyrCys859095AlaArgSerIleGlyPheLeuGluSerAspAlaPheAspIleTrpGly100105110GlnGlyThrThrValThrValSerSerGlyGlyGlyGlySerGlyGly115120125GlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGluIle130135140ValLeuMetGlnSerProGlyThrLeuSerLeuSerProGlyGluArg145150155160AlaThrLeuSerCysArgAlaSerGlnSerPheSerAspGlySerLeu165170175AlaTrpTyrGlnGlnLysProGlyGlnProProArgLeuValIleTyr180185190AspAlaSerLysArgAlaThrGlyIleProAspArgPheSerGlySer195200205ArgSerGlyThrGluPheThrLeuThrIleSerSerLeuGlnSerGlu210215220AspPheAlaValTyrSerCysGlnGlnTyrTyrAsnTrpProProThr225230235240PheGlyGlnGlyThrArgLeuGluIleLys24525016762DNA人工序列16cgggtgcggctgcaggagtcgggcccaggactggtgaagccttcggagaccctgtccctc60acctgcactgtctctggtggctccatcagcagtagtagttactactggggctggatccgc120cagcccccagggaaggggctggagtggattgggagtatctattatagtgggagcacctac180tacaacccgtccctcaagagtcgagtcaccatatcagtagacacgtccaagaaccagttc240tccctgaagctgagctctgtgaccgccgcggacacggccgtgtattactgtgcgagagag300tatagtggctacgatggggcttatgttggctactggggccagggaaccctggtcaccgtc360tcgagcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggc420ggtgctagccagtctgtcctgacgcagccgccctcagtgtctggggccccagggcagagg480gtcaccatctcctgcactgggagcaactccaacatccgggcaggttatgatgtacactgg540taccagcagcttccaggaacagtccccaaactcctcatctatggtaacagcaatcgaccc600tcaggggtccctgaccgattctctggctccaagtctggcacctcagcctccctggccatc660agtggcctccagtccgaagatgagggtaattacttctgtgctacatgggatgacagcctg720tggggctgggtgttcggcgcagggaccgagctgaccgtccta76217254PRT人工序列17ArgValArgLeuGlnGluSerGlyProGlyLeuValLysProSerGlu151015ThrLeuSerLeuThrCysThrValSerGlyGlySerIleSerSerSer202530SerTyrTyrTrpGlyTrpIleArgGlnProProGlyLysGlyLeuGlu354045TrpIleGlySerIleTyrTyrSerGlySerThrTyrTyrAsnProSer505560LeuLysSerArgValThrIleSerValAspThrSerLysAsnGlnPhe65707580SerLeuLysLeuSerSerValThrAlaAlaAspThrAlaValTyrTyr859095CysAlaArgGluTyrSerGlyTyrAspGlyAlaTyrValGlyTyrTrp100105110GlyGlnGlyThrLeuValThrValSerSerGlyGlyGlyGlySerGly115120125GlyGlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGln130135140SerValLeuThrGlnProProSerValSerGlyAlaProGlyGlnArg145150155160ValThrIleSerCysThrGlySerAsnSerAsnIleArgAlaGlyTyr165170175AspValHisTrpTyrGlnGlnLeuProGlyThrValProLysLeuLeu180185190IleTyrGlyAsnSerAsnArgProSerGlyValProAspArgPheSer195200205GlySerLysSerGlyThrSerAlaSerLeuAlaIleSerGlyLeuGln210215220SerGluAspGluGlyAsnTyrPheCysAlaThrTrpAspAspSerLeu225230235240TrpGlyTrpValPheGlyAlaGlyThrGluLeuThrValLeu24525018747DNA人工序列18caggtccagttggtgcagtctggggctgaggtgaagaagcctgggtcctcggtgaaggtc60tcctgcaagacttctggaggcacctttagtaattatgctatcaactgggtgcgacaggcc120cctggacaagggcttgagtggatgggagtgatcatccctatgtttggtccagcaaactac180gtacagaagttccagggcagagtcacaattaccgcggacgaaaccacgagcacagcctac240atggagctgagcagcctgagatctgaggacacggccatctattactgtgcgagagacttg300gctccagctggcttctacggtatggacgtctggggccaagggaccacggtcaccgtctcg360agcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggt420gctagcgacattgtgttgactcagtctccatcttccgtgtctgcatctgtaggagacaga480gtcaccatcacttgtcgggcgagtcagggtattagcaactggttagcctggtatcagcag540aagccagggaaagcccctaaactcctcatctatgctgcatccagtttacaaagtggggtc600ccatcaaggttcagcggcagtagatctgggacagatttcactctcaccatcagcagcctg660cagcctgaagattttgcaacttactattgtcaacaggctaggaatttccccttcaccttc720ggccaagggacacgactggagattaaa74719249PRT人工序列19GlnValGlnLeuValGlnSerGlyAlaGluValLysLysProGlySer151015SerValLysValSerCysLysThrSerGlyGlyThrPheSerAsnTyr202530AlaIleAsnTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyValIleIleProMetPheGlyProAlaAsnTyrValGlnLysPhe505560GlnGlyArgValThrIleThrAlaAspGluThrThrSerThrAlaTyr65707580MetGluLeuSerSerLeuArgSerGluAspThrAlaIleTyrTyrCys859095AlaArgAspLeuAlaProAlaGlyPheTyrGlyMetAspValTrpGly100105110GlnGlyThrThrValThrValSerSerGlyGlyGlyGlySerGlyGly115120125GlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerAspIle130135140ValLeuThrGlnSerProSerSerValSerAlaSerValGlyAspArg145150155160ValThrIleThrCysArgAlaSerGlnGlyIleSerAsnTrpLeuAla165170175TrpTyrGlnGlnLysProGlyLysAlaProLysLeuLeuIleTyrAla180185190AlaSerSerLeuGlnSerGlyValProSerArgPheSerGlySerArg195200205SerGlyThrAspPheThrLeuThrIleSerSerLeuGlnProGluAsp210215220PheAlaThrTyrTyrCysGlnGlnAlaArgAsnPheProPheThrPhe225230235240GlyGlnGlyThrArgLeuGluIleLys24520756DNA人工序列20caggtgcagctgttgcagtctggggctgaggtgaagaagcctgggtcctcggtgaaggtc60tcctgcaaggcttctggaggcaccttcagcagctatgctatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggagggatcatccctatctttggtacagcaaactac180gcacagaagttccagggcagagtcacgattaccgcggacgaatccacgagcacagcctac240atggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagacacccc300tacgactactacggtatggacgtctggggccaagggacaacggtcaccgtctcgagcggt360ggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggtgctagc420gaaattgtgttgacacagtctccactctccctgcccgtcacccctggagagccggcctcc480atctcctgcaggtctagtcagagcctcctgcatagtaatggatacaactatttggattgg540tacctgcagaagccagggcagtctccacagctcctgatctatttgggttctaatcgggcc600tccggggtccctgacaggttcagtggcagtggatcaggcacagattttacactgaaaatc660agcagagtggaggctgaggatgttggggtttattactgcatgcaagctctacaaactccg720tggacgttcggccaagggaccaaagtggatatcaaa75621252PRT人工序列21GlnValGlnLeuLeuGlnSerGlyAlaGluValLysLysProGlySer151015SerValLysValSerCysLysAlaSerGlyGlyThrPheSerSerTyr202530AlaIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyGlyIleIleProIlePheGlyThrAlaAsnTyrAlaGlnLysPhe505560GlnGlyArgValThrIleThrAlaAspGluSerThrSerThrAlaTyr65707580MetGluLeuSerSerLeuArgSerGluAspThrAlaValTyrTyrCys859095AlaArgHisProTyrAspTyrTyrGlyMetAspValTrpGlyGlnGly100105110ThrThrValThrValSerSerGlyGlyGlyGlySerGlyGlyGlyGly115120125SerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGluIleValLeu130135140ThrGlnSerProLeuSerLeuProValThrProGlyGluProAlaSer145150155160IleSerCysArgSerSerGlnSerLeuLeuHisSerAsnGlyTyrAsn165170175TyrLeuAspTrpTyrLeuGlnLysProGlyGlnSerProGlnLeuLeu180185190IleTyrLeuGlySerAsnArgAlaSerGlyValProAspArgPheSer195200205GlySerGlySerGlyThrAspPheThrLeuLysIleSerArgValGlu210215220AlaGluAspValGlyValTyrTyrCysMetGlnAlaLeuGlnThrPro225230235240TrpThrPheGlyGlnGlyThrLysValAspIleLys24525022738DNA人工序列22cgggtgcggctgcaggagtcgggcccaggactggtgaagccttcacagaccctgtccctc60acctgcactgtctctggtggctccatcagcagtagtaactggtggagttgggtccgccag120cccccagggaaggggctggagtggattggggaaatctatcatagtgggagcaccaactac180aacccgtccctcaagagtcgagtcaccatatcagtagacaagtccaagaaccagttctcc240ctgaagctgagctctgtgaccgccgcggacacggccgtgtattactgtgcgagagatcgg300gcgatacgcgatgcttttgatatctggggccaagggacaacggtcaccgtctcgagcggt360ggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggtgctagc420gacatccagatgacccagtctccatcgtccctgtctgcatctgtgggagacagagtcacc480atcacttgccgggcaagtcagagcgttagcagctatttaaattggtatcagcagaaacca540gggaaagcccctaacctcctgatctatgctgcatccagtttgcaaagtggggtcccatca600aggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacct660gaagattttgcaacttactactgtcaacagagttacagtaccccccttttcggcggaggg720accaaactggagatcaaa73823246PRT人工序列23ArgValArgLeuGlnGluSerGlyProGlyLeuValLysProSerGln151015ThrLeuSerLeuThrCysThrValSerGlyGlySerIleSerSerSer202530AsnTrpTrpSerTrpValArgGlnProProGlyLysGlyLeuGluTrp354045IleGlyGluIleTyrHisSerGlySerThrAsnTyrAsnProSerLeu505560LysSerArgValThrIleSerValAspLysSerLysAsnGlnPheSer65707580LeuLysLeuSerSerValThrAlaAlaAspThrAlaValTyrTyrCys859095AlaArgAspArgAlaIleArgAspAlaPheAspIleTrpGlyGlnGly100105110ThrThrValThrValSerSerGlyGlyGlyGlySerGlyGlyGlyGly115120125SerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerAspIleGlnMet130135140ThrGlnSerProSerSerLeuSerAlaSerValGlyAspArgValThr145150155160IleThrCysArgAlaSerGlnSerValSerSerTyrLeuAsnTrpTyr165170175GlnGlnLysProGlyLysAlaProAsnLeuLeuIleTyrAlaAlaSer180185190SerLeuGlnSerGlyValProSerArgPheSerGlySerGlySerGly195200205ThrAspPheThrLeuThrIleSerSerLeuGlnProGluAspPheAla210215220ThrTyrTyrCysGlnGlnSerTyrSerThrProLeuPheGlyGlyGly225230235240ThrLysLeuGluIleLys24524759DNA人工序列24gaagtgcagctggtgcagtctgggggaggcgtggtccagcctgggaggtccctgagactc60tcctgtgcagcctctggattcaccttcagtagctatggcatgcactgggtccgccaggct120ccaggcaaggggctggagtgggtggcagttatatcatatgatggaagtaataaatactat180gcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtat240ctgcaaatgaacagcctgagagctgaggacacggctgtgtattactgtgcgaaagtcctg300actcctgggccttactactactacggtatggacgtctggggccaagggaccacggtcacc360gtctcgagcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggt420ggcggtgctagcgaagttatgttgatgcagtctccaggcaccctgtctttgtctccaggg480gaaagagccaccctctcctgcagggccagtcagagtgttagcatcagctacttagcctgg540taccagcagaaacctggccaggctcccaggctcctcatctatggtacatctagcagggcc600actggcatcccagacaggttcagtggcagtgggtctgggacagacttcactctcaccatc660agcagactggagcctgaagattttgcagtgtattactgtcagcagtatggtagctcaccc720ccattcactttcggccctgggaccaaactggaaatcaaa75925253PRT人工序列25GluValGlnLeuValGlnSerGlyGlyGlyValValGlnProGlyArg151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerSerTyr202530GlyMetHisTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045AlaValIleSerTyrAspGlySerAsnLysTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnSerLysAsnThrLeuTyr65707580LeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValTyrTyrCys859095AlaLysValLeuThrProGlyProTyrTyrTyrTyrGlyMetAspVal100105110TrpGlyGlnGlyThrThrValThrValSerSerGlyGlyGlyGlySer115120125GlyGlyGlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSer130135140GluValMetLeuMetGlnSerProGlyThrLeuSerLeuSerProGly145150155160GluArgAlaThrLeuSerCysArgAlaSerGlnSerValSerIleSer165170175TyrLeuAlaTrpTyrGlnGlnLysProGlyGlnAlaProArgLeuLeu180185190IleTyrGlyThrSerSerArgAlaThrGlyIleProAspArgPheSer195200205GlySerGlySerGlyThrAspPheThrLeuThrIleSerArgLeuGlu210215220ProGluAspPheAlaValTyrTyrCysGlnGlnTyrGlySerSerPro225230235240ProPheThrPheGlyProGlyThrLysLeuGluIleLys24525026768DNA人工序列26cgggtgcggctgcaggagtcgggccctggcctggtgaagtcctcacagaccctgtccctc60acctgcagtgtctctggtgactccatcagtagtggtaaatactactggacctggatccgg120cagcccgccgggaagggactggagtggcttgggcgcatccattccagtgggtttgcccag180tacaacccctccctcaagggtcgtctcaccatctctatagacacgtccaagaaccagttc240tccctgaacctgagctctgtgaccgctgcggacacggccgtgtattactgtgcgagacta300cccacgccgacgtacttctacggtatggacgtctggggccaagggaccacggtcaccgtc360tcgagcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggc420ggtgctagcgaaactgtgatgacccagtctccagactccctggctgtgtctctgggcgag480agggccaccatcaactgcaagtccagccagagtattttatacagctccaacaataagaac540tacttagcttggtaccagcagaaaccaggacagcctcctaggctgctcatttactgggcc600tctacccggcaatccggggtccctgaccgattcagtggtagcgggtctgggacagatttc660actctcaccatcagcagcctgcggcctgaagatgtggctgtttattactgtcaacaatat720tatggtgctccgatcaccttcggccaagggacacgactggagattaaa76827256PRT人工序列27ArgValArgLeuGlnGluSerGlyProGlyLeuValLysSerSerGln151015ThrLeuSerLeuThrCysSerValSerGlyAspSerIleSerSerGly202530LysTyrTyrTrpThrTrpIleArgGlnProAlaGlyLysGlyLeuGlu354045TrpLeuGlyArgIleHisSerSerGlyPheAlaGlnTyrAsnProSer505560LeuLysGlyArgLeuThrIleSerIleAspThrSerLysAsnGlnPhe65707580SerLeuAsnLeuSerSerValThrAlaAlaAspThrAlaValTyrTyr859095CysAlaArgLeuProThrProThrTyrPheTyrGlyMetAspValTrp100105110GlyGlnGlyThrThrValThrValSerSerGlyGlyGlyGlySerGly115120125GlyGlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGlu130135140ThrValMetThrGlnSerProAspSerLeuAlaValSerLeuGlyGlu145150155160ArgAlaThrIleAsnCysLysSerSerGlnSerIleLeuTyrSerSer165170175AsnAsnLysAsnTyrLeuAlaTrpTyrGlnGlnLysProGlyGlnPro180185190ProArgLeuLeuIleTyrTrpAlaSerThrArgGlnSerGlyValPro195200205AspArgPheSerGlySerGlySerGlyThrAspPheThrLeuThrIle210215220SerSerLeuArgProGluAspValAlaValTyrTyrCysGlnGlnTyr225230235240TyrGlyAlaProIleThrPheGlyGlnGlyThrArgLeuGluIleLys24525025528759DNA人工序列28caggtgcagctggtggagtctgggggaggcttggtacagcctggccggtccctgagactc60tcctgtgtagcctctggattcacctttgatgatcatgccatgcactgggtcaggcaaact120ccagagaagggcctggagtgggtctcaggtattagttggaatggaggtgacatacgctat180gcggactctgtgaagggccgattcatcatctccagagacaacgccaagaactccctgcat240ctgcaaatgaacagtctgagaggtgaagacacggctgtgtattactgtgcgagagatggt300ggatatagtgttcttagggcttttgatatctggggccaagggaccacggtcaccgtctcg360agcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggt420gctagccagtctgtgttgacgcagccgccctcagtgtctggggccccggggcagagggtc480accatctcctgcactgggagcagctccaacatcggggcaggttatgatgtacactggtac540cagcagcttccaggaacagcccccaaactcctcatctatggtaacagcaatcggccctca600ggggtccctgaccgattctctggctccaagtctggcacctcagcctccctggccatcact660gggctccaggctgaggatgaggctgattattactgccagtcctatgacagcagcctgagt720ggttgggtgttcggcggaggaacccagctgatcatttta75929253PRT人工序列29GlnValGlnLeuValGluSerGlyGlyGlyLeuValGlnProGlyArg151015SerLeuArgLeuSerCysValAlaSerGlyPheThrPheAspAspHis202530AlaMetHisTrpValArgGlnThrProGluLysGlyLeuGluTrpVal354045SerGlyIleSerTrpAsnGlyGlyAspIleArgTyrAlaAspSerVal505560LysGlyArgPheIleIleSerArgAspAsnAlaLysAsnSerLeuHis65707580LeuGlnMetAsnSerLeuArgGlyGluAspThrAlaValTyrTyrCys859095AlaArgAspGlyGlyTyrSerValLeuArgAlaPheAspIleTrpGly100105110GlnGlyThrThrValThrValSerSerGlyGlyGlyGlySerGlyGly115120125GlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerGlnSer130135140ValLeuThrGlnProProSerValSerGlyAlaProGlyGlnArgVal145150155160ThrIleSerCysThrGlySerSerSerAsnIleGlyAlaGlyTyrAsp165170175ValHisTrpTyrGlnGlnLeuProGlyThrAlaProLysLeuLeuIle180185190TyrGlyAsnSerAsnArgProSerGlyValProAspArgPheSerGly195200205SerLysSerGlyThrSerAlaSerLeuAlaIleThrGlyLeuGlnAla210215220GluAspGluAlaAspTyrTyrCysGlnSerTyrAspSerSerLeuSer225230235240GlyTrpValPheGlyGlyGlyThrGlnLeuIleIleLeu24525030750DNA人工序列30cgggtgcggctgcaggagtcgggccctggcctggtgaagtcctcacagaccctgtccctc60acctgcagtgtctctggtgactccatcagtagtggtaaatactactggacctggatccgg120cagcccgccgggaagggactggagtggcttgggcgcatccattccagtgggtttgcccag180tacaacccctccctcaagggtcgactcaccatatcagtggacacgcgcaagaatgagttc240tccctgaagctgagctctgtgaccgctgcggacacggccgtgtattactgtgcggctacg300gtggtaactccggtcgactctgcttttgatatctggggccaagggacaatggtcaccgtc360tcgagcggtggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggc420ggtgctagcgatacagtgatgacacagtctccatcctccctgtctgcatctgtaggagac480agagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcag540cagaaaccagggaaagcccctaagctcctgatctatgctgcatccagtttgcaaagtggg600gtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagt660ctgcaacctgaagattttgcaacttactactgtcaacagagttacagtaccccgctcact720ttcggcggagggaccaaggtggagatcaaa75031250PRT人工序列31ArgValArgLeuGlnGluSerGlyProGlyLeuValLysSerSerGln151015ThrLeuSerLeuThrCysSerValSerGlyAspSerIleSerSerGly202530LysTyrTyrTrpThrTrpIleArgGlnProAlaGlyLysGlyLeuGlu354045TrpLeuGlyArgIleHisSerSerGlyPheAlaGlnTyrAsnProSer505560LeuLysGlyArgLeuThrIleSerValAspThrArgLysAsnGluPhe65707580SerLeuLysLeuSerSerValThrAlaAlaAspThrAlaValTyrTyr859095CysAlaAlaThrValValThrProValAspSerAlaPheAspIleTrp100105110GlyGlnGlyThrMetValThrValSerSerGlyGlyGlyGlySerGly115120125GlyGlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerAsp130135140ThrValMetThrGlnSerProSerSerLeuSerAlaSerValGlyAsp145150155160ArgValThrIleThrCysArgAlaSerGlnSerIleSerSerTyrLeu165170175AsnTrpTyrGlnGlnLysProGlyLysAlaProLysLeuLeuIleTyr180185190AlaAlaSerSerLeuGlnSerGlyValProSerArgPheSerGlySer195200205GlySerGlyThrAspPheThrLeuThrIleSerSerLeuGlnProGlu210215220AspPheAlaThrTyrTyrCysGlnGlnSerTyrSerThrProLeuThr225230235240PheGlyGlyGlyThrLysValGluIleLys24525032762DNA人工序列32gaggtgcagctggaggagtctgggggaggcgtggtccagcctgggaggtccctgagactc60tcctgtgcagcctctggattcacctttagcagctatgccatgagctgggtccgccaggct120ccagggaaggggctggagtgggtctcagctattagtggtagtggtggtagcacatactac180gcagactccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtat240ctgcaaatgaacagcctgagagccgaggacacggccgtatattactgtgcgaaagattac300tatgatagtagtggttatttcgctgggggtgctgcttttgatatctggggccaagggaca360acggtcaccgtctcgagcggtggtggcggttctggtggtggtggtagcggtggcggtggt420agtggcggtggcggtgctagcgaaacgacactcacgcagtctccagccaccctgtctgtg480tctccaggggacagcgccaccctctcctgcagggccagtcgctatgttggcaacaacttg540gcctggtaccaccagaagcctggccaggctcccaggctcctcatctatgacgcatccacc600agggccactggtgtcccaggcagattcagtggcagtgggtttgggacagacttcactctc660accatttccagcctgaggtctgagaattttgcagtttatttctgtcagcaatatgataac720tggcccctgaccttcggccaagggacacgactggagattaaa76233254PRT人工序列33GluValGlnLeuGluGluSerGlyGlyGlyValValGlnProGlyArg151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerSerTyr202530AlaMetSerTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045SerAlaIleSerGlySerGlyGlySerThrTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnSerLysAsnThrLeuTyr65707580LeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValTyrTyrCys859095AlaLysAspTyrTyrAspSerSerGlyTyrPheAlaGlyGlyAlaAla100105110PheAspIleTrpGlyGlnGlyThrThrValThrValSerSerGlyGly115120125GlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlySerGlyGlyGly130135140GlyAlaSerGluThrThrLeuThrGlnSerProAlaThrLeuSerVal145150155160SerProGlyAspSerAlaThrLeuSerCysArgAlaSerArgTyrVal165170175GlyAsnAsnLeuAlaTrpTyrHisGlnLysProGlyGlnAlaProArg180185190LeuLeuIleTyrAspAlaSerThrArgAlaThrGlyValProGlyArg195200205PheSerGlySerGlyPheGlyThrAspPheThrLeuThrIleSerSer210215220LeuArgSerGluAsnPheAlaValTyrPheCysGlnGlnTyrAspAsn225230235240TrpProLeuThrPheGlyGlnGlyThrArgLeuGluIleLys24525034759DNA人工序列34gaggttcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggtttccggatacaccctcactgaattatccatgcactgggtgcgacaggct120cctggaaaagggcttgagtggatgggaggttttgatcctgaagatggtgaaacaatctac180gcacagaagttccagggcagagtcaccatgaccgaggacacatctacagacacagcctac240atggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcaacagagtat300agtggtggtagctactactactactactacggtatggacgtctggggccaagggaccacg360gtcaccgtctcgagcggtggtggcggttctggtggtggtggtagcggtggcggtggtagt420ggcggtggcggtgctagcgaaattgtgttgacccagactccatcctccctgtctgcatct480gtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaat540tggtatcagcagaaaccagggaaagcccctaagctcctgatctatgctgcatccagtttg600caaagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcacc660atcagcagtctgcaacctgaagattttgcaacttactactgtcaacagagttacagtacc720ccgtacacttttggccaggggaccaagctggagatcaaa75935253PRT人工序列35GluValGlnLeuValGlnSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysValSerGlyTyrThrLeuThrGluLeu202530SerMetHisTrpValArgGlnAlaProGlyLysGlyLeuGluTrpMet354045GlyGlyPheAspProGluAspGlyGluThrIleTyrAlaGlnLysPhe505560GlnGlyArgValThrMetThrGluAspThrSerThrAspThrAlaTyr65707580MetGluLeuSerSerLeuArgSerGluAspThrAlaValTyrTyrCys859095AlaThrGluTyrSerGlyGlySerTyrTyrTyrTyrTyrTyrGlyMet100105110AspValTrpGlyGlnGlyThrThrValThrValSerSerGlyGlyGly115120125GlySerGlyGlyGlyGlySerGlyGlyGlyGlySerGlyGlyGlyGly130135140AlaSerGluIleValLeuThrGlnThrProSerSerLeuSerAlaSer145150155160ValGlyAspArgValThrIleThrCysArgAlaSerGlnSerIleSer165170175SerTyrLeuAsnTrpTyrGlnGlnLysProGlyLysAlaProLysLeu180185190LeuIleTyrAlaAlaSerSerLeuGlnSerGlyValProSerArgPhe195200205SerGlySerGlySerGlyThrAspPheThrLeuThrIleSerSerLeu210215220GlnProGluAspPheAlaThrTyrTyrCysGlnGlnSerTyrSerThr225230235240ProTyrThrPheGlyGlnGlyThrLysLeuGluIleLys24525036759DNA人工序列36cagctgcagctgcaggagtcgggccctggcctggtgaagtcctcacagaccctgtccctc60acctgcagtgtctctggtgactccatcagtagtggtaaatactactggacctggatccgg120cagcccgccgggaagggactggagtggcttgggcgcatccattccagtgggtttgcccag180tacaacccctccctcaagggtcgactcaccatatcagtggacacgcgcaagaatgagttc240tccctaaaaatgacctctgtgactgccgcagacacggccgtctattactgtgcgagaggc300ggctggaacgacccctttgactcctggggccagggaaccctggtcactgtctcgagcggt360ggtggcggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggtgctagc420gatatccagatgacccagtctccagactccctggctgtgtctctgggcgagagggccacc480atcaactgcaagtccagccagagtgttttatacagctccaacaataagaactacttagct540tggtaccagcagaaaccaggacagcctcctaagctgctcatttactgggcatctacccgg600gaatccggggtccctgaccgattcagtgtcagcgggtctgggacagatttcactctcacc660atcagcagcctgcatgctgaagatgtggcagtttattactgtcagcaatattatagtact720cctatcactttcggccctgggaccaagctggagatcaaa75937253PRT人工序列37GlnLeuGlnLeuGlnGluSerGlyProGlyLeuValLysSerSerGln151015ThrLeuSerLeuThrCysSerValSerGlyAspSerIleSerSerGly202530LysTyrTyrTrpThrTrpIleArgGlnProAlaGlyLysGlyLeuGlu354045TrpLeuGlyArgIleHisSerSerGlyPheAlaGlnTyrAsnProSer505560LeuLysGlyArgLeuThrIleSerValAspThrArgLysAsnGluPhe65707580SerLeuLysMetThrSerValThrAlaAlaAspThrAlaValTyrTyr859095CysAlaArgGlyGlyTrpAsnAspProPheAspSerTrpGlyGlnGly100105110ThrLeuValThrValSerSerGlyGlyGlyGlySerGlyGlyGlyGly115120125SerGlyGlyGlyGlySerGlyGlyGlyGlyAlaSerAspIleGlnMet130135140ThrGlnSerProAspSerLeuAlaValSerLeuGlyGluArgAlaThr145150155160IleAsnCysLysSerSerGlnSerValLeuTyrSerSerAsnAsnLys165170175AsnTyrLeuAlaTrpTyrGlnGlnLysProGlyGlnProProLysLeu180185190LeuIleTyrTrpAlaSerThrArgGluSerGlyValProAspArgPhe195200205SerValSerGlySerGlyThrAspPheThrLeuThrIleSerSerLeu210215220HisAlaGluAspValAlaValTyrTyrCysGlnGlnTyrTyrSerThr225230235240ProIleThrPheGlyProGlyThrLysLeuGluIleLys24525038744DNA人工序列38caggtgcagctacaggagtcgggcccaggactggtgaagccttcggagaccctgtccctc60acctgcactgtctctggttactccatcagcagtggttactactggggctggatccggcag120cccccagggaaggggctggagtggattgggagtatctatcatagtgggagcacctactac180aacccgtccctcaagagtcgagtcaccatatcagtagacacgtccaagaaccagttctcc240ctgaagctgagctctgtgaccgccgcagacacggccgtgtattactgtgcgagagaccta300caggattggttcgacccctggggccagggaaccctggtcaccgtctcgagcggtggtggc360ggttctggtggtggtggtagcggtggcggtggtagtggcggtggcggtgctagcctggct420gtgctgactcacgcaccctcagcgtctgggacccccgggcagagagtcaccatctcttgt480tctggaagcaagtccaacatcggaagtaattctgttaactggtatcagcacctccccgga540acggcccccaaactcctcatacatactaatgatcagcggccctcaggggtccctgaccga600ttcgctggctccaagtctggcacctcagcatccttgaccatcagtggcctcaggcctgaa660gatgaggcggattattactgtgcaacatgggatgacagcatgagtggtccggtgttcggc720ggtgggaccgagctgaccgtccta74439248PRT人工序列39GlnValGlnLeuGlnGluSerGlyProGlyLeuValLysProSerGlu151015ThrLeuSerLeuThrCysThrValSerGlyTyrSerIleSerSerGly202530TyrTyrTrpGlyTrpIleArgGlnProProGlyLysGlyLeuGluTrp354045IleGlySerIleTyrHisSerGlySerThrTyrTyrAsnProSerLeu505560LysSerArgValThrIleSerValAspThrSerLysAsnGlnPheSer65707580LeuLysLeuSerSerValThrAlaAlaAspThrAlaValTyrTyrCys859095AlaArgAspLeuGlnAspTrpPheAspProTrpGlyGlnGlyThrLeu100105110ValThrValSerSerGlyGlyGlyGlySerGlyGlyGlyGlySerGly115120125GlyGlyGlySerGlyGlyGlyGlyAlaSerLeuAlaValLeuThrHis130135140AlaProSerAlaSerGlyThrProGlyGlnArgValThrIleSerCys145150155160SerGlySerLysSerAsnIleGlySerAsnSerValAsnTrpTyrGln165170175HisLeuProGlyThrAlaProLysLeuLeuIleHisThrAsnAspGln180185190ArgProSerGlyValProAspArgPheAlaGlySerLysSerGlyThr195200205SerAlaSerLeuThrIleSerGlyLeuArgProGluAspGluAlaAsp210215220TyrTyrCysAlaThrTrpAspAspSerMetSerGlyProValPheGly225230235240GlyGlyThrGluLeuThrValLeu24540372DNA人工序列40gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgacgacacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgatgatgcttttgatatctggggccaagggacaacggtc360accgtctcgagc37241124PRT人工序列41GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerAspAspThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProAspAspAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer11512042327DNA人工序列42cagcttgtgctgactcagtcgccctcagtgtccgtgtccccaggacagacagccagcatc60acctgctctggagataagttgggagataaatatgcttactggtatcagcagaagccaggc120caggcccctgtgctggtcatctattatgatagcgaccggccctcagggatccctgagcga180ttctctggctccaactctgggaacacggccaccctgaccatcagcagggtcgaagccggg240gatgaggccgactattactgtcaggtgtgggatagtagtagtgatcaagtggtattcggc300ggaggcacccagctgaccgtcctcggt32743109PRT人工序列43GlnLeuValLeuThrGlnSerProSerValSerValSerProGlyGln151015ThrAlaSerIleThrCysSerGlyAspLysLeuGlyAspLysTyrAla202530TyrTrpTyrGlnGlnLysProGlyGlnAlaProValLeuValIleTyr354045TyrAspSerAspArgProSerGlyIleProGluArgPheSerGlySer505560AsnSerGlyAsnThrAlaThrLeuThrIleSerArgValGluAlaGly65707580AspGluAlaAspTyrTyrCysGlnValTrpAspSerSerSerAspGln859095ValValPheGlyGlyGlyThrGlnLeuThrValLeuGly10010544363DNA人工序列44gaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactc60tcctgtgcagcctctggattcaccttcagtaattatgctatgcactgggtccgccaggct120ccaggcaaggggctggagtgggtggcagttatatcatatgatggaagcgataaatactac180gcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtat240ctgcaaatgaaaagcctgagagctgaggacacggctgtgtattactgtgcgagatcaatc300gggtttcttgagagcgatgcttttgatatctggggccaagggaccacggtcaccgtctcg360agc36345121PRT人工序列45GluValGlnLeuValGluSerGlyGlyGlyValValGlnProGlyArg151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerAsnTyr202530AlaMetHisTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045AlaValIleSerTyrAspGlySerAspLysTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnSerLysAsnThrLeuTyr65707580LeuGlnMetLysSerLeuArgAlaGluAspThrAlaValTyrTyrCys859095AlaArgSerIleGlyPheLeuGluSerAspAlaPheAspIleTrpGly100105110GlnGlyThrThrValThrValSerSer11512046321DNA人工序列46gacatcgtgctgacacagtctccatcctccctgtctgcatctgtaggagacagagtcacc60atcacttgccaggcgagtcacggcatttccaactttttaaattggtatcagcagaaacca120ggaaaagcccctaagctcctcatctacgatgcatccactttggaaacaggggtcccatca180aggttcagtggaagtggatctgggacagattttagattcaccatcagcagcctgcagcct240gaagatattgcaacatattactgtcaacaatttgataatctcccgatcaccttcggccaa300gggacacgactggagattaaa32147107PRT人工序列47AspIleValLeuThrGlnSerProSerSerLeuSerAlaSerValGly151015AspArgValThrIleThrCysGlnAlaSerHisGlyIleSerAsnPhe202530LeuAsnTrpTyrGlnGlnLysProGlyLysAlaProLysLeuLeuIle354045TyrAspAlaSerThrLeuGluThrGlyValProSerArgPheSerGly505560SerGlySerGlyThrAspPheArgPheThrIleSerSerLeuGlnPro65707580GluAspIleAlaThrTyrTyrCysGlnGlnPheAspAsnLeuProIle859095ThrPheGlyGlnGlyThrArgLeuGluIleLys10010548354DNA人工序列48gaggtgcagctgttgcagtctgggggaggcttggtacagcctggagggtccctgagactc60tcctgtgcagcctctggattcaccttcagtagttatgaaatgaactgggtccgccaggct120ccagggaaggggctggagtgggtttcatacattagtagtagtggtagtaccatatactac180gcagactctgtgaagggccgattcaccatctccagagacaacgccaagaactcactgtat240ctgcaaatgaacagcctgagagccgaggacacggctgtgtattactgtgcgagagttgga300ctccttgatgcttttgatatctggggccaagggaccatggtcaccgtctcgagc35449118PRT人工序列49GluValGlnLeuLeuGlnSerGlyGlyGlyLeuValGlnProGlyGly151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerSerTyr202530GluMetAsnTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045SerTyrIleSerSerSerGlySerThrIleTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnAlaLysAsnSerLeuTyr65707580LeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValTyrTyrCys859095AlaArgValGlyLeuLeuAspAlaPheAspIleTrpGlyGlnGlyThr100105110MetValThrValSerSer11550333DNA人工序列50cagtctgtcttgacgcagccgccctcagtgtctgcggccccaggacagaaggtcaccatc60tcctgctctggaagcagctccaacattgggaataattatgtatcctggtaccagctgatc120ccagaaaaagcccccagactcctcatttatgacgatgataagcgaccctccgggattcct180gaccgattctctggctcccagtctggcacgtcagccaccctgggcatcaccggactccag240actggggacgaggccgattatttctgcggaacatgggataacagcctgagtggtgcggta300ttcggcggaggaacccagctgatcattttaggt33351111PRT人工序列51GlnSerValLeuThrGlnProProSerValSerAlaAlaProGlyGln151015LysValThrIleSerCysSerGlySerSerSerAsnIleGlyAsnAsn202530TyrValSerTrpTyrGlnLeuIleProGluLysAlaProArgLeuLeu354045IleTyrAspAspAspLysArgProSerGlyIleProAspArgPheSer505560GlySerGlnSerGlyThrSerAlaThrLeuGlyIleThrGlyLeuGln65707580ThrGlyAspGluAlaAspTyrPheCysGlyThrTrpAspAsnSerLeu859095SerGlyAlaValPheGlyGlyGlyThrGlnLeuIleIleLeuGly10010511052363DNA人工序列52gaggtgcatctggtagagtctgggggaggcgtggtccagcctgggaggtccctgagactc60tcctgtgcagcctctggattcaccttcagtaactatgctatgcactgggtccgccaggct120ccaggcaaggggctggagtgggtggcagttatatcatatgatggaaacaatcaatactac180gcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtat240ctgcaaatgaacagcctgagagctgaggacacggctgtgttttactgtgcgagatcaatc300ggattccttgagagcgatgcttttgatatctggggccaagggacaacggtcaccgtctcg360agc36353121PRT人工序列53GluValHisLeuValGluSerGlyGlyGlyValValGlnProGlyArg151015SerLeuArgLeuSerCysAlaAlaSerGlyPheThrPheSerAsnTyr202530AlaMetHisTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal354045AlaValIleSerTyrAspGlyAsnAsnGlnTyrTyrAlaAspSerVal505560LysGlyArgPheThrIleSerArgAspAsnSerLysAsnThrLeuTyr65707580LeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValPheTyrCys859095AlaArgSerIleGlyPheLeuGluSerAspAlaPheAspIleTrpGly100105110GlnGlyThrThrValThrValSerSer11512054324DNA人工序列54gaaatagtgttgatgcagtctccaggcaccctgtctttgtctccaggggaaagagccacc60ctctcctgcagggccagtcaaagttttagtgacgggtccttagcctggtaccagcagaaa120cctggccagcctcccagactcgtcatctatgatgcatcgaagcgggccactggcatccct180gacaggttcagtggcagtaggtctgggacagagttcactctcaccatcagcagcctgcag240tctgaagattttgcagtttattcctgtcagcagtattataactggcctcccaccttcggc300caagggacacgactggagattaaa32455108PRT人工序列55GluIleValLeuMetGlnSerProGlyThrLeuSerLeuSerProGly151015GluArgAlaThrLeuSerCysArgAlaSerGlnSerPheSerAspGly202530SerLeuAlaTrpTyrGlnGlnLysProGlyGlnProProArgLeuVal354045IleTyrAspAlaSerLysArgAlaThrGlyIleProAspArgPheSer505560GlySerArgSerGlyThrGluPheThrLeuThrIleSerSerLeuGln65707580SerGluAspPheAlaValTyrSerCysGlnGlnTyrTyrAsnTrpPro859095ProThrPheGlyGlnGlyThrArgLeuGluIleLys10010556357DNA人工序列56cgggtgcggctgcaggagtcgggcccaggactggtgaagccttcacagaccctgtccctc60acctgcactgtctctggtggctccatcagcagtagtaactggtggagttgggtccgccag120cccccagggaaggggctggagtggattggggaaatctatcatagtgggagcaccaactac180aacccgtccctcaagagtcgagtcaccatatcagtagacaagtccaagaaccagttctcc240ctgaagctgagctctgtgaccgccgcggacacggccgtgtattactgtgcgagagatcgg300gcgatacgcgatgcttttgatatctggggccaagggacaacggtcaccgtctcgagc35757119PRT人工序列57ArgValArgLeuGlnGluSerGlyProGlyLeuValLysProSerGln151015ThrLeuSerLeuThrCysThrValSerGlyGlySerIleSerSerSer202530AsnTrpTrpSerTrpValArgGlnProProGlyLysGlyLeuGluTrp354045IleGlyGluIleTyrHisSerGlySerThrAsnTyrAsnProSerLeu505560LysSerArgValThrIleSerValAspLysSerLysAsnGlnPheSer65707580LeuLysLeuSerSerValThrAlaAlaAspThrAlaValTyrTyrCys859095AlaArgAspArgAlaIleArgAspAlaPheAspIleTrpGlyGlnGly100105110ThrThrValThrValSerSer11558318DNA人工序列58gacatccagatgacccagtctccatcgtccctgtctgcatctgtgggagacagagtcacc60atcacttgccgggcaagtcagagcgttagcagctatttaaattggtatcagcagaaacca120gggaaagcccctaacctcctgatctatgctgcatccagtttgcaaagtggggtcccatca180aggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacct240gaagattttgcaacttactactgtcaacagagttacagtaccccccttttcggcggaggg300accaaactggagatcaaa31859106PRT人工序列59AspIleGlnMetThrGlnSerProSerSerLeuSerAlaSerValGly151015AspArgValThrIleThrCysArgAlaSerGlnSerValSerSerTyr202530LeuAsnTrpTyrGlnGlnLysProGlyLysAlaProAsnLeuLeuIle354045TyrAlaAlaSerSerLeuGlnSerGlyValProSerArgPheSerGly505560SerGlySerGlyThrAspPheThrLeuThrIleSerSerLeuGlnPro65707580GluAspPheAlaThrTyrTyrCysGlnGlnSerTyrSerThrProLeu859095PheGlyGlyGlyThrLysLeuGluIleLys10010560363DNA人工序列60caggtgcagctggtggagtctgggggaggcttggtacagcctggccggtccctgagactc60tcctgtgtagcctctggattcacctttgatgatcatgccatgcactgggtcaggcaaact120ccagagaagggcctggagtgggtctcaggtattagttggaatggaggtgacatacgctat180gcggactctgtgaagggccgattcatcatctccagagacaacgccaagaactccctgcat240ctgcaaatgaacagtctgagaggtgaagacacggctgtgtattactgtgcgagagatggt300ggatatagtgttcttagggcttttgatatctggggccaagggaccacggtcaccgtctcg360agc36361121PRT人工序列61GlnValGlnLeuValGluSerGlyGlyGlyLeuValGlnProGlyArg151015SerLeuArgLeuSerCysValAlaSerGlyPheThrPheAspAspHis202530AlaMetHisTrpValArgGlnThrProGluLysGlyLeuGluTrpVal354045SerGlyIleSerTrpAsnGlyGlyAspIleArgTyrAlaAspSerVal505560LysGlyArgPheIleIleSerArgAspAsnAlaLysAsnSerLeuHis65707580LeuGlnMetAsnSerLeuArgGlyGluAspThrAlaValTyrTyrCys859095AlaArgAspGlyGlyTyrSerValLeuArgAlaPheAspIleTrpGly100105110GlnGlyThrThrValThrValSerSer11512062336DNA人工序列62cagtctgtgttgacgcagccgccctcagtgtctggggccccggggcagagggtcaccatc60tcctgcactgggagcagctccaacatcggggcaggttatgatgtacactggtaccagcag120cttccaggaacagcccccaaactcctcatctatggtaacagcaatcggccctcaggggtc180cctgaccgattctctggctccaagtctggcacctcagcctccctggccatcactgggctc240caggctgaggatgaggctgattattactgccagtcctatgacagcagcctgagtggttgg300gtgttcggcggaggaacccagctgatcattttaggt33663112PRT人工序列63GlnSerValLeuThrGlnProProSerValSerGlyAlaProGlyGln151015ArgValThrIleSerCysThrGlySerSerSerAsnIleGlyAlaGly202530TyrAspValHisTrpTyrGlnGlnLeuProGlyThrAlaProLysLeu354045LeuIleTyrGlyAsnSerAsnArgProSerGlyValProAspArgPhe505560SerGlySerLysSerGlyThrSerAlaSerLeuAlaIleThrGlyLeu65707580GlnAlaGluAspGluAlaAspTyrTyrCysGlnSerTyrAspSerSer859095LeuSerGlyTrpValPheGlyGlyGlyThrGlnLeuIleIleLeuGly100105110641341DNA人工序列64caggtgcagctacagcagtggggcgcaggactgttgaagccttcggagaccctgtccctc60acctgcgctgtctatggtgggtccttcagtgattactactggaactggatccgccagccc120ccagggaaggggctggagtggattggggaaatcaatcataatggaaacaccaactccaac180ccgtccctcaagagtcgagtcaccctatcactagacacgtccaagaaccagttctccctg240aagctgaggtctgtgaccgccgcggacacggctgtgtattactgtgcgtttggatatagt300gactacgagtacaactggttcgacccctggggccagggaaccctggtcaccgtctcctca360gctagcaccaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgag420agcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg480tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca540ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacc600tacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtcc660aaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtc720ttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacg780tgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggat840ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtac900cgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaag960tgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaa1020gggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaag1080aaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggag1140tgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactcc1200gacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggagggg1260aatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagc1320ctctccctgtctctgggtaaa134165447PRT人工序列65GlnValGlnLeuGlnGlnTrpGlyAlaGlyLeuLeuLysProSerGlu151015ThrLeuSerLeuThrCysAlaValTyrGlyGlySerPheSerAspTyr202530TyrTrpAsnTrpIleArgGlnProProGlyLysGlyLeuGluTrpIle354045GlyGluIleAsnHisAsnGlyAsnThrAsnSerAsnProSerLeuLys505560SerArgValThrLeuSerLeuAspThrSerLysAsnGlnPheSerLeu65707580LysLeuArgSerValThrAlaAlaAspThrAlaValTyrTyrCysAla859095PheGlyTyrSerAspTyrGluTyrAsnTrpPheAspProTrpGlyGln100105110GlyThrLeuValThrValSerSerAlaSerThrLysGlyProSerVal115120125PheProLeuAlaProCysSerArgSerThrSerGluSerThrAlaAla130135140LeuGlyCysLeuValLysAspTyrPheProGluProValThrValSer145150155160TrpAsnSerGlyAlaLeuThrSerGlyValHisThrPheProAlaVal165170175LeuGlnSerSerGlyLeuTyrSerLeuSerSerValValThrValPro180185190SerSerSerLeuGlyThrLysThrTyrThrCysAsnValAspHisLys195200205ProSerAsnThrLysValAspLysArgValGluSerLysTyrGlyPro210215220ProCysProProCysProAlaProGluPheLeuGlyGlyProSerVal225230235240PheLeuPheProProLysProLysAspThrLeuMetIleSerArgThr245250255ProGluValThrCysValValValAspValSerGlnGluAspProGlu260265270ValGlnPheAsnTrpTyrValAspGlyValGluValHisAsnAlaLys275280285ThrLysProArgGluGluGlnPheAsnSerThrTyrArgValValSer290295300ValLeuThrValLeuHisGlnAspTrpLeuAsnGlyLysGluTyrLys305310315320CysLysValSerAsnLysGlyLeuProSerSerIleGluLysThrIle325330335SerLysAlaLysGlyGlnProArgGluProGlnValTyrThrLeuPro340345350ProSerGlnGluGluMetThrLysAsnGlnValSerLeuThrCysLeu355360365ValLysGlyPheTyrProSerAspIleAlaValGluTrpGluSerAsn370375380GlyGlnProGluAsnAsnTyrLysThrThrProProValLeuAspSer385390395400AspGlySerPhePheLeuTyrSerArgLeuThrValAspLysSerArg405410415TrpGlnGluGlyAsnValPheSerCysSerValMetHisGluAlaLeu420425430HisAsnHisTyrThrGlnLysSerLeuSerLeuSerLeuGlyLys43544044566642DNA人工序列66gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggaaagagccacc60ctctcctgcagggccagtcagagtattagcagctacttagcctggtaccaacagaaacct120ggccaggctcccaggctcctcatctatgatgcatccaacagggccactggcatcccagcc180aggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcct240gaagattttgcagtttattactgtcagcagcgtagcaactggcctctcacttttggccag300gggaccaacctggagatcaaacgtacggtggcggcgccatctgtcttcatcttcccgcca360tctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctat420cccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccag480gagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacg540ctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggc600ctgagctcgcccgtcacaaagagcttcaacaggggagagtgt64267214PRT人工序列67GluIleValLeuThrGlnSerProAlaThrLeuSerLeuSerProGly151015GluArgAlaThrLeuSerCysArgAlaSerGlnSerIleSerSerTyr202530LeuAlaTrpTyrGlnGlnLysProGlyGlnAlaProArgLeuLeuIle354045TyrAspAlaSerAsnArgAlaThrGlyIleProAlaArgPheSerGly505560SerGlySerGlyThrAspPheThrLeuThrIleSerSerLeuGluPro65707580GluAspPheAlaValTyrTyrCysGlnGlnArgSerAsnTrpProLeu859095ThrPheGlyGlnGlyThrAsnLeuGluIleLysArgThrValAlaAla100105110ProSerValPheIlePheProProSerAspGluGlnLeuLysSerGly115120125ThrAlaSerValValCysLeuLeuAsnAsnPheTyrProArgGluAla130135140LysValGlnTrpLysValAspAsnAlaLeuGlnSerGlyAsnSerGln145150155160GluSerValThrGluGlnAspSerLysAspSerThrTyrSerLeuSer165170175SerThrLeuThrLeuSerLysAlaAspTyrGluLysHisLysValTyr180185190AlaCysGluValThrHisGlnGlyLeuSerSerProValThrLysSer195200205PheAsnArgGlyGluCys210682004DNA人工序列68ctccagccaggggctgaggtcccggtggtgtgggcccaggagggggctcctgcccagctc60ccctgcagccccacaatccccctccaggatctcagccttctgcgaagagcaggggtcact120tggcagcatcagccagacagtggcccgcccgctgccgcccccggccatcccctggccccc180ggccctcacccggcggcgccctcctcctgggggcccaggccccgccgctacacggtgctg240agcgtgggtcccggaggcctgcgcagcgggaggctgcccctgcagccccgcgtccagctg300gatgagcgcggccggcagcgcggggacttctcgctatggctgcgcccagcccggcgcgcg360gacgccggcgagtaccgcgccgcggtgcacctcagggaccgcgccctctcctgccgcctc420cgtctgcgcctgggccaggcctcgatgactgccagccccccaggatctctcagagcctcc480gactgggtcattttgaactgctccttcagccgccctgaccgcccagcctctgtgcattgg540ttccggaaccggggccagggccgagtccctgtccgggagtccccccatcaccacttagcg600gaaagcttcctcttcctgccccaagtcagccccatggactctgggccctggggctgcatc660ctcacctacagagatggcttcaacgtctccatcatgtataacctcactgttctgggtctg720gagcccccaactcccttgacagtgtacgctggagcaggttccagggtggggctgccctgc780cgcctgcctgctggtgtggggacccggtctttcctcactgccaagtggactcctcctggg840ggaggccctgacctcctggtgactggagacaatggcgactttacccttcgactagaggat900gtgagccaggcccaggctgggacctacacctgccatatccatctgcaggaacagcagctc960aatgccactgtcacattggcaatcatcacagtgactcccaaatcctttgggtcacctgga1020tccctggggaagctgctttgtgaggtgactccagtatctggacaagaacgctttgtgtgg1080agctctctggacaccccatcccagaggagtttctcaggaccttggctggaggcacaggag1140gcccagctcctttcccagccttggcaatgccagctgtaccagggggagaggcttcttgga1200gcagcagtgtacttcacagagctgtctagcccaggtgcccaacgctctgggagagcccca1260ggtgccctcccagcaggccacctcgatatcgagggtcgtatggatgagcccagagggccc1320acaatcaagccctgtcctccatgcaaatgcccagcacctaacctcttgggtggaccatcc1380gtcttcatcttccctccaaagatcaaggatgtactcatgatctccctgagccccatagtc1440acatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctggtttgtg1500aacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagtact1560ctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttc1620aaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaaccc1680aaagggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgact1740aagaaacaggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtg1800gagtggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcctggac1860tctgatggttcttacttcatgtacagcaagctgagagtggaaaagaagaactgggtggaa1920agaaatagctactcctgttcagtggtccacgagggtctgcacaatcaccacacgactaag1980agcttctcccggactccaggtaaa200469668PRT人工序列69LeuGlnProGlyAlaGluValProValValTrpAlaGlnGluGlyAla151015ProAlaGlnLeuProCysSerProThrIleProLeuGlnAspLeuSer202530LeuLeuArgArgAlaGlyValThrTrpGlnHisGlnProAspSerGly354045ProProAlaAlaAlaProGlyHisProLeuAlaProGlyProHisPro505560AlaAlaProSerSerTrpGlyProArgProArgArgTyrThrValLeu65707580SerValGlyProGlyGlyLeuArgSerGlyArgLeuProLeuGlnPro859095ArgValGlnLeuAspGluArgGlyArgGlnArgGlyAspPheSerLeu100105110TrpLeuArgProAlaArgArgAlaAspAlaGlyGluTyrArgAlaAla115120125ValHisLeuArgAspArgAlaLeuSerCysArgLeuArgLeuArgLeu130135140GlyGlnAlaSerMetThrAlaSerProProGlySerLeuArgAlaSer145150155160AspTrpValIleLeuAsnCysSerPheSerArgProAspArgProAla165170175SerValHisTrpPheArgAsnArgGlyGlnGlyArgValProValArg180185190GluSerProHisHisHisLeuAlaGluSerPheLeuPheLeuProGln195200205ValSerProMetAspSerGlyProTrpGlyCysIleLeuThrTyrArg210215220AspGlyPheAsnValSerIleMetTyrAsnLeuThrValLeuGlyLeu225230235240GluProProThrProLeuThrValTyrAlaGlyAlaGlySerArgVal245250255GlyLeuProCysArgLeuProAlaGlyValGlyThrArgSerPheLeu260265270ThrAlaLysTrpThrProProGlyGlyGlyProAspLeuLeuValThr275280285GlyAspAsnGlyAspPheThrLeuArgLeuGluAspValSerGlnAla290295300GlnAlaGlyThrTyrThrCysHisIleHisLeuGlnGluGlnGlnLeu305310315320AsnAlaThrValThrLeuAlaIleIleThrValThrProLysSerPhe325330335GlySerProGlySerLeuGlyLysLeuLeuCysGluValThrProVal340345350SerGlyGlnGluArgPheValTrpSerSerLeuAspThrProSerGln355360365ArgSerPheSerGlyProTrpLeuGluAlaGlnGluAlaGlnLeuLeu370375380SerGlnProTrpGlnCysGlnLeuTyrGlnGlyGluArgLeuLeuGly385390395400AlaAlaValTyrPheThrGluLeuSerSerProGlyAlaGlnArgSer405410415GlyArgAlaProGlyAlaLeuProAlaGlyHisLeuAspIleGluGly420425430ArgMetAspGluProArgGlyProThrIleLysProCysProProCys435440445LysCysProAlaProAsnLeuLeuGlyGlyProSerValPheIlePhe450455460ProProLysIleLysAspValLeuMetIleSerLeuSerProIleVal465470475480ThrCysValValValAspValSerGluAspAspProAspValGlnIle485490495SerTrpPheValAsnAsnValGluValHisThrAlaGlnThrGlnThr500505510HisArgGluAspTyrAsnSerThrLeuArgValValSerAlaLeuPro515520525IleGlnHisGlnAspTrpMetSerGlyLysGluPheLysCysLysVal530535540AsnAsnLysAspLeuProAlaProIleGluArgThrIleSerLysPro545550555560LysGlySerValArgAlaProGlnValTyrValLeuProProProGlu565570575GluGluMetThrLysLysGlnValThrLeuThrCysMetValThrAsp580585590PheMetProGluAspIleTyrValGluTrpThrAsnAsnGlyLysThr595600605GluLeuAsnTyrLysAsnThrGluProValLeuAspSerAspGlySer610615620TyrPheMetTyrSerLysLeuArgValGluLysLysAsnTrpValGlu625630635640ArgAsnSerTyrSerCysSerValValHisGluGlyLeuHisAsnHis645650655HisThrThrLysSerPheSerArgThrProGlyLys660665701278DNA人工序列70tcagggcctgggaaagagctccccgtggtgtgggcccaggagggagctcccgtccatctt60ccctgcagcctcaaatcccccaacctggatcctaactttctacgaagaggaggggttatc120tggcaacatcaaccagacagtggccaacccactcccatcccggcccttgaccttcaccag180gggatgccctcgcctagacaacccgcacccggtcgctacacggtgctgagcgtggctcca240ggaggcctgcgcagcgggaggcagcccctgcatccccacgtgcagctggaggagcgcggc300ctccagcgcggggacttctctctgtggttgcgcccagctctgcgcaccgatgcgggcgag360taccacgccaccgtgcgcctcccgaaccgcgccctctcctgcagtctccgcctgcgcgtc420ggccaggcctcgatgattgctagtccctcaggagtcctcaagctgtctgattgggtcctt480ttgaactgctccttcagccgtcctgaccgcccagtctctgtgcactggttccagggccag540aaccgagtgcctgtctacaactcaccgcgtcattttttagctgaaactttcctgttactg600ccccaagtcagccccctggactctgggacctggggctgtgtcctcacctacagagatggc660ttcaatgtctccatcacgtacaacctcaaggttctgggtctggagcccgtagcccctctg720acagtgtacgctgctgaaggttctagggtggagctgccctgtcatttgcccccaggagtg780gggaccccttctttgctcattgccaagtggactcctcctggaggaggtcctgagctcccc840gtggctggaaagagtggcaattttacccttcaccttgaggctgtgggtctggcacaggct900gggacctacacctgtagcatccatctgcagggacagcagctcaatgccactgtcacgttg960gcggtcatcacagtgactcccaaatccttcgggttacctggctcccgggggaagctgttg1020tgtgaggtaaccccggcatctggaaaggaaagatttgtgtggcgtcccctgaacaatctg1080tccaggagttgcccgggccctgtgctggagattcaggaggccaggctccttgctgagcga1140tggcagtgtcagctgtacgagggccagaggcttcttggagcgacagtgtacgccgcagag1200tctagctcaggcgcccacagtgctaggagaatctcaggtgaccttaaaggaggccatctc1260catcatcaccatcatcat127871426PRT人工序列71SerGlyProGlyLysGluLeuProValValTrpAlaGlnGluGlyAla151015ProValHisLeuProCysSerLeuLysSerProAsnLeuAspProAsn202530PheLeuArgArgGlyGlyValIleTrpGlnHisGlnProAspSerGly354045GlnProThrProIleProAlaLeuAspLeuHisGlnGlyMetProSer505560ProArgGlnProAlaProGlyArgTyrThrValLeuSerValAlaPro65707580GlyGlyLeuArgSerGlyArgGlnProLeuHisProHisValGlnLeu859095GluGluArgGlyLeuGlnArgGlyAspPheSerLeuTrpLeuArgPro100105110AlaLeuArgThrAspAlaGlyGluTyrHisAlaThrValArgLeuPro115120125AsnArgAlaLeuSerCysSerLeuArgLeuArgValGlyGlnAlaSer130135140MetIleAlaSerProSerGlyValLeuLysLeuSerAspTrpValLeu145150155160LeuAsnCysSerPheSerArgProAspArgProValSerValHisTrp165170175PheGlnGlyGlnAsnArgValProValTyrAsnSerProArgHisPhe180185190LeuAlaGluThrPheLeuLeuLeuProGlnValSerProLeuAspSer195200205GlyThrTrpGlyCysValLeuThrTyrArgAspGlyPheAsnValSer210215220IleThrTyrAsnLeuLysValLeuGlyLeuGluProValAlaProLeu225230235240ThrValTyrAlaAlaGluGlySerArgValGluLeuProCysHisLeu245250255ProProGlyValGlyThrProSerLeuLeuIleAlaLysTrpThrPro260265270ProGlyGlyGlyProGluLeuProValAlaGlyLysSerGlyAsnPhe275280285ThrLeuHisLeuGluAlaValGlyLeuAlaGlnAlaGlyThrTyrThr290295300CysSerIleHisLeuGlnGlyGlnGlnLeuAsnAlaThrValThrLeu305310315320AlaValIleThrValThrProLysSerPheGlyLeuProGlySerArg325330335GlyLysLeuLeuCysGluValThrProAlaSerGlyLysGluArgPhe340345350ValTrpArgProLeuAsnAsnLeuSerArgSerCysProGlyProVal355360365LeuGluIleGlnGluAlaArgLeuLeuAlaGluArgTrpGlnCysGln370375380LeuTyrGluGlyGlnArgLeuLeuGlyAlaThrValTyrAlaAlaGlu385390395400SerSerSerGlyAlaHisSerAlaArgArgIleSerGlyAspLeuLys405410415GlyGlyHisLeuHisHisHisHisHisHis42042572372DNA人工序列72gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgacgacacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgatgaagcttttgatatctggggccaagggacaacggtc360accgtctcgagc37273124PRT人工序列73GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerAspAspThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProAspGluAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer11512074372DNA人工序列74gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgacgagacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgatgatgcttttgatatctggggccaagggacaacggtc360accgtctcgagc37275124PRT人工序列75GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerAspGluThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProAspAspAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer11512076372DNA人工序列76gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgaggacacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgatgatgcttttgatatctggggccaagggacaacggtc360accgtctcgagc37277124PRT人工序列77GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerGluAspThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProAspAspAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer11512078372DNA人工序列78gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgacgacacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgaagatgcttttgatatctggggccaagggacaacggtc360accgtctcgagc37279124PRT人工序列79GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerAspAspThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProGluAspAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer11512080372DNA人工序列80gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgacgagacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgaagatgcttttgatatctggggccaagggacaacggtc360accgtctcgagc37281124PRT人工序列81GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerAspGluThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProGluAspAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer11512082372DNA人工序列82gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgaggacacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgatgaagcttttgatatctggggccaagggacaacggtc360accgtctcgagc37283124PRT人工序列83GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerGluAspThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProAspGluAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer11512084372DNA人工序列84gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgacgagacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgatgaagcttttgatatctggggccaagggacaacggtc360accgtctcgagc37285124PRT人工序列85GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerAspGluThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProAspGluAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer11512086372DNA人工序列86gaggttcagctgttggagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc60tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc120cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat180gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac240atggagctgaggagcctgagatctgaggacacggccgtgtattactgtgcgagagatggc300tggtgggagctactacgtcccgaagatgcttttgatatctggggccaagggacaacggtc360accgtctcgagc37287124PRT人工序列87GluValGlnLeuLeuGluSerGlyAlaGluValLysLysProGlyAla151015SerValLysValSerCysLysAlaSerGlyTyrThrPheThrSerTyr202530GlyIleSerTrpValArgGlnAlaProGlyGlnGlyLeuGluTrpMet354045GlyTrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeu505560GlnGlyArgValThrMetThrThrAspThrSerThrSerThrAlaTyr65707580MetGluLeuArgSerLeuArgSerGluAspThrAlaValTyrTyrCys859095AlaArgAspGlyTrpTrpGluLeuLeuArgProGluAspAlaPheAsp100105110IleTrpGlyGlnGlyThrThrValThrValSerSer115120885PRT人工序列88SerTyrGlyIleSer158917PRT人工序列89TrpIleSerAlaTyrAsnGlyAsnThrAsnTyrAlaGlnLysLeuGln151015Gly9015PRT人工序列90AspGlyTrpTrpGluLeuLeuArgProAspAspAlaPheAspIle1510159111PRT人工序列91SerGlyAspLysLeuGlyAspLysTyrAlaTyr1510927PRT人工序列92TyrAspSerAspArgProSer159311PRT人工序列93GlnValTrpAspSerSerSerAspGlnValVal1510

权利要求：1.一种结合淋巴细胞活化基因-3LAG-3的抗体，其中该抗体具有显著改善的抑制LAG-3与主要组织相容性MHCII类分子之结合的作用。2.权利要求1的抗体，包含重链可变区和轻链可变区，其中重链可变区包含如下的氨基酸序列：序列41、序列45、序列49、序列53、序列57、序列61、序列75或序列77；轻链可变区包含如下的氨基酸序列：序列43、序列47、序列51、序列55、序列59或序列63。3.权利要求1或2的抗体，包含如下的重链可变区和轻链可变区的组合：1氨基酸序列41和43；2氨基酸序列45和47；3氨基酸序列49和51；4氨基酸序列53和55；5氨基酸序列57和59；6氨基酸序列61和63；7氨基酸序列75和43；或8氨基酸序列77和43。4.权利要求1-3任一项的抗体，包含重链可变区和轻链可变区，其中重链可变区包含氨基酸序列41，轻链可变区包含氨基酸序列43。5.一种分离的抗LAG-3抗体，包含重链可变区和轻链可变区，其中重链可变区包含：a重链可变区CDR1，包含序列SYGIS序列88；b重链可变区CDR2，包含序列WISAYNGNTNYAQKLQG序列89；和c重链可变区CDR3，包含序列DGWWELLRPDDAFDI序列90；轻链可变区包含：d轻链可变区CDR1，包含序列SGDKLGDKYAY序列91；e轻链可变区CDR2，包含序列YDSDRPS序列92；和f轻链可变区CDR3，包含序列QVWDSSSDQVV序列93。6.权利要求5的抗体，包含重链可变区和轻链可变区，其中：1重链可变区包含氨基酸序列41，轻链可变区包含氨基酸序列43；2重链可变区包含氨基酸序列75，轻链可变区包含氨基酸序列43；和3重链可变区包含氨基酸序列77，轻链可变区包含氨基酸序列43。7.权利要求1-6任一项所述的抗体，其为单克隆抗体、人类抗体、人源化抗体或嵌合抗体。8.权利要求1-7任一项所述的抗体，其为结合LAG-3的抗体片段。9.权利要求8的抗体，其中所述抗体片段为Fab、Fab'-SH、Fv、scFv或Fab'2片段。10.权利要求1-7任一项所述的抗体，其为全长抗体。

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