CN115867295A - 用于靶向hpv感染细胞的组合物和方法 - Google Patents
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- C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
Abstract
公开了用于靶向治疗癌症例如HPV相关癌症的组合物和方法。尤其是,公开了修饰的T细胞受体(TCR)T细胞,其可与过继性细胞转移一起用于靶向和杀伤癌细胞,减少抗原逃逸。因此,还公开了在患有HPV相关癌症的受试者中提供抗肿瘤免疫的方法,其涉及过继性转移所公开的TCR‑T细胞。
Description
相关申请
本申请要求享有2020年3月23日提交的美国临时专利申请系列号62/993,442的优先权的权益,其全部内容通过引用并入本文。
背景技术
过继性细胞转移(ACT)涉及向患者体内植入或输注特定细胞,通常是免疫细胞和/或源自免疫系统的细胞(例如,致敏、修饰和/或工程化的淋巴细胞),目的是识别、靶向和/或破坏疾病相关的细胞。过继免疫疗法(例如,T细胞疗法)已成为治疗许多疾病和疾患的有前景的方法,包括移植后淋巴增生性疾患、感染性疾病(例如,病毒感染)和自身免疫性疾病。过继性T细胞疗法也是一种有前景的癌症治疗方式,在临床试验中显示出令人鼓舞的结果。输注从患者的转移性瘤肿中分离并在离体扩增的肿瘤浸润性淋巴细胞(TIL),已经在一些患者中与转移性黑素瘤和宫颈癌的完全消退相关。然而,这种自体过继性T细胞疗法的制造通常很耗时,并且对晚期患者的用途有限。因此,迫切需要开发一种“现成的”策略来快速提供过继性T细胞疗法。这可以潜在地通过基因工程淋巴细胞(例如,T细胞,如细胞毒性T细胞)以表达肿瘤或疾病靶向部分来实现,如嵌合抗原受体(CAR)或工程化的T细胞受体(TCR)。这种策略在B细胞恶性肿瘤、黑素瘤和滑膜细胞肉瘤的临床试验中显示出令人鼓舞的早期结果。然而,将这种方法扩展到上皮癌的努力通常依赖于肿瘤和健康组织共有的靶标(例如,抗原),因此受到T细胞介导的靶向、肿瘤外毒性的限制。这种肿瘤外毒性可以通过靶向健康组织不表达的肿瘤抗原来避免,但很少有抗原是恶性细胞独有的,并且通常由特定的上皮癌家族表达。
皮肤或粘膜的选择性感染是HPV的典型特征,其复制与这些膜中细胞的成熟密切相关。在全球范围内,HPV感染每年导致约530,000例宫颈癌病例(约270,000例死亡),其中大多数(86%的病例,88%的死亡)发生在发展中国家。总体而言,HPV占全球癌症负担的5.2%。在美国,每年估计有26,000例新的癌症可归因于HPV,其中女性约17,000例,男性约9,000例。最常见的HPV类型是低风险的HPV-6和HPV-11,它们导致90%的生殖器疣和一种称为复发性呼吸道乳头状瘤病的疾病,其中肿瘤在气道中生长。在慢性淋巴细胞白血病(CLL)和血液和骨髓移植(BMT)患者中,HPV还在非黑素瘤皮肤癌(NMSC)的发展中起作用,包括皮肤鳞状细胞癌(SCC)。尤其是HPV-16和HPV-18,占头颈癌(HNSCC)和宫颈癌、肛门癌、阴道癌、外阴癌、阴茎癌、舌根癌、喉癌和扁桃体癌的大多数。目前HNSCC的标准治疗选择包括且并入了手术、放疗和同时化疗(例如、顺铂和/或西妥昔单抗)。不幸的是,采用这种方式的患者的治疗后负担可能是巨大的且永久性的,并且可能包括吞咽困难、发音困难、口干、疤痕和外貌损害以及牙关紧闭。然而,HPV相关的癌前病变,例如外阴、阴道、肛门、阴茎的癌前病变以及生殖器疣,通常使用冷冻疗法(即,使用极冷来破坏组织)、化学烧灼(即,使用化学物质破坏组织)、以及激光或手术切除进行物理消除来治疗。值得注意的是,在这种癌前病变中,单独物理消除并不是很有效,因为20-30%或更多的病例会复发,由于消除HPV的步骤失败,病变在先前治疗的部位复发,以及由于新的感染,病变在新的部位复发。当这种情况发生时,放疗和化疗的使用会相对地成功;然而,大约50%的HPV相关癌症患者仍然死于该疾病。显然,迫切需要新的治疗策略来控制HPV相关癌症的负担。
发明内容
本发明至少部分地基于以下发现:HPV抗原,特别是除了E6和E7以外的HPV抗原,可用于HPV相关疾病(例如,HPV相关的癌症,例如,头颈癌、胃肠道癌、泌尿生殖器癌和妇科癌症)的靶向治疗。在一些方面,本文提供了免疫细胞,其表达靶向HPV抗原的工程化的TCR(例如,TCR-T细胞,TCR-T)。
本文公开的本发明的方面包括对人乳头瘤病毒(HPV)16具有抗原特异性的T细胞受体(TCR)多肽。在一些实施方案中,所述TCR包含选自表1和/或13中所列氨基酸序列的至少一个互补决定区3α(CDR3α)和至少一个CDR3β氨基酸序列。在本发明的一些实施方案中,本文公开的TCR多肽对包含至少一个表位的抗原具有特异性,所述表位具有选自表1、11和/或13中所列氨基酸序列的氨基酸序列,例如SEQ ID NO:1-12、217、或218。
在本发明的某些方面,本文公开了治疗受试者中的癌症或癌前病变的方法,所述方法包括施用有效量的包含细胞的过继性免疫治疗组合物,所述细胞表达本文考虑的TCR多肽。在优选的实施方案中,癌症或病变是HPV相关的癌症或病变。在本发明的一些方面,本文公开了包含用于过继免疫疗法的细胞的细胞库。在一些实施方案中,此类库的细胞表达本文考虑的TCR。在某些优选的实施方案,所述表达TCR的细胞的HLA限制性是已知的。在某些实施方案中,如本文公开的,治疗HPV相关的癌症或癌前病变包括施用有效量的过继免疫疗法组合物,所述组合物包含选自本文所考虑的细胞库的表达TCR的细胞。
附图说明
图1显示了HPV16-E5-NLD表位特异性CD8+T细胞的分选通路,其通过双细胞因子捕获测定法检测,并通过双阳性(IFNγ和TNFα)单细胞分选到96孔PCR板中。
图2显示含有CDR3α和CDR3β的TCR区段的琼脂糖凝胶电泳图像。简而言之,对单个细胞进行RT-PCR,对所得cDNA进行两轮巢式PCR。在第一轮中,TCRα和TCRβ转录本扩增是通过外部、正义Vα和Vβ区段特异性引物和反义Cα和Cβ区段特异性引物的多重综合小组实现的。对第一轮PCR产物进行两个单独的第二轮PCR,分别包括(1)外部正义Vα和反义Cα区段特异性引物的多重小组或(2)外部正义Vβ和反义Cβ区段特异性引物。来自同一细胞的成对TCRα和TCRβ产物被加载到相邻的泳道中,并显示在成对的标记列中。阴性对照(H1-H12)PCR反应显示在底行(右泳道)中。在梯形泳道中,显示了300bp的标志物。
图3显示E2-TLQ-TCR氨基酸序列(SEQ ID NO.209),指示相关特征。
图4显示E5-NLD-TCR氨基酸(SEQ ID NO.210),指示相关特征。
图5显示了示例性慢病毒构建体(E5-NLD-TCR),指示相关特征。图5公开了SEQ IDNO:233的“SGSG接头”。
图6显示E6-AFR-TCR氨基酸序列(SEQ ID NO.211),指示相关特征。
图7显示E6-TIH-TCR氨基酸序列(SEQ ID NO.212),指示相关特征。
图8显示E6-HDI-TCR氨基酸序列(SEQ ID NO.213),指示相关特征。
图9显示E6-KQR-TCR氨基酸序列(SEQ ID NO.214),指示相关特征。
图10显示E7-TPT-TCR氨基酸序列(SEQ ID NO.215),指示相关特征。
图11显示E5-SAF-TCR氨基酸序列(SEQ ID NO.216),指示相关特征。
图12,A-C,显示将HPV特异性TCR慢病毒转移到Jurkat细胞中,通过流式细胞术证实了TCR表达。点图显示了未转导的对照和用(A)E2-TLQ-TCR、(B)E5-NLD-TCR和(C)E6-TIH-TCR转导的Jurkat细胞中的TCR表达。
图13,A和B,显示将HPV特异性TCR慢病毒转移到Jurkat细胞中赋予抗原特异性。慢病毒TCR转导的Jurkat细胞与肽脉冲的、HLA匹配或不匹配的LCL共同孵育。24小时后,通过流式细胞术检查CD69表达。细胞计数分析显示(A)E5-NLD-lentiTCR(限于HLA-C*05:01和C*08:02)和(B)E2-TLQ-lentiTCR(限于HLA A*02:01)转导的Jurkat细胞表达CD69。
图14显示将HPV特异性TCR慢病毒转移到PBMC中赋予了TCR表达。简而言之,PBMC的慢病毒转导在刺激后48小时进行。在第8天和第15天(再刺激后第7天),通过流式细胞术评估TCR表达。显示了E5-NLD-TCR转导的PBMC TCR表达的代表性数据,即,抗TCRVα12.1阳性,CD8+细胞。
图15显示通过多参数细胞内细胞因子染色(ICS)测定法评估的转基因TCR的抗原特异性。简而言之,未转导和E5-NLD-慢病毒转导的PBMC用E5抗原肽(NLD肽;SEQ ID NO.1)刺激,并孵育5小时。点图显示CD8+细胞和CD4+细胞中CD107、IFNγ、TNFα和IL-2的表达(最后一行)。
图16显示通过回顾ICS测定法测量的TCR-T细胞对同源抗原的亲合力(avidity)。用HLA匹配的LCL(用不同浓度肽(10-6、10-7、10-8、10-9、10-10、10-11、10-12和10-13mole/L)脉冲)刺激转导和未转导的PBMC 4小时,并通过ICS测定法测量IFNγ表达。折线图显示用HLA匹配的(C*05:01和C*08:02)LCL刺激后,E5-NLD慢病毒转导的PBMC IFNγ表达。
图17,A-C,显示E2-TLQ-T对CaSki细胞系(HPV16+,HLA-A*02:01+)的细胞溶解(A),未转导T细胞对CaSki细胞系(HPV16+,HLA-A*02:01+ve)的细胞溶解+(B),以及E2-TLQ-T和未转导T细胞对SCC70细胞系(HPV16-ve,HLA-A*02:01+)的细胞溶解(C)。UT=未转导的T细胞;E2 TCR=E2-TLQ-TCR转导的T细胞。
具体实施方式
概述
工程化TCR疗法的使用提供了几个优点。患者自身的T细胞可能具有所需的特异性,并允许在短时间内产生足够数量的T细胞,同时避免T细胞耗尽。在本发明的一些实施方案中,如本文所公开的,TCR可以被转导到免疫效应细胞中,例如中央记忆T细胞或具有干细胞特征的T细胞,这可以确保在转移后更好的持久性和功能。优选地,TCR被转导到细胞毒性T细胞(CD8+T细胞;CTL)。这种TCR工程化的T细胞(TCR-T细胞)可以输注到癌症患者体内,例如通过化疗或辐射使淋巴细胞减少的癌症患者,允许有效植入但抑制免疫抑制。如本文所公开,本发明至少部分涉及重组表达靶向HPV抗原的人工T细胞受体(TCR)的免疫细胞。
值得注意的是,HPV癌蛋白E6和E7是组成型表达的,对HPV相关癌症的存活很重要,但在健康组织中不存在。据报道,至少在HNSCC中,HPV16整合到宿主基因组中导致E2早期基因的破坏,该基因是E6和E7癌基因表达的负调节因子,因此使E6和E7抗原成为研究的主要焦点。然而,最近在HNSCC中的癌症基因组测序表明,大多数含有杂合附加型形式的HPV的此类癌症(例如,肿瘤),包括除E6和E7之外的其他HPV抗原。此外,较高的E2表达抑制E6和E7的表达,进一步改变HPV抗原的表达谱和随后的肿瘤内免疫T细胞浸润。此外,针对HPV癌蛋白的过继性T细胞疗法通常限于HLA-A*02:01,这是美国最常见的I类等位基因,在大约40-50%的欧洲人后裔中表达。不幸的是,HPV感染可以选择性地下调受感染细胞表面的HLA-A和HLA-B,而不影响HLA-C的表达。因此,可以通过过继性T细胞疗法(例如,TCR-T疗法)靶向其他早期蛋白,而不是E6和E7抗原,或靶向其他早期蛋白与E6和E7抗原的组合,以提供比单独靶向E6和E7更好的疗效。同样,对不同早期抗原(例如,不是E6和E7抗原,或者除E6和E7抗原之外还有其他抗原)特异的并限于HLA B和HLA-C等位基因的TCR序列,可以为HPV相关疾病(包括各种癌症)提供更好的疗效和预后。因此,本文公开的本发明的方面包括特异性靶向HPV16抗原,优选早期HPV16抗原E1、E2、E4和E5的TCR,其具有HLA-A、HLA-B和HLA-C等位基因限制性。本文还提供了免疫效应细胞(例如,T细胞),其经基因工程化以表达所述抗原特异性TCR(例如,TCR-T)。
在一些实施方案中,如本文所述,TCR-T细胞经工程化以抵消恶性细胞微环境(例如,肿瘤微环境)的任何致耐受性影响,通过例如但不限于阻止或抑制PD-1信号传导。在某些实施方案中,本文所述的TCR可对病毒或非病毒抗原敏感或选择性靶向病毒或非病毒抗原。理想的靶标不应该在任何正常组织/器官上表达,或者至少不在重要的正常组织(心脏、肝脏、CNS、肺和其他可能对短暂损伤特别敏感的组织)或密切相关的正常细胞对应物(例如,干细胞和/或祖细胞)中表达,以尽量减少副作用(例如,靶向/肿瘤外或旁观者效应)。本文还公开了免疫效应细胞,例如T细胞或自然杀伤(NK)细胞,其经工程化以表达选择性结合HPV抗原(例如,野生型和/或突变型HPV16)的重组TCR多肽。因此,还公开了在患有HPV相关疾病或恶性肿瘤的受试者中提供靶向免疫(例如,抗肿瘤免疫)的方法,所述方法包括过继转移公开的经工程化的免疫效应细胞以表达所公开的TCR多肽。
在肿瘤微环境中,癌细胞和宿主免疫细胞相互作用,可能导致促进或抑制癌症进展。理想情况下,免疫系统将识别癌细胞并动员免疫反应来消除癌症。不幸的是,在T细胞水平上,抑制性受体(例如,PD-1和Tim-3)的上调与T细胞功能障碍相关。这已在慢性HCV感染患者的循环和肝脏中的丙型肝炎病毒(HCV)特异性和HCV非特异性CD8+T细胞上观察到。通过离体抑制PD-1和Tim-3与其各自配体(即,B7-H1,也称为PD-L1,和半乳糖凝集素-9)的结合,可部分恢复T细胞增殖和IFN-γ分泌。更重要的是,最近的报道表明,长期施用IFN-α(一种持续性HCV感染的标准疗法)会促进幼稚T细胞中端粒缺失。鉴于缩短的T细胞端粒与终末分化之间的相关性(特征在于增殖潜能降低),IFN-α诱导的T细胞“耗尽”可能代表了HCV感染患者免疫疗法的重要障碍。在本文公开的某些方面,本发明采用检查点抑制策略。检查点抑制剂疗法靶向刺激或抑制免疫反应的免疫系统的关键调节物。这种免疫检查点可以在癌症疾病状态下被利用(例如,被肿瘤利用),以逃避免疫系统的攻击。检查点抑制剂研究已经注意到PD-1抑制剂疗法的活性(El-Khoueiry等人,(2017).“Nivolumab in patients withadvanced hepatocellular carcinoma(CheckMate 040):an open-label,non-comparative,phase 1/2dose escalation and expansion trial.”Lancet 389(10088):2492-2502),FDA已批准了纳武单抗(Nivolumab)用于客观反应率为20%的HCC的二线治疗。
定义
为了方便起见,这里收集了说明书、实施例和所附权利要求书中使用的某些术语。
冠词“一(a)”和“一种(an)”在本文中用于指该冠词的语法对象中的一个或多个(即至少一个)。举例来说,“一种元件”是指一个元件或多于一个元件。
如本文所用,术语“施用”是指向受试者提供药剂或组合物,包括但不限于由医学专业人员施用和自我施用。这样的试剂可以包括例如本文所述的肽、本文提供的抗原呈递细胞和/或本文提供的CTL。
术语“氨基酸”旨在涵盖所有分子,无论是天然的还是合成的,它们既包括氨基官能团又包括酸官能团,并且能够被包括在天然存在的氨基酸的聚合物中。示例性氨基酸包括天然存在的氨基酸;其类似物、衍生物和同系物;具有变体侧链的氨基酸类似物;以及上述任何一种的所有立体异构体。
如本文所用,术语“抗体”可以指完整抗体及其抗原结合片段。完整抗体是包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链的糖蛋白。每条重链包括重链可变区(本文缩写为VH)和重链恒定区。每条轻链包括轻链可变区(本文缩写为VL)和轻链恒定区。VH和VL区可以进一步细分为高变区,称为互补决定区(CDR),其间散布着更为保守的区,称为框架区(FR)。重链和轻链的可变区包含与抗原相互作用的结合结构域。抗体的恒定区可介导免疫球蛋白与宿主组织或因子的结合,包括免疫系统的各种细胞(例如,效应细胞)和经典补体系统的第一组分(C1q)。术语“抗体”包括例如单克隆抗体、多克隆抗体、嵌合抗体、人源化抗体、人抗体、多特异性抗体(例如,双特异性抗体)、单链抗体和抗原结合抗体片段。
如本文所用,术语抗体的“抗原结合片段”和“抗原结合部分”是指保留结合抗原的能力的抗体的一个或多个片段。包含在术语抗体的“抗原结合片段”内的结合片段的示例包括Fab、Fab'、F(ab')2、Fv、scFv、二硫键连接的Fv、Fd、双抗体、单链抗体、骆驼抗体、分离的CDRH3、设计的锚蛋白重复蛋白(DARPin)和保留完整抗体可变区的至少一部分的其他抗体片段。这些抗体片段可以使用常规重组和/或酶促技术获得,并且可以以与完整抗体相同的方式筛选其抗原结合。
术语“抗原结合位点”是指特异性结合抗原表位的抗体或T细胞的区域。
术语“结合”或“相互作用”是指缔合,其可以是两个分子之间稳定的缔合,例如肽和结合配偶体或结合剂(例如小分子)之间稳定的缔合,该缔合是由于,例如,在生理条件下的静电、疏水、离子和/或氢键相互作用产生。
术语“生物样品”、“组织样品”或简称“样品”分别是指从受试者的组织获得的细胞的集合。组织样品的来源可以是实体组织,如来自新鲜的、冷冻的和/或保存的器官、组织样品、活组织检查或抽吸物;血液或任何血液成分、血清、血液;体液,例如脑脊液、羊水、腹膜液或间质液、尿液、唾液、粪便、泪液;或来自受试者妊娠或发育中任何时间的细胞。
如本文所用,术语“癌症”包括但不限于实体瘤和血源性肿瘤。术语癌症包括皮肤、组织、器官、骨骼、软骨、血液和血管的疾病,包括子宫颈、肛门、阴道、外阴、阴茎、舌根、喉和扁桃体的疾病。术语“癌症”进一步包括原发性和转移性癌症。
术语“嵌合分子”是指通过连接两个或更多个在其天然状态下分别存在的分子而产生的单个分子。单个嵌合分子具有其所有组成分子所期望的所有功能。嵌合分子的一个类型是融合蛋白。
术语“表位”是指能够特异性结合抗体或免疫细胞(例如,T细胞)的蛋白决定簇。表位通常由分子的化学活性表面组群组成,例如氨基酸或糖侧链。某些表位可由T细胞受体(TCR)或抗体能够结合的特定氨基酸序列定义。
术语“融合蛋白”是指两个或更多个多肽通过肽键连接形成的多肽,所述肽键在一个多肽的氨基末端和另一个多肽的羧基末端之间形成。融合蛋白可以通过组成多肽的化学偶联形成,或者其可以作为单个多肽从编码单个连续融合蛋白的核酸序列表达。单链融合蛋白是具有单个连续多肽骨架的融合蛋白。可以使用分子生物学中的常规技术制备融合蛋白:将两个基因框内连接成单个核酸,然后在产生融合蛋白的条件下在合适的宿主细胞中表达所述核酸。
“基因构建体”是指核酸,例如载体、质粒、病毒基因组等,其包括多肽的或以其他方式可转录成生物活性RNA(例如、反义、诱饵、核酶等)的“编码序列”,可以将所述构建体转染到细胞(例如,哺乳动物细胞)中,并且可以在用构建体转染的细胞中表达所述编码序列。基因构建体可以包括与编码序列可操作地连接的一种或多种调节元件、以及内含子序列、多聚腺苷酸化位点、复制起点、标志物基因等。
术语“接头”是本领域公认的并且是指连接两个化合物(例如两个多肽)的分子或分子组。接头可以由单个连接分子组成或可以包含连接分子和间隔分子,所述间隔分子旨在将连接分子和化合物分开特定距离。
术语“可操作地连接”是指核酸与另一核酸序列的功能关系。启动子、增强子、转录和翻译终止位点以及其他信号序列是与其他序列可操作连接的核酸序列的示例。例如,DNA与转录控制元件的可操作连接是指DNA和启动子之间的物理和功能关系,使得这种DNA的转录由特异性识别、结合和转录DNA的RNA聚合酶从启动子开始。
如本文所用,短语“药学上可接受的”是指那些试剂、化合物、材料、组合物和/或剂型,在合理的医学判断范围内,适合用于与人和动物组织接触,而没有过度的毒性、刺激、过敏反应或其他问题或并发症,具有相称的合理获益/风险比。
如本文所用,短语“药学上可接受的载体”是指药学上可接受的材料、组合物或运载体,例如液体或固体填充剂、稀释剂、赋形剂或溶剂包封材料,其涉及将试剂从一个器官或身体的一部分携带或运输到另一个器官或身体的一部分。在与制剂的其他成分相容并且对患者是无害的意义上,载体必须是“可接受的”。可以用作药学上可接受的载体的材料的一些例子包括:(1)糖类,如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素、醋酸纤维素;(4)黄蓍胶粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,如可可脂和栓剂蜡;(9)油类,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇类,例如丙二醇;(11)多元醇,如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯类,例如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格溶液;(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酐;(22)药物制剂中使用的其他无毒相容物质。
术语“多核苷酸”和“核酸”可互换使用。它们是指天然或合成分子,或它们的一些组合,包含单个核苷酸或两个或更多个核苷酸,通过一个核苷酸的3'位置处的磷酸基团连接到另一个核苷酸的5'末端。核苷酸的聚合形式不受长度限制并且可以包含脱氧核糖核苷酸或核糖核苷酸或其类似物。多核苷酸可以具有任何三维结构,并且可以执行任何功能。以下是多核苷酸的非限制性示例:基因或基因片段的编码或非编码区、根据连锁分析定义的一个或多个基因座、外显子、内含子、信使RNA(mRNA)、转运RNA、核糖体RNA、核酶、cDNA、重组多核苷酸、分支多核苷酸、质粒、载体、任何序列的分离的DNA、任何序列的分离的RNA、核酸探针和引物。多核苷酸可以包含修饰的核苷酸,例如甲基化的核苷酸和核苷酸类似物。如果存在,可以在聚合物组装之前或之后赋予核苷酸结构修饰。例如,可以通过与标记组分缀合进一步修饰多核苷酸。在本文提供的所有核酸序列中,U核苷酸可与T核苷酸互换。多核苷酸不一定与天然存在该核酸的细胞关联,和/或可操作地连接到其天然连接的多核苷酸。
术语“多肽”或者“分离的多肽”是指在某些实施方案中由重组DNA或RNA制备的多肽,或合成来源的多肽,或其组合,其(1)不与通常在自然界中与其一起发现的蛋白相关,(2)分离自其通常发生的细胞,(3)不含从同一细胞来源中分离的其他蛋白,(4)由来自不同物种的细胞表达,或(5)在自然界中不存在。
当用于指特定多肽时,术语“多肽片段”或者“片段”是指这样的多肽,其相比参考多肽本身氨基酸残基缺失,但剩余氨基酸序列通常与参考多肽相同。此类缺失可发生在参考多肽的氨基末端或羧基末端,或两者。片段通常至少约5、6、8或10个氨基酸长,至少约14个氨基酸长,至少约20、30、40或50个氨基酸长,至少约75个氨基酸长,或至少约100、150、200、300、500或更多个氨基酸长。片段可以保留参考多肽的一种或多种生物活性。在各种实施方案中,片段可以包含参考多肽的酶活性和/或相互作用位点。在其他实施方案中,片段可以具有免疫原性特性。
术语“癌前病变”或者“癌前病症”是指与癌症风险增加相关的非典型细胞和/或组织。术语“癌前病变”可以指例如异型增生、良性瘤形成或原位癌。
如本文所用,“预防”病症的治疗剂是指这样的化合物,当在疾患或病症发作之前向统计样品施用时,相对于未治疗的对照样品,降低了治疗样品中疾患或病症的发生,或相对于未治疗的对照样品,延迟了疾患或病症的一种或多种症状的发作或降低了其严重程度。
如本文所用,“特异性结合”是指抗体或TCR与预定抗原结合的能力或肽与其预定结合配偶体结合的能力。通常,抗体或肽以对应于约10-7M或更小的KD的亲和力与其预定抗原或结合配偶体特异性结合,并且与其结合非特异性的、无关抗原/结合配偶体(例如,BSA、酪蛋白肽)的亲和力相比,其以至少低10倍、至少低100倍或至少低1000倍的亲和力(以KD表示)结合预定的抗原/结合配偶体。
如本文所用,“间隔物”是指连接蛋白质(包括融合蛋白)的肽。通常,间隔物除了连接蛋白质或保持蛋白质之间的一些最小距离或其他空间关系之外,没有特定的生物活性。然而,可以选择间隔物的组成氨基酸以影响分子的某些性质,例如分子的折叠、净电荷或疏水性。
如本文所用,当指多肽(包括抗体)或受体时,术语“特异性结合”或者“特异性的结合”是指结合反应,其由蛋白质和其他生物制品的异质群中存在的蛋白质或多肽或受体决定。因此,在指定条件下(例如,在抗体的免疫测定条件),当特定的配体或抗体不以显著的量结合样品中存在的其他蛋白质、或不以显著的量结合配体或抗体可能在生物体中接触的其他蛋白时,其“特异性结合”其特定的“靶标”(例如,抗体特异性结合内皮抗原)。通常,“特异性结合”第二分子的第一分子与第二分子的亲和力常数(Ka)大于约105M–1(例如,106M–1、107M–1、108M–1、109M–1、1010M–1、1011M–1、和1012M–1或更大)。例如,在TCR结合MHC(例如,I类MHC或II类MHC)上呈递的肽的能力的情况下;通常,TCR以至少约10-4M或更小的KD的亲和力特异性结合其肽/MHC,并且与其结合非特异性的、无关肽/MHC复合物(例如,包含BSA肽或酪蛋白肽的肽/MHC复合物)的亲和力相比,其以至少低10倍、至少低100倍或至少低1000倍的亲和力(以KD表示)结合预定的抗原/结合配偶体。
如本文所用,术语“受试者”是指选择用于治疗或疗法的人或非人动物。
术语“转化”、“转染”、或者“转导”是指核酸(例如,表达载体)引入受体细胞(例如,哺乳动物细胞),包括将核酸引入所述细胞的染色体DNA。
如本文所用,术语“治疗”是指被设计为在临床病理过程中改变被治疗个体的自然病程的临床干预。理想的治疗效果包括降低进展速度、改善或减轻病理状态、以及缓解或改善特定疾病、疾患或病症的预后。例如,如果缓解或消除了与特定疾病、疾患或病症相关的一种或多种症状,则可以成功“治疗”个体。
术语“变体”是指具有保守氨基酸取代、非保守氨基酸取代(例如,简并变体)的氨基酸或肽序列、编码氨基酸的每个密码子(例如,DNA和RNA)摆动位置内的取代、添加到肽的C-末端的氨基酸的氨基酸或肽序列、或与参考序列具有60%、70%、80%、90%、95%、96%、97%、98%、99%序列同一性的肽。
术语“载体”是指可以使核酸在生物体、细胞或细胞组分之间增殖和/或转移的装置。载体包括已经连接核酸分子的质粒、病毒、噬菌体、原病毒、噬菌粒、转座子和人工染色体等,它们可以自主复制或者不能自主复制、或者可以整合到宿主细胞的染色体中。这样的载体可以包括任何载体(例如,质粒、粘粒或噬菌体染色体),其含有适合被细胞表达的基因构建体(例如,与转录控制元件连接)。
在某些实施方案中,本发明的试剂可以单独使用或与其他类型的治疗剂联合施用。如本文所用,短语“联合施用”或者“组合施用”指两种或更多种不同治疗剂的任何形式(例如,包含本文公开的TCR-T细胞和免疫检查点抑制剂的组合物)的施用,以便在先前施用的治疗剂在体内仍然有效的同时施用第二试剂(例如,这两种试剂在受试者中同时有效,这可能包括两种试剂的协同作用)。例如,不同的治疗剂可以在相同的制剂中施用,或者在单独的制剂中同时或相继施用。在一些优选的实施方案中,TCR-T细胞表达(例如,在细胞表面存在或分泌)其他治疗剂。在某些实施方案中,不同治疗剂(例如,TCR-T和免疫检查点阻断分子)可以彼此在约一小时、约12小时、约24小时、约36小时、约48小时、约72小时或约一周内施用。类似地,在一些实施方案中,如本文所述的此类组合物可在治疗方案中与适合于所治疗的特定疾病、病症、损伤或疾患的其他治疗、疗法或干预组合联合使用。因此,本发明的治疗剂和组合物可以与一种或多种治疗方式组合同时或相继施用,例如,化疗、放疗、手术或其任意组合。例如但不限于,本发明的不同治疗剂和组合物(例如,单独的TCR-T或TCR-T与免疫检查点阻断分子组合)可以在化疗、放疗或手术约1小时内、约12小时内、约24小时内、约36小时内、约48小时内、约72小时内、或在约一周内施用。因此,接受这种治疗的受试者可以受益于不同治疗剂和方式的组合效果。
T细胞受体(TCR)
TCR是免疫球蛋白超家族的异二聚体细胞表面蛋白,其与参与介导信号转导的CD3复合物的不变蛋白相关。TCR以αβ和γδ形式存在,它们在结构上相似但具有不同的解剖位置和功能。天然αβTCR的细胞外结构域由两个多肽(α链和β链)组成,每个多肽都包含膜近端恒定结构域和膜远端可变结构域,每个都包含链内二硫键。类似于免疫球蛋白铰链区的短区段将免疫球蛋白样结构域连接到膜(通过跨膜区)并包含形成链间二硫键的半胱氨酸残基。
可变结构域包含称为互补决定区(CDR)的高度多态性的环,其负责与呈递肽的主要组织相容性复合物(MHC)结合。在可变结构域内,天然异二聚体αβTCR的每个α链和β链包含可变区、连接区和恒定区;β链通常在可变区和连接区之间也包含短的多样性区,但该多样性区通常被认为是连接区的一部分。每个可变区包含三个嵌入框架序列的CDR(互补决定区),一个是名为CDR3的超可变区,其是负责识别MHC上呈递的抗原的主要CDR。有几种类型的α链可变区(Vα)和几种类型的β链可变区(Vβ)区,通过其框架、CDR1和CDR2序列以及部分定义的CDR3序列来区分它们。
在本发明的一些方面,本文提供了工程化的TCR,其可以在免疫效应细胞中表达,以增强针对特定靶标的活性(例如,抗肿瘤活性)。本文提供的TCR序列能够特异性结合包含HPV表位的抗原肽(即,具有抗原特异性)。表达此类工程化的TCR的T细胞(例如,细胞毒性T细胞;CTL)可用于预防和/或治疗HPV感染和/或癌症(例如,表达HPV表位的癌症)和/或癌前病变。在一些实施方案中,TCR序列(和与其特异性结合的HPV表位序列)包含表1中列出的序列。因此,在一些实施方案中,本发明的抗原识别构建体(例如,TCR)包含组合的CDR1、CDR2和CDR3序列,其显示各自的可变链等位基因和CDR3序列。本发明的优选实施方案包括TCR构建体,其包含表1和13中列出的至少一个或多个CDR3(例如,SEQ ID NO.13至52,或219至226),或其变体(例如,在氨基酸序列中具有保守取代,例如,1-5个这样的保守取代),但更优选所有三个CDR序列CDR1、CDR2和CDR3。在一些这样的实施方案中,所述TCR包含选自SEQID NO.13至52、或219至226中所列氨基酸序列的至少一个互补决定区3α(CDR3α)和至少一个CDR3β氨基酸序列。在某些优选实施例中,TCR多肽包含在SEQ ID NO.13和14,SEQ IDNO.15和16,SEQ ID NO.17和18,SEQ ID NO.25和26,SEQ ID NO.27和28,SEQ ID NO.29和30,SEQ ID NO.51和52,SEQ ID NO.219和220,或SEQ ID NO.225和226中列出的CDR3α氨基酸序列和CDR3β氨基酸。
在一些实施方案中,本文公开的TCR多肽对HPV抗原具有特异性,优选对源自除E6和E7之外的HPV肽的HPV抗原具有特异性。在本发明特别优选的实施方案中,本文公开的TCR多肽对HPV16肽E1、E2、E4、E5中的任一种或其组合具有抗原特异性。最优选地,TCR多肽对包含至少一个表位的抗原具有特异性,该表位具有选自SEQ ID NO:1-12、217或218中所列氨基酸序列的氨基酸序列。
表1:HPV特异性TCR序列
包含本文公开的本发明的T细胞受体的α和β链可以通过本领域技术人员已知的重组方法和策略产生。例如,参见等人(2011)A Practical Approach to T-CellReceptor Cloning and Expression.PLOS ONE 6(11):e27930,其通过引用整体并入本文。可用于构建本发明的TCR的α和β链的基因序列是本领域技术人员已知的并且可以在诸如免疫遗传学和免疫信息学数据库(例如,International ImMunoGeneTics Information)中找到,本文出于示例性目的引用,但不限于此。此类基因可用作插入本文提供的序列的框架,用于本发明的TCR。相关领域的技术人员知道TCR将在免疫细胞(例如,T细胞或其前体细胞)的细胞表面表达,并将理解通常包括(例如,在氨基末端)信号肽序列(即,定位序列)。应当理解,一旦含有信号肽的多肽在细胞表面表达,信号肽通常在多肽加工(例如,在内质网中)和易位到细胞表面的过程中被蛋白水解去除。因此,多肽(例如本文公开的TCR)通常作为缺乏信号肽的成熟蛋白在细胞表面表达,而多肽的前体形式包括信号肽。信号肽可以是受体天然存在的信号肽,或者可以源自不同的蛋白质或是合成的。
优选地,本发明的TCR(例如,α和β链)的核苷酸序列被克隆到载体中,例如作为载体插入物。所述插入序列可以是为了在人组织中表达而优化的密码子。在一些这样的实施方案中,本发明的TCR是完全人的TCR。本发明的TCR可以被部分鼠源化(例如,每个TCRα和β链的恒定区氨基酸可以被小鼠恒定区的氨基酸替换)。优选地,设计载体插入物,使得TCR的α和β链由单个连续的开放阅读框合成。这样的载体插入物可以包含连续的开放阅读框,其中编码TCR的α和β链的序列被接头序列分开,例如包含在阅读框内的自切割2A寡肽序列的接头。在某些优选的实施方案中,此类自切割接头进一步包含弗林蛋白酶切割位点。例如但不限于,本文考虑的TCR构建体的核苷酸序列及其序列特征描述于表2-9中。
表2:E5-NLD-TCR构建体特征
表3:E6-HDI-TCR构建体特征
表4:E2-TLQ-TCR构建体特征
表5:E6-TIH-TCR构建体特征
表6:E6-AFR-TCR构建体特征
表7:E6-KQR-TCR构建体特征
表8:E7-TPT-TCR构建体特征
表9:E5-SAF-TCR构建体特征
同样,由本文考虑的构建体编码的示例性TCR(例如,TCRα/β肽链)描述于图3、4和6-11中。在一些实施方案中,在细胞表面表达的TCR包含至少一个TCR链,该链包含表10中列出的氨基酸序列。在优选的实施方案中,此类TCR包含TCRα链和TCRβ链,其各自分别包含表10中列出的氨基酸序列。例如,TCR可包含具有SEQ ID NO.59所列出的氨基酸序列的TCRβ链和具有SEQ ID NO.60所列出的氨基酸序列的TCRα链;或具有SEQ ID NO.61所列出的氨基酸序列的TCRβ链和具有SEQ ID NO.62所列出的氨基酸序列的TCRα链。
表10:工程化的TCRα和β链
类似地,本发明的实施方案包括免疫效应细胞(例如,T细胞),其已经用这种构建体转导以表达工程化的TCR。
在一些实施方案中,本文公开的TCR特异性结合表11中列出的表位。
表11:HPV特异性表位
在某些实施方案中,可以使用本领域已知的多种策略应用和/或施用TCR(例如,表达工程化TCR的免疫效应细胞)。例如(但不限于),TRUCK(被重新定向用于通用细胞因子杀伤的T细胞)共表达修饰的(例如,人工/重组/外源的)TCR和抗肿瘤细胞因子。细胞因子表达可以是组成型的或由T细胞活化诱导。通过TCR特异性靶向,局部产生的促炎细胞因子将内源性免疫细胞募集到肿瘤部位,并可增强抗肿瘤反应。
或者,可以通过本领域已知的方法对同种异体TCR-T细胞进行工程化,使其不再表达内源性T细胞受体(TCR)和/或主要组织相容性复合物(MHC)分子,从而分别改善外源性TCR的表达和/或功能和/或预防或减少移植物抗宿主病(GVHD)或排斥。
可以对TCR-T细胞进行工程化以共表达TCR和趋化因子受体,该受体与肿瘤配体结合,从而增强肿瘤归巢。
经工程化对免疫抑制具有抗性的TCR-T细胞可经遗传修饰,不再表达各种免疫检查点分子(例如,细胞毒性T淋巴细胞相关抗原4(CTLA4)或程序性细胞死亡蛋白1(PD-1))。示例性“敲低”和“敲除”技术包括但不限于RNA干扰(RNAi)(例如,asRNA、miRNA、shRNA、siRNA等)和CRISPR干扰(CRISPRi)(例如,CRISPR-Cas9)。在某些实施方案中,TCR-T细胞经工程化以表达检查点分子的显性失活形式。在一些这样的实施方案中,免疫检查点分子的细胞外配体结合结构域(即,胞外域)融合到跨膜膜上以竞争配体结合。例如,PD-1的细胞外配体结合结构域可与CD8跨膜结构域融合,从而竞争来自靶细胞的PD-1配体。在一些实施方案中,TCR-T细胞经工程化以表达免疫检查点开关受体,以利用靶细胞上存在的抑制性免疫检查点配体。在此类实施方案中,免疫检查点分子的细胞外配体结合结构域融合至信号传导、刺激和/或共刺激结构域。例如,PD-1的细胞外配体结合结构域可以融合至CD28结构域,从而在阻断PD-1信号传导的同时提供CD28共刺激。在进一步的实施方案中,TCR-T细胞可以与阻断免疫检查点信号传导的适体或单克隆抗体一起施用。在一些这样的实施方案中,TCR-T细胞(例如,TCR-T细胞疗法)与PD-1阻断方法组合,例如施用PD-1/PD-L1拮抗性适体或抗PD-1/PD-L1抗体。在优选的实施方案中,TCR-T细胞和PD-1通路阻断抗体联合施用。在进一步的实施方案中,TCR-T细胞经工程化以表达或表达并分泌免疫检查点阻断抗体,例如抗PD-1或抗PD-L1或其片段。在更进一步的实施方案中,TCR-T细胞与表达本文所述的免疫检查点阻断分子的载体一起施用(例如,工程化的病毒)。
可以使用T细胞的诱导型凋亡来设计自毁TCR-T细胞,例如,通过更昔洛韦与基因修饰淋巴细胞中的胸苷激酶结合或通过小分子二聚体活化人半胱天冬酶9。
标记的TCR-T细胞表达修饰的TCR与现有单克隆抗体试剂结合的肿瘤表位。在出现无法耐受的不良反应时,施用单克隆抗体清除TCR-T细胞并缓解症状,而不会产生额外的肿瘤外效应。
双特异性TCR-T细胞可以进一步表达另一TCR或嵌合抗原受体(CAR),其相对于第一修饰的TCR具有不同的抗原/配体结合靶标,例如,其他癌症相关抗原,包括肿瘤抗原。
肿瘤抗原包括由肿瘤细胞产生的引起免疫反应的蛋白质;特别是T细胞介导的免疫反应。额外的抗原结合结构域可以是抗体或肿瘤抗原的天然配体。额外的抗原结合结构域的选择将取决于待治疗的特定癌症类型。肿瘤抗原在本领域是众所周知的并且包括,例如神经胶质瘤相关抗原、癌胚抗原(CEA)、EGFRvIII、IL-11Ra、IL-13Ra、EGFR、FAP、B7H3、Kit、CA LX、CS-1、MUC1、BCMA、bcr-abl、HER2、β-人绒毛膜促性腺激素、甲胎蛋白(AFP)、ALK、替代和/或特异性CD19表位、TIM3、细胞周期蛋白B1、凝集素反应性AFP、Fos相关抗原1、ADRB3、甲状腺球蛋白、EphA2、RAGE-1、RU1、RU2、SSX2、AKAP-4、LCK、OY-TES1、PAX5、SART3、CLL-1、岩藻糖基GM1、GloboH、MN-CA IX、EPCAM、EVT6-AML、TGS5、人端粒酶逆转录酶、plysialic acid、PLAC1、RU1、RU2(AS)、肠羧基酯酶、lewisY、sLe、LY6K、HSP70、HSP27、muthsp70-2、M-CSF、MYCN、RhoC、TRP-2、CYPIBI、BORIS、前列腺酶、前列腺特异性抗原(PSA)、PAX3、PAP、NY-ESO-1、LAGE-la、LMP2、NCAM、p53、p53突变体、Ras突变体、gplOO、prostein、OR51E2、PANX3、PSMA、PSCA、Her2/neu、hTERT、HMWMAA、HAVCR1、VEGFR2、PDGFR-β、存活蛋白和端粒酶、legumain、HPV E6、E7、精子蛋白17、SSEA-4、酪氨酸酶、TARP、WT1、前列腺癌肿瘤抗原-1(PCTA-1)、ML-IAP、MAGE、MAGE-A1、MAGE-A2、MAGE-C1、MAGE-C2、膜联蛋白-A2、MAD-CT-1、MAD-CT-2、MelanA/MART 1、XAGE1、ELF2M、ERG(TMPRSS2 ETS融合基因)、NA17、中性粒细胞弹性蛋白酶、肉瘤易位断点、NY-BR-1、EphrinB2、CD20、CD22、CD24、CD30、TIM3、CD38、CD44v6、CD97、CD171、CD179a、雄激素受体、FAP、胰岛素生长因子(IGF)-I、IGFII、IGF-I受体、GD2、o-乙酰基-GD2、GD3、GM3、GPRC5D、GPR20、CXORF61、叶酸受体(FRa)、叶酸受体β、ROR1、Flt3、TAG72、TN Ag、Tie2、TEM1、TEM7R、CLDN6、TSHR、UPK2和间皮素。在某些优选的实施方案中,肿瘤抗原选自叶酸受体(FRa)、间皮素、EGFRvIII、IL-13Ra、CD123、CD19、TIM3、BCMA、GD2、CLL-1、CA-IX、MUC1、HER2和其任何组合。
肿瘤抗原的其他非限制性例子包括以下:分化抗原,如酪氨酸酶、TRP-1、TRP-2和肿瘤特异性多系抗原如MAGE-1、MAGE-3、BAGE、GAGE-1、GAGE-2、pi 5;过表达的胚胎抗原,如CEA;过表达的癌基因和突变的肿瘤抑制基因,如p53、Ras、HER-2/neu;由染色体易位产生的独特肿瘤抗原;如BCR-ABL、E2A-PRL、H4-RET、IGH-IGK、MYL-RAR;和病毒抗原,例如,爱泼斯坦-巴尔病毒抗原EBVA和人乳头瘤病毒(HPV)抗原E6和E7。其他大的基于蛋白的抗原包括SCCA、GP73、FC-GP73、TSP-180、MAGE-4、MAGE-5、MAGE-6、RAGE、NY-ESO、pl85erbB2、pl80erbB-3、c-met、nm-23H1、PSA、CA 19-9、CA 72-4、CAM 17.1、NuMa、K-ras、β-连环蛋白、CDK4、Mum-1、p15、p16、43-9F、5T4、791Tgp72、甲胎蛋白、β-HCG、BCA225、BTAA、CA125、CA 15-3\CA 27.29\BCAA、CA 195、CA 242、CA-50、CAM43、CD68\P1、CO-029、FGF-5、G250、Ga733\EpCAM、HTgp-175、M344、MA-50、MG7-Ag、MOV18、NB/70K、NY-CO-1、RCASl、SDCCAG16、TA-90\Mac-2结合蛋白\亲环蛋白C-相关蛋白、TAAL6、TAG72、TLP、TPS、GPC3、MUC16、TAG-72、LMP1、EBMA-1、BARF-1、CS1、CD319、HER1、B7H6、L1CAM、IL6和MET。
一般而言,关于本文公开的方法,几乎任何应用于CAR-T细胞的策略都可以应用于本文公开的TCR-T细胞。
核酸和载体
还公开了编码公开的HPV抗原特异性TCR的多核苷酸和多核苷酸载体,其允许在公开的免疫效应细胞中表达HPV抗原特异性TCR。在一些实施方案中,本文公开的多核苷酸和多核苷酸载体包含表2-9中列出的任何一种核酸序列。在本发明的某些方面,本文提供的是分离的核酸,其包含编码一种或多种肽的核苷酸序列,所述肽包含TCRα和/或TCRβ链。在一些实施方案中,由本文公开的核酸编码的肽包含选自SEQ ID NO.13-52、59-70、209-216中任何一种的氨基酸序列或其片段。
编码公开的TCR及其区域的核酸序列可以使用本领域已知的重组方法获得,例如通过从表达该基因的细胞中筛选文库,通过从已知包含该基因的载体衍生基因,或通过使用标准技术直接从含有该基因的细胞和组织中分离。或者,感兴趣的基因可以合成产生,而不是克隆。
编码TCR的核酸的表达通常通过将编码TCR多肽的核酸可操作地连接至启动子,并将构建体整合到表达载体中来实现。典型的克隆和/或表达载体含有转录和翻译终止子、起始序列和用于调节所需核酸序列表达的启动子。
可以通过本领域已知的方法将编码本发明的TCR的α和β链的核酸序列置于单个表达载体中。例如但不限于,编码本文所述的TCR的核酸序列可以包含编码核糖体跳跃序列的核酸序列,例如编码2A肽的序列。在小核糖核酸病毒的口疮病毒亚组中鉴定的2A肽会导致核糖体从一个密码子“跳跃”到下一个密码子,而不会在密码子编码的两个氨基酸之间形成肽键。因此,当多肽被框内的2A寡肽序列分隔时(例如,当TCR的α和β链被2A寡肽序列分隔时),可以从mRNA内的单个连续开放阅读框合成两个多肽。这种核糖体“跳跃”或“自切割”机制或在本领域中是众所周知的并且已知被几种载体用于表达由单个信使RNA编码的几种蛋白。例如,2A寡肽序列可以与弗林蛋白酶切割识别位点一起使用。优选地,弗林蛋白酶识别位点位于2A寡肽序列的上游。最优选地,弗林蛋白酶识别位点序列和2A寡肽序列由GSG接头分开。这样的组合弗林蛋白酶切割位点、氨基酸间隔区以及随后的2A核糖体跳跃肽的双顺反子慢病毒载体是本领域已知的。例如,参见Yang等人(2008)Development of optimalbicistronic lentiviral vectors facilitates high-level TCR gene expression androbust tumor cell recognition,Gene Therapy,第15卷,第1411–1423页,其通过引用整体并入本文。自切割弗林蛋白酶-间隔区-2A位点上游的所得肽可在其羧基末端保留弗林蛋白酶识别序列(例如,在图3、4和6-11中所示的FURIN切割位点)。同样,在没有任何翻译后修饰(例如去除信号肽序列)的情况下,自切割弗林蛋白酶-间隔区-2A位点下游的所得肽可在其氨基末端保留氨基酸(例如,在图3、4和6-11中所示的F2A接头序列的末端脯氨酸)。或者,α和β链可以各自放置在单独的表达载体中。
公开的核酸可以克隆到多种类型的载体中。例如,可以将核酸克隆到载体中,所述载体包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。特别感兴趣的载体包括表达载体、复制载体、探针生成载体和测序载体。
此外,表达载体可以以病毒载体的形式提供给细胞。病毒载体技术在本领域中是众所周知的并且例如描述在Sambrook等人(2001,Molecular Cloning:A LaboratoryManual,Cold Spring Harbor Laboratory,New York),以及其他病毒学和分子生物学手册。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。通常,合适的载体包含在至少一种生物体中具有功能的复制起点、启动子序列、方便的限制性内切核酸酶位点和一种或多种可选择的标志物。在一些实施方案中,多核苷酸载体是慢病毒或逆转录病毒载体。
已经开发了许多基于病毒的系统用于将基因转移到哺乳动物细胞中。例如,逆转录病毒为基因递送系统提供了一个方便的平台。可以使用本领域已知的技术将选择的基因插入载体并包装在逆转录病毒颗粒中。然后可以分离重组病毒并将其在体内或者离体递送至受试者的细胞。优选地,基因转移到哺乳动物细胞中(例如,PBMC)。
合适的启动子的一个示例是立即早期巨细胞病毒(CMV)启动子序列。该启动子序列是强的组成型启动子序列,能够驱动与其可操作连接的任何多核苷酸序列的高水平表达。合适的启动子的另一个示例是延伸生长因子-1α(EF-1α;EF1a)。然而,也可以使用其他组成型启动子序列,包括但不限于猿猴病毒40(SV40)早期启动子、MND(骨髓增殖性肉瘤病毒)启动子、小鼠乳腺肿瘤病毒(MMTV)、人免疫缺陷病毒(HIV)长末端重复(LTR)启动子、MoMuLV启动子、禽白血病病毒启动子、爱泼斯坦-巴尔病毒立即早期启动子、劳斯肉瘤病毒启动子,以及人基因启动子,例如但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。或者,启动子也可以是诱导型启动子。诱导型启动子的示例包括但不限于金属硫蛋白(metallothionine)启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
额外的启动子元件(例如,增强子)调节转录起始的频率。通常,这些启动子位于起始位点上游30-110bp的区域,尽管最近已显示许多启动子也包含起始位点下游的功能元件。启动子元件之间的间距通常是灵活的,因此当元件相对于彼此倒置或移动时,启动子功能得以保留。
为了评估TCR多肽或其部分的表达,待引入细胞中的表达载体还可以包含可选择的标志物基因或报告基因或两者,以促进从尝试通过病毒载体转染或感染的细胞群中鉴定和选择表达细胞。在其他方面,可选择的标志物可携带在单独的DNA片段上并用于共转染步骤中。可选择的标志物和报告基因的侧翼都可以有适当的调节序列,以确保在宿主细胞中表达。有用的可选择的标志物包括,例如,抗生素抗性基因。
报告基因用于鉴定可能转染的细胞和评估调节序列的功能。一般而言,报告基因是不存在于受体生物体或组织中或不被受体生物体或组织表达的基因,其编码通过一些容易检测的特征来证明其表达的多肽,例如,酶活性。在将DNA引入受体细胞后的合适时间测定报告基因的表达。合适的报告基因可以包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌型碱性磷酸酶的基因或绿色荧光蛋白基因。合适的表达系统是众所周知的并且可以使用已知技术制备或商业获得。通常,具有显示最高水平的报告基因表达的最小5'侧翼区域的构建体被鉴定为启动子。此类启动子区域可与报告基因连接并用于评估试剂调节启动子驱动的转录的能力。
将基因引入到细胞中并表达的方法是本领域已知的。在表达载体的情况下,通过本领域中的任何方法可以容易地将该载体引入宿主细胞中,例如,哺乳动物、细菌、酵母或昆虫细胞。例如,表达载体可以通过物理、化学或生物方法转移到宿主细胞中。
将多核苷酸引入宿主细胞的物理方法包括磷酸钙沉淀、脂质转染、粒子轰击、显微注射、电穿孔等。用于产生包含载体和/或外源核酸的细胞的方法是本领域众所周知的。例如,参见Sambrook等人(2001,Molecular Cloning:A Laboratory Manual,Cold SpringHarbor Laboratory,New York)。
将感兴趣的多核苷酸引入宿主细胞的生物方法包括使用DNA和RNA载体。病毒载体,特别是逆转录病毒载体,已成为最广泛使用的将基因插入哺乳动物(例如,人细胞)的方法。
用于将多核苷酸引入宿主细胞的化学方法包括胶体分散系统,例如大分子复合物、纳米胶囊、微球、珠和基于脂质的系统,包括水包油乳剂、胶束、混合胶束和脂质体。用作体外和体内递送载体的示例性胶体系统是脂质体(例如,一种人造膜囊泡)。
在使用非病毒递送系统的情况下,示例性递送载体是脂质体。在另一个方面,核酸可以与脂质结合。与脂质结合的核酸可以封装在脂质体的水性内部、散布在脂质体的脂质双层中、通过与脂质体和寡核苷酸均结合的连接分子与脂质体连接、包埋在脂质体中、与脂质体复合、分散在含有脂质的溶液中、与脂质混合、与脂质组合、作为悬浮液包含在脂质中、包含或与胶束复合、或以其他方式与脂质结合。与脂质、脂质/DNA或脂质/表达载体结合的组合物不限于溶液中的任何特定结构。例如,它们可以以双层结构、作为胶束或具有“塌陷”结构存在。它们也可以简单地散布在溶液中,可能形成大小或形状不均匀的聚集体。脂质是脂肪物质,其可以是天然存在的或合成的脂质。例如,脂质包括天然存在于细胞质中的脂肪滴以及含有长链脂肪烃及其衍生物的化合物类别,例如脂肪酸、醇、胺、氨基醇和醛。适合应用的脂质可以从商业来源获得。例如,二肉豆蔻基磷脂酰胆碱(“DMPC”)可以从Sigma,St.Louis,MO.获得;双十六烷基磷酸(“DCP”)可从K&K Laboratories(Plainview,NY)获得;胆固醇(“Choi”)可以从Calbiochem-Behring获得;二肉豆蔻基磷脂酰甘油(“DMPG”)和其他脂质可以从Avanti Polar Lipids,Inc,(Birmingham,Ala.)获得。
免疫细胞
本文公开的本发明TCR的α和β链可以在不同宿主细胞或相同宿主细胞中独立表达。在优选的实施方案中,将α链和β链引入相同的宿主细胞以允许形成功能性T细胞受体。最优选地,经工程化以表达本发明公开的TCR的全部或部分的宿主细胞包括免疫细胞(例如,免疫效应细胞)。这样的细胞可以从待治疗(即,自体细胞)的受试者获得(即,供体)。然而,在一些实施方案中,使用免疫细胞系或不是受试者自身细胞的供体细胞(即,同种异体细胞)。免疫效应细胞可以从多种来源获得,包括外周血单个核细胞(PBMC)、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、胸腔积液、脾组织和肿瘤。可以使用本领域技术人员已知的许多技术(例如FicollTM分离),从采集自受试者和/或供体的血液中获得免疫效应细胞。例如,来自个体循环血液的细胞可以通过单采术获得。在一些实施方案中,免疫效应细胞通过裂解红细胞和去除单核细胞从外周血淋巴细胞中分离,例如通过PERCOLLTM梯度离心或通过逆流离心淘析。可以通过阳性或阴性选择技术进一步分离免疫效应细胞的特定亚群。例如,可以使用针对阳性选择细胞特有的表面标志物的抗体组合来分离免疫效应细胞,例如,通过与抗体缀合的珠一起孵育足够的时间来阳性选择所需的免疫效应细胞。或者,免疫效应细胞群的富集可以通过使用针对阴性选择细胞特有的表面标志物的抗体组合进行阴性选择来完成。
在一些实施方案中,免疫效应细胞包括参与保护身体免受传染病和外来物质侵袭的任何白细胞。例如,免疫效应细胞可以包括淋巴细胞、单核细胞、巨噬细胞、树突状细胞、肥大细胞、嗜中性粒细胞、嗜碱性粒细胞、嗜酸性粒细胞或其任何组合。例如,免疫效应细胞可以包括T淋巴细胞,优选细胞毒性T淋巴细胞(CTL)。
通过在细胞表面存在的T细胞受体(TCR),可以将T细胞或T淋巴细胞与其他淋巴细胞(例如B细胞和自然杀伤细胞(NK细胞))区分开来。它们被称为T细胞,是因为它们在胸腺中成熟(尽管有些也在扁桃体中成熟)。存在一些T细胞亚组,每个亚组都有不同的功能。
T辅助细胞(TH细胞)在免疫过程中辅助其他白细胞,所述免疫过程包括B细胞成熟为浆细胞和记忆B细胞,以及细胞毒性T细胞和巨噬细胞的活化。这些细胞也称为CD4+T细胞,因为它们在其表面表达CD4糖蛋白。辅助T细胞在MHC II类分子向其呈递肽抗原时被激活,所述MHC II类分子在抗原呈递细胞(APC)表面上表达。一旦被激活,其迅速分裂并分泌称为细胞因子的小蛋白,调节或辅助主动免疫反应。这些细胞可以分化成几种亚型之一,包括TH1、TH2、TH3、TH17、TH9或TFH,其分泌不同的细胞因子以促进不同类型的免疫反应。
细胞毒性T细胞(TC细胞或CTL)破坏病毒感染和肿瘤细胞的细胞,并且还参与移植排斥。这些细胞也被称为CD8+T细胞,因为它们在其表面上表达CD8糖蛋白。这些细胞通过与存在于所有有核细胞表面上的MHC I类分子结合的抗原结合来识别其靶标。通过调节性T细胞分泌的IL-10、腺苷和其他分子,CD8+细胞可以被灭活到无活力状态,从而防止自身免疫性疾病。
记忆T细胞是抗原特异性T细胞的一个亚组,在感染消退后会长期存在。当再次暴露于其同源抗原时,其迅速扩增为大量效应T细胞,从而为免疫系统提供针对过去感染的“记忆”。记忆细胞可以是CD4+或CD8+。记忆T细胞通常表达细胞表面蛋白CD45RO。
调节性T细胞(Treg细胞),以前称为抑制性T细胞,对于维持免疫耐受至关重要。它们的主要作用是关闭T细胞介导的免疫,使免疫反应结束,并抑制在胸腺中逃逸阴性选择过程的自身反应性T细胞。已经描述了两大类CD4+Treg细胞——天然存在的Treg细胞和适应性Treg细胞。
自然杀伤T(NKT)细胞(不要与自然杀伤(NK)细胞混淆)将适应性免疫系统与固有免疫系统联系起来。与识别主要组织相容性复合物(MHC)分子呈递的肽抗原的传统T细胞不同,NKT细胞识别由称为CD1d的分子呈递的糖脂抗原。
在一些实施方案中,T细胞包括CD4+细胞的混合物。在其他实施方案中,基于细胞表面表达富集T细胞的一个或多个亚组。例如,在某些情况下,T包含细胞毒性CD8+T淋巴细胞。在一些实施方案中,T细胞包括γδT细胞,其具有独特的T细胞受体(TCR),所述T细胞受体具有一条γ链和一条δ链,而不是α和β链。
自然杀伤(NK)细胞是CD56+CD3–大颗粒淋巴细胞,其可以杀伤病毒感染的和转化的细胞,并构成固有免疫系统的关键细胞亚组(Godfrey J,等人Leuk Lymphoma 2012 53:1666–1676)。不同于细胞毒性CD8+T淋巴细胞,NK细胞无需事先致敏即可对肿瘤细胞产生细胞毒性,并且可以根除MHC-I阴性细胞(Narni-Mancinelli E,等人Int Immunol 2011 23:427–431)。NK细胞是更安全的效应细胞,因为其可以避免细胞因子风暴的潜在致命并发症(Morgan RA,等人Mol Ther 2010 18:843–851)、肿瘤溶解综合征(Porter DL,等人N EnglJ Med 2011 365:725–733)、以及靶向、肿瘤外效应。尽管NK细胞作为癌细胞的杀手具有众所周知的作用,并且已广泛记载了NK细胞损伤对多发性骨髓瘤(MM)的进展至关重要(Godfrey J,等人,Leuk Lymphoma 2012 53:1666–1676;Fauriat C,等人,Leukemia 200620:732–733),但是,在公开的TCR之前,可能增强NK细胞介导的抗MM活性的方法在很大程度上尚未被人们探索。
虽然固有免疫反应在控制初始的HPV感染中起重要作用,但长期保护依赖于适应性免疫反应,包括体液和细胞介导的免疫。在免疫功能正常的个体中,大多数HPV感染在初始感染的2年内被清除。在自发消退的病变中经常观察到CD4+和CD8+T细胞的浸润。尽管HPV疫苗具有预防作用并且基于L1蛋白,但这种病毒抗原与HPV相关疾病的治疗无关。L1蛋白仅在HPV复制的后期表达,特别是在终末分化的角质形成细胞中表达。相反,与HPV复制周期相关的其他蛋白,即,E1、E2、E4、E5、E6和E7可能为免疫治疗策略提供重要的靶点。这主要是由于所有这些蛋白的表达保持在感染的多个阶段的事实。虽然对免疫治疗策略设计的大部分重点都集中在E6和E7抗原上,但重要的是要认识到其他早期蛋白参与HPV复制,因此这些蛋白的表达保持在感染的多个阶段。这突出了这些蛋白作为旨在消除持续感染HPV的细胞的免疫疗法的潜在靶标的重要性,而不管发病机制的阶段如何。事实上,以前使用动物模型(犬和兔)的研究表明,用编码密码子优化的E1或E2基因的DNA疫苗免疫导致乳头状瘤的完全消退。这些动物模型中的主要保护模式是通过诱导对E1和E2抗原的有效T细胞反应来介导的。在患有HPV诱导的宫颈病变(C1N1至C1N3)的人受试者中使用编码E2的改良牛痘Ankara载体进行的进一步临床研究表明,宫颈病变完全消除,从C1N3消退为C1N1,并且HPV病毒载量显著降低。同样,E2特异性T细胞免疫的诱导与临床反应密切相关。抗载体抗体的开发导致对加强免疫反应不佳,一些患者在研究完成后表现出病变复发。此外,这种疗法需要将载体直接注射到子宫组织中才能有效,从而限制了其在普通人群中的广泛使用。
因此,本文提供了通过过继转移自体或同种异体HPV特异性的、表达TCR的细胞(例如,本文所述的TCR-T细胞)来预防和治疗HPV相关疾病和癌症的方法。此类方法可包括产生和/或使用肽特异性T细胞(例如,CTL、CD8+T细胞和/或CD4+T细胞)。肽特异性T细胞的产生是本领域已知的,并且可以包括,例如,孵育包含T细胞的样品(例如,PBMC样品、富集样品或分离的T细胞样品)和抗原肽(即,包含T细胞表位的肽)或呈递一种或多种此类T细胞表位的抗原呈递细胞(APC)(例如,呈递包含I类MHC复合物上的CTL表位的肽的APC),从而诱导肽特异性T细胞的致敏(例如,活化和增殖)。在一些实施方案中,抗原肽包含任何病毒蛋白的序列(即,抗原)。例如,但不限于,免疫细胞(例如,CTL)对病毒抗原致敏,所述病毒抗原来自人乳头瘤病毒(HPV)、爱泼斯坦-巴尔病毒(EBV)、巨细胞病毒(CMV)、B.K.病毒(BKV)、约翰坎宁安病毒(JCV)、小核糖核酸病毒(例如,甲型肝炎病毒)、嗜肝DNA病毒(例如,乙型肝炎病毒)、肝炎病毒(例如,丙型肝炎病毒)、delta病毒(例如,丁型肝炎病毒)、肝炎病毒(例如,戊型肝炎病毒)中的任一、或其任何组合。在优选的实施方案中,包含CTL的样品(即,PBMC样品)与抗原肽(例如,抗原HPV16肽,例如表1、11和13中公开的那些)或本文提供的抗原呈递细胞(APC)(例如,“肽脉冲的”细胞,其在I类MHC复合物上呈递包含本文所述的HPV表位的所述肽)一起在培养物中孵育。在一些实施方案中,APC对于从中获得T细胞的受试者是自体的。在一些实施方案中,将含有T细胞的样品与本文提供的APC孵育2次或更多次。在一些实施方案中,在至少一种细胞因子的存在下,将T细胞与APC孵育。在一些实施方案中,细胞因子是IL-4、IL-7和/或IL-15。使用APC诱导T细胞增殖的示例性方法提供于,例如美国专利公开号2015/0017723中,其通过引用并入本文。在一些实施方案中,抗原是除E6和E7之外的HPV抗原。
在一些方面,本文提供了包含本文提供的TCR-T细胞的组合物(例如,预防和/或治疗组合物)。在一些实施方案中,通过向受试者施用有效量的组合物,此类组合物用于治疗和/或预防受试者的癌症、和/或癌前病变、和/或HPV感染。在一些实施方案中,经工程化的TCR-T细胞对于受试者不是自体的。在一些实施方案中,TCR-T细胞对于受试者是自体的。在一些实施方案中,在将TCR-T细胞施用于受试者之前,将其存储在细胞库中。因此,在一些实施方案中,包含一种或多种本发明的经工程化的TCR多肽的所公开的免疫效应细胞是同种异体或自体的免疫效应细胞。优选地,此类TCR-T细胞的等位基因HLA限制性(即,对特定HLA-A、HLA-B或HLA-C等位基因的限制性)是已知的。在一些实施方案中,用于产生本发明的TCR-T细胞的T细胞是肽特异性的(即,对抗原肽如病毒肽敏感)。在一些实施方案中,用于产生本发明的TCR-T细胞的T细胞是多功能T细胞,即,能够诱导多种免疫效应物功能的T细胞,相比于例如仅产生单个免疫效应物(例如单个生物标志物,例如细胞因子或CD107a)的细胞,其提供了针对病原体更有效的免疫反应。在慢性感染期间,多功能性较弱、单功能性、甚至“疲惫型”T细胞可能主导免疫反应,从而对针对病毒相关并发症的保护产生负面影响。在进一步优选的实施方案中,本发明的TCR-T细胞是多功能的。在某些实施方案中,用于产生本发明的TCR-T细胞的至少50%的T细胞是CD4+T细胞。在一些这样的实施方案中,所述T细胞少于50% CD4+T细胞。在更进一步的实施方案中,所述T细胞主要是CD4+T细胞。在一些实施方案中,用于产生本发明的TCR-T细胞的至少50%的T细胞是CD8+T细胞。在一些这样的实施方案中,所述T细胞少于50% CD8+T细胞。在更进一步的实施方案中,所述T细胞主要是CD8+T细胞。在一些实施方案中,T细胞(例如,本文所述的供体样品、致敏T细胞和/或TCR-T细胞)在施用于受试者之前储存在细胞文库或细胞库中。
在一些实施方案中,表达所公开的TCR的经工程化的TCR-T细胞进一步表达影响免疫检查点阻断的显性失活突变(例如,表达显性失活形式的免疫检查点分子,例如PD-1)。不旨在详尽列表,免疫检查点分子选自程序性死亡1(PD-1)、细胞毒性T淋巴细胞抗原4(CTLA-4)、B和T淋巴细胞减毒剂(BTLA)、T细胞免疫球蛋白粘蛋白3(TIM-3)、淋巴细胞激活蛋白3(LAG-3)、具有Ig和ITIM结构域的T细胞免疫受体(TIGIT)、白细胞相关免疫球蛋白样受体1(LAIR1)、自然杀伤细胞受体2B4(2B4)和CD160。免疫检查点分子也可以是转化生长因子β(TGF-β)受体。在某些优选实施方案中,免疫检查点分子是CTLA-4。在特别优选的实施方案中,免疫检查点分子是PD-1。
治疗方法
表达所公开的TCR的免疫效应细胞可以引发针对表达HPV抗原的癌细胞(例如,HPV相关癌症)的治疗上有益的免疫反应。例如,由公开的TCR修饰的免疫效应细胞引发的抗肿瘤免疫反应可以是主动或被动免疫反应。此外,TCR介导的免疫反应可以是过继性免疫治疗方法的一部分,其中TCR修饰的免疫效应细胞诱导特异性针对HPV抗原的免疫反应,优选针对不是E6和E7抗原的HPV抗原、或针对E6和E7抗原以及其他HPV抗原。
过继转移表达经工程化的TCR的免疫效应细胞是一种有前景的抗癌疗法。因此,在本发明的一些方面,本文提供了治疗受试者中HPV相关癌症或癌前病变的方法,所述方法包括施用有效量的包含本文所考虑的表达TCR的细胞的过继免疫疗法组合物。在收集患者的免疫效应细胞后,可以对细胞进行基因工程化以表达所公开的HPV抗原特异性TCR,从而调整所述免疫效应细胞(例如,T细胞)的特异性抗原性,并将其输回患者体内。此外,从患者以外的供体获得的免疫效应细胞(即,对患者为同种异体)可以被基因工程化以表达所公开的HPV抗原特异性TCR,然后将含有TCR的细胞输注到患者。在某些具体实施方案中,包含抗HPV抗原TCR多肽的免疫效应细胞是同种异体HPV特异性细胞毒性T细胞。
公开的TCR修饰的免疫效应细胞可以单独施用,或者作为药物组合物与稀释剂和/或与其他组分如IL-2、IL-15或其他细胞因子或细胞群组合施用。简而言之,药物组合物可包含如本文所述的靶向细胞群,以及与一种或多种药学或生理学上可接受的载体、稀释剂或赋形剂组合。这样的组合物可以包含缓冲剂,例如中性缓冲盐水、磷酸盐缓冲盐水等;碳水化合物,例如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸,例如甘氨酸;抗氧化剂;螯合剂,例如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。在一些实施方案中,用于所公开方法的组合物被配制用于静脉内施用。可以以任何适合治疗MM的方式施用药物组合物。施用的量和频率将由这样的因素决定:如患者的状况和患者疾病的严重程度,尽管适当的剂量可以通过临床试验来确定。
当指出“免疫学上的有效量”、“抗肿瘤有效量”、“肿瘤抑制有效量”或“治疗量”时,待施用的本发明组合物的精确量由医生考虑患者(受试者)的年龄、体重、肿瘤大小、感染或转移程度以及状况等个体差异来确定。
在某些实施方案中,可能需要将活化的T细胞施用于受试者,然后再抽血(或进行单采术),根据所公开的方法从其中活化T细胞,并将这些活化并扩增的T细胞重新输注到患者。这个过程可以每几周进行多次。在某些实施方案中,可以从10cc至400cc的抽血中活化T细胞。在某些实施方案中,从20cc、30cc、40cc、50cc、60cc、70cc、80cc、90cc或100cc的抽血中活化T细胞。使用这种多次抽血/多次回输方案可用于选择某些T细胞群。
可以任何方便的方式进行所公开组合物的施用,包括通过注射、输注或植入。本文所述的组合物可以通过以下方式施用于患者:通过皮下、皮内、肿瘤内、鞘内、节内、髓内、肌肉内、胸膜内、颅内直接施用于器官,通过静脉内(iv)注射或腹膜内注射施用。在一些实施方案中,所公开的组合物通过皮内或皮下注射施用于患者。在一些实施方案中,所公开的组合物通过静脉内注射施用。也可以将组合物直接注射到肿瘤、淋巴结或感染部位。
在某些实施方案中,本文提供了治疗受试者的HPV感染和/或癌症和/或癌前病变的方法,所述方法包括向所述受试者施用本文提供的药物组合物。
在一些实施方案中,本文提供了一种治疗受试者中HPV感染的方法。在某些此类实施方案中,所治疗的受试者是免疫低下的。例如,所述受试者可能患有T细胞缺乏症。所述受试者可能患有白血病、淋巴瘤或多发性骨髓瘤。在一些实施方案中,所述受试者感染了HIV和/或患有艾滋病。在进一步的实施方案中,所述受试者已经进行了组织、器官和/或骨髓移植。在一些这样的实施方案中,向所述受试者施用免疫抑制药物。在一些实施方案中,所述受试者已经经历和/或正在经历化疗。在一些实施方案中,所述受试者已经经历和/或正在经历放疗。
在某些实施方案中,所公开的TCR修饰的免疫效应细胞与(例如,之前、同时或之后的)任何数量的相关治疗方式结合施用于患者,所述相关治疗方式包括但不限于沙利度胺、地塞米松、硼替佐米和来那度胺。在进一步的实施方案中,TCR修饰的免疫效应细胞可以与化疗;放疗;免疫抑制剂如环孢菌素、硫唑嘌呤、甲氨蝶呤、霉酚酸酯和FK506;抗体或其他免疫消融剂如CAM PATH、抗CD3抗体或其他抗体疗法;细胞毒素;氟达利滨;环孢菌素;FK506;雷帕霉素;霉酚酸;类固醇;FR901228;细胞因子和辐射组合使用。在一些实施方案中,TCR修饰的免疫效应细胞与(例如,之前、同时或之后的)骨髓移植、T细胞消融疗法(使用化疗剂如氟达拉滨、外照射放射疗法(XRT)、环磷酰胺或抗体如OKT3或CAMPATH)结合施用于患者。在其他实施方案中,本发明的细胞组合物在B细胞消融疗法(例如与CD20反应的试剂,例如,Rituxan)之后施用。例如,在一些实施方案中,受试者可以经历高剂量化疗、然后进行外周血干细胞移植的标准治疗。在某些实施方案中,移植后,受试者接受本发明的扩增的免疫细胞的输注。可以在手术之前或之后施用扩增的细胞。在一些实施方案中,还向受试者施用抑制HPV复制的抗病毒药物。例如,在一些实施方案中,向受试者施用普达非洛、咪喹莫特、sinecatechins、鬼臼树脂、三氯乙酸或二氯乙酸。在一些实施方案中,还用物理地影响HPV感染的病变和/或HPV相关肿瘤的干预来治疗受试者。例如,在一些实施方案中,用手术切除、化学消融、冷冻疗法或烧灼治疗病变。
所公开方法的癌症可以是受试者中任何HPV感染的细胞(例如,任何表达HPV抗原的细胞),这些细胞经历不受调节的生长、侵袭或转移。在一些实施方案中,受试者患有癌症或癌前病变。本文所述的方法可用于治疗任何此类癌性或癌前病变。在一些实施方案中,癌症和/或癌前病变表达一种或多种本文提供的HPV表位(例如,表1、11和13中列出的HPV表位)。在一些实施方案中,癌前病变包括异常细胞变化和/或癌前细胞变化。可通过本文提供的方法和组合物治疗的癌前病变包括但不限于宫颈上皮内瘤变(CIN)、鳞状上皮内病变(SIL)或宫颈疣。表达HPV抗原的癌症是本领域已知的并且包括鳞状细胞癌和实体瘤。可以通过本文提供的方法和组合物治疗的癌症包括但不限于来自宫颈、肛门、阴道、外阴、阴茎、舌根、喉、扁桃体、膀胱、血液、骨、骨髓、脑、乳腺、结肠、食道、胃肠道、牙龈、头、肾、肝、肺、鼻咽、颈、卵巢、前列腺、皮肤、非黑素瘤皮肤癌(NMSC)、皮肤鳞状细胞癌(SCC)、胃、睾丸、舌、或子宫的癌细胞。另外,癌症可以具体地是以下组织学类型,尽管其不限于这些:恶性肿瘤;癌;未分化癌;巨细胞和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;移行细胞癌;乳头状移行细胞癌;腺癌;恶性胃泌素瘤;胆管癌;肝细胞癌;合并肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤息肉中的腺癌;腺癌,家族性结肠息肉病;实体癌;恶性类癌;支气管肺泡腺癌;乳头状腺癌;发色癌;嗜酸细胞癌;嗜酸腺癌;嗜碱性粒细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡性腺癌;乳头状和滤泡状腺癌;非包膜硬化性癌;肾上腺皮质癌;子宫内膜样癌;皮肤附属物癌;大汗腺腺癌;皮脂腺癌;耵聍腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液性腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;乳腺佩吉特病;腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生;恶性胸腺瘤;恶性卵巢间质瘤;恶性泡膜细胞瘤;恶性颗粒细胞瘤;和恶性母细胞瘤;支持细胞癌;恶性间质细胞瘤;恶性脂质细胞瘤;恶性副神经节瘤;恶性乳腺外副神经节瘤;嗜铬细胞瘤;血管球肉瘤;恶性黑素瘤;无色素性黑素瘤;浅表扩散性黑素瘤;巨大色素痣中的恶性黑素瘤;上皮样细胞黑素瘤;恶性蓝色痣;肉瘤;纤维肉瘤;恶性纤维组织细胞瘤;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;腺泡横纹肌肉瘤;间质肉瘤;恶性混合瘤;苗勒管混合瘤;肾母细胞瘤;肝母细胞瘤;癌性肉瘤;恶性间充质瘤;恶性布伦纳瘤;恶性间叶状肿瘤;滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚胎癌;恶性畸胎瘤;恶性卵巢甲状腺瘤;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮瘤;卡波西肉瘤;恶性血管外皮瘤;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;恶性软骨母细胞瘤;间充质软骨肉瘤;骨巨细胞瘤;尤因氏肉瘤;恶性牙源性肿瘤;成釉细胞牙肉瘤;恶性成釉细胞瘤;成釉细胞纤维肉瘤;恶性松果体瘤;脊索瘤;恶性胶质瘤;室管膜瘤;星形细胞瘤;原生质星形细胞瘤;纤维星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;少突胶质母细胞瘤;原始神经外胚层肿瘤;小脑肉瘤;神经节神经母细胞瘤;成神经细胞瘤;视网膜母细胞瘤;嗅觉神经源性肿瘤;恶性脑膜瘤;神经纤维肉瘤;恶性神经鞘瘤;恶性颗粒细胞瘤;恶性淋巴瘤;霍奇金病;霍奇金淋巴瘤;副肉芽肿;小淋巴细胞恶性淋巴瘤;弥漫性大细胞恶性淋巴瘤;滤泡性恶性淋巴瘤;蕈样肉芽肿;其他特定的非霍奇金淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增殖性小肠疾病;白血病;淋巴样白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓性白血病;嗜碱性粒细胞白血病;嗜酸性粒细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;骨髓肉瘤;和毛细胞白血病。
公开的TCR修饰的免疫效应细胞(例如,TCR-T细胞)可以与任何具有细胞毒性或细胞抑制作用的化合物、部分或基团组合使用。药物部分包括化疗剂,其可作为微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂或DNA嵌入剂发挥作用,特别是作为用于癌症治疗的那些试剂。示例性的抗癌化合物包括但不限于阿来珠单抗阿立维甲酸/>阿那曲唑/>贝伐单抗/>贝沙罗汀硼替佐米/>博舒替尼/>本妥昔单抗/>卡博替尼(CometriqTM)、卡非佐米(KyprolisTM)、西妥昔单抗/>克唑替尼达沙替尼/>Denileukin diftitox/>盐酸埃罗替尼依维莫司/>依西美坦/>氟尔西坦/>吉非替尼/>依替莫单抗替舒坦/>甲磺酸伊马替尼/>依匹木单抗(YervoyTM)、二甲苯磺酸拉帕替尼/>来曲唑/>尼洛替尼奥法木单抗/>帕尼单抗/>盐酸帕唑帕尼帕妥珠单抗(PerjetaTM)、普拉曲沙/>雷戈非尼/>利妥昔单抗/>罗米地辛/>甲苯磺酸索拉非尼/>苹果酸舒尼替尼/>他莫昔芬、替莫罗莫司/>托瑞米芬/>托西妥单抗和131I-托西妥玛单抗/>曲妥珠单抗/>维甲酸凡德他尼/>维拉非尼/>伏立诺他/>和阿柏西普/>其他化疗剂的示例包含但不限于烷化剂,如塞替派和环磷酰胺;烷基磺酸盐,如白消安、英丙舒凡(improsulfan)和哌泊舒凡;氮丙啶类,如苯并多巴(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimines)和甲基氨基吖啶类(methylamelamines),包含六甲蜜胺(altretamine)、曲他胺、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲密胺(trimethylolomelamine);多聚乙酰类(acetogenins)(尤其是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(包含合成类似物托泊替康(topotecan));苔藓抑素;多烯酮类化合物(callystatin);CC-1065(包含其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);隐藻素(cryptophycin)(特别是隐藻素1和隐藻素8);多拉司他汀;倍癌霉素(duocarmycin)(包含合成类似物、KW-2189和CB1-TM1);艾榴素(eleutherobin);水鬼蕉亭(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥类(nitrogen mustards),如苯丁酸氮芥、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌氮芥、异环磷酰胺、二氯甲基二乙胺(mechlorethamine)、盐酸氧化二氯甲基二乙胺(mechlorethamine oxide hydrochloride)、美法仑、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀、曲磷胺(trofosfamide)、乌拉莫司汀(uracil mustard);亚硝基脲类,如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素,如烯二炔类抗生素(enediyneantibiotics)(例如,加里刹霉素(calicheamicin)、尤其是加里刹霉素γ1和加里刹霉素ω1;达内霉素(dynemicin),包含达内霉素A;二磷酸盐,如氯膦酸盐;埃斯培拉霉素(esperamicin);以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团、阿克拉霉素(aclacinomysins)、放线菌素、蒽霉素(authrarnycin)、偶氮丝氨酸(azaserine)、博来霉素、放线菌素C、卡拉比星(carabicin)、卡诺霉素(caminomycin)、嗜癌菌素、色霉素(chromomycins)、放线菌素D、柔红霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、阿霉素(包含吗啉代-阿霉素、氰基吗啉代-阿霉素、2-吡咯啉-阿霉素和脱氧阿霉素(deoxydoxorubicin))、表柔比星、依索比星(esorubicin)、伊达比星、麻西罗霉素、丝裂霉素类,如丝裂霉素C、霉酚酸、诺拉霉素、橄榄霉素类(olivomycins)、培洛霉素、泊非霉素(porfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链佐星、杀结核菌素、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星;抗代谢物,如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物,如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、二脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷;雄激素类(androgens),如卡鲁睾酮、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇、美雄烷(mepitiostane)、睾内酯;抗肾上腺素物质(anti-adrenals),如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂(folic acidreplenisher),如亚叶酸(folinic acid);醋葡醛内酯;醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸;恩尿嘧啶;安吖啶;百垂布西(bestrabucil);比生群;依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛;地吖醌;依氟鸟氨酸(elformithine);依利醋铵(elliptinium acetate);埃坡霉素(epothilone);依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);美登素类化合物(maytansinoids),如美登素和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌;莫哌达醇(mopidanmol);尼曲吖啶(nitraerine);喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙肼;丙卡巴肼;PSK多糖复合物);雷佐生;利索新;西佐喃(sizofuran);锗螺胺(spirogermanium);细交链孢菌酮酸;三亚胺醌;2,2’,2”-三氯三乙胺;单端孢霉烯类(trichothecenes)(尤其是T-2毒素、粘液霉素A(verracurin A)、杆孢菌素A和蛇形菌素(anguidine));氨基甲酸乙酯;长春地辛(vindesine);达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;加西托新(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;塞替派;紫杉烷类,例如,紫杉醇和多西他赛(doxetaxel);苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯嘌呤;甲氨蝶呤;铂配位络合物,如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊甙(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;盐酸米托蒽醌;替尼泊甙;依达曲沙;柔红霉素;氨喋呤;希罗达(xeloda);伊班膦酸盐(ibandronate);伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(difluoromethylornithine)(DMFO);类视黄醇(retinoids),如视黄酸;卡培他滨;以及上述中任一种的药学上可接受的盐、酸或衍生物。
在一些实施方案中,还向受试者施用免疫治疗剂。免疫疗法是指利用受试者的免疫系统治疗癌症的治疗,例如,癌症疫苗、细胞因子、利用癌症特异性抗体、T细胞疗法、和树突状细胞疗法。
在一些实施方案中,还向受试者施用免疫调节蛋白。免疫调节蛋白的示例包含但不限于:B淋巴细胞化学引诱物(“BLC”)、C-C基序趋化因子11(“Eotaxin-1”)、嗜酸性粒细胞趋化蛋白2(“Eotaxin-2”)、粒细胞集落刺激因子(“G-CSF”)、粒巨噬细胞集落刺激因子(“GM-CSF”)、1-309、胞间粘附分子1(“ICAM-1”)、干扰素γ(“IFN-γ”)、白细胞介素-1α(“IL-1α”)、白细胞介素-1β(“IL-1β”)、白细胞介素1受体拮抗剂(“IL-1ra”)、白细胞介素-2(“IL-2”)、白细胞介素-4(“IL-4”)、白细胞介素-5(“IL-5”)、白细胞介素-6(“IL-6”)、白细胞介素-6可溶性受体(“IL-6sR”)、白细胞介素-7(“IL-7”)、白细胞介素-8(“IL-8”)、白细胞介素-10(“IL-10”)、白细胞介素-11(“IL-11”)、白细胞介素-12的β亚基(“IL-12p40”或“IL-12p70”)、白细胞介素-13(“IL-13”)、白细胞介素-15(“IL-15”)、白细胞介素-16(“IL-16”)、白细胞介素-17(“IL-17”)、趋化因子(C-C基序)配体2(“MCP-1”)、巨噬细胞集落剌激因子(“M-CSF”)、干扰素γ诱导的单核因子(“MIG”)、趋化因子(C-C基序)配体2(“MIP-1α”)、趋化因子(C-C基序)配体4(“MIP-1β”)、巨噬细胞炎性蛋白-1-δ(“MIP-1δ”)、血小板源性生长因子亚基B(“PDGF-BB”)、趋化因子(C-C基序)配体5、调控活化的正常T细胞表达和分泌的因子(“RANTES”)、TIMP金属肽酶抑制剂1(“TIMP-1”)、TIMP金属肽酶抑制剂2(“TIMP-2”)、肿瘤坏死因子淋巴毒素α(“TNFα”)、肿瘤坏死因子淋巴毒素-β(“TNFβ”)、可溶性1型TNF受体(“sTNFRI”)、sTNFRIIAR、脑源性神经营养因子(“BDNF”)、碱性成纤维细胞生长因子(“bFGF”)、骨形态生成蛋白4(“BMP-4”)、骨形态生成蛋白5(“BMP-5”)、骨形态生成蛋白7(“BMP-7”)、神经生长因子(“b-NGF”)、表皮生长因子(“EGF”)、表皮生长因子受体(“EGFR”)、内分泌腺性血管内皮生长因子(“EG-VEGF”)、成纤维细胞生长因子4(“FGF-4”)、角质形成细胞生长因子(“FGF-7”)、生长分化因子15(“GDF-15”)、胶质细胞源性神经营养因子(“GDNF”)、生长激素、肝素结合EGF样生长因子(“HB-EGF”)、肝细胞生长因子(“HGF”)、胰岛素样生长因子结合蛋白1(“IGFBP-1”)、胰岛素样生长因子结合蛋白2(“IGFBP-2”)、胰岛素样生长因子结合蛋白3(“IGFBP-3”)、胰岛素样生长因子结合蛋白4(“IGFBP-4”)、胰岛素样生长因子结合蛋白6(“IGFBP-6”)、胰岛素样生长因子1(“IGF-1”)、胰岛素、巨噬细胞集落刺激因子(“M-CSF R”)、神经生长因子受体(“NGF R”)、神经营养因子-3(“NT-3”)、神经营养因子-4(“NT-4”)、破骨细胞生成抑制因子(“Osteoprotegerin”)、血小板源性生长因子受体(“PDGF-AA”)、磷脂酰肌醇-聚糖生物合成(“PIGF”)、Skp、滞蛋白(Cullin)、含F框的复合物(“SCF”)、干细胞因子受体(“SCFR”)、转化生长因子α(“TGFα”)、转化生长因子β-1(“TGFβ1”)、转化生长因子β-3(“TGFβ3”)、血管内皮生长因子(“VEGF”)、血管内皮生长因子受体2(“VEGFR2”)、血管内皮生长因子受体3(“VEGFR3”)、VEGF-D 6Ckine、酪氨酸蛋白激酶受体FIFO(“Axl”)、细胞素(“BTC”)、粘膜相关上皮趋化因子(“CCL28”)、趋化因子(C-C基序)配体27(“CTACK”)、趋化因子(C-X-C基序)配体16(“CXCL16”)、C-X-C基序趋化因子5(“ENA-78”)、趋化因子(C-C基序)配体26(“Eotaxin-3”)、粒细胞趋化蛋白2(“GCP-2”)、GRO、趋化因子(C-C基序)配体14(“HCC-l”)、趋化因子(C-C基序)配体16(“HCC-4”)、白细胞介素-9(“IL-9”)、白细胞介素-17F(“IL-17F”)、白细胞介素-18-结合蛋白(“IL-18BPa”)、白细胞介素-28A(“IL-28A”)、白细胞介素29(“IL-29”)、白细胞介素31(“IL-31”)、C-X-C基序趋化因子10(“IP-10”)、趋化因子受体CXCR3(“I-TAC”)、白血病抑制因子(“LIF”)、轻型趋化因子(C基序)配体(“Lymphotactin”)、单核细胞化学引诱物蛋白2(“MCP-2”)、单核细胞化学引诱物蛋白3(“MCP-3”)、单核细胞化学引诱物蛋白4(“MCP-4”)、巨噬细胞源性趋化因子(“MDC”)、巨噬细胞移动抑制因子(“MIF”)、趋化因子(C-C基序)配体20(“MIP-3α”)、C-C基序趋化因子19(“MIP-3β”)、趋化因子(C-C基序)配体23(“MPIF-1”)、巨噬细胞刺激蛋白α链(“MSPα”)、核小体组装蛋白1样4(“NAP-2”)、分泌性磷蛋白1(“Osteopontin”)、肺部活化调控细胞因子(“PARC”)、血小板因子4(“PF4”)、基质细胞源性因子-1α(“SDF-1α”)、趋化因子(C-C基序)配体17(“TARC”)、胸腺表达趋化因子(“TECK”)、胸腺基质淋巴细胞生成素(“TSLP4-IBB”)、CD166抗原(“ALCAM”)、分化群80(“B7-1”)、肿瘤坏死因子受体超家族成员17(“BCMA”)、分化群14(“CD14”)、分化群30(“CD30”)、分化群40(“CD40配体”)、癌胚抗原相关细胞粘附分子1(胆汁糖蛋白)(“CEACAM-1”)、死亡受体6(“DR6”)、脱氧胸苷激酶(“Dtk”)、1型膜糖蛋白(“内皮素”)、受体酪氨酸蛋白激酶erbB-3(“ErbB3”)、内皮细胞白细胞粘附分子1(“E-选择素”)、凋亡抗原1(“Fas”)、Fms样酪氨酸激酶3(“Flt-3L”)、肿瘤坏死因子受体超家族成员1(“GITR”)、肿瘤坏死因子受体超家族成员14(“HVEM”)、胞间粘附分子3(“ICAM-3”)、IL-1R4、IL-1RI、IL-10Rβ、IL-17R、IL-2Rγ、IL-21R、溶酶体膜蛋白2(“LIMPII”)、中性粒细胞明胶酶相关脂质运载蛋白(“脂质运载蛋白-2”)、CD62L(“L-选择素”)、淋巴管内皮细胞(“LYVE-1”)、I类MHC多肽相关序列A(“MICA”)、I类MHC多肽相关序列B(“MICB”)、NRGl-βl、β型血小板源性生长因子受体(“PDGF Rβ”)、血小板内皮细胞粘附分子(“PECAM-1”)、RAGE、甲型肝炎病毒细胞受体1(“TIM-1”)、肿瘤坏死因子受体超家族成员IOC(“TRAIL R3”)、Trappin蛋白转谷氨酰胺酶结合结构域(“Trappin-2”)、尿激酶受体(“uPAR”)、血管细胞粘附蛋白1(“VCAM-1”)、XEDAR、激活素A、刺鼠相关蛋白(“AgRP”)、核糖核酸酶5(“血管生成素”)、血管生成素1、血管抑素、组织蛋白酶S、CD40、隐藏家族蛋白IB(“Cripto-1”)、DAN、Dickkopf相关蛋白1(“DKK-1”)、E-钙粘附素、上皮细胞粘附分子(“EpCAM”)、Fas配体(FasL或CD95L)、Fcg RIIB/C、FoUistatin、半乳凝素-7、胞间粘附分子2(“ICAM-2”)、IL-13Rl、IL-13R2、IL-17B、IL-2Ra、IL-2Rb、IL-23、LAP、神经元细胞粘附分子(“NrCAM”)、纤溶酶原激活物抑制剂-1(“PAI-1”)、血小板源性生长因子受体(“PDGF-AB”)、抵抗素、基质细胞衍生因子1(“SDF-1β”)、sgpl30、分泌型卷曲相关蛋白2(“ShhN”)、唾液酸结合性免疫球蛋白样凝集素(“Siglec-5”)、ST2、转化生长因子-β2(“TGFβ2”)、Tie-2、血小板生成素(“TPO”)、肿瘤坏死因子受体超家族成员10D(“TRAIL R4”)、骨髓细胞上表达的触发受体1(“TREM-1”)、血管内皮生长因子C(“VEGF-C”)、VEGFRl、脂联素、降脂蛋白(“AND”)、甲胎蛋白(“AFP”)、血管生成素样4(“ANGPTL4”)、β-2-微球蛋白(“B2M”)、基底细胞粘附分子(“BCAM”)、糖抗原125(“CA125”)、癌抗原15-3(“CA15-3”)、癌胚抗原(“CEA”)、cAMP受体蛋白(“CRP”)、人表皮生长因子受体2(“ErbB2”)、卵泡抑素、促卵泡激素(“FSH”)、趋化因子(C-X-C基序)配体1(“GROα”)、人绒毛膜促性腺激素(“βHCG”)、胰岛素样生长因子1受体(“IGF-1sR”)、IL-1sRII、IL-3、IL-18Rβ、IL-21、瘦素、基质金属蛋白酶-1(“MMP-1”)、基质金属蛋白酶-2(“MMP-2”)、基质金属蛋白酶-3(“MMP-3”)、基质金属蛋白酶-8(“MMP-8”)、基质金属蛋白酶-9(“MMP-9”)、基质金属蛋白酶-10(“MMP-10”)、基质金属蛋白酶-13(“MMP-13”)、神经细胞粘附分子(“NCAM-1”)、巢蛋白(“Nidogen-1”)、神经元特异性烯醇酶(“NSE”)、制瘤素M(“OSM”)、降钙素原、催乳素、前列腺特异性抗原(“PSA”)、唾液酸结合性Ig样凝集素9(“Siglec-9”)、ADAM 17肽链内切酶(“TACE”)、甲状腺球蛋白、金属蛋白酶抑制剂4(“TIMP-4”)、TSH2B4、含解聚素和金属蛋白酶结构域的蛋白质9(“ADAM-9”)、血管生成素2、肿瘤坏死因子配体超家族成员13、酸性富亮氨酸核磷蛋白32家族成员B(“APRIL”)、骨形态生成蛋白2(“BMP-2”)、骨形态生成蛋白9(“BMP-9”)、补体成分5a(“C5a”)、组织蛋白酶L、CD200、CD97、趋化素、肿瘤坏死因子受体超家族成员6B(“DcR3”)、脂肪酸结合蛋白2(“FABP2”)、成纤维细胞活化蛋白α(“FAP”)、成纤维细胞生长因子19(“FGF-19”)、半乳凝素-3、肝细胞生长因子受体(“HGFR”)、IFN-α/βR2、胰岛素样生长因子2(“IGF-2”)、胰岛素样生长因子2受体(“IGF-2R”)、白细胞介素-1受体6(“IL-1R6”)、白细胞介素24(“IL-24”)、白细胞介素33(“IL-33”)、激肽释放酶14、天冬酰胺酰肽链内切酶(“Legumain”)、氧化型低密度脂蛋白受体1(“LOX-1”)、甘露糖结合凝集素(“MBL”)、脑啡肽酶(“NEP”)、易位相关Notch同源物1(果蝇)(“Notch-1”)、肾母细胞瘤过度表达(“NOV”)、骨激活素(Osteoactivin)、程序性细胞死亡蛋白1(“PD-1”)、N-乙酰胞壁酰-L-丙氨酸酰胺酶(“PGRP-5”)、丝氨酸蛋白酶抑制剂A4、分泌型卷曲相关蛋白3(“sFRP-3”)、血栓调节蛋白、Toll样受体2(“TLR2”)、肿瘤坏死因子受体超家族成员10A(“TRAIL Rl”)、转铁蛋白(“TRF”)、WIF-lACE-2、白蛋白、AMICA、血管生成素4、B-细胞活化因子(“BAFF”)、糖抗原19-9(“CA19-9”)、CD 163、丛生蛋白、CRT AM、趋化因子(C-X-C基序)配体14(“CXCL14”)、胱抑素C、饰胶蛋白(“DCN”)、Dickkopf相关蛋白3(“Dkk-3”)、δ样蛋白1(“DLL1”)、胎球蛋白A、肝素结合生长因子1(“aFGF”)、叶酸受体α(“FOLR1”)、弗林蛋白酶、GPCR相关分选蛋白1(“GASP-1”)、GPCR相关分选蛋白2(“GASP-2”)、粒细胞集落刺激因子受体(“GCSFR”)、丝氨酸蛋白酶hepsin(“HAI-2”)、白细胞介素-17B受体(“IL-17B R”)、白细胞介素27(“IL-27”)、淋巴细胞活化基因3(“LAG-3”)、载脂蛋白A-V(“LDL R”)、胃蛋白酶原I、视黄醇结合蛋白4(“RBP4”)、SOST、硫酸类肝素蛋白多糖(“Syndecan-1”)、肿瘤坏死因子受体超家族成员13B(“TACI”)、组织因子通路抑制剂(“TFPI”)、TSP-1、肿瘤坏死因子受体超家族成员10b(“TRAIL R2”)、TRANCE、肌钙蛋白I、尿激酶纤维蛋白溶酶原激活剂(“uPA”)、钙粘附素5、2型或VE-钙粘附素(血管内皮细胞)也称为CD144(“VE-钙粘附素”)、WNTl诱导的信号传导通路蛋白1(“WISP-1”)、以及核因子κB受体活化因子(“RANK”)。在某些优选实施方案中,还向受试者施用IFN-gamma(IFNγ)。在特别优选的实施方案中,在施用本文公开的TCR-修饰的免疫效应细胞(例如,本文公开的包含本文公开的TCR-T细胞的过继免疫疗法组合物)之前,用IFNγ(例如用低剂量的IFNγ)预治疗受试者。
公开的TCR可以与免疫检查点抑制剂组合使用。免疫检查点抑制广义上是指抑制癌细胞产生妨碍或下调免疫反应的检查点。两种已知的免疫检查点通路涉及通过细胞毒性T淋巴细胞抗原4(CTLA-4)和程序性死亡1(PD-1)受体的信号传导。这些蛋白是共同信号传导分子CD28-B7家族的成员,在T细胞功能的所有阶段都发挥重要作用。PD-1受体(也称为CD279)在活化的T细胞表面表达。其配体PD-L1(B7-H1;CD274)和PD-L2(B7-DC;CD273)表达于APC(如树突状细胞或巨噬细胞)的表面。PD-L1是主要的配体,而PD-L2具有更加受限的表达模式。当配体与PD-1结合时,抑制信号传递到T细胞,从而减少细胞因子的产生并抑制T细胞增殖。检查点抑制剂包括但不限于阻断PD-1(纳武单抗(BMS-936558或MDX1106)、CT-011、MK-3475、AMP-514);PD-L1(MDX-1105(BMS-936559)、MPDL3280A、MSB0010718C);PD-L2(rHIgM12B7、AMP-224);CTLA-4(依匹木单抗(MDX-010)、曲美母单抗(Tremelimumab)(CP-675,206));IDO;B7-H3(MGA271);B7-H4;TIM3;LAG-3(BMS-986016)的适体和抗体。
美国专利号8,008,449中描述了针对程序性死亡1(PD-1)的人单克隆抗体和使用抗PD-1抗体单独或与其他免疫治疗剂组合治疗癌症的方法,该专利通过引用并入本文。美国专利号8,552,154中描述了抗PD-L1抗体及其用途,该专利通过引用并入本文。美国专利号8,617,546描述了包含抗PD-1抗体或抗PD-L1抗体的抗癌剂,该专利通过引用并入本文。
在一些实施方案中,PDL1抑制剂包括特异性结合PDL1的抗体,例如BMS-936559(Bristol-Myers Squibb)或MPDL3280A(Roche)。在一些实施方案中,PD-1抑制剂包括特异性结合PD-1的抗体,例如lambrolizumab(Merck)、纳武单抗(Bristol-Myers Squibb)或MEDI4736(AstraZeneca)。美国专利号8,008,449中描述了针对PD-1的人单克隆抗体和使用抗PD-1抗体单独或与其他免疫治疗剂组合治疗癌症的方法,该专利通过引用并入本文。美国专利号8,552,154中描述了抗PD-L1抗体及其用途,该专利通过引用并入本文。美国专利号8,617,546描述了包含抗PD-1抗体或抗PD-L1抗体的抗癌剂,该专利通过引用并入本文。
所公开的TCR可与其他癌症免疫疗法组合使用。存在两种不同类型的免疫疗法:被动免疫疗法使用免疫系统的组分来引导针对癌细胞的靶向细胞毒活性,而不必在患者体内启动免疫反应,而主动免疫疗法则主动触发内源性免疫反应。被动策略包括使用B细胞响应特定抗原产生的单克隆抗体(mAb)。1970年代杂交瘤技术的发展和肿瘤特异性抗原的鉴定使得可以开发能够特异性靶向肿瘤细胞的单克隆抗体药物,以使肿瘤细胞被免疫系统破坏。其中包括利妥昔单抗(Rituxan,Genentech),其与B细胞恶性肿瘤(例如,非霍奇金淋巴瘤(NHL))表面上高度表达的CD20蛋白结合。利妥昔单抗已被FDA批准用于于化疗组合治疗NHL和慢性淋巴细胞白血病(CLL)。另一个重要的mAb是曲妥珠单抗(Herceptin;Genentech),其通过靶向HER2的表达,彻底革新了HER2(人表皮生长因子受体2)阳性乳腺癌的治疗。
产生最佳的“杀手”CD8 T细胞反应还需要T细胞受体活化和共刺激,这可以通过连接肿瘤坏死因子受体家族成员(包括OX40(CD134)和4-1BB(CD137))来提供。OX40特别令人感兴趣,因为用活化性(激动剂)抗OX40mAb治疗可增强T细胞分化和细胞溶解功能,从而增强针对各种肿瘤的抗肿瘤免疫。
在一些实施方案中,此类另外的治疗剂可选自抗代谢物,例如甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、氟达拉滨、5-氟尿嘧啶、地卡巴肼(decarbazine)、羟基脲、天冬酰胺酶、吉西他滨或克拉屈滨。
在一些实施方案中,此类另外的治疗剂可以选自烷化剂,例如二氯甲基二乙胺、噻替派(thioepa)、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲佐菌素、达卡巴嗪(DTIC)、丙卡巴肼、丝裂霉素C、顺铂和其他铂衍生物,如卡铂。
在一些实施方案中,此类另外的治疗剂可以选自抗有丝分裂剂,例如紫杉烷类,例如多西紫杉醇和紫杉醇,以及长春花生物碱,例如长春地辛、长春新碱、长春花碱和长春瑞滨。
在一些实施方案中,此类另外的治疗剂可以选自拓扑异构酶抑制剂,例如拓扑替康或伊立替康,或细胞抑制药物,例如依托泊苷和替尼泊苷。
在一些实施方案中,此类另外的治疗剂可以选自生长因子抑制剂,例如ErbBl(EGFR)的抑制剂(例如EGFR抗体,例如zalutumumab、西妥昔单抗、帕尼单抗或尼妥珠单抗或其他EGFR抑制剂,如吉非替尼或埃罗替尼),另一ErbB2抑制剂(HER2/neu)(如HER2抗体,例如曲妥珠单抗、曲妥珠单抗-DM1或帕妥珠单抗)或EGFR和HER2的抑制剂,例如拉帕替尼)。
在一些实施方案中,此类另外的治疗剂可以选自酪氨酸激酶抑制剂,例如伊马替尼(Glivec,Gleevec STI571)或拉帕替尼。
因此,在一些实施方案中,所公开的抗体与奥法木单抗、扎诺木单抗(zanolimumab)、达雷木单抗、雷珠单抗、尼妥珠单抗、帕尼单抗、hu806、达克珠单抗(Zenapax)、巴利昔单抗(Simulect)、英夫利昔单抗(Remicade)、阿达木单抗(Humira)、那他珠单抗(Tysabri)、奥马珠单抗(Xolair)、依法珠单抗(Raptiva)和/或利妥昔单抗组合使用。
在一些实施方案中,与TCR组合使用以治疗上述疾患的治疗剂可以是抗癌细胞因子、趋化因子或其组合。合适的细胞因子和生长因子的示例包括IFNγ、IL-2、IL-4、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、IL-18、IL-23、IL-24、IL-27、IL-28a、IL-28b、IL-29、KGF、IFNα(例如,INFa2b)、IFNβ、GM-CSF、CD40L、Flt3配体、干细胞因子、ancestim和TNFa。合适的趋化因子可以包括来自人CXC和C-C趋化因子家族的Glu-Leu-Arg(ELR)-阴性趋化因子,例如IP-10、MCP-3、MIG和SDF-1a。合适的细胞因子包括细胞因子衍生物、细胞因子变体、细胞因子片段和细胞因子融合蛋白。
在一些实施方案中,与CAR组合使用以治疗如上所述的疾患的治疗剂可以是细胞周期控制/凋亡调节剂(或“调节剂”)。细胞周期控制/凋亡调节剂可以包括靶向和调节细胞周期控制/凋亡调节剂的分子,例如(i)cdc-25(例如NSC663284),(ii)过度刺激细胞周期的细胞周期蛋白依赖性激酶(例如flavopiridol(L868275,HMR1275),7-羟基星形孢菌素(UCN-01,Kw-2401)和核抑制剂(R-roscovitine,CYC202)),和(iii)端粒酶调节剂(例如BIBR1532,SOT-095,GRN163和例如在US 6,440,735和US 6,713,055中描述的组合物)。干扰凋亡通路的分子的非限制性示例包括TNF相关的凋亡诱导配体(TRAIL)/凋亡-2配体(Apo-2L)、活化TRAIL受体的抗体、IFN和反义Bcl-2。
在一些实施方案中,与TCR组合使用以治疗上述疾患的治疗剂可以是激素调节剂(例如,激素疗法),例如用于抗雄激素和抗雌激素疗法的试剂。此类激素调节剂的示例是他莫昔芬、艾多昔芬、氟维司群、屈洛昔芬、托瑞米芬、雷洛昔芬、己烯雌酚、乙炔雌二醇/estinyl、抗雄激素(例如氟他明/eulexin)、孕激素(例如己酸羟孕酮、醋酸甲羟孕酮/provera、醋酸甲地孕酮/megace)、肾上腺皮质激素(如氢化可的松、强的松)、促黄体激素释放激素(及其类似物和其他LHRH激动剂如布舍瑞林和戈舍瑞林)、芳香酶抑制剂(如阿那曲唑/arimidex、氨鲁米特/cytraden、依西美坦)或激素抑制剂(如奥曲肽/sandostatin)。
在一些实施方案中,与TCR联合使用以治疗上述疾患的治疗剂可以是抗癌核酸或抗癌抑制性RNA分子。
在一些实施方案中,所公开的TCR与放疗联合施用。放疗可以包括向患者提供放射或放射性药物的相关施用。放射源可以在接受治疗的患者的外部或内部(例如,放射治疗可以是外束放射治疗(EBRT)或近距离放射治疗(BT)的形式)。可用于实施此类方法的放射性元素包括:例如,镭、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘化物-123、碘化物-131和铟-111。
在一些实施方案中,所公开的TCR与手术联合施用。
实施例
实施例1:HPV特异性T细胞系的产生:
洗涤冷冻保存的来自HNSCC患者的HPV+PBMC,并重新悬浮在完全RPMI培养基中并孵育过夜(即,37℃,6.5%CO2)。用浓度为1μg/ml的HPV16抗原表位刺激细胞(5×106)并孵育一小时。然后洗涤细胞并在24孔板进一步生长(即,孵育)14天。在第2天向培养物补充含有200IU/ml的白细胞介素-2(IL-2)的R10培养基,然后每3天补充一次,直至14天。在第14天,通过台盼蓝排除法计数活的T细胞,随后在液氮中冷冻保存。
实施例2:通过双重细胞因子捕获测定法对抗原特异性CTL进行分选:
将冷冻保存的T细胞(10×106)快速解冻、洗涤并重新悬浮在含有120IU/ml IL-2的10ml完全培养基中并孵育过夜。过夜的培养物中的1ml细胞等分试样被用作“刺激物”(例如,抗原呈递)群。对于刺激物培养物,加入1μg/ml的抗原肽(例如,选自SEQ ID NO.1-12、217和218的相应肽),孵育1小时;然后用完全培养基洗涤3次。然后将刺激物细胞以1:9的比例添加到CTL(即,“响应者”细胞),放入48孔中(约5-10×106每孔)并孵育3小时。孵育后,将CTL在冰冷的缓冲液(PBS,2mM EDTA和0.5% BSA)中洗涤并在4℃下以400g离心10分钟。然后将细胞重新悬浮在每106个细胞80μl的冷的完全培养基和10μl IFNγ和TNFα捕获试剂(与细胞表面特异性抗体缀合的抗细胞因子抗体,Miltenyi Biotec;Bergisch Gladbach,Germany)中,并在冰上孵育5分钟。然后将细胞在暖的完全培养基中离心,将细胞稀释至105个细胞/ml,轻轻混合试管(例如,每5分钟手动转动一次试管,或将其放置在旋转混合器中(例如Miltenyi MACSmixTM,在低旋转设置下),在37℃孵育箱中45分钟。孵育后,用冰冷的缓冲液加满每个管并离心(300g,10分钟,4℃),然后再用冷缓冲液洗涤一次。将每106个细胞重新悬浮在80μl冷的缓冲液中,含有×2.5μl抗CD3 BV421、×1μl抗CD8 perCPCy5.5、×2.5μl抗CD4 PE、×0.2μl NIR活-死、×10μl IFNγ检测抗体PE、×10μl TNFα检测抗体APC,并在冰上孵育10分钟,然后在冰冷的缓冲液中洗涤。然后将细胞重新悬浮在300μl冷的缓冲液中并过滤(0.45μm),用于荧光活化的细胞分选(FACS)。单个、IFNγ和TNFα双阳性HPV特异性CD8+T细胞被分选到96孔PCR板的各个孔中(图1),最后一排孔留空,用作PCR阴性对照。分选后,将板储存在-80℃下,直到下游加工。
实施例3:RT-PCR、多重巢式PCR和测序:
使用SuperScriptTMVILOTMcDNA合成试剂盒(InvitrogenTM,Thermo FisherScientific;MA,USA)在2.5μl反应混合物中从96孔PCR板中的单个细胞合成互补DNA(cDNA),每个反应混合物包含0.5μl的5×VILO反应混合物、0.25μl的10×Superscript逆转录酶和0.1%的Triton X-100。
每个细胞的TCR转录本通过多重巢式PCR在含有2.5μl cDNA的25μl反应混合物中进行扩增。设计长度为17至23个碱基对的引物,用于靶向相关V基因以及TRAC和TRBC基因的每个家族,最多允许三个简并碱基对。产生了总共40对外部/内部正义TRAV、27对正义TRBV、以及反义TRAC和TRBC基因片段各1对的特异性引物(表12)。为了包含在巢式PCR中,TRAV和TRBV引物被多重化,每个引物的浓度为5μM,TRAC和TRBC引物被重构为5μM的浓度。第一轮(外部)PCR使用0.75U Taq DNA聚合酶、2.5μl 10×PCR缓冲液(含有KCl、(NH4)2SO4、和15mMMgCl2、0.5μl的10mM脱氧核苷酸三磷酸(dNTPs)、0.1μM的各外部正义TRAV(T细胞受体α可变)和TRBV(T细胞受体β可变)引物,以及各外部反义TRAC(T细胞受体α恒定)和TRBC(T细胞受体β恒定)引物,如表12所列出。外部PCR产物的等分试样(2.5μl)作为模板用于两个单独的第二轮(内部)PCR,25μl反应中分别包含
(i)内部正义TRAV引物和内部反义TRAC引物;或
(ii)内部正义TRBV引物和内部反义TRBC引物,列于表12。
第二轮PCR不使用10×PCR缓冲液,而是使用PCR缓冲液(QiagenGmbH;Hilden,Germany),其含有两种用于凝胶加载的染料标志物。内部PCR产物(5μl)在2%琼脂糖凝胶上以80V运行,以选择阳性孔进行进一步分析(图2)。
表12:PCR引物
这些阳性PCR产物被纯化并用作模板,用于染料终止子测序。将包含0.5μM TRAC或TRBC内部引物的每种反应混合物添加到含有约7μl纯化的PCR产物的96孔板中(约20μl总量/孔),并对反应进行PCR热循环。通过乙醇沉淀纯化延伸测序产物,样品用于毛细管电泳测序。通过IMGT/V-QUEST分析来自TCRα和TCRβ板的序列,IMGT/V-QUEST是一种用于免疫球蛋白和T细胞受体核苷酸序列的综合比对工具,可从国际ImMunoGeneTics主页在线获得。简而言之,将每个测序孔的核苷酸序列作为T细胞受体(TR)核苷酸序列输入IMGT/V-QUEST在线工具,IMGT/V-QUEST通过比对输入序列与IMGT参考目录鉴定出CDR3区域;V、D和J基因;以及等位基因。在已测序的克隆中,选择最大共表达的TCRα和TCRβ序列并用于生成TCR慢病毒构建体。
结果
在Jurkat细胞(初步筛选)和PBMC(二次筛选)中检查了表达和功能活性的经鉴定和测序的克隆(即,HPV特异性TCR氨基酸序列)在下表13所示。
表13:HPV特异性TCR序列
实施例4:TCR慢病毒构建体:
合成TCR核苷酸序列并将载体插入物克隆到pLV慢病毒骨架中。插入序列是为了在人组织中表达而优化的密码子。为了人恒定区的部分鼠源化,一些氨基酸被小鼠恒定区替换。T细胞受体α恒定区氨基酸Pro91、Glu92、Ser93、Ser94(参见InternationalImMunoGeneTics informationAccession#X02883|TRAC*01|Homo sapiens)分别被Ser、Asp、Val、Pro氨基酸替换。T细胞受体β恒定区Glu18、Ser22、Phe133、Glu136、Gln139(参见International ImMunoGeneTics information/>Accession#’s M12887|TRBC1*01|Homo sapiens和M12888|TRBC2*01|Homo sapiens)分别被Lys、Ala、Ile、Ala、His氨基酸替换。对于具有额外链间二硫键的构建体,用半胱氨酸代替α链的Thr48和β链的Ser57。载体插入物还设计用于编码由弗林蛋白酶-2A自切割肽连接的已鉴定TCR的α链和β链(每个TCR链的恒定区部分鼠源化)。
每个TCR慢病毒构建体的核苷酸序列及其相关特征在表2至11显示。类似地,图3、图4和图6-11分别描述了每个表达的TCR构建体的氨基酸序列及其序列特征。
实施例5:Jurkat细胞经工程化以表达来自不同HPV抗原(E2、E5和E6)的1aHPV-TCR
并展示抗原识别(初步筛选):
通过用TCR pLV载体和包装质粒(pVSV、pMDL和pREV)共转染293T细胞产生TCR慢病毒上清液。转染后两天,收集TCR慢病毒上清液。
在96孔板中用慢病毒转导40μl中的40,000个Jurkat细胞(感染复数(MOI)为50)。在转导后第3天,通过流式细胞术测量TCR表达来检查转导。
进一步证实转导的Jurkat细胞具有工程化TCR的抗原特异性和HLA限制性。简而言之,在R-0(无FBS)培养基中用肽(1μg/ml)刺激淋巴样干细胞(LCL)并孵育1小时。然后用完全RPMI培养基在2300rpm洗涤(5x)刺激的抗原呈递LCL,2分钟。然后,将转导的Jurkat细胞(2×105/孔)与等数量的肽脉冲LCL(HLA-匹配或不匹配)在96孔U型底板中在完全培养基中共培养,孵育24小时并通过流式细胞术分析。
对于细胞计数分析,用含有2% FBS的PBS(洗涤缓冲液)洗涤细胞,并将沉淀重新悬浮在50μL洗涤缓冲液中,其中含有FITC缀合的抗Vα12.1(E5-NLD TCR,clone-6D6.6;Thermofisher)、或PE缀合的抗Vβ2(E6-HDI,clone-MPB2D5,Beckman Coulter)、抗Vβ11(E6-AFR-TCR,C21;Beckman Coulter)、抗Vβ14(E6-TIH-TCR,clone-REA557;Miltenyi Biotec)、或抗Vβ22(E2-TLQ-TCR,clone-IMMU 546;Beckman Coulter);和近红外活-死排除染料,然后在4℃下孵育30分钟。然后用洗涤缓冲液洗涤细胞两次,在分析前重新悬浮在含有1%多聚甲醛的PBS中。
结果
到第3天,用E2-TLQ-TCR、E5-NLD-TCR、E6-TIH-TCR慢病毒转导后,Jurkat细胞显示TCR表达,如分别由抗Vβ22、Vα12.1、和Vβ14抗体所检测的(见图12)。
同样,与肽脉冲LCL共孵育后,用E5-NLD-TCR(HLA-C*05:01和C*08:02限制性)和E2-TLQ-TCR(HLA-A*02:01限制性)转导的Jurkat细胞表现出CD69表达(如用抗人CD69抗体,Clone-FN50所检测的)(见图13)。
实施例6:经工程化以表达来自E5抗原的TCR(E5-NLD-TCR)的T细胞显示多功能活
性和高功能亲合力(二次筛选)
从健康供体中分离人外周血单个核细胞(PBMC)。在转导之前,将PBMC在含有CD3和CD28激动剂的完全培养基中培养2天,所述激动剂用于提供初级、共刺激信号,用于优化和有效的T细胞活化和扩增。
通过向包被的96孔板(Takara Bio USA,Inc.;CA,U.S.A.)添加慢病毒上清液(至多80-90μl/孔)进行转导。将板在2,000g和32℃下离心2小时。弃去上清液并用PBS洗涤板。添加PBMC(20,000个/孔)并将板在32℃下以1,500rpm离心10分钟。大约16小时后,将细胞转移到24孔组织培养处理板中,并在IL-2(200IU/ml)存在下培养7天。在第8天,用肽脉冲的自体PBMC以2:1的效靶比再刺激转导的T细胞,并在完全RPMI培养基中培养。在第2天以200IU/ml添加IL-2,然后每3天添加一次,直至21天。在再刺激后的第7天和第14天,通过台盼蓝排除法目测计数活的T细胞并用于TCR表达研究和功能测定法。冷冻保存任何剩余的细胞。
将转导的T细胞与同源肽抗原在含有莫能菌素、布雷菲德菌素和抗CD107a抗体的R10培养基中孵育。孵育4小时后,用含有2%FBS的PBS(洗涤缓冲液)洗涤细胞,并将沉淀重新悬浮在洗涤缓冲液中,其中含有FITC缀合的抗CD4和PerCP-Cy5.5缀合的抗CD8抗体的用于IFNγ分析,或含有PerCP-Cy5.5缀合的抗CD8和PE-Cy7缀合的抗CD4,然后在4℃下孵育30分钟。然后用PBS洗涤细胞两次,固定并透化20分钟。然后洗涤细胞并与PE缀合的抗IL-2、Alexa Fluor 700缀合的抗IFNγ和APC缀合的抗TNF在4℃下孵育30分钟。用透化洗涤缓冲液洗涤染色的细胞两次,重新悬浮于含有1%多聚甲醛的PBS中,并通过流式细胞术进行分析。
结果
数据表明E5-NLD-TCR在PBMC中成功转导(参见图14)。此外,转导的CD8+T细胞与用相同肽刺激的未转导的细胞相比,显示更高的CD107、IFNγ、TNFα和IL-2表达(参见图15)。转导的CD4+T细胞表现出与CD8+T细胞相当的TNFα和IL-2表达。然而,CD4+T细胞中的IFNγ和CD107明显较低,这表明CD8共同受体在靶标结合中的贡献。
实施例7:经工程化以表达来自E5抗原的TCR(E5-NLD-TCR)的T细胞显示高功能亲
合力(二次筛选)
在含有莫能菌素和布雷菲德菌素的R10培养基中,在37℃、6.5% CO2条件下用HLA匹配的LCL刺激转导和未转导的T细胞4小时,所述LCL用不同浓度的同源抗原肽脉冲(即,(10-6,10-7,10-8,10-9,10-10,10-11,10-12和10-13mole/L))。然后洗涤细胞并将沉淀重新悬浮在含有FITC缀合的抗CD4和PerCP-Cy5.5缀合的抗CD8抗体的洗涤缓冲液中。在4℃下与缀合抗体孵育30分钟后,洗涤、固定并透化细胞20分钟。然后洗涤细胞并与PE-抗-IFNγ在4℃下孵育30分钟。将染色的细胞进一步洗涤并重新悬浮在含有1%多聚甲醛的PBS中,通过流式细胞术进行分析。
结果
如图16所示,在用HLA匹配(C*05:01和C*08:02)、脉冲的LCL刺激的E5-NLD-lenti-转导的PBMC中诱导了IFNγ表达。值得注意的是,CD8+T细胞显示识别用低至10pmol/L的NLD肽(SEQ ID NO.1)脉冲的LCL;基本上证明了功能亲合力高于介导肿瘤消退的其他基因疗法试验中使用的TCR基因工程化的T细胞(Draper等人,Clin Cancer Res 21:4431-4439,2015;Doran等人,Journal of Clinical Oncology 2019 37:30,2759-2768)。
实施例8:经工程化以表达来自E2抗原的TCR(E5-TLQ-TCR)的T细胞特异性识别并
杀伤HLA-A2+HPV-16+肿瘤细胞。(体外细胞溶解)
E2-TLQ-TCR-T细胞介导的肿瘤细胞系的细胞溶解,效靶比(E/T)为10:1和5:1。简而言之,2×104个靶细胞每孔(CaSki(HPV+)和SCC70(HPV-))接种并过夜培养(17小时)。当细胞指数接近平台期时以指定的比例添加效应T细胞(E2-TLQ-TCR-T细胞)(参见图17),共培养约4天以评估随时间推移的细胞裂解(cytolosis)。也包括作为对照的IFNγ处理的(100μ/ml)靶细胞;将IFNγ添加到靶细胞培养物中,持续24小时,并在测定法前用完全RPMI培养基洗涤培养物。
每15分钟通过实时细胞分析、通过每个孔中贴壁细胞的电阻抗评估靶细胞裂解,直至实验结束。结果报告为细胞指数值。
用E2-TLQ-TCR-T细胞(图17,A)和“未转导的”对照T细胞(图17,B)攻击CaSki细胞系(HPV16+;HLA-A*02:01+)。E2-TLQ-TCR-T细胞(HLA-A*02:01限制性)诱导HPV16+癌细胞系(CaSki)的细胞溶解,如添加E2-TLQ-TCR-T细胞后细胞指数的下降所示。观察到与未处理相比,IFNγ处理的靶(CaSki)细胞有更大的细胞溶解,这可能与增强的抗原加工和MHC分子的表达相关。然而,当以相同的效靶比添加时,未转导的T细胞未显示出细胞溶解。
用E2-TLQ-TCR T细胞和未转导的T细胞(UT)攻击对照细胞系SCC70(HPV16-和HLA-A*02:01+)。10:1效靶比的E2-TLQ-T细胞诱导抗原特异性细胞溶解,而在HPV16-细胞系(SCC70)中未观察到细胞溶解。(图17,C)
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等同物
已经描述了本发明的多个实施方案。然而,应当理解,在不背离本发明的精神和范围的情况下可以进行各种修改。因此,其他实施方案在以下权利要求的范围内。除非另有定义,否则本文中使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。
本领域技术人员将认识到、或能够仅使用常规实验来确定本文描述的本发明的特定实施方案的许多等同实施方案。此类等同实施方案旨在包括在以下权利要求中。
序列表
<110>昆士兰医学研究所理事会
<120>用于靶向HPV感染细胞的组合物和方法
<130> QAH-02325
<140>
<141>
<150> 62/993,442
<151> 2020-03-23
<160> 233
<170> PatentIn version 3.5
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Cys Ala Leu Ser Glu Gly Gly Gly Ser Gln Gly Asn Leu Ile Phe
1 5 10 15
<210> 14
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 14
Cys Ala Ser Ser Pro Glu Leu Ala Gly Pro Gln Glu Thr Gln Tyr Phe
1 5 10 15
<210> 15
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 15
Cys Ala Val Ser Asp Arg His Asp Met Arg Phe
1 5 10
<210> 16
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 16
Cys Ala Ser Ser Tyr Ser Pro Glu Arg His Glu Gln Phe Phe
1 5 10
<210> 17
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 17
Cys Ala Ser Glu Gly His Asp Met Arg Phe
1 5 10
<210> 18
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 18
Cys Ala Ser Ser Thr Glu Ala Gly Gly Pro Thr Gly Glu Leu Phe Phe
1 5 10 15
<210> 19
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 19
Cys Ile Val Arg Asp Arg Ser Tyr Gly Gln Asn Phe Val Phe
1 5 10
<210> 20
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 20
Cys Ser Ala Arg Glu Gly Tyr Arg Ser Tyr Phe
1 5 10
<210> 21
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 21
Cys Ala Arg Gly Leu Glu Asn Ala Gly Asn Met Leu Thr Phe
1 5 10
<210> 22
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 22
Cys Ala Thr Ser Val Arg Gly Thr Gln Pro Gln His Phe Phe
1 5 10
<210> 23
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 23
Cys Ala Leu Ser Glu Arg Gly Ser Gly Gly Phe Lys Thr Ile Phe
1 5 10 15
<210> 24
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 24
Cys Ala Ser Ser Ser Gly Glu Lys Gly Gln Gly Ala Pro Val Ser Ser
1 5 10 15
Tyr Glu Gln Tyr Phe Phe
20
<210> 25
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 25
Cys Ala Phe Thr Tyr Gly Gly Ser Gln Gly Asn Leu Ile Phe
1 5 10
<210> 26
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 26
Cys Ala Ser Arg Ala Ser Val Gly Val Gly Thr Gly Glu Leu Phe Phe
1 5 10 15
<210> 27
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 27
Cys Ala Leu Ser Gly Asn Met Leu Thr Phe
1 5 10
<210> 28
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 28
Cys Ala Ser Ser Glu Gly Val Gly Gln Arg Asp Glu Gln Phe Phe
1 5 10 15
<210> 29
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 29
Cys Ala Ala Ser Trp Glu Gly Gly Gly Ala Asp Gly Leu Thr Phe
1 5 10 15
<210> 30
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 30
Cys Ala Ser Arg Gly Gln Gly Val Tyr Arg Ser Ser Tyr Asn Glu Gln
1 5 10 15
Phe Phe
<210> 31
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 31
Cys Ala Val Arg Asp Thr Gly Tyr Gly Gln Asn Phe Val Phe
1 5 10
<210> 32
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 32
Cys Ala Ser Ser Pro Gln Gly Arg Ile Asn Ser Pro Leu His Phe
1 5 10 15
<210> 33
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 33
Cys Ile Leu Ser Ala His Asp Tyr Lys Leu Ser Phe
1 5 10
<210> 34
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 34
Cys Ala Ser Ser Gln Gly Gly Leu Asn Ser Pro Leu His Phe
1 5 10
<210> 35
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 35
Cys Ala Met Arg Val Ala Glu Gly Ser Gln Gly Asn Leu Ile Phe
1 5 10 15
<210> 36
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 36
Cys Ala Ser Ser Pro Trp Gly Arg Gly Gly Ser Pro Leu His Phe
1 5 10 15
<210> 37
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 37
Cys Ala Val Lys Phe Asn Thr Asp Gln Gly Gly Lys Leu Ile Phe
1 5 10 15
<210> 38
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 38
Cys Ala Ser Ser Pro Gln Gly Arg Ile Asn Ser Pro Leu His Phe
1 5 10 15
<210> 39
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 39
Cys Ala Leu Gly Ser Ser Gly Thr Tyr Lys Tyr Ile
1 5 10
<210> 40
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 40
Cys Ala Ser Ser Gly Pro Gly Gln Gly His Asn Gln Pro Gln His Phe
1 5 10 15
<210> 41
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 41
Cys Ala Met Arg Glu Ala Asn Asp Met Arg Phe
1 5 10
<210> 42
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 42
Cys Ala Ser Ser Phe Leu Val Leu Ala Val Ser Tyr Asn Glu Gln Phe
1 5 10 15
Phe
<210> 43
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 43
Cys Ala Glu Thr Leu Gly Leu Asp Gln Gly Gly Lys Leu Ile Phe
1 5 10 15
<210> 44
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 44
Cys Ser Thr Ala Gly Glu Thr Asp Thr Gln Tyr Phe
1 5 10
<210> 45
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 45
Cys Ala Thr Asp Glu Gly Thr Ala Ser Lys Leu Thr Phe
1 5 10
<210> 46
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 46
Cys Ser Val Glu Trp Thr Ser Gly Ser Gly Glu Thr Gln Tyr Phe
1 5 10 15
<210> 47
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 47
Cys Ala Thr Asp Ala Gly Ser Asp Tyr Lys Leu Ser Phe
1 5 10
<210> 48
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 48
Cys Ala Ser Ser Leu Glu Pro Gln Tyr Phe
1 5 10
<210> 49
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 49
Cys Ala Thr Asp Glu Gly Thr Gly Asn Gln Phe Tyr Phe
1 5 10
<210> 50
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 50
Cys Ala Ser Ser Trp Asp Thr Gly Thr Glu Thr Gln Tyr Phe
1 5 10
<210> 51
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 51
Cys Ala Phe Pro Ser Ser Gly Thr Tyr Lys Tyr Ile Phe
1 5 10
<210> 52
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 52
Cys Ala Ser Thr Ala Gly Thr Asp Thr Gln Tyr Phe
1 5 10
<210> 53
<211> 9395
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多核苷酸
<400> 53
aagcttaatg tagtcttatg caatactctt gtagtcttgc aacatggtaa cgatgagtta 60
gcaacatgcc ttacaaggag agaaaaagca ccgtgcatgc cgattggtgg aagtaaggtg 120
gtacgatcgt gccttattag gaaggcaaca gacgggtctg acatggattg gacgaaccac 180
tgaattgccg cattgcagag atattgtatt taagtgccta gctcgataca taaacgggtc 240
tctctggtta gaccagatct gagcctggga gctctctggc taactaggga acccactgct 300
taagcctcaa taaagcttgc cttgagtgct tcaagtagtg tgtgcccgtc tgttgtgtga 360
ctctggtaac tagagatccc tcagaccctt ttagtcagtg tggaaaatct ctagcagtgg 420
cgcccgaaca gggacttgaa agcgaaaggg aaaccagagg agctctctcg acgcaggact 480
cggcttgctg aagcgcgcac ggcaagaggc gaggggcggc gactggtgag tacgccaaaa 540
attttgacta gcggaggcta gaaggagaga gatgggtgcg agagcgtcag tattaagcgg 600
gggagaatta gatcgcgatg ggaaaaaatt cggttaaggc cagggggaaa gaaaaaatat 660
aaattaaaac atatagtatg ggcaagcagg gagctagaac gattcgcagt taatcctggc 720
ctgttagaaa catcagaagg ctgtagacaa atactgggac agctacaacc atcccttcag 780
acaggatcag aagaacttag atcattatat aatacagtag caaccctcta ttgtgtgcat 840
caaaggatag agataaaaga caccaaggaa gctttagaca agatagagga agagcaaaac 900
aaaagtaaga ccaccgcaca gcaagcggcc gctgatcttc agacctggag gaggagatat 960
gagggacaat tggagaagtg aattatataa atataaagta gtaaaaattg aaccattagg 1020
agtagcaccc accaaggcaa agagaagagt ggtgcagaga gaaaaaagag cagtgggaat 1080
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 1140
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 1200
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 1260
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcctggggat 1320
ttggggttgc tctggaaaac tcatttgcac cactgctgtg ccttggaatg ctagttggag 1380
taataaatct ctggaacaga tttggaatca cacgacctgg atggagtggg acagagaaat 1440
taacaattac acaagcttaa tacactcctt aattgaagaa tcgcaaaacc agcaagaaaa 1500
gaatgaacaa gaattattgg aattagataa atgggcaagt ttgtggaatt ggtttaacat 1560
aacaaattgg ctgtggtata taaaattatt cataatgata gtaggaggct tggtaggttt 1620
aagaatagtt tttgctgtac tttctatagt gaatagagtt aggcagggat attcaccatt 1680
atcgtttcag acccacctcc caaccccgag gggacccgac aggcccgaag gaatagaaga 1740
agaaggtgga gagagagaca gagacagatc cattcgatta gtgaacggat ctcgacggta 1800
tcggttaact tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 1860
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaattcaa 1920
aattttatcg atgcctcccc gtcaccaccc cccccaaccc gccccgaccg gagctgagag 1980
taattcatac aaaaggactc gcccctgcct tggggaatcc cagggaccgt cgttaaactc 2040
ccactaacgt agaacccaga gatcgctgcg ttcccgcccc ctcacccgcc cgctctcgtc 2100
atcactgagg tggagaagag catgcgtgag gctccggtgc ccgtcagtgg gcagagcgca 2160
catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc ggtgcctaga 2220
gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc ctttttcccg 2280
agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt tttcgcaacg 2340
ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta 2400
cgggttatgg cccttgcgtg ccttgaatta cttccacgcc cctggctgca gtacgtgatt 2460
cttgatcccg agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga 2520
gccccttcgc ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga 2580
atctggtggc accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat 2640
ttttgatgat atcctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa 2700
gatctgcaca ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc 2760
cagcgcacat gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg 2820
tagtctcaag ctggccggcc tgctctggtg cctggcctcg cgccgccgtg tatcgccccg 2880
ccctgggcgg caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt 2940
cccggccctg ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt 3000
gagtcaccca cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc 3060
acggagtacc gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg 3120
tctttaggtt ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag 3180
actgaagtta ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag 3240
tttggatctt ggttcattct caagcctcag acagtggttc aaagtttttt tcttccattt 3300
caggtgtcgt gaaaactacc cctctagata atacgactca ctatagggcc cgggttggat 3360
ccgccgccac catgggcaca agcctgctgt gttgggtcgt gctgggcttt ctgggcacag 3420
atcatacagg cgccggtgtc agccagtctc ctcggtacaa agtgaccaag cgcggacagg 3480
atgtggccct gagatgcgat cctatctctg gccacgtgtc cctgtactgg tacagacagg 3540
ctctcggaca gggccccgag ttcctgacct acttcaatta cgaggcccag caggacaaga 3600
gcggcctgcc taacgataga ttcagcgccg aaagacccga gggcagcatc agcacactga 3660
ccatccagag aaccgagcag agggacagcg ccatgtacag atgtgccagc tctcctgaac 3720
tggccggacc tcaagagaca cagtacttcg gccctggcac cagactgctg gtgctggaag 3780
atctgaacaa ggtgttccct ccagaggtgg ccgtgttcga gccttctaag gccgagattg 3840
cccacacaca gaaagccaca ctcgtgtgcc tggccaccgg cttttttccc gatcacgtgg 3900
aactgtcttg gtgggtcaac ggcaaagagg tgcacagcgg cgtctgtacc gatcctcagc 3960
ctctgaaaga gcagcccgct ctgaacgaca gcagatactg cctgagcagc agactgagag 4020
tgtccgccac cttctggcag aaccccagaa accacttcag atgccaggtg cagttctacg 4080
gcctgagcga gaacgatgag tggacccagg atagagccaa gcctgtgaca cagatcgtgt 4140
ctgccgaagc ctggggcaga gccgattgtg gaattaccag cgccagctac catcagggcg 4200
tgctgtctgc cacaatcctg tacgagattc tgctgggcaa agccactctg tacgccgtgc 4260
tggtgtctgc cctggtgctg atggccatgg tcaagcggaa ggacttcaga gccaagagat 4320
ccggctccgg cgcaccggtg aaacagactt tgaattttga ccttctcaag ttggcaggag 4380
acgttgagtc caaccctggg cccatgctga cagccagcct gctgagagcc gtgatcgcct 4440
ctatctgtgt ggtgtccagc atggctcaga aagtgacaca ggcccagacc gagatcagcg 4500
tggtggaaaa agaagatgtg accctggact gcgtgtacga gacacgggac accacctact 4560
acctgttttg gtacaagcag cctcctagcg gcgagctggt gttcctgatc agacggaaca 4620
gcttcgacga gcagaacgag atctccggcc ggtacagctg gaacttccag aagtccacca 4680
gcagcttcaa cttcaccatc accgcctctc aggtggtgga ctccgccgtg tatttttgcg 4740
ccctgtctga aggcggcgga agccagggca atctgatctt tggcaagggc accaagctga 4800
gcgtgaagcc caacattcag aaccccgatc ctgccgtgta ccagctgaga gacagcaaga 4860
gcagcgacaa gtccgtgtgt ctgttcaccg acttcgacag ccagaccaac gtgtcccaga 4920
gcaaggacag cgacgtgtac atcaccgata agtgcgtgct ggacatgcgg agcatggact 4980
tcaagagcaa cagcgccgtg gcctggtcca acaagagcga tttcgcctgc gccaacgcct 5040
tcaacaacag cattatcccc gaggacacat tcttccccag ctccgatgtg ccctgcgacg 5100
tgaagctggt cgagaagtcc tttgagacag acaccaacct gaatttccag aacctgtccg 5160
tgatcggctt cagaatcctg ctgctgaaag tggccggctt caacctgctg atgaccctga 5220
gactctggtc cagctaatga gtcgacaatc aacctctgga ttacaaaatt tgtgaaagat 5280
tgactggtat tcttaactat gttgctcctt ttacgctatg tggatacgct gctttaatgc 5340
ctttgtatca tgctattgct tcccgtatgg ctttcatttt ctcctccttg tataaatcct 5400
ggttgctgtc tctttatgag gagttgtggc ccgttgtcag gcaacgtggc gtggtgtgca 5460
ctgtgtttgc tgacgcaacc cccactggtt ggggcattgc caccacctgt cagctccttt 5520
ccgggacttt cgctttcccc ctccctattg ccacggcgga actcatcgcc gcctgccttg 5580
cccgctgctg gacaggggct cggctgttgg gcactgacaa ttccgtggtg ttgtcgggga 5640
agctgacgtc ctttccatgg ctgctcgcct gtgttgccac ctggattctg cgcgggacgt 5700
ccttctgcta cgtcccttcg gccctcaatc cagcggacct tccttcccgc ggcctgctgc 5760
cggctctgcg gcctcttccg cgtcttcgcc ttcgccctca gacgagtcgg atctcccttt 5820
gggccgcctc cccgcctgga attcgagctc ggtaccttta agaccaatga cttacaaggc 5880
agctgtagat cttagccact ttttaaaaga aaagggggga ctggaagggc taattcactc 5940
ccaacgaaga caagatctgc tttttgcttg tactgggtct ctctggttag accagatctg 6000
agcctgggag ctctctggct aactagggaa cccactgctt aagcctcaat aaagcttgcc 6060
ttgagtgctt caagtagtgt gtgcccgtct gttgtgtgac tctggtaact agagatccct 6120
cagacccttt tagtcagtgt ggaaaatctc tagcagtagt agttcatgtc atcttattat 6180
tcagtattta taacttgcaa agaaatgaat atcagagagt gagaggaact tgtttattgc 6240
agcttataat ggttacaaat aaagcaatag catcacaaat ttcacaaata aagcattttt 6300
ttcactgcat tctagttgtg gtttgtccaa actcatcaat gtatcttatc atgtctggct 6360
ctagctatcc cgcccctaac tccgcccatc ccgcccctaa ctccgcccag ttccgcccat 6420
tctccgcccc atggctgact aatttttttt atttatgcag aggccgaggc cgcctcggcc 6480
tctgagctat tccagaagta gtgaggaggc ttttttggag gcctagggac gtacccaatt 6540
cgccctatag tgagtcgtat tacgcgcgct cactggccgt cgttttacaa cgtcgtgact 6600
gggaaaaccc tggcgttacc caacttaatc gccttgcagc acatccccct ttcgccagct 6660
ggcgtaatag cgaagaggcc cgcaccgatc gcccttccca acagttgcgc agcctgaatg 6720
gcgaatggga cgcgccctgt agcggcgcat taagcgcggc gggtgtggtg gttacgcgca 6780
gcgtgaccgc tacacttgcc agcgccctag cgcccgctcc tttcgctttc ttcccttcct 6840
ttctcgccac gttcgccggc tttccccgtc aagctctaaa tcgggggctc cctttagggt 6900
tccgatttag tgctttacgg cacctcgacc ccaaaaaact tgattagggt gatggttcac 6960
gtagtgggcc atcgccctga tagacggttt ttcgcccttt gacgttggag tccacgttct 7020
ttaatagtgg actcttgttc caaactggaa caacactcaa ccctatctcg gtctattctt 7080
ttgatttata agggattttg ccgatttcgg cctattggtt aaaaaatgag ctgatttaac 7140
aaaaatttaa cgcgaatttt aacaaaatat taacgcttac aatttaggtg gcacttttcg 7200
gggaaatgtg cgcggaaccc ctatttgttt atttttctaa atacattcaa atatgtatcc 7260
gctcatgaga caataaccct gataaatgct tcaataatat tgaaaaagga agagtatgag 7320
tattcaacat ttccgtgtcg cccttattcc cttttttgcg gcattttgcc ttcctgtttt 7380
tgctcaccca gaaacgctgg tgaaagtaaa agatgctgaa gatcagttgg gtgcacgagt 7440
gggttacatc gaactggatc tcaacagcgg taagatcctt gagagttttc gccccgaaga 7500
acgttttcca atgatgagca cttttaaagt tctgctatgt ggcgcggtat tatcccgtat 7560
tgacgccggg caagagcaac tcggtcgccg catacactat tctcagaatg acttggttga 7620
gtactcacca gtcacagaaa agcatcttac ggatggcatg acagtaagag aattatgcag 7680
tgctgccata accatgagtg ataacactgc ggccaactta cttctgacaa cgatcggagg 7740
accgaaggag ctaaccgctt ttttgcacaa catgggggat catgtaactc gccttgatcg 7800
ttgggaaccg gagctgaatg aagccatacc aaacgacgag cgtgacacca cgatgcctgt 7860
agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc tagcttcccg 7920
gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc tgcgctcggc 7980
ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg ggtctcgcgg 8040
tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta tctacacgac 8100
ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag gtgcctcact 8160
gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga ttgatttaaa 8220
acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc tcatgaccaa 8280
aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa agatcaaagg 8340
atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa aaaaaccacc 8400
gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc cgaaggtaac 8460
tggcttcagc agagcgcaga taccaaatac tgttcttcta gtgtagccgt agttaggcca 8520
ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc tgttaccagt 8580
ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac gatagttacc 8640
ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca gcttggagcg 8700
aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg ccacgcttcc 8760
cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag gagagcgcac 8820
gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt ttcgccacct 8880
ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat ggaaaaacgc 8940
cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc acatgttctt 9000
tcctgcgtta tcccctgatt ctgtggataa ccgtattacc gcctttgagt gagctgatac 9060
cgctcgccgc agccgaacga ccgagcgcag cgagtcagtg agcgaggaag cggaagagcg 9120
cccaatacgc aaaccgcctc tccccgcgcg ttggccgatt cattaatgca gctggcacga 9180
caggtttccc gactggaaag cgggcagtga gcgcaacgca attaatgtga gttagctcac 9240
tcattaggca ccccaggctt tacactttat gcttccggct cgtatgttgt gtggaattgt 9300
gagcggataa caatttcaca caggaaacag ctatgaccat gattacgcca agcgcgcaat 9360
taaccctcac taaagggaac aaaagctgga gctgc 9395
<210> 54
<211> 9386
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多核苷酸
<400> 54
aagcttaatg tagtcttatg caatactctt gtagtcttgc aacatggtaa cgatgagtta 60
gcaacatgcc ttacaaggag agaaaaagca ccgtgcatgc cgattggtgg aagtaaggtg 120
gtacgatcgt gccttattag gaaggcaaca gacgggtctg acatggattg gacgaaccac 180
tgaattgccg cattgcagag atattgtatt taagtgccta gctcgataca taaacgggtc 240
tctctggtta gaccagatct gagcctggga gctctctggc taactaggga acccactgct 300
taagcctcaa taaagcttgc cttgagtgct tcaagtagtg tgtgcccgtc tgttgtgtga 360
ctctggtaac tagagatccc tcagaccctt ttagtcagtg tggaaaatct ctagcagtgg 420
cgcccgaaca gggacttgaa agcgaaaggg aaaccagagg agctctctcg acgcaggact 480
cggcttgctg aagcgcgcac ggcaagaggc gaggggcggc gactggtgag tacgccaaaa 540
attttgacta gcggaggcta gaaggagaga gatgggtgcg agagcgtcag tattaagcgg 600
gggagaatta gatcgcgatg ggaaaaaatt cggttaaggc cagggggaaa gaaaaaatat 660
aaattaaaac atatagtatg ggcaagcagg gagctagaac gattcgcagt taatcctggc 720
ctgttagaaa catcagaagg ctgtagacaa atactgggac agctacaacc atcccttcag 780
acaggatcag aagaacttag atcattatat aatacagtag caaccctcta ttgtgtgcat 840
caaaggatag agataaaaga caccaaggaa gctttagaca agatagagga agagcaaaac 900
aaaagtaaga ccaccgcaca gcaagcggcc gctgatcttc agacctggag gaggagatat 960
gagggacaat tggagaagtg aattatataa atataaagta gtaaaaattg aaccattagg 1020
agtagcaccc accaaggcaa agagaagagt ggtgcagaga gaaaaaagag cagtgggaat 1080
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 1140
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 1200
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 1260
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcctggggat 1320
ttggggttgc tctggaaaac tcatttgcac cactgctgtg ccttggaatg ctagttggag 1380
taataaatct ctggaacaga tttggaatca cacgacctgg atggagtggg acagagaaat 1440
taacaattac acaagcttaa tacactcctt aattgaagaa tcgcaaaacc agcaagaaaa 1500
gaatgaacaa gaattattgg aattagataa atgggcaagt ttgtggaatt ggtttaacat 1560
aacaaattgg ctgtggtata taaaattatt cataatgata gtaggaggct tggtaggttt 1620
aagaatagtt tttgctgtac tttctatagt gaatagagtt aggcagggat attcaccatt 1680
atcgtttcag acccacctcc caaccccgag gggacccgac aggcccgaag gaatagaaga 1740
agaaggtgga gagagagaca gagacagatc cattcgatta gtgaacggat ctcgacggta 1800
tcggttaact tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 1860
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaattcaa 1920
aattttatcg atgcctcccc gtcaccaccc cccccaaccc gccccgaccg gagctgagag 1980
taattcatac aaaaggactc gcccctgcct tggggaatcc cagggaccgt cgttaaactc 2040
ccactaacgt agaacccaga gatcgctgcg ttcccgcccc ctcacccgcc cgctctcgtc 2100
atcactgagg tggagaagag catgcgtgag gctccggtgc ccgtcagtgg gcagagcgca 2160
catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc ggtgcctaga 2220
gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc ctttttcccg 2280
agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt tttcgcaacg 2340
ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta 2400
cgggttatgg cccttgcgtg ccttgaatta cttccacgcc cctggctgca gtacgtgatt 2460
cttgatcccg agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga 2520
gccccttcgc ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga 2580
atctggtggc accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat 2640
ttttgatgat atcctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa 2700
gatctgcaca ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc 2760
cagcgcacat gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg 2820
tagtctcaag ctggccggcc tgctctggtg cctggcctcg cgccgccgtg tatcgccccg 2880
ccctgggcgg caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt 2940
cccggccctg ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt 3000
gagtcaccca cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc 3060
acggagtacc gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg 3120
tctttaggtt ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag 3180
actgaagtta ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag 3240
tttggatctt ggttcattct caagcctcag acagtggttc aaagtttttt tcttccattt 3300
caggtgtcgt gaaaactacc cctctagata atacgactca ctatagggcc cgggttggat 3360
ccgccgccac catgctgctg ctcctgctgc ttctcggccc tggaatttct ctgctgctgc 3420
ctggatctct ggccggctct ggacttggag ctgtggtgtc tcagcacccc tcttgggtca 3480
tctgcaagag cggcaccagc gtgaagatcg agtgcagaag cctggacttc caggccacca 3540
ccatgttctg gtacagacag ttccccaagc agagcctgat gctgatggcc acctctaacg 3600
agggcagcaa ggccacatat gagcagggcg tcgagaagga caagttcctg atcaaccacg 3660
ccagcctgac actgagcacc ctgacagtga caagcgccca tcctgaggac agcagcttct 3720
acatctgcag cgccagagag ggctacagaa gctactttgg ccctggcacc agactgaccg 3780
tgctggaaga tctgaagaac gtgttcccac ctgaggtggc cgtgttcgag ccttctaagg 3840
ccgagattgc ccacacacag aaagccacac tcgtgtgcct ggccaccggc ttttttcccg 3900
atcacgtcga actgtcttgg tgggtcaacg gcaaagaggt gcacagcggc gtctgtaccg 3960
atcctcagcc tctgaaagag cagcccgctc tgaacgacag cagatactgc ctgagcagca 4020
gactgagagt gtccgccacc ttctggcaga accccagaaa ccacttcaga tgccaggtgc 4080
agttctacgg cctgagcgag aacgatgagt ggacccagga tagagccaag cctgtgacac 4140
agatcgtgtc tgccgaagcc tggggcagag ccgattgtgg aattaccagc gccagctacc 4200
atcagggcgt gctgtctgcc acaatcctgt acgagatcct gctgggcaaa gccactctgt 4260
acgccgtgct ggtgtctgcc ctggtcctga tggctatggt caagagaaag gacagccggg 4320
gccgggccaa gcggtccggc tccggcgcac cggtgaaaca gactttgaat tttgaccttc 4380
tcaagttggc aggagacgtt gagtccaacc ctgggcccat gagactggtg gccagagtga 4440
ccgtgttcct gaccttcggc accatcatcg acgccaagac aacccagcct cctagcatgg 4500
attgtgccga gggcagagcc gccaacctgc cttgtaatca cagcaccatc agcggcaacg 4560
agtacgtgta ctggtacaga cagatccact ctcagggccc tcagtacatc atccacggcc 4620
tgaagaacaa cgagacaaac gagatggcca gcctgatcat caccgaggac agaaagagca 4680
gcaccctgat cctgcctcac gccacactga gagataccgc cgtgtactac tgcatcgtgc 4740
gggacagaag ctacggccag aacttcgtgt ttggccctgg caccagactg agcgtgctgc 4800
cctatattca gaaccccgat ccagccgtgt accagctgag agacagcaag tccagcgaca 4860
agagcgtgtg cctgttcacc gacttcgaca gccagaccaa cgtgtcccag agcaaggaca 4920
gcgacgtgta catcaccgat aagtgcgtgc tggacatgcg gagcatggac ttcaagagca 4980
acagcgccgt ggcctggtcc aacaagagcg atttcgcctg cgccaacgcc ttcaacaaca 5040
gcattatccc cgaggacaca ttcttcccca gctccgatgt gccctgcgac gtgaagctgg 5100
tggaaaagag cttcgagaca gacaccaacc tgaacttcca gaacctgagc gtgatcggct 5160
tccgcatcct gctgctgaaa gtggccggct tcaacctgct gatgaccctg agactgtggt 5220
ccagctaatg agtcgacaat caacctctgg attacaaaat ttgtgaaaga ttgactggta 5280
ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc 5340
atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt 5400
ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg 5460
ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt 5520
tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct 5580
ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg aagctgacgt 5640
cctttccatg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg tccttctgct 5700
acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc 5760
ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct 5820
ccccgcctgg aattcgagct cggtaccttt aagaccaatg acttacaagg cagctgtaga 5880
tcttagccac tttttaaaag aaaagggggg actggaaggg ctaattcact cccaacgaag 5940
acaagatctg ctttttgctt gtactgggtc tctctggtta gaccagatct gagcctggga 6000
gctctctggc taactaggga acccactgct taagcctcaa taaagcttgc cttgagtgct 6060
tcaagtagtg tgtgcccgtc tgttgtgtga ctctggtaac tagagatccc tcagaccctt 6120
ttagtcagtg tggaaaatct ctagcagtag tagttcatgt catcttatta ttcagtattt 6180
ataacttgca aagaaatgaa tatcagagag tgagaggaac ttgtttattg cagcttataa 6240
tggttacaaa taaagcaata gcatcacaaa tttcacaaat aaagcatttt tttcactgca 6300
ttctagttgt ggtttgtcca aactcatcaa tgtatcttat catgtctggc tctagctatc 6360
ccgcccctaa ctccgcccat cccgccccta actccgccca gttccgccca ttctccgccc 6420
catggctgac taattttttt tatttatgca gaggccgagg ccgcctcggc ctctgagcta 6480
ttccagaagt agtgaggagg cttttttgga ggcctaggga cgtacccaat tcgccctata 6540
gtgagtcgta ttacgcgcgc tcactggccg tcgttttaca acgtcgtgac tgggaaaacc 6600
ctggcgttac ccaacttaat cgccttgcag cacatccccc tttcgccagc tggcgtaata 6660
gcgaagaggc ccgcaccgat cgcccttccc aacagttgcg cagcctgaat ggcgaatggg 6720
acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt ggttacgcgc agcgtgaccg 6780
ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt cttcccttcc tttctcgcca 6840
cgttcgccgg ctttccccgt caagctctaa atcgggggct ccctttaggg ttccgattta 6900
gtgctttacg gcacctcgac cccaaaaaac ttgattaggg tgatggttca cgtagtgggc 6960
catcgccctg atagacggtt tttcgccctt tgacgttgga gtccacgttc tttaatagtg 7020
gactcttgtt ccaaactgga acaacactca accctatctc ggtctattct tttgatttat 7080
aagggatttt gccgatttcg gcctattggt taaaaaatga gctgatttaa caaaaattta 7140
acgcgaattt taacaaaata ttaacgctta caatttaggt ggcacttttc ggggaaatgt 7200
gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag 7260
acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca 7320
tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc 7380
agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat 7440
cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc 7500
aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgta ttgacgccgg 7560
gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc 7620
agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat 7680
aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga 7740
gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc 7800
ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg tagcaatggc 7860
aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc ggcaacaatt 7920
aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg cccttccggc 7980
tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg gtatcattgc 8040
agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga cggggagtca 8100
ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac tgattaagca 8160
ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa aacttcattt 8220
ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca aaatccctta 8280
acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag gatcttcttg 8340
agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac cgctaccagc 8400
ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag 8460
cagagcgcag ataccaaata ctgttcttct agtgtagccg tagttaggcc accacttcaa 8520
gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag tggctgctgc 8580
cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac cggataaggc 8640
gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc gaacgaccta 8700
caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag 8760
aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca cgagggagct 8820
tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc tctgacttga 8880
gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc 8940
ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct ttcctgcgtt 9000
atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata ccgctcgccg 9060
cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc gcccaatacg 9120
caaaccgcct ctccccgcgc gttggccgat tcattaatgc agctggcacg acaggtttcc 9180
cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg agttagctca ctcattaggc 9240
accccaggct ttacacttta tgcttccggc tcgtatgttg tgtggaattg tgagcggata 9300
acaatttcac acaggaaaca gctatgacca tgattacgcc aagcgcgcaa ttaaccctca 9360
ctaaagggaa caaaagctgg agctgc 9386
<210> 55
<211> 9398
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多核苷酸
<400> 55
aagcttaatg tagtcttatg caatactctt gtagtcttgc aacatggtaa cgatgagtta 60
gcaacatgcc ttacaaggag agaaaaagca ccgtgcatgc cgattggtgg aagtaaggtg 120
gtacgatcgt gccttattag gaaggcaaca gacgggtctg acatggattg gacgaaccac 180
tgaattgccg cattgcagag atattgtatt taagtgccta gctcgataca taaacgggtc 240
tctctggtta gaccagatct gagcctggga gctctctggc taactaggga acccactgct 300
taagcctcaa taaagcttgc cttgagtgct tcaagtagtg tgtgcccgtc tgttgtgtga 360
ctctggtaac tagagatccc tcagaccctt ttagtcagtg tggaaaatct ctagcagtgg 420
cgcccgaaca gggacttgaa agcgaaaggg aaaccagagg agctctctcg acgcaggact 480
cggcttgctg aagcgcgcac ggcaagaggc gaggggcggc gactggtgag tacgccaaaa 540
attttgacta gcggaggcta gaaggagaga gatgggtgcg agagcgtcag tattaagcgg 600
gggagaatta gatcgcgatg ggaaaaaatt cggttaaggc cagggggaaa gaaaaaatat 660
aaattaaaac atatagtatg ggcaagcagg gagctagaac gattcgcagt taatcctggc 720
ctgttagaaa catcagaagg ctgtagacaa atactgggac agctacaacc atcccttcag 780
acaggatcag aagaacttag atcattatat aatacagtag caaccctcta ttgtgtgcat 840
caaaggatag agataaaaga caccaaggaa gctttagaca agatagagga agagcaaaac 900
aaaagtaaga ccaccgcaca gcaagcggcc gctgatcttc agacctggag gaggagatat 960
gagggacaat tggagaagtg aattatataa atataaagta gtaaaaattg aaccattagg 1020
agtagcaccc accaaggcaa agagaagagt ggtgcagaga gaaaaaagag cagtgggaat 1080
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 1140
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 1200
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 1260
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcctggggat 1320
ttggggttgc tctggaaaac tcatttgcac cactgctgtg ccttggaatg ctagttggag 1380
taataaatct ctggaacaga tttggaatca cacgacctgg atggagtggg acagagaaat 1440
taacaattac acaagcttaa tacactcctt aattgaagaa tcgcaaaacc agcaagaaaa 1500
gaatgaacaa gaattattgg aattagataa atgggcaagt ttgtggaatt ggtttaacat 1560
aacaaattgg ctgtggtata taaaattatt cataatgata gtaggaggct tggtaggttt 1620
aagaatagtt tttgctgtac tttctatagt gaatagagtt aggcagggat attcaccatt 1680
atcgtttcag acccacctcc caaccccgag gggacccgac aggcccgaag gaatagaaga 1740
agaaggtgga gagagagaca gagacagatc cattcgatta gtgaacggat ctcgacggta 1800
tcggttaact tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 1860
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaattcaa 1920
aattttatcg atgcctcccc gtcaccaccc cccccaaccc gccccgaccg gagctgagag 1980
taattcatac aaaaggactc gcccctgcct tggggaatcc cagggaccgt cgttaaactc 2040
ccactaacgt agaacccaga gatcgctgcg ttcccgcccc ctcacccgcc cgctctcgtc 2100
atcactgagg tggagaagag catgcgtgag gctccggtgc ccgtcagtgg gcagagcgca 2160
catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc ggtgcctaga 2220
gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc ctttttcccg 2280
agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt tttcgcaacg 2340
ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta 2400
cgggttatgg cccttgcgtg ccttgaatta cttccacgcc cctggctgca gtacgtgatt 2460
cttgatcccg agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga 2520
gccccttcgc ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga 2580
atctggtggc accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat 2640
ttttgatgat atcctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa 2700
gatctgcaca ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc 2760
cagcgcacat gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg 2820
tagtctcaag ctggccggcc tgctctggtg cctggcctcg cgccgccgtg tatcgccccg 2880
ccctgggcgg caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt 2940
cccggccctg ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt 3000
gagtcaccca cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc 3060
acggagtacc gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg 3120
tctttaggtt ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag 3180
actgaagtta ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag 3240
tttggatctt ggttcattct caagcctcag acagtggttc aaagtttttt tcttccattt 3300
caggtgtcgt gaaaactacc cctctagata atacgactca ctatagggcc cgggttggat 3360
ccgccgccac catggatacc tggctcgtgt gctgggccat cttcagcctg ctgaaagccg 3420
gactgaccga gcctgaagtg acccagacac ctagccacca agtgacacag atgggccaag 3480
aagtgatcct gcgctgcgtg cccatcagca accacctgta cttctactgg tacagacaga 3540
tcctgggcca gaaagtggag ttcctggtgt ccttctacaa caacgagatc agcgagaagt 3600
ccgagatctt cgacgaccag ttcagcgtgg aaagacccga cggcagcaac ttcaccctga 3660
agatcagaag caccaagctg gaggacagcg ccatgtactt ttgcgccagc agagcctctg 3720
tcggcgttgg aacaggcgag ctgtttttcg gcgagggcag cagactgacc gtgctggaag 3780
atctgaagaa cgtgttccca cctgaggtgg ccgtgttcga gccttctaag gccgagattg 3840
cccacacaca gaaagccaca ctcgtgtgcc tggccaccgg cttttttccc gatcacgtgg 3900
aactgtcttg gtgggtcaac ggcaaagagg tgcacagcgg cgtctgtacc gatcctcagc 3960
cactgaaaga gcagcccgct ctgaacgaca gcagatactg cctgtcctcc agactgagag 4020
tgtccgccac cttctggcag aaccccagaa accacttcag atgccaggtg cagttctacg 4080
gcctgagcga gaacgatgag tggacccagg atagagccaa gcctgtgact cagatcgtgt 4140
ctgccgaagc ctggggcaga gccgattgtg gaattaccag cgccagctac catcagggcg 4200
tgctgtctgc cacaatcctg tacgagatcc tgctgggcaa agccactctg tacgccgtgc 4260
tggtgtctgc cctggtgctg atggccatgg tcaagcggaa ggatagcaga ggcagagcca 4320
agagatccgg ctccggcgca ccggtgaaac agactttgaa ttttgacctt ctcaagttgg 4380
caggagacgt tgagtccaac cctgggccca tgaccagagt gtctctgctg tgggccgtcg 4440
tggtgtccac atgtctggaa tctggcatgg cccagaccgt gacacagagc cagcctgaga 4500
tgtctgtgca agaggccgag acagtgaccc tgagctgcac ctacgatacc agcgagagca 4560
actactacct gttctggtac aagcagcctc ctagccggca gatgatcctg gtcatcagac 4620
aagaggccta taagcagcag aacgccaccg agaacagatt cagcgtgaac ttccagaagg 4680
ccgccaagag cttcagcctg aagatcagcg atagccagct gggcgacacc gccatgtact 4740
tttgcgcctt tacctacggc ggcagccagg gcaatctgat ctttggcaag ggcaccaagc 4800
tgagcgtgaa gcccaacatt cagaaccccg atcctgccgt gtaccagctg agagacagca 4860
agagcagcga caagagcgtg tgcctgttca ccgacttcga cagccagacc aacgtgtccc 4920
agagcaagga cagcgacgtg tacatcaccg ataagtgcgt gctggacatg cggagcatgg 4980
acttcaagag caacagcgcc gtggcctggt ccaacaagag cgatttcgcc tgcgccaacg 5040
ccttcaacaa cagcattatc cccgaggaca cattcttccc cagctccgat gtgccctgcg 5100
acgtgaagct ggtggaaaag agcttcgaga cagacaccaa cctgaatttc cagaacctgt 5160
ccgtgatcgg cttcagaatc ctgctgctga aagtggccgg cttcaacctg ctgatgaccc 5220
tgcgactttg gagcagctaa tgagtcgaca atcaacctct ggattacaaa atttgtgaaa 5280
gattgactgg tattcttaac tatgttgctc cttttacgct atgtggatac gctgctttaa 5340
tgcctttgta tcatgctatt gcttcccgta tggctttcat tttctcctcc ttgtataaat 5400
cctggttgct gtctctttat gaggagttgt ggcccgttgt caggcaacgt ggcgtggtgt 5460
gcactgtgtt tgctgacgca acccccactg gttggggcat tgccaccacc tgtcagctcc 5520
tttccgggac tttcgctttc cccctcccta ttgccacggc ggaactcatc gccgcctgcc 5580
ttgcccgctg ctggacaggg gctcggctgt tgggcactga caattccgtg gtgttgtcgg 5640
ggaagctgac gtcctttcca tggctgctcg cctgtgttgc cacctggatt ctgcgcggga 5700
cgtccttctg ctacgtccct tcggccctca atccagcgga ccttccttcc cgcggcctgc 5760
tgccggctct gcggcctctt ccgcgtcttc gccttcgccc tcagacgagt cggatctccc 5820
tttgggccgc ctccccgcct ggaattcgag ctcggtacct ttaagaccaa tgacttacaa 5880
ggcagctgta gatcttagcc actttttaaa agaaaagggg ggactggaag ggctaattca 5940
ctcccaacga agacaagatc tgctttttgc ttgtactggg tctctctggt tagaccagat 6000
ctgagcctgg gagctctctg gctaactagg gaacccactg cttaagcctc aataaagctt 6060
gccttgagtg cttcaagtag tgtgtgcccg tctgttgtgt gactctggta actagagatc 6120
cctcagaccc ttttagtcag tgtggaaaat ctctagcagt agtagttcat gtcatcttat 6180
tattcagtat ttataacttg caaagaaatg aatatcagag agtgagagga acttgtttat 6240
tgcagcttat aatggttaca aataaagcaa tagcatcaca aatttcacaa ataaagcatt 6300
tttttcactg cattctagtt gtggtttgtc caaactcatc aatgtatctt atcatgtctg 6360
gctctagcta tcccgcccct aactccgccc atcccgcccc taactccgcc cagttccgcc 6420
cattctccgc cccatggctg actaattttt tttatttatg cagaggccga ggccgcctcg 6480
gcctctgagc tattccagaa gtagtgagga ggcttttttg gaggcctagg gacgtaccca 6540
attcgcccta tagtgagtcg tattacgcgc gctcactggc cgtcgtttta caacgtcgtg 6600
actgggaaaa ccctggcgtt acccaactta atcgccttgc agcacatccc cctttcgcca 6660
gctggcgtaa tagcgaagag gcccgcaccg atcgcccttc ccaacagttg cgcagcctga 6720
atggcgaatg ggacgcgccc tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc 6780
gcagcgtgac cgctacactt gccagcgccc tagcgcccgc tcctttcgct ttcttccctt 6840
cctttctcgc cacgttcgcc ggctttcccc gtcaagctct aaatcggggg ctccctttag 6900
ggttccgatt tagtgcttta cggcacctcg accccaaaaa acttgattag ggtgatggtt 6960
cacgtagtgg gccatcgccc tgatagacgg tttttcgccc tttgacgttg gagtccacgt 7020
tctttaatag tggactcttg ttccaaactg gaacaacact caaccctatc tcggtctatt 7080
cttttgattt ataagggatt ttgccgattt cggcctattg gttaaaaaat gagctgattt 7140
aacaaaaatt taacgcgaat tttaacaaaa tattaacgct tacaatttag gtggcacttt 7200
tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta 7260
tccgctcatg agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat 7320
gagtattcaa catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt 7380
ttttgctcac ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg 7440
agtgggttac atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga 7500
agaacgtttt ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg 7560
tattgacgcc gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt 7620
tgagtactca ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg 7680
cagtgctgcc ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg 7740
aggaccgaag gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga 7800
tcgttgggaa ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc 7860
tgtagcaatg gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc 7920
ccggcaacaa ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc 7980
ggcccttccg gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg 8040
cggtatcatt gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac 8100
gacggggagt caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc 8160
actgattaag cattggtaac tgtcagacca agtttactca tatatacttt agattgattt 8220
aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 8280
caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 8340
aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 8400
accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 8460
aactggcttc agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg 8520
ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 8580
agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 8640
accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 8700
gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 8760
tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 8820
cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 8880
cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 8940
cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt 9000
ctttcctgcg ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga 9060
taccgctcgc cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga 9120
gcgcccaata cgcaaaccgc ctctccccgc gcgttggccg attcattaat gcagctggca 9180
cgacaggttt cccgactgga aagcgggcag tgagcgcaac gcaattaatg tgagttagct 9240
cactcattag gcaccccagg ctttacactt tatgcttccg gctcgtatgt tgtgtggaat 9300
tgtgagcgga taacaatttc acacaggaaa cagctatgac catgattacg ccaagcgcgc 9360
aattaaccct cactaaaggg aacaaaagct ggagctgc 9398
<210> 56
<211> 9365
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多核苷酸
<400> 56
aagcttaatg tagtcttatg caatactctt gtagtcttgc aacatggtaa cgatgagtta 60
gcaacatgcc ttacaaggag agaaaaagca ccgtgcatgc cgattggtgg aagtaaggtg 120
gtacgatcgt gccttattag gaaggcaaca gacgggtctg acatggattg gacgaaccac 180
tgaattgccg cattgcagag atattgtatt taagtgccta gctcgataca taaacgggtc 240
tctctggtta gaccagatct gagcctggga gctctctggc taactaggga acccactgct 300
taagcctcaa taaagcttgc cttgagtgct tcaagtagtg tgtgcccgtc tgttgtgtga 360
ctctggtaac tagagatccc tcagaccctt ttagtcagtg tggaaaatct ctagcagtgg 420
cgcccgaaca gggacttgaa agcgaaaggg aaaccagagg agctctctcg acgcaggact 480
cggcttgctg aagcgcgcac ggcaagaggc gaggggcggc gactggtgag tacgccaaaa 540
attttgacta gcggaggcta gaaggagaga gatgggtgcg agagcgtcag tattaagcgg 600
gggagaatta gatcgcgatg ggaaaaaatt cggttaaggc cagggggaaa gaaaaaatat 660
aaattaaaac atatagtatg ggcaagcagg gagctagaac gattcgcagt taatcctggc 720
ctgttagaaa catcagaagg ctgtagacaa atactgggac agctacaacc atcccttcag 780
acaggatcag aagaacttag atcattatat aatacagtag caaccctcta ttgtgtgcat 840
caaaggatag agataaaaga caccaaggaa gctttagaca agatagagga agagcaaaac 900
aaaagtaaga ccaccgcaca gcaagcggcc gctgatcttc agacctggag gaggagatat 960
gagggacaat tggagaagtg aattatataa atataaagta gtaaaaattg aaccattagg 1020
agtagcaccc accaaggcaa agagaagagt ggtgcagaga gaaaaaagag cagtgggaat 1080
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 1140
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 1200
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 1260
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcctggggat 1320
ttggggttgc tctggaaaac tcatttgcac cactgctgtg ccttggaatg ctagttggag 1380
taataaatct ctggaacaga tttggaatca cacgacctgg atggagtggg acagagaaat 1440
taacaattac acaagcttaa tacactcctt aattgaagaa tcgcaaaacc agcaagaaaa 1500
gaatgaacaa gaattattgg aattagataa atgggcaagt ttgtggaatt ggtttaacat 1560
aacaaattgg ctgtggtata taaaattatt cataatgata gtaggaggct tggtaggttt 1620
aagaatagtt tttgctgtac tttctatagt gaatagagtt aggcagggat attcaccatt 1680
atcgtttcag acccacctcc caaccccgag gggacccgac aggcccgaag gaatagaaga 1740
agaaggtgga gagagagaca gagacagatc cattcgatta gtgaacggat ctcgacggta 1800
tcggttaact tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 1860
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaattcaa 1920
aattttatcg atgcctcccc gtcaccaccc cccccaaccc gccccgaccg gagctgagag 1980
taattcatac aaaaggactc gcccctgcct tggggaatcc cagggaccgt cgttaaactc 2040
ccactaacgt agaacccaga gatcgctgcg ttcccgcccc ctcacccgcc cgctctcgtc 2100
atcactgagg tggagaagag catgcgtgag gctccggtgc ccgtcagtgg gcagagcgca 2160
catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc ggtgcctaga 2220
gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc ctttttcccg 2280
agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt tttcgcaacg 2340
ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta 2400
cgggttatgg cccttgcgtg ccttgaatta cttccacgcc cctggctgca gtacgtgatt 2460
cttgatcccg agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga 2520
gccccttcgc ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga 2580
atctggtggc accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat 2640
ttttgatgat atcctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa 2700
gatctgcaca ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc 2760
cagcgcacat gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg 2820
tagtctcaag ctggccggcc tgctctggtg cctggcctcg cgccgccgtg tatcgccccg 2880
ccctgggcgg caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt 2940
cccggccctg ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt 3000
gagtcaccca cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc 3060
acggagtacc gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg 3120
tctttaggtt ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag 3180
actgaagtta ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag 3240
tttggatctt ggttcattct caagcctcag acagtggttc aaagtttttt tcttccattt 3300
caggtgtcgt gaaaactacc cctctagata atacgactca ctatagggcc cgggttggat 3360
ccgccgccac catgggacct cagctgctgg gatacgtggt gctgtgtctg cttggagccg 3420
gacctctgga agcccaagtg acacagaacc ccagatacct gatcaccgtg accggcaaga 3480
aactgaccgt gacctgcagc cagaacatga accacgagta catgagctgg tacagacagg 3540
accctggcct gggcctgaga cagatctact acagcatgaa cgtggaagtg accgacaagg 3600
gcgacgtgcc cgagggctac aaggtgtcca gaaaagagaa gcggaacttc ccactgatcc 3660
tggaaagccc atctcctaac cagaccagcc tgtacttctg cgccagctct cctcagggca 3720
gaatcaacag ccctctgcac ttcggcaacg gcaccagact gacagtgacc gaggacctga 3780
acaaggtgtt ccctccagag gtggccgtgt tcgagccttc taaggccgag attgcccaca 3840
cacagaaagc cacactcgtg tgcctggcca ccggcttttt tcccgatcac gtggaactgt 3900
cttggtgggt caacggcaaa gaggtgcaca gcggcgtctg taccgatcct cagcctctga 3960
aagagcagcc cgctctgaac gacagcagat actgcctgag cagcagactg agagtgtccg 4020
ccaccttctg gcagaaccct cggaaccact tcagatgcca ggtgcagttc tacggcctga 4080
gcgagaacga tgagtggacc caggatagag ccaagcctgt gactcagatc gtgtctgccg 4140
aagcctgggg cagagccgat tgtggaatta ccagcgccag ctaccatcag ggcgtgctgt 4200
ctgccacaat cctgtacgag atcctgctgg gcaaagccac tctgtacgcc gtgctggttt 4260
ctgctctggt gctgatggcc atggtcaagc ggaaggactt cagagccaag agatccggct 4320
ccggcgcacc ggtgaaacag actttgaatt ttgaccttct caagttggca ggagacgttg 4380
agtccaaccc tgggcccatg tggggagtgt tcctgctgta cgtgtccatg aagatgggcg 4440
gcaccaccgg ccagaacatc gatcagccta cagagatgac cgccaccgag ggcgccatcg 4500
tgcagatcaa ttgcacctac cagaccagcg gcttcaacgg cctgttctgg tatcagcagc 4560
atgccggcga ggcccctacc ttcctgagct acaatgtgct ggacggcctg gaagagaagg 4620
gcagattcag cagcttcctg tccagaagca agggctacag ctacctgctg ctgaaagaac 4680
tgcagatgaa ggacagcgcc tcctacctgt gcgccgtcag agatacaggc tacggccaga 4740
atttcgtgtt cggccctggc accagactga gcgtgctgcc ctatattcag aaccccgatc 4800
ctgccgtgta ccagctgaga gacagcaaga gcagcgacaa gagcgtgtgc ctgttcaccg 4860
acttcgacag ccagaccaac gtgtcccaga gcaaggactc cgacgtgtac atcaccgata 4920
agtgcgtgct ggacatgcgg agcatggact tcaagagcaa cagcgccgtg gcctggtcca 4980
acaagagcga tttcgcctgc gccaacgcct tcaacaacag cattatcccc gaggacacat 5040
tcttcccaag cagcgacgtg ccctgcgacg tgaagctggt ggaaaagagc ttcgagacag 5100
acaccaacct gaacttccag aacctgagcg tgatcggctt cagaatcctg ctgcttaagg 5160
tggccggctt caatctgctg atgaccctga gactgtggtc cagctaatga gtcgacaatc 5220
aacctctgga ttacaaaatt tgtgaaagat tgactggtat tcttaactat gttgctcctt 5280
ttacgctatg tggatacgct gctttaatgc ctttgtatca tgctattgct tcccgtatgg 5340
ctttcatttt ctcctccttg tataaatcct ggttgctgtc tctttatgag gagttgtggc 5400
ccgttgtcag gcaacgtggc gtggtgtgca ctgtgtttgc tgacgcaacc cccactggtt 5460
ggggcattgc caccacctgt cagctccttt ccgggacttt cgctttcccc ctccctattg 5520
ccacggcgga actcatcgcc gcctgccttg cccgctgctg gacaggggct cggctgttgg 5580
gcactgacaa ttccgtggtg ttgtcgggga agctgacgtc ctttccatgg ctgctcgcct 5640
gtgttgccac ctggattctg cgcgggacgt ccttctgcta cgtcccttcg gccctcaatc 5700
cagcggacct tccttcccgc ggcctgctgc cggctctgcg gcctcttccg cgtcttcgcc 5760
ttcgccctca gacgagtcgg atctcccttt gggccgcctc cccgcctgga attcgagctc 5820
ggtaccttta agaccaatga cttacaaggc agctgtagat cttagccact ttttaaaaga 5880
aaagggggga ctggaagggc taattcactc ccaacgaaga caagatctgc tttttgcttg 5940
tactgggtct ctctggttag accagatctg agcctgggag ctctctggct aactagggaa 6000
cccactgctt aagcctcaat aaagcttgcc ttgagtgctt caagtagtgt gtgcccgtct 6060
gttgtgtgac tctggtaact agagatccct cagacccttt tagtcagtgt ggaaaatctc 6120
tagcagtagt agttcatgtc atcttattat tcagtattta taacttgcaa agaaatgaat 6180
atcagagagt gagaggaact tgtttattgc agcttataat ggttacaaat aaagcaatag 6240
catcacaaat ttcacaaata aagcattttt ttcactgcat tctagttgtg gtttgtccaa 6300
actcatcaat gtatcttatc atgtctggct ctagctatcc cgcccctaac tccgcccatc 6360
ccgcccctaa ctccgcccag ttccgcccat tctccgcccc atggctgact aatttttttt 6420
atttatgcag aggccgaggc cgcctcggcc tctgagctat tccagaagta gtgaggaggc 6480
ttttttggag gcctagggac gtacccaatt cgccctatag tgagtcgtat tacgcgcgct 6540
cactggccgt cgttttacaa cgtcgtgact gggaaaaccc tggcgttacc caacttaatc 6600
gccttgcagc acatccccct ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc 6660
gcccttccca acagttgcgc agcctgaatg gcgaatggga cgcgccctgt agcggcgcat 6720
taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag 6780
cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc 6840
aagctctaaa tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc 6900
ccaaaaaact tgattagggt gatggttcac gtagtgggcc atcgccctga tagacggttt 6960
ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa 7020
caacactcaa ccctatctcg gtctattctt ttgatttata agggattttg ccgatttcgg 7080
cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat 7140
taacgcttac aatttaggtg gcacttttcg gggaaatgtg cgcggaaccc ctatttgttt 7200
atttttctaa atacattcaa atatgtatcc gctcatgaga caataaccct gataaatgct 7260
tcaataatat tgaaaaagga agagtatgag tattcaacat ttccgtgtcg cccttattcc 7320
cttttttgcg gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg tgaaagtaaa 7380
agatgctgaa gatcagttgg gtgcacgagt gggttacatc gaactggatc tcaacagcgg 7440
taagatcctt gagagttttc gccccgaaga acgttttcca atgatgagca cttttaaagt 7500
tctgctatgt ggcgcggtat tatcccgtat tgacgccggg caagagcaac tcggtcgccg 7560
catacactat tctcagaatg acttggttga gtactcacca gtcacagaaa agcatcttac 7620
ggatggcatg acagtaagag aattatgcag tgctgccata accatgagtg ataacactgc 7680
ggccaactta cttctgacaa cgatcggagg accgaaggag ctaaccgctt ttttgcacaa 7740
catgggggat catgtaactc gccttgatcg ttgggaaccg gagctgaatg aagccatacc 7800
aaacgacgag cgtgacacca cgatgcctgt agcaatggca acaacgttgc gcaaactatt 7860
aactggcgaa ctacttactc tagcttcccg gcaacaatta atagactgga tggaggcgga 7920
taaagttgca ggaccacttc tgcgctcggc ccttccggct ggctggttta ttgctgataa 7980
atctggagcc ggtgagcgtg ggtctcgcgg tatcattgca gcactggggc cagatggtaa 8040
gccctcccgt atcgtagtta tctacacgac ggggagtcag gcaactatgg atgaacgaaa 8100
tagacagatc gctgagatag gtgcctcact gattaagcat tggtaactgt cagaccaagt 8160
ttactcatat atactttaga ttgatttaaa acttcatttt taatttaaaa ggatctaggt 8220
gaagatcctt tttgataatc tcatgaccaa aatcccttaa cgtgagtttt cgttccactg 8280
agcgtcagac cccgtagaaa agatcaaagg atcttcttga gatccttttt ttctgcgcgt 8340
aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg gtggtttgtt tgccggatca 8400
agagctacca actctttttc cgaaggtaac tggcttcagc agagcgcaga taccaaatac 8460
tgttcttcta gtgtagccgt agttaggcca ccacttcaag aactctgtag caccgcctac 8520
atacctcgct ctgctaatcc tgttaccagt ggctgctgcc agtggcgata agtcgtgtct 8580
taccgggttg gactcaagac gatagttacc ggataaggcg cagcggtcgg gctgaacggg 8640
gggttcgtgc acacagccca gcttggagcg aacgacctac accgaactga gatacctaca 8700
gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga aaggcggaca ggtatccggt 8760
aagcggcagg gtcggaacag gagagcgcac gagggagctt ccagggggaa acgcctggta 8820
tctttatagt cctgtcgggt ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc 8880
gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc 8940
cttttgctgg ccttttgctc acatgttctt tcctgcgtta tcccctgatt ctgtggataa 9000
ccgtattacc gcctttgagt gagctgatac cgctcgccgc agccgaacga ccgagcgcag 9060
cgagtcagtg agcgaggaag cggaagagcg cccaatacgc aaaccgcctc tccccgcgcg 9120
ttggccgatt cattaatgca gctggcacga caggtttccc gactggaaag cgggcagtga 9180
gcgcaacgca attaatgtga gttagctcac tcattaggca ccccaggctt tacactttat 9240
gcttccggct cgtatgttgt gtggaattgt gagcggataa caatttcaca caggaaacag 9300
ctatgaccat gattacgcca agcgcgcaat taaccctcac taaagggaac aaaagctgga 9360
gctgc 9365
<210> 57
<211> 9386
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多核苷酸
<400> 57
aagcttaatg tagtcttatg caatactctt gtagtcttgc aacatggtaa cgatgagtta 60
gcaacatgcc ttacaaggag agaaaaagca ccgtgcatgc cgattggtgg aagtaaggtg 120
gtacgatcgt gccttattag gaaggcaaca gacgggtctg acatggattg gacgaaccac 180
tgaattgccg cattgcagag atattgtatt taagtgccta gctcgataca taaacgggtc 240
tctctggtta gaccagatct gagcctggga gctctctggc taactaggga acccactgct 300
taagcctcaa taaagcttgc cttgagtgct tcaagtagtg tgtgcccgtc tgttgtgtga 360
ctctggtaac tagagatccc tcagaccctt ttagtcagtg tggaaaatct ctagcagtgg 420
cgcccgaaca gggacttgaa agcgaaaggg aaaccagagg agctctctcg acgcaggact 480
cggcttgctg aagcgcgcac ggcaagaggc gaggggcggc gactggtgag tacgccaaaa 540
attttgacta gcggaggcta gaaggagaga gatgggtgcg agagcgtcag tattaagcgg 600
gggagaatta gatcgcgatg ggaaaaaatt cggttaaggc cagggggaaa gaaaaaatat 660
aaattaaaac atatagtatg ggcaagcagg gagctagaac gattcgcagt taatcctggc 720
ctgttagaaa catcagaagg ctgtagacaa atactgggac agctacaacc atcccttcag 780
acaggatcag aagaacttag atcattatat aatacagtag caaccctcta ttgtgtgcat 840
caaaggatag agataaaaga caccaaggaa gctttagaca agatagagga agagcaaaac 900
aaaagtaaga ccaccgcaca gcaagcggcc gctgatcttc agacctggag gaggagatat 960
gagggacaat tggagaagtg aattatataa atataaagta gtaaaaattg aaccattagg 1020
agtagcaccc accaaggcaa agagaagagt ggtgcagaga gaaaaaagag cagtgggaat 1080
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 1140
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 1200
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 1260
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcctggggat 1320
ttggggttgc tctggaaaac tcatttgcac cactgctgtg ccttggaatg ctagttggag 1380
taataaatct ctggaacaga tttggaatca cacgacctgg atggagtggg acagagaaat 1440
taacaattac acaagcttaa tacactcctt aattgaagaa tcgcaaaacc agcaagaaaa 1500
gaatgaacaa gaattattgg aattagataa atgggcaagt ttgtggaatt ggtttaacat 1560
aacaaattgg ctgtggtata taaaattatt cataatgata gtaggaggct tggtaggttt 1620
aagaatagtt tttgctgtac tttctatagt gaatagagtt aggcagggat attcaccatt 1680
atcgtttcag acccacctcc caaccccgag gggacccgac aggcccgaag gaatagaaga 1740
agaaggtgga gagagagaca gagacagatc cattcgatta gtgaacggat ctcgacggta 1800
tcggttaact tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 1860
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaattcaa 1920
aattttatcg atgcctcccc gtcaccaccc cccccaaccc gccccgaccg gagctgagag 1980
taattcatac aaaaggactc gcccctgcct tggggaatcc cagggaccgt cgttaaactc 2040
ccactaacgt agaacccaga gatcgctgcg ttcccgcccc ctcacccgcc cgctctcgtc 2100
atcactgagg tggagaagag catgcgtgag gctccggtgc ccgtcagtgg gcagagcgca 2160
catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc ggtgcctaga 2220
gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc ctttttcccg 2280
agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt tttcgcaacg 2340
ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta 2400
cgggttatgg cccttgcgtg ccttgaatta cttccacgcc cctggctgca gtacgtgatt 2460
cttgatcccg agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga 2520
gccccttcgc ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga 2580
atctggtggc accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat 2640
ttttgatgat atcctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa 2700
gatctgcaca ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc 2760
cagcgcacat gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg 2820
tagtctcaag ctggccggcc tgctctggtg cctggcctcg cgccgccgtg tatcgccccg 2880
ccctgggcgg caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt 2940
cccggccctg ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt 3000
gagtcaccca cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc 3060
acggagtacc gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg 3120
tctttaggtt ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag 3180
actgaagtta ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag 3240
tttggatctt ggttcattct caagcctcag acagtggttc aaagtttttt tcttccattt 3300
caggtgtcgt gaaaactacc cctctagata atacgactca ctatagggcc cgggttggat 3360
ccgccgccac catgaccatc cggctgctgt gctatatggg cttctacttc ctcggagccg 3420
gcctgatgga agccgacatc taccagacac ctagatacct ggtcatcggc accggcaaga 3480
aaatcaccct ggaatgcagc cagaccatgg gccacgacaa gatgtactgg tatcagcagg 3540
accccggcat ggaactgcac ctgatccact acagctacgg cgtgaacagc accgagaagg 3600
gcgatctgtc tagcgagagc accgtgtcca gaatccggac cgagcacttc ccactgacac 3660
tggaaagcgc tagacccagc cacaccagcc agtacctgtg tgcctcttct ggacctggac 3720
agggccacaa tcagcctcag cactttggcg acggcaccag actgagcatc ctggaagatc 3780
tgaacaaggt gttccctcca gaggtggccg tgttcgagcc ttctaaggcc gagattgccc 3840
acacacagaa agccacactc gtgtgcctgg ccaccggctt ttttcccgat cacgtggaac 3900
tgtcttggtg ggtcaacggc aaagaggtgc acagcggcgt ctgtaccgat cctcagcctc 3960
tgaaagagca gcccgctctg aacgacagca gatactgcct gagcagcaga ctgagagtgt 4020
ccgccacctt ctggcagaac cccagaaacc acttcagatg ccaggttcag ttctacggcc 4080
tgagcgagaa cgacgagtgg acccaggata gagccaagcc tgtgacacag atcgtgtctg 4140
ccgaagcctg gggcagagcc gattgtggaa ttaccagcgc cagctaccat cagggcgtgc 4200
tgtctgccac aatcctgtac gagatcctgc tgggcaaagc cactctgtac gccgtgctgg 4260
tgtctgccct ggtgctgatg gccatggtca agcggaagga cttcagagcc aagagatccg 4320
gctccggcgc accggtgaaa cagactttga attttgacct tctcaagttg gcaggagacg 4380
ttgagtccaa ccctgggccc atgctgacag cctctctgct gagagccgtg atcgccagca 4440
tctgtgtggt gtctagcatg gcccagaaag tgacacaggc ccagaccgag atcagcgtgg 4500
tggaaaaaga agatgtgacc ctggactgcg tgtacgagac acgggacacc acctactacc 4560
tgttctggta caagcagcct cctagcggcg agctggtgtt cctgatcaga cggaacagct 4620
tcgacgagca gaacgagatc tccggccggt acagctggaa cttccagaag tccaccagca 4680
gcttcaactt caccatcacc gccagccagg tggtggatag cgccgtgtat ttttgtgccc 4740
tgggcagcag cggcacctac aagtacatct ttggcaccgg caccagactg aaggtgctgg 4800
ccaacattca gaaccccgat cctgccgtgt accagctgag agacagcaag agcagcgaca 4860
agagcgtgtg cctgttcacc gacttcgaca gccagaccaa cgtgtcccag agcaaggaca 4920
gcgacgtgta catcaccgat aagtgcgtgc tggacatgcg gagcatggac ttcaagagca 4980
acagcgccgt ggcctggtcc aacaagagcg atttcgcctg cgccaacgcc ttcaacaaca 5040
gcattatccc cgaggacaca ttcttcccca gctccgatgt gccctgcgac gtgaagctgg 5100
tcgagaagtc cttcgagaca gacaccaacc tgaatttcca gaacctgagc gtgatcggct 5160
tcagaatcct gctgctgaaa gtggccggct tcaacctgct gatgaccctg agactctggt 5220
ccagctaatg agtcgacaat caacctctgg attacaaaat ttgtgaaaga ttgactggta 5280
ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc 5340
atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt 5400
ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg 5460
ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt 5520
tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct 5580
ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg aagctgacgt 5640
cctttccatg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg tccttctgct 5700
acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc 5760
ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct 5820
ccccgcctgg aattcgagct cggtaccttt aagaccaatg acttacaagg cagctgtaga 5880
tcttagccac tttttaaaag aaaagggggg actggaaggg ctaattcact cccaacgaag 5940
acaagatctg ctttttgctt gtactgggtc tctctggtta gaccagatct gagcctggga 6000
gctctctggc taactaggga acccactgct taagcctcaa taaagcttgc cttgagtgct 6060
tcaagtagtg tgtgcccgtc tgttgtgtga ctctggtaac tagagatccc tcagaccctt 6120
ttagtcagtg tggaaaatct ctagcagtag tagttcatgt catcttatta ttcagtattt 6180
ataacttgca aagaaatgaa tatcagagag tgagaggaac ttgtttattg cagcttataa 6240
tggttacaaa taaagcaata gcatcacaaa tttcacaaat aaagcatttt tttcactgca 6300
ttctagttgt ggtttgtcca aactcatcaa tgtatcttat catgtctggc tctagctatc 6360
ccgcccctaa ctccgcccat cccgccccta actccgccca gttccgccca ttctccgccc 6420
catggctgac taattttttt tatttatgca gaggccgagg ccgcctcggc ctctgagcta 6480
ttccagaagt agtgaggagg cttttttgga ggcctaggga cgtacccaat tcgccctata 6540
gtgagtcgta ttacgcgcgc tcactggccg tcgttttaca acgtcgtgac tgggaaaacc 6600
ctggcgttac ccaacttaat cgccttgcag cacatccccc tttcgccagc tggcgtaata 6660
gcgaagaggc ccgcaccgat cgcccttccc aacagttgcg cagcctgaat ggcgaatggg 6720
acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt ggttacgcgc agcgtgaccg 6780
ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt cttcccttcc tttctcgcca 6840
cgttcgccgg ctttccccgt caagctctaa atcgggggct ccctttaggg ttccgattta 6900
gtgctttacg gcacctcgac cccaaaaaac ttgattaggg tgatggttca cgtagtgggc 6960
catcgccctg atagacggtt tttcgccctt tgacgttgga gtccacgttc tttaatagtg 7020
gactcttgtt ccaaactgga acaacactca accctatctc ggtctattct tttgatttat 7080
aagggatttt gccgatttcg gcctattggt taaaaaatga gctgatttaa caaaaattta 7140
acgcgaattt taacaaaata ttaacgctta caatttaggt ggcacttttc ggggaaatgt 7200
gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag 7260
acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca 7320
tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc 7380
agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat 7440
cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc 7500
aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgta ttgacgccgg 7560
gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc 7620
agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat 7680
aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga 7740
gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc 7800
ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg tagcaatggc 7860
aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc ggcaacaatt 7920
aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg cccttccggc 7980
tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg gtatcattgc 8040
agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga cggggagtca 8100
ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac tgattaagca 8160
ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa aacttcattt 8220
ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca aaatccctta 8280
acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag gatcttcttg 8340
agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac cgctaccagc 8400
ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag 8460
cagagcgcag ataccaaata ctgttcttct agtgtagccg tagttaggcc accacttcaa 8520
gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag tggctgctgc 8580
cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac cggataaggc 8640
gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc gaacgaccta 8700
caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag 8760
aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca cgagggagct 8820
tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc tctgacttga 8880
gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc 8940
ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct ttcctgcgtt 9000
atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata ccgctcgccg 9060
cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc gcccaatacg 9120
caaaccgcct ctccccgcgc gttggccgat tcattaatgc agctggcacg acaggtttcc 9180
cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg agttagctca ctcattaggc 9240
accccaggct ttacacttta tgcttccggc tcgtatgttg tgtggaattg tgagcggata 9300
acaatttcac acaggaaaca gctatgacca tgattacgcc aagcgcgcaa ttaaccctca 9360
ctaaagggaa caaaagctgg agctgc 9386
<210> 58
<211> 9407
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多核苷酸
<400> 58
aagcttaatg tagtcttatg caatactctt gtagtcttgc aacatggtaa cgatgagtta 60
gcaacatgcc ttacaaggag agaaaaagca ccgtgcatgc cgattggtgg aagtaaggtg 120
gtacgatcgt gccttattag gaaggcaaca gacgggtctg acatggattg gacgaaccac 180
tgaattgccg cattgcagag atattgtatt taagtgccta gctcgataca taaacgggtc 240
tctctggtta gaccagatct gagcctggga gctctctggc taactaggga acccactgct 300
taagcctcaa taaagcttgc cttgagtgct tcaagtagtg tgtgcccgtc tgttgtgtga 360
ctctggtaac tagagatccc tcagaccctt ttagtcagtg tggaaaatct ctagcagtgg 420
cgcccgaaca gggacttgaa agcgaaaggg aaaccagagg agctctctcg acgcaggact 480
cggcttgctg aagcgcgcac ggcaagaggc gaggggcggc gactggtgag tacgccaaaa 540
attttgacta gcggaggcta gaaggagaga gatgggtgcg agagcgtcag tattaagcgg 600
gggagaatta gatcgcgatg ggaaaaaatt cggttaaggc cagggggaaa gaaaaaatat 660
aaattaaaac atatagtatg ggcaagcagg gagctagaac gattcgcagt taatcctggc 720
ctgttagaaa catcagaagg ctgtagacaa atactgggac agctacaacc atcccttcag 780
acaggatcag aagaacttag atcattatat aatacagtag caaccctcta ttgtgtgcat 840
caaaggatag agataaaaga caccaaggaa gctttagaca agatagagga agagcaaaac 900
aaaagtaaga ccaccgcaca gcaagcggcc gctgatcttc agacctggag gaggagatat 960
gagggacaat tggagaagtg aattatataa atataaagta gtaaaaattg aaccattagg 1020
agtagcaccc accaaggcaa agagaagagt ggtgcagaga gaaaaaagag cagtgggaat 1080
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 1140
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 1200
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 1260
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcctggggat 1320
ttggggttgc tctggaaaac tcatttgcac cactgctgtg ccttggaatg ctagttggag 1380
taataaatct ctggaacaga tttggaatca cacgacctgg atggagtggg acagagaaat 1440
taacaattac acaagcttaa tacactcctt aattgaagaa tcgcaaaacc agcaagaaaa 1500
gaatgaacaa gaattattgg aattagataa atgggcaagt ttgtggaatt ggtttaacat 1560
aacaaattgg ctgtggtata taaaattatt cataatgata gtaggaggct tggtaggttt 1620
aagaatagtt tttgctgtac tttctatagt gaatagagtt aggcagggat attcaccatt 1680
atcgtttcag acccacctcc caaccccgag gggacccgac aggcccgaag gaatagaaga 1740
agaaggtgga gagagagaca gagacagatc cattcgatta gtgaacggat ctcgacggta 1800
tcggttaact tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 1860
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaattcaa 1920
aattttatcg atgcctcccc gtcaccaccc cccccaaccc gccccgaccg gagctgagag 1980
taattcatac aaaaggactc gcccctgcct tggggaatcc cagggaccgt cgttaaactc 2040
ccactaacgt agaacccaga gatcgctgcg ttcccgcccc ctcacccgcc cgctctcgtc 2100
atcactgagg tggagaagag catgcgtgag gctccggtgc ccgtcagtgg gcagagcgca 2160
catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc ggtgcctaga 2220
gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc ctttttcccg 2280
agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt tttcgcaacg 2340
ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta 2400
cgggttatgg cccttgcgtg ccttgaatta cttccacgcc cctggctgca gtacgtgatt 2460
cttgatcccg agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga 2520
gccccttcgc ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga 2580
atctggtggc accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat 2640
ttttgatgat atcctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa 2700
gatctgcaca ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc 2760
cagcgcacat gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg 2820
tagtctcaag ctggccggcc tgctctggtg cctggcctcg cgccgccgtg tatcgccccg 2880
ccctgggcgg caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt 2940
cccggccctg ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt 3000
gagtcaccca cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc 3060
acggagtacc gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg 3120
tctttaggtt ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag 3180
actgaagtta ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag 3240
tttggatctt ggttcattct caagcctcag acagtggttc aaagtttttt tcttccattt 3300
caggtgtcgt gaaaactacc cctctagata atacgactca ctatagggcc cgggttggat 3360
ccgccgccac catgctgctg ctcctgctgc ttctcggccc tggaatttct ctgctgctgc 3420
ctggatctct ggccggctct ggacttggag ctgtggtgtc tcagcacccc tcttgggtca 3480
tctgcaagag cggcaccagc gtgaagatcg agtgcagaag cctggacttc caggccacca 3540
ccatgttctg gtacagacag ttccccaagc agagcctgat gctgatggcc acctctaacg 3600
agggctgcaa ggccacatat gagcagggcg tcgagaagga caagttcctg atcaaccacg 3660
ccagcctgac actgagcacc ctgacagtga caagcgccca tcctgaggac agcagcttct 3720
acatctgtag cacagccggc gagacagaca cccagtattt tggccctggc accagactga 3780
ccgtgctgga agatctgaag aacgtgttcc cacctgaggt ggccgtgttc gagccttcta 3840
aggccgagat tgcccacaca cagaaagcca cactcgtgtg tctggccacc ggcttctatc 3900
ccgatcacgt cgaactgtct tggtgggtca acggcaaaga ggtgcacagc ggcgtctgta 3960
ccgatcctca gcctctgaaa gagcagcccg ctctgaacga cagcagatac tgcctgagca 4020
gcagactgag agtgtccgcc accttctggc agaaccccag aaaccacttc agatgccagg 4080
tgcagttcta cggcctgagc gagaacgatg agtggaccca ggatagagcc aagcctgtga 4140
cacagatcgt gtctgccgaa gcctggggca gagccgattg tggaattacc agcgccagct 4200
accatcaggg cgtgctgtct gccacaatcc tgtacgagat cctgctgggc aaagccactc 4260
tgtacgccgt gctggtgtct gccctggtcc tgatggctat ggtcaagaga aaggacagcc 4320
ggggcagagc caagagatcc ggctccggcg caccggtgaa acagactttg aattttgacc 4380
ttctcaagtt ggcaggagac gttgagtcca accctgggcc catggccgga atcagagccc 4440
tgttcatgta cctgtggctg cagctggact gggtgtccag aggcgaatct gtgggactgc 4500
atctgcccac actgagcgtg caagagggcg acaacagcat catcaactgc gcctacagca 4560
acagcgccag cgactacttc atctggtaca agcaagagag cggcaagggc cctcagttca 4620
tcatcgacat ccggtccaac atggacaagc ggcaaggcca gagagtgacc gtcctgctga 4680
acaagaccgt gaagcacctg agcctgcaga tcgccgctac acagcctggc gatagcgccg 4740
tgtacttctg tgccgaaaca ctgggcctcg accaaggcgg caagctgatc tttggacagg 4800
gcacagagct gagcgtgaag cccaacattc agaaccccga tcctgccgtg taccagctga 4860
gagacagcaa gtccagcgac aagagcgtgt gcctgttcac cgacttcgac agccagacca 4920
acgtgtccca gagcaaggac agcgacgtgt acatcaccga taagtgcgtg ctggacatgc 4980
ggagcatgga cttcaagagc aactccgccg tggcctggtc caacaagagc gatttcgcct 5040
gcgccaacgc cttcaacaac tctattatcc ccgaggacac attcttcccc agctccgatg 5100
tgccctgcga cgtgaagctg gtggaaaaga gcttcgagac agacaccaac ctgaacttcc 5160
agaacctgtc cgtgatcggc ttccgcatcc tgctgctgaa agtggccggc ttcaacctgc 5220
tgatgaccct gagactgtgg tccagctaat gagtcgacaa tcaacctctg gattacaaaa 5280
tttgtgaaag attgactggt attcttaact atgttgctcc ttttacgcta tgtggatacg 5340
ctgctttaat gcctttgtat catgctattg cttcccgtat ggctttcatt ttctcctcct 5400
tgtataaatc ctggttgctg tctctttatg aggagttgtg gcccgttgtc aggcaacgtg 5460
gcgtggtgtg cactgtgttt gctgacgcaa cccccactgg ttggggcatt gccaccacct 5520
gtcagctcct ttccgggact ttcgctttcc ccctccctat tgccacggcg gaactcatcg 5580
ccgcctgcct tgcccgctgc tggacagggg ctcggctgtt gggcactgac aattccgtgg 5640
tgttgtcggg gaagctgacg tcctttccat ggctgctcgc ctgtgttgcc acctggattc 5700
tgcgcgggac gtccttctgc tacgtccctt cggccctcaa tccagcggac cttccttccc 5760
gcggcctgct gccggctctg cggcctcttc cgcgtcttcg ccttcgccct cagacgagtc 5820
ggatctccct ttgggccgcc tccccgcctg gaattcgagc tcggtacctt taagaccaat 5880
gacttacaag gcagctgtag atcttagcca ctttttaaaa gaaaaggggg gactggaagg 5940
gctaattcac tcccaacgaa gacaagatct gctttttgct tgtactgggt ctctctggtt 6000
agaccagatc tgagcctggg agctctctgg ctaactaggg aacccactgc ttaagcctca 6060
ataaagcttg ccttgagtgc ttcaagtagt gtgtgcccgt ctgttgtgtg actctggtaa 6120
ctagagatcc ctcagaccct tttagtcagt gtggaaaatc tctagcagta gtagttcatg 6180
tcatcttatt attcagtatt tataacttgc aaagaaatga atatcagaga gtgagaggaa 6240
cttgtttatt gcagcttata atggttacaa ataaagcaat agcatcacaa atttcacaaa 6300
taaagcattt ttttcactgc attctagttg tggtttgtcc aaactcatca atgtatctta 6360
tcatgtctgg ctctagctat cccgccccta actccgccca tcccgcccct aactccgccc 6420
agttccgccc attctccgcc ccatggctga ctaatttttt ttatttatgc agaggccgag 6480
gccgcctcgg cctctgagct attccagaag tagtgaggag gcttttttgg aggcctaggg 6540
acgtacccaa ttcgccctat agtgagtcgt attacgcgcg ctcactggcc gtcgttttac 6600
aacgtcgtga ctgggaaaac cctggcgtta cccaacttaa tcgccttgca gcacatcccc 6660
ctttcgccag ctggcgtaat agcgaagagg cccgcaccga tcgcccttcc caacagttgc 6720
gcagcctgaa tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg 6780
tggttacgcg cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt 6840
tcttcccttc ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc 6900
tccctttagg gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg 6960
gtgatggttc acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg 7020
agtccacgtt ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct 7080
cggtctattc ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg 7140
agctgattta acaaaaattt aacgcgaatt ttaacaaaat attaacgctt acaatttagg 7200
tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc 7260
aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag 7320
gaagagtatg agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg 7380
ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt 7440
gggtgcacga gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt 7500
tcgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt 7560
attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa 7620
tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag 7680
agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac 7740
aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac 7800
tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac 7860
cacgatgcct gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac 7920
tctagcttcc cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact 7980
tctgcgctcg gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg 8040
tgggtctcgc ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt 8100
tatctacacg acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat 8160
aggtgcctca ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta 8220
gattgattta aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa 8280
tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga 8340
aaagatcaaa ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac 8400
aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt 8460
tccgaaggta actggcttca gcagagcgca gataccaaat actgttcttc tagtgtagcc 8520
gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat 8580
cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag 8640
acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc 8700
cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag 8760
cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac 8820
aggagagcgc acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg 8880
gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct 8940
atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc 9000
tcacatgttc tttcctgcgt tatcccctga ttctgtggat aaccgtatta ccgcctttga 9060
gtgagctgat accgctcgcc gcagccgaac gaccgagcgc agcgagtcag tgagcgagga 9120
agcggaagag cgcccaatac gcaaaccgcc tctccccgcg cgttggccga ttcattaatg 9180
cagctggcac gacaggtttc ccgactggaa agcgggcagt gagcgcaacg caattaatgt 9240
gagttagctc actcattagg caccccaggc tttacacttt atgcttccgg ctcgtatgtt 9300
gtgtggaatt gtgagcggat aacaatttca cacaggaaac agctatgacc atgattacgc 9360
caagcgcgca attaaccctc actaaaggga acaaaagctg gagctgc 9407
<210> 59
<211> 295
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 59
Glu Pro Glu Val Thr Gln Thr Pro Ser His Gln Val Thr Gln Met Gly
1 5 10 15
Gln Glu Val Ile Leu Arg Cys Val Pro Ile Ser Asn His Leu Tyr Phe
20 25 30
Tyr Trp Tyr Arg Gln Ile Leu Gly Gln Lys Val Glu Phe Leu Val Ser
35 40 45
Phe Tyr Asn Asn Glu Ile Ser Glu Lys Ser Glu Ile Phe Asp Asp Gln
50 55 60
Phe Ser Val Glu Arg Pro Asp Gly Ser Asn Phe Thr Leu Lys Ile Arg
65 70 75 80
Ser Thr Lys Leu Glu Asp Ser Ala Met Tyr Phe Cys Ala Ser Arg Ala
85 90 95
Ser Val Gly Val Gly Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg
100 105 110
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
115 120 125
Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala Thr
130 135 140
Leu Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser
145 150 155 160
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
165 170 175
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
180 185 190
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
195 200 205
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
210 215 220
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
225 230 235 240
Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln
245 250 255
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
260 265 270
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
275 280 285
Lys Arg Lys Asp Ser Arg Gly
290 295
<210> 60
<211> 256
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 60
Ala Gln Thr Val Thr Gln Ser Gln Pro Glu Met Ser Val Gln Glu Ala
1 5 10 15
Glu Thr Val Thr Leu Ser Cys Thr Tyr Asp Thr Ser Glu Ser Asn Tyr
20 25 30
Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Arg Gln Met Ile Leu Val
35 40 45
Ile Arg Gln Glu Ala Tyr Lys Gln Gln Asn Ala Thr Glu Asn Arg Phe
50 55 60
Ser Val Asn Phe Gln Lys Ala Ala Lys Ser Phe Ser Leu Lys Ile Ser
65 70 75 80
Asp Ser Gln Leu Gly Asp Thr Ala Met Tyr Phe Cys Ala Phe Thr Tyr
85 90 95
Gly Gly Ser Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser
100 105 110
Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg
115 120 125
Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp
130 135 140
Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr
145 150 155 160
Asp Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser
165 170 175
Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe
180 185 190
Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val
195 200 205
Pro Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn
210 215 220
Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu
225 230 235 240
Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
245 250 255
<210> 61
<211> 291
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 61
Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Thr Lys Arg Gly Gln Asp
1 5 10 15
Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His Val Ser Leu Tyr Trp
20 25 30
Tyr Arg Gln Ala Leu Gly Gln Gly Pro Glu Phe Leu Thr Tyr Phe Asn
35 40 45
Tyr Glu Ala Gln Gln Asp Lys Ser Gly Leu Pro Asn Asp Arg Phe Ser
50 55 60
Ala Glu Arg Pro Glu Gly Ser Ile Ser Thr Leu Thr Ile Gln Arg Thr
65 70 75 80
Glu Gln Arg Asp Ser Ala Met Tyr Arg Cys Ala Ser Ser Pro Glu Leu
85 90 95
Ala Gly Pro Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu
100 105 110
Val Leu Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe
115 120 125
Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala Thr Leu Val
130 135 140
Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
145 150 155 160
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro
165 170 175
Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser
180 185 190
Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe
195 200 205
Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr
210 215 220
Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp
225 230 235 240
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val
245 250 255
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
260 265 270
Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg
275 280 285
Lys Asp Phe
290
<210> 62
<211> 257
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 62
Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser Val Val Glu Lys
1 5 10 15
Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg Asp Thr Thr Tyr
20 25 30
Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu Leu Val Phe Leu
35 40 45
Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile Ser Gly Arg Tyr
50 55 60
Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn Phe Thr Ile Thr
65 70 75 80
Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser Glu
85 90 95
Gly Gly Gly Ser Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu
100 105 110
Ser Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu
115 120 125
Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe
130 135 140
Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile
145 150 155 160
Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn
165 170 175
Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala
180 185 190
Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp
195 200 205
Val Pro Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr
210 215 220
Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu
225 230 235 240
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
245 250 255
Ser
<210> 63
<211> 311
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 63
Met Thr Ile Arg Leu Leu Cys Tyr Met Gly Phe Tyr Phe Leu Gly Ala
1 5 10 15
Gly Leu Met Glu Ala Asp Ile Tyr Gln Thr Pro Arg Tyr Leu Val Ile
20 25 30
Gly Thr Gly Lys Lys Ile Thr Leu Glu Cys Ser Gln Thr Met Gly His
35 40 45
Asp Lys Met Tyr Trp Tyr Gln Gln Asp Pro Gly Met Glu Leu His Leu
50 55 60
Ile His Tyr Ser Tyr Gly Val Asn Ser Thr Glu Lys Gly Asp Leu Ser
65 70 75 80
Ser Glu Ser Thr Val Ser Arg Ile Arg Thr Glu His Phe Pro Leu Thr
85 90 95
Leu Glu Ser Ala Arg Pro Ser His Thr Ser Gln Tyr Leu Cys Ala Ser
100 105 110
Ser Gly Pro Gly Gln Gly His Asn Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu Glu Asp Leu Asn Lys Val Phe Pro Pro Glu
130 135 140
Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr
195 200 205
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro
210 215 220
Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn
225 230 235 240
Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser
245 250 255
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
260 265 270
His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
275 280 285
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala
290 295 300
Met Val Lys Arg Lys Asp Phe
305 310
<210> 64
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 64
Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser Val Val Glu Lys Glu
1 5 10 15
Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg Asp Thr Thr Tyr Tyr
20 25 30
Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu Leu Val Phe Leu Ile
35 40 45
Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile Ser Gly Arg Tyr Ser
50 55 60
Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn Phe Thr Ile Thr Ala
65 70 75 80
Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys Ala Leu Gly Ser Ser
85 90 95
Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys Val Leu
100 105 110
Ala Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
115 120 125
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
130 135 140
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
145 150 155 160
Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
165 170 175
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
180 185 190
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys
195 200 205
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
210 215 220
Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val
225 230 235 240
Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
245 250
<210> 65
<211> 289
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 65
Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly Lys Lys
1 5 10 15
Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met Ser Trp
20 25 30
Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr Ser Met
35 40 45
Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr Lys Val
50 55 60
Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser Pro Ser
65 70 75 80
Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Pro Gln Gly Arg
85 90 95
Ile Asn Ser Pro Leu His Phe Gly Asn Gly Thr Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
115 120 125
Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala Thr Leu Val Cys Leu
130 135 140
Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
145 150 155 160
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys
165 170 175
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
180 185 190
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
195 200 205
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
210 215 220
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
225 230 235 240
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser
245 250 255
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
260 265 270
Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
275 280 285
Phe
<210> 66
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 66
Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly Ala Ile
1 5 10 15
Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly Leu Phe
20 25 30
Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser Tyr Asn
35 40 45
Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe Leu Ser
50 55 60
Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln Met Lys
65 70 75 80
Asp Ser Ala Ser Tyr Leu Cys Ala Val Arg Asp Thr Gly Tyr Gly Gln
85 90 95
Asn Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu Pro Tyr Ile
100 105 110
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
115 120 125
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
130 135 140
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu
145 150 155 160
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
165 170 175
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
180 185 190
Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys Asp Val Lys
195 200 205
Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn
210 215 220
Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
225 230 235 240
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
245 250
<210> 67
<211> 296
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 67
Gly Ser Gly Leu Gly Ala Val Val Ser Gln His Pro Ser Trp Val Ile
1 5 10 15
Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe
20 25 30
Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu
35 40 45
Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln
50 55 60
Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu
65 70 75 80
Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr
85 90 95
Ile Cys Ser Ala Arg Glu Gly Tyr Arg Ser Tyr Phe Gly Pro Gly Thr
100 105 110
Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val
115 120 125
Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala
130 135 140
Thr Leu Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu
145 150 155 160
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
165 170 175
Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys
180 185 190
Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg
195 200 205
Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp
210 215 220
Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala
225 230 235 240
Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His
245 250 255
Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
260 265 270
Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met
275 280 285
Val Lys Arg Lys Asp Ser Arg Gly
290 295
<210> 68
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 68
Lys Thr Thr Gln Pro Pro Ser Met Asp Cys Ala Glu Gly Arg Ala Ala
1 5 10 15
Asn Leu Pro Cys Asn His Ser Thr Ile Ser Gly Asn Glu Tyr Val Tyr
20 25 30
Trp Tyr Arg Gln Ile His Ser Gln Gly Pro Gln Tyr Ile Ile His Gly
35 40 45
Leu Lys Asn Asn Glu Thr Asn Glu Met Ala Ser Leu Ile Ile Thr Glu
50 55 60
Asp Arg Lys Ser Ser Thr Leu Ile Leu Pro His Ala Thr Leu Arg Asp
65 70 75 80
Thr Ala Val Tyr Tyr Cys Ile Val Arg Asp Arg Ser Tyr Gly Gln Asn
85 90 95
Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu Pro Tyr Ile Gln
100 105 110
Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp
115 120 125
Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser
130 135 140
Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp
145 150 155 160
Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn
165 170 175
Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro
180 185 190
Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys Asp Val Lys Leu
195 200 205
Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu
210 215 220
Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn
225 230 235 240
Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
245 250
<210> 69
<211> 297
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 69
Gly Ser Gly Leu Gly Ala Val Val Ser Gln His Pro Ser Trp Val Ile
1 5 10 15
Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe
20 25 30
Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu
35 40 45
Met Leu Met Ala Thr Ser Asn Glu Gly Cys Lys Ala Thr Tyr Glu Gln
50 55 60
Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu
65 70 75 80
Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr
85 90 95
Ile Cys Ser Thr Ala Gly Glu Thr Asp Thr Gln Tyr Phe Gly Pro Gly
100 105 110
Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu
115 120 125
Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys
130 135 140
Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu
145 150 155 160
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
165 170 175
Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr
180 185 190
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro
195 200 205
Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn
210 215 220
Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser
225 230 235 240
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
245 250 255
His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
260 265 270
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala
275 280 285
Met Val Lys Arg Lys Asp Ser Arg Gly
290 295
<210> 70
<211> 259
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 70
Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp
1 5 10 15
Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe
20 25 30
Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp
35 40 45
Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu
50 55 60
Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln
65 70 75 80
Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Thr Leu Gly Leu Asp
85 90 95
Gln Gly Gly Lys Leu Ile Phe Gly Gln Gly Thr Glu Leu Ser Val Lys
100 105 110
Pro Asn Ile Gln Asn Pro Asp Ser Val Lys Pro Asn Pro Ala Val Tyr
115 120 125
Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr
130 135 140
Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val
145 150 155 160
Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys
165 170 175
Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala
180 185 190
Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser
195 200 205
Ser Asp Val Pro Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr
210 215 220
Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile
225 230 235 240
Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu
245 250 255
Trp Ser Ser
<210> 71
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 71
aactgcacgt accagacatc 20
<210> 72
<211> 18
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 72
gatgtgcacc aagactcc 18
<210> 73
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 73
aagatcaggt caacgttgc 19
<210> 74
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 74
ctccatggac tcatatgaag g 21
<210> 75
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 75
cttttcctga gtgtccgag 19
<210> 76
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 76
caccctgacc tgcaactata c 21
<210> 77
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 77
agctgcacgt actctgtcag 20
<210> 78
<211> 18
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 78
ctcactggag ttgggatg 18
<210> 79
<211> 17
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 79
gccaccctgg ttaaagg 17
<210> 80
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 80
cactgtctct gaaggagcc 19
<210> 81
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 81
gagctgaggt gcaactactc 20
<210> 82
<211> 18
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 82
ctaacagagg ccacccag 18
<210> 83
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 83
tggtatgtcc aatatcctgg 20
<210> 84
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 84
caagtggagc agagtcctc 19
<210> 85
<211> 18
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 85
cartgttcca gagggagc 18
<210> 86
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 86
catccttcaa ccctgagtg 19
<210> 87
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 87
cagcgcctca gactacttc 19
<210> 88
<211> 22
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 88
aagataactc aaacccaacc ag 22
<210> 89
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 89
agtggagctg aagtgcaac 19
<210> 90
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 90
ggagaagagg atcctcagg 19
<210> 91
<211> 22
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 91
tccagtatct aaacaaagag cc 22
<210> 92
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 92
aggtaactca agcgcagac 19
<210> 93
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 93
cacagtcagc ggtttaagag 20
<210> 94
<211> 18
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 94
ttcctgcagc tctgagtg 18
<210> 95
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 95
gtcctccaga cctgattctc 20
<210> 96
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 96
tgcttatgag aacactgcg 19
<210> 97
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 97
ctcagtcact gcatgttcag 20
<210> 98
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 98
ggacttcacc acgtactgc 19
<210> 99
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 99
gcaaacctgc cttgtaatc 19
<210> 100
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 100
agccaaattc aatggagag 19
<210> 101
<211> 22
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 101
tcagtttcta agcatccaag ag 22
<210> 102
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 102
gcaagttaag caaaattcac c 21
<210> 103
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 103
caacaaccag tgcagagtc 19
<210> 104
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 104
agaactggag cagagtcctc 20
<210> 105
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 105
ggtcaacagc tgaatcagag 20
<210> 106
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 106
gaagacaagg tggtacaaag c 21
<210> 107
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 107
gcacatatga caccagtgag 20
<210> 108
<211> 18
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 108
ctgttcctga gcatgcag 18
<210> 109
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 109
gcatctgtga ctatgaactg c 21
<210> 110
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 110
aatgaagtgg agcagagtcc 20
<210> 111
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 111
gaccagcttg acatcacag 19
<210> 112
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 112
tcgatgatca attctcagtt g 21
<210> 113
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 113
caaaatacct ggtcacacag 20
<210> 114
<211> 18
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 114
tcgcttctca cctgaatg 18
<210> 115
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 115
gattctcagg kckccagttc 20
<210> 116
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 116
gtaccaacag gycctgggt 19
<210> 117
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 117
actcagaccc caaaattcc 19
<210> 118
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 118
actggcaaag gagaagtcc 19
<210> 119
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 119
trtgatccaa tttcaggtca 20
<210> 120
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 120
gswtctytgc agaraggcc 19
<210> 121
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 121
gatcacagca actggacag 19
<210> 122
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 122
tgtwctggta tcgacaagac c 21
<210> 123
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 123
cgattttctg cagagacgc 19
<210> 124
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 124
argtgacaga ratgggacaa 20
<210> 125
<211> 19
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 125
agcgataaag gaagcatcc 19
<210> 126
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 126
ccaacaatcg attcttagct g 21
<210> 127
<211> 20
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 127
agtgaccctg agttgttctc 20
<210> 128
<211> 22
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 128
gtctttgatg aaacaggtat gc 22
<210> 129
<211> 18
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 129
cagaccccca gacacaag 18
<210> 130
<211> 21
<212> DNA
合成的引物 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 130
catagatgag tcaggaatgc c 21
<210> 131
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 131
agttgtgaac agaatttgaa cc 22
<210> 132
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 132
aagtttctca tcaaccatgc 20
<210> 133
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 133
gcgattctca tctcaatgc 19
<210> 134
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 134
cctacggttg atctattact cc 22
<210> 135
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 135
actacacctc atccactatt cc 22
<210> 136
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 136
tggtatcgac aagacccag 19
<210> 137
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 137
ttctggtacc gtcagcaac 19
<210> 138
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 138
tccagctgct cttctactcc 20
<210> 139
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 139
tagaactgga cttgacagcg 20
<210> 140
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 140
gcacccacat ttctktctta c 21
<210> 141
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 141
cactctgtgt ccaatgctta c 21
<210> 142
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 142
atgcacctat tcagtctctg g 21
<210> 143
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 143
attatatcac gtggtaccaa cag 23
<210> 144
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 144
tacacagaca gctcctccac 20
<210> 145
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 145
tggtaccgac aagatccag 19
<210> 146
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 146
acaatttgca gtggtacagg 20
<210> 147
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 147
gtcaacacct tcagcttctc 20
<210> 148
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 148
agagtgaaac ctccttccac 20
<210> 149
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 149
tttgaggctg aatttaagag g 21
<210> 150
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 150
aaccaaggac tccagcttc 19
<210> 151
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 151
atcagaggtt ttgaggctg 19
<210> 152
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 152
gaaaccactt ctttccactt g 21
<210> 153
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 153
gaaagaactg cactcttcaa tg 22
<210> 154
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 154
aagatggaag gtttacagca c 21
<210> 155
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 155
tcagacagtg cctcaaacta c 21
<210> 156
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 156
cagtgaaaca tctctctctg c 21
<210> 157
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 157
aggctgtgac tctggactg 19
<210> 158
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 158
gtccagtact ccagacaacg 20
<210> 159
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 159
ccaccatgaa ctgcagttac 20
<210> 160
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 160
tgacagttcc ttccacctg 19
<210> 161
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 161
tgtgaccttg gactgtgtg 19
<210> 162
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 162
tctggtatag gcaagatcct g 21
<210> 163
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 163
aacttggttc tcaactgcag 20
<210> 164
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 164
ctgactctgt gaacaatttg c 21
<210> 165
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 165
tgcattattg atagccatac g 21
<210> 166
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 166
tgccttacac tggtacagat g 21
<210> 167
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 167
tataagcaaa ggcctggtg 19
<210> 168
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 168
cgacagattc actcccag 18
<210> 169
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 169
ttcacttgcc ttgtaaccac 20
<210> 170
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 170
ctcactgtgt actgcaactc c 21
<210> 171
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 171
ctgctgaagg tcctacattc 20
<210> 172
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 172
agaagcatgg tgaagcac 18
<210> 173
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 173
atctcaccat aaactgcacg 20
<210> 174
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 174
acctggctat ggtacaagc 19
<210> 175
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 175
atctctggtt gtccacgag 19
<210> 176
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 176
cagcaggcag atgattctc 19
<210> 177
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 177
tcaaccactt cagacagact g 21
<210> 178
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 178
ggaggcggaa atattaaaga c 21
<210> 179
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 179
ttgtttatgc tgagctcagg 20
<210> 180
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 180
tgttgctctt gaagtccata g 21
<210> 181
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 181
ttcactctga agatccggtc 20
<210> 182
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 182
aatcttcaca tcaattccct g 21
<210> 183
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 183
cctgcagcca gaagactc 18
<210> 184
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 184
cttggagctg grsgactc 18
<210> 185
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 185
tctgagctga atgtgaacg 19
<210> 186
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 186
gtgtrcccag gatatgaacc 20
<210> 187
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 187
tggttatagt gtctccagag c 21
<210> 188
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 188
tcyactctga mgwtccagcg 20
<210> 189
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 189
tgrmgatyca gcgcaca 17
<210> 190
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 190
gtaccaacag agcctggac 19
<210> 191
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 191
tccycctcac tctggagtc 19
<210> 192
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 192
gactccactc tcaagatcca 20
<210> 193
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 193
cyactctgar gatccagcc 19
<210> 194
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 194
cattctgaac tgaacatgag c 21
<210> 195
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 195
attctactct gaaggtgcag c 21
<210> 196
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 196
ataacttcca atccaggagg 20
<210> 197
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 197
gaaagatttt cagctaagtg cc 22
<210> 198
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 198
tgttcactgg taccgacag 19
<210> 199
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 199
cgattttctg ctgaatttcc 20
<210> 200
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 200
ttcctctcac tgtgacatcg 20
<210> 201
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 201
actctgacag tgaccagtgc 20
<210> 202
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 202
gcaatcctgt cctcagaac 19
<210> 203
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 203
gatggataca gtgtctctcg a 21
<210> 204
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 204
cagagaaggg agatctttcc 20
<210> 205
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 205
ttcyccctga tyctggagtc 20
<210> 206
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 206
tctgactgtg agcaacatga g 21
<210> 207
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 207
agaatctctc agcctccaga c 21
<210> 208
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的引物
<400> 208
ttctgatggc tcaaacacag 20
<210> 209
<211> 622
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 209
Met Asp Thr Trp Leu Val Cys Trp Ala Ile Phe Ser Leu Leu Lys Ala
1 5 10 15
Gly Leu Thr Glu Pro Glu Val Thr Gln Thr Pro Ser His Gln Val Thr
20 25 30
Gln Met Gly Gln Glu Val Ile Leu Arg Cys Val Pro Ile Ser Asn His
35 40 45
Leu Tyr Phe Tyr Trp Tyr Arg Gln Ile Leu Gly Gln Lys Val Glu Phe
50 55 60
Leu Val Ser Phe Tyr Asn Asn Glu Ile Ser Glu Lys Ser Glu Ile Phe
65 70 75 80
Asp Asp Gln Phe Ser Val Glu Arg Pro Asp Gly Ser Asn Phe Thr Leu
85 90 95
Lys Ile Arg Ser Thr Lys Leu Glu Asp Ser Ala Met Tyr Phe Cys Ala
100 105 110
Ser Arg Ala Ser Val Gly Val Gly Thr Gly Glu Leu Phe Phe Gly Glu
115 120 125
Gly Ser Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro
130 135 140
Glu Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln
145 150 155 160
Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val
165 170 175
Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys
180 185 190
Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg
195 200 205
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn
210 215 220
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu
225 230 235 240
Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val
245 250 255
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser
260 265 270
Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
275 280 285
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met
290 295 300
Ala Met Val Lys Arg Lys Asp Ser Arg Gly Arg Ala Lys Arg Ser Gly
305 310 315 320
Ser Gly Ala Pro Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu
325 330 335
Ala Gly Asp Val Glu Ser Asn Pro Gly Pro Met Thr Arg Val Ser Leu
340 345 350
Leu Trp Ala Val Val Val Ser Thr Cys Leu Glu Ser Gly Met Ala Gln
355 360 365
Thr Val Thr Gln Ser Gln Pro Glu Met Ser Val Gln Glu Ala Glu Thr
370 375 380
Val Thr Leu Ser Cys Thr Tyr Asp Thr Ser Glu Ser Asn Tyr Tyr Leu
385 390 395 400
Phe Trp Tyr Lys Gln Pro Pro Ser Arg Gln Met Ile Leu Val Ile Arg
405 410 415
Gln Glu Ala Tyr Lys Gln Gln Asn Ala Thr Glu Asn Arg Phe Ser Val
420 425 430
Asn Phe Gln Lys Ala Ala Lys Ser Phe Ser Leu Lys Ile Ser Asp Ser
435 440 445
Gln Leu Gly Asp Thr Ala Met Tyr Phe Cys Ala Phe Thr Tyr Gly Gly
450 455 460
Ser Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys
465 470 475 480
Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
485 490 495
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
500 505 510
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
515 520 525
Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
530 535 540
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
545 550 555 560
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys
565 570 575
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
580 585 590
Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val
595 600 605
Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
610 615 620
<210> 210
<211> 621
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 210
Met Gly Thr Ser Leu Leu Cys Trp Val Val Leu Gly Phe Leu Gly Thr
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Thr
20 25 30
Lys Arg Gly Gln Asp Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Val Ser Leu Tyr Trp Tyr Arg Gln Ala Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Asn Tyr Glu Ala Gln Gln Asp Lys Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Ser Ala Glu Arg Pro Glu Gly Ser Ile Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Glu Gln Arg Asp Ser Ala Met Tyr Arg Cys Ala
100 105 110
Ser Ser Pro Glu Leu Ala Gly Pro Gln Glu Thr Gln Tyr Phe Gly Pro
115 120 125
Gly Thr Arg Leu Leu Val Leu Glu Asp Leu Asn Lys Val Phe Pro Pro
130 135 140
Glu Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln
145 150 155 160
Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val
165 170 175
Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys
180 185 190
Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg
195 200 205
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn
210 215 220
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu
225 230 235 240
Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val
245 250 255
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser
260 265 270
Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
275 280 285
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met
290 295 300
Ala Met Val Lys Arg Lys Asp Phe Arg Ala Lys Arg Ser Gly Ser Gly
305 310 315 320
Ala Pro Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly
325 330 335
Asp Val Glu Ser Asn Pro Gly Pro Met Leu Thr Ala Ser Leu Leu Arg
340 345 350
Ala Val Ile Ala Ser Ile Cys Val Val Ser Ser Met Ala Gln Lys Val
355 360 365
Thr Gln Ala Gln Thr Glu Ile Ser Val Val Glu Lys Glu Asp Val Thr
370 375 380
Leu Asp Cys Val Tyr Glu Thr Arg Asp Thr Thr Tyr Tyr Leu Phe Trp
385 390 395 400
Tyr Lys Gln Pro Pro Ser Gly Glu Leu Val Phe Leu Ile Arg Arg Asn
405 410 415
Ser Phe Asp Glu Gln Asn Glu Ile Ser Gly Arg Tyr Ser Trp Asn Phe
420 425 430
Gln Lys Ser Thr Ser Ser Phe Asn Phe Thr Ile Thr Ala Ser Gln Val
435 440 445
Val Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser Glu Gly Gly Gly Ser
450 455 460
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
465 470 475 480
Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys
485 490 495
Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr
500 505 510
Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys
515 520 525
Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala
530 535 540
Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser
545 550 555 560
Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys Asp
565 570 575
Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe
580 585 590
Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala
595 600 605
Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
610 615 620
<210> 211
<211> 618
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 211
Met Thr Ile Arg Leu Leu Cys Tyr Met Gly Phe Tyr Phe Leu Gly Ala
1 5 10 15
Gly Leu Met Glu Ala Asp Ile Tyr Gln Thr Pro Arg Tyr Leu Val Ile
20 25 30
Gly Thr Gly Lys Lys Ile Thr Leu Glu Cys Ser Gln Thr Met Gly His
35 40 45
Asp Lys Met Tyr Trp Tyr Gln Gln Asp Pro Gly Met Glu Leu His Leu
50 55 60
Ile His Tyr Ser Tyr Gly Val Asn Ser Thr Glu Lys Gly Asp Leu Ser
65 70 75 80
Ser Glu Ser Thr Val Ser Arg Ile Arg Thr Glu His Phe Pro Leu Thr
85 90 95
Leu Glu Ser Ala Arg Pro Ser His Thr Ser Gln Tyr Leu Cys Ala Ser
100 105 110
Ser Gly Pro Gly Gln Gly His Asn Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu Glu Asp Leu Asn Lys Val Phe Pro Pro Glu
130 135 140
Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr
195 200 205
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro
210 215 220
Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn
225 230 235 240
Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser
245 250 255
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
260 265 270
His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
275 280 285
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala
290 295 300
Met Val Lys Arg Lys Asp Phe Arg Ala Lys Arg Ser Gly Ser Gly Ala
305 310 315 320
Pro Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp
325 330 335
Val Glu Ser Asn Pro Gly Pro Met Leu Thr Ala Ser Leu Leu Arg Ala
340 345 350
Val Ile Ala Ser Ile Cys Val Val Ser Ser Met Ala Gln Lys Val Thr
355 360 365
Gln Ala Gln Thr Glu Ile Ser Val Val Glu Lys Glu Asp Val Thr Leu
370 375 380
Asp Cys Val Tyr Glu Thr Arg Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr
385 390 395 400
Lys Gln Pro Pro Ser Gly Glu Leu Val Phe Leu Ile Arg Arg Asn Ser
405 410 415
Phe Asp Glu Gln Asn Glu Ile Ser Gly Arg Tyr Ser Trp Asn Phe Gln
420 425 430
Lys Ser Thr Ser Ser Phe Asn Phe Thr Ile Thr Ala Ser Gln Val Val
435 440 445
Asp Ser Ala Val Tyr Phe Cys Ala Leu Gly Ser Ser Gly Thr Tyr Lys
450 455 460
Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys Val Leu Ala Asn Ile Gln
465 470 475 480
Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp
485 490 495
Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser
500 505 510
Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp
515 520 525
Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn
530 535 540
Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro
545 550 555 560
Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys Asp Val Lys Leu
565 570 575
Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu
580 585 590
Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn
595 600 605
Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
610 615
<210> 212
<211> 611
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 212
Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Pro Gln Gly Arg Ile Asn Ser Pro Leu His Phe Gly Asn Gly Thr
115 120 125
Arg Leu Thr Val Thr Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val
130 135 140
Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
180 185 190
Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys
195 200 205
Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg
210 215 220
Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp
225 230 235 240
Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala
245 250 255
Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His
260 265 270
Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
275 280 285
Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met
290 295 300
Val Lys Arg Lys Asp Phe Arg Ala Lys Arg Ser Gly Ser Gly Ala Pro
305 310 315 320
Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val
325 330 335
Glu Ser Asn Pro Gly Pro Met Trp Gly Val Phe Leu Leu Tyr Val Ser
340 345 350
Met Lys Met Gly Gly Thr Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu
355 360 365
Met Thr Ala Thr Glu Gly Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln
370 375 380
Thr Ser Gly Phe Asn Gly Leu Phe Trp Tyr Gln Gln His Ala Gly Glu
385 390 395 400
Ala Pro Thr Phe Leu Ser Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys
405 410 415
Gly Arg Phe Ser Ser Phe Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu
420 425 430
Leu Leu Lys Glu Leu Gln Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala
435 440 445
Val Arg Asp Thr Gly Tyr Gly Gln Asn Phe Val Phe Gly Pro Gly Thr
450 455 460
Arg Leu Ser Val Leu Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr
465 470 475 480
Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr
485 490 495
Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val
500 505 510
Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys
515 520 525
Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala
530 535 540
Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser
545 550 555 560
Ser Asp Val Pro Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr
565 570 575
Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile
580 585 590
Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu
595 600 605
Trp Ser Ser
610
<210> 213
<211> 618
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 213
Met Leu Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Ala Arg Glu Gly Tyr Arg Ser Tyr
115 120 125
Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val
130 135 140
Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala
145 150 155 160
His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Phe Pro
165 170 175
Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser
180 185 190
Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn
195 200 205
Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe
210 215 220
Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly
225 230 235 240
Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr
245 250 255
Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr
260 265 270
Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu
275 280 285
Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu
290 295 300
Val Leu Met Ala Met Val Lys Arg Lys Asp Ser Arg Gly Arg Ala Lys
305 310 315 320
Arg Ser Gly Ser Gly Ala Pro Val Lys Gln Thr Leu Asn Phe Asp Leu
325 330 335
Leu Lys Leu Ala Gly Asp Val Glu Ser Asn Pro Gly Pro Met Arg Leu
340 345 350
Val Ala Arg Val Thr Val Phe Leu Thr Phe Gly Thr Ile Ile Asp Ala
355 360 365
Lys Thr Thr Gln Pro Pro Ser Met Asp Cys Ala Glu Gly Arg Ala Ala
370 375 380
Asn Leu Pro Cys Asn His Ser Thr Ile Ser Gly Asn Glu Tyr Val Tyr
385 390 395 400
Trp Tyr Arg Gln Ile His Ser Gln Gly Pro Gln Tyr Ile Ile His Gly
405 410 415
Leu Lys Asn Asn Glu Thr Asn Glu Met Ala Ser Leu Ile Ile Thr Glu
420 425 430
Asp Arg Lys Ser Ser Thr Leu Ile Leu Pro His Ala Thr Leu Arg Asp
435 440 445
Thr Ala Val Tyr Tyr Cys Ile Val Arg Asp Arg Ser Tyr Gly Gln Asn
450 455 460
Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu Pro Tyr Ile Gln
465 470 475 480
Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp
485 490 495
Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser
500 505 510
Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp
515 520 525
Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn
530 535 540
Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro
545 550 555 560
Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys Asp Val Lys Leu
565 570 575
Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu
580 585 590
Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn
595 600 605
Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
610 615
<210> 214
<211> 630
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 214
Met Leu Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Cys Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Thr Ala Gly Glu Thr Asp Thr Gln
115 120 125
Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn
130 135 140
Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile
145 150 155 160
Ala His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Phe
165 170 175
Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His
180 185 190
Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu
195 200 205
Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr
210 215 220
Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr
225 230 235 240
Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val
245 250 255
Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile
260 265 270
Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr
275 280 285
Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala
290 295 300
Leu Val Leu Met Ala Met Val Lys Arg Lys Asp Ser Arg Gly Arg Ala
305 310 315 320
Lys Arg Ser Gly Ser Gly Ala Pro Val Lys Gln Thr Leu Asn Phe Asp
325 330 335
Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn Pro Gly Pro Met Ala
340 345 350
Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp Trp Val
355 360 365
Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln
370 375 380
Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser
385 390 395 400
Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe
405 410 415
Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val
420 425 430
Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala
435 440 445
Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Thr Leu
450 455 460
Gly Leu Asp Gln Gly Gly Lys Leu Ile Phe Gly Gln Gly Thr Glu Leu
465 470 475 480
Ser Val Lys Pro Asn Ile Gln Asn Pro Asp Ser Val Lys Pro Asn Pro
485 490 495
Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys
500 505 510
Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp
515 520 525
Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met
530 535 540
Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe
545 550 555 560
Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe
565 570 575
Phe Pro Ser Ser Asp Val Pro Cys Asp Val Lys Leu Val Glu Lys Ser
580 585 590
Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly
595 600 605
Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
610 615 620
Leu Arg Leu Trp Ser Ser
625 630
<210> 215
<211> 614
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 215
Met Gly Cys Arg Leu Leu Cys Cys Val Val Phe Cys Leu Leu Gln Ala
1 5 10 15
Gly Pro Leu Asp Thr Ala Val Ser Gln Thr Pro Lys Tyr Leu Val Thr
20 25 30
Gln Met Gly Asn Asp Lys Ser Ile Lys Cys Glu Gln Asn Leu Gly His
35 40 45
Asp Thr Met Tyr Trp Tyr Lys Gln Asp Ser Lys Lys Phe Leu Lys Ile
50 55 60
Met Phe Ser Tyr Asn Asn Lys Glu Leu Ile Ile Asn Glu Thr Val Pro
65 70 75 80
Asn Arg Phe Ser Pro Lys Ser Pro Asp Lys Ala His Leu Asn Leu His
85 90 95
Ile Asn Ser Leu Glu Leu Gly Asp Ser Ala Val Tyr Phe Cys Ala Ser
100 105 110
Ser Gln Gly Thr Gly Arg Gly Asn Thr Glu Ala Phe Phe Gly Gln Gly
115 120 125
Thr Arg Leu Thr Val Val Glu Asp Leu Asn Lys Val Phe Pro Pro Glu
130 135 140
Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr
195 200 205
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro
210 215 220
Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn
225 230 235 240
Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser
245 250 255
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
260 265 270
His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
275 280 285
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala
290 295 300
Met Val Lys Arg Lys Asp Phe Arg Ala Lys Arg Ser Gly Ser Gly Ala
305 310 315 320
Pro Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp
325 330 335
Val Glu Ser Asn Pro Gly Pro Met Arg Gln Val Ala Arg Val Ile Val
340 345 350
Phe Leu Thr Leu Ser Thr Leu Ser Leu Ala Lys Thr Thr Gln Pro Ile
355 360 365
Ser Met Asp Ser Tyr Glu Gly Gln Glu Val Asn Ile Thr Cys Ser His
370 375 380
Asn Asn Ile Ala Thr Asn Asp Tyr Ile Thr Trp Tyr Gln Gln Phe Pro
385 390 395 400
Ser Gln Gly Pro Arg Phe Ile Ile Gln Gly Tyr Lys Thr Lys Val Thr
405 410 415
Asn Glu Val Ala Ser Leu Phe Ile Pro Ala Asp Arg Lys Ser Ser Thr
420 425 430
Leu Ser Leu Pro Arg Val Ser Leu Ser Asp Thr Ala Val Tyr Tyr Cys
435 440 445
Leu Val Gly Pro Tyr Phe Gly Gly Gly Ser Tyr Gln Leu Thr Phe Gly
450 455 460
Lys Gly Thr Lys Leu Ser Val Ile Pro Asn Ile Gln Asn Pro Asp Pro
465 470 475 480
Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys
485 490 495
Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp
500 505 510
Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met
515 520 525
Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe
530 535 540
Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe
545 550 555 560
Phe Pro Ser Ser Asp Val Pro Cys Asp Val Lys Leu Val Glu Lys Ser
565 570 575
Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly
580 585 590
Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
595 600 605
Leu Arg Leu Trp Ser Ser
610
<210> 216
<211> 629
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 216
Met Gly Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gln Gly Ala Val Gly Thr Asp Thr Gln Tyr Phe Gly
115 120 125
Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Arg Lys Thr Leu Lys Asn
130 135 140
Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile
145 150 155 160
Ala His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr
165 170 175
Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His
180 185 190
Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu
195 200 205
Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr
210 215 220
Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr
225 230 235 240
Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val
245 250 255
Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile
260 265 270
Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr
275 280 285
Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala
290 295 300
Leu Val Leu Met Ala Met Val Lys Arg Lys Asp Ser Arg Gly Arg Ala
305 310 315 320
Lys Arg Ser Gly Ser Gly Ala Pro Val Lys Gln Thr Leu Asn Phe Asp
325 330 335
Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn Pro Gly Pro Met Thr
340 345 350
Arg Val Ser Leu Leu Trp Ala Val Val Val Ser Thr Cys Leu Glu Ser
355 360 365
Gly Met Ala Gln Thr Val Thr Gln Ser Gln Pro Glu Met Ser Val Gln
370 375 380
Glu Ala Glu Thr Val Thr Leu Ser Cys Thr Tyr Asp Thr Ser Glu Asn
385 390 395 400
Asn Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Arg Gln Met Ile
405 410 415
Leu Val Ile Arg Gln Glu Ala Tyr Lys Gln Gln Asn Ala Thr Glu Asn
420 425 430
Arg Phe Ser Val Asn Phe Gln Lys Ala Ala Lys Ser Phe Ser Leu Lys
435 440 445
Ile Ser Asp Ser Gln Leu Gly Asp Thr Ala Met Tyr Phe Cys Ala Phe
450 455 460
Met Lys Pro Asp Gly Ser Gly Asn Thr Gly Lys Leu Ile Phe Gly Gln
465 470 475 480
Gly Thr Thr Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala
485 490 495
Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu
500 505 510
Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser
515 520 525
Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met Asp
530 535 540
Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala
545 550 555 560
Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe
565 570 575
Pro Ser Ser Asp Val Pro Cys Asp Val Lys Leu Val Glu Lys Ser Phe
580 585 590
Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe
595 600 605
Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu
610 615 620
Arg Leu Trp Ser Ser
625
<210> 217
<211> 19
<212> PRT
<213> 人乳头瘤病毒 16
<400> 217
Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln Pro Glu Thr Thr
1 5 10 15
Asp Leu Tyr
<210> 218
<211> 9
<212> PRT
<213> 人乳头瘤病毒 16
<400> 218
Ser Ala Phe Arg Cys Phe Ile Val Tyr
1 5
<210> 219
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 219
Cys Leu Val Gly Pro Tyr Phe Gly Gly Gly Ser Tyr Gln Leu Thr Phe
1 5 10 15
<210> 220
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 220
Cys Ala Ser Ser Gln Gly Thr Gly Arg Gly Asn Thr Glu Ala Phe Phe
1 5 10 15
<210> 221
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 221
Cys Ala Val Arg Glu Lys Gly Thr Gly Asn Gln Phe Tyr Phe
1 5 10
<210> 222
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 222
Cys Ala Ser Ser Leu Pro Gln Gly Thr Pro Glu Thr Gln Tyr Phe
1 5 10 15
<210> 223
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 223
Cys Gly Leu Ser Trp Gly Asp Lys Thr Asp Lys Leu Ile Phe
1 5 10
<210> 224
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 224
Cys Ala Ser Ser Pro Ser Leu Ala Gly Val Val Pro Gly Glu Leu Phe
1 5 10 15
Phe
<210> 225
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 225
Cys Ala Phe Met Lys Pro Asp Gly Ser Gly Asn Thr Gly Lys Leu Ile
1 5 10 15
Phe
<210> 226
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 226
Cys Ala Ser Ser Leu Gly Gln Gly Ala Val Gly Thr Asp Thr Gln Tyr
1 5 10 15
Phe
<210> 227
<211> 9374
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多核苷酸
<400> 227
aagcttaatg tagtcttatg caatactctt gtagtcttgc aacatggtaa cgatgagtta 60
gcaacatgcc ttacaaggag agaaaaagca ccgtgcatgc cgattggtgg aagtaaggtg 120
gtacgatcgt gccttattag gaaggcaaca gacgggtctg acatggattg gacgaaccac 180
tgaattgccg cattgcagag atattgtatt taagtgccta gctcgataca taaacgggtc 240
tctctggtta gaccagatct gagcctggga gctctctggc taactaggga acccactgct 300
taagcctcaa taaagcttgc cttgagtgct tcaagtagtg tgtgcccgtc tgttgtgtga 360
ctctggtaac tagagatccc tcagaccctt ttagtcagtg tggaaaatct ctagcagtgg 420
cgcccgaaca gggacttgaa agcgaaaggg aaaccagagg agctctctcg acgcaggact 480
cggcttgctg aagcgcgcac ggcaagaggc gaggggcggc gactggtgag tacgccaaaa 540
attttgacta gcggaggcta gaaggagaga gatgggtgcg agagcgtcag tattaagcgg 600
gggagaatta gatcgcgatg ggaaaaaatt cggttaaggc cagggggaaa gaaaaaatat 660
aaattaaaac atatagtatg ggcaagcagg gagctagaac gattcgcagt taatcctggc 720
ctgttagaaa catcagaagg ctgtagacaa atactgggac agctacaacc atcccttcag 780
acaggatcag aagaacttag atcattatat aatacagtag caaccctcta ttgtgtgcat 840
caaaggatag agataaaaga caccaaggaa gctttagaca agatagagga agagcaaaac 900
aaaagtaaga ccaccgcaca gcaagcggcc gctgatcttc agacctggag gaggagatat 960
gagggacaat tggagaagtg aattatataa atataaagta gtaaaaattg aaccattagg 1020
agtagcaccc accaaggcaa agagaagagt ggtgcagaga gaaaaaagag cagtgggaat 1080
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 1140
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 1200
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 1260
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcctggggat 1320
ttggggttgc tctggaaaac tcatttgcac cactgctgtg ccttggaatg ctagttggag 1380
taataaatct ctggaacaga tttggaatca cacgacctgg atggagtggg acagagaaat 1440
taacaattac acaagcttaa tacactcctt aattgaagaa tcgcaaaacc agcaagaaaa 1500
gaatgaacaa gaattattgg aattagataa atgggcaagt ttgtggaatt ggtttaacat 1560
aacaaattgg ctgtggtata taaaattatt cataatgata gtaggaggct tggtaggttt 1620
aagaatagtt tttgctgtac tttctatagt gaatagagtt aggcagggat attcaccatt 1680
atcgtttcag acccacctcc caaccccgag gggacccgac aggcccgaag gaatagaaga 1740
agaaggtgga gagagagaca gagacagatc cattcgatta gtgaacggat ctcgacggta 1800
tcggttaact tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 1860
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaattcaa 1920
aattttatcg atgcctcccc gtcaccaccc cccccaaccc gccccgaccg gagctgagag 1980
taattcatac aaaaggactc gcccctgcct tggggaatcc cagggaccgt cgttaaactc 2040
ccactaacgt agaacccaga gatcgctgcg ttcccgcccc ctcacccgcc cgctctcgtc 2100
atcactgagg tggagaagag catgcgtgag gctccggtgc ccgtcagtgg gcagagcgca 2160
catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc ggtgcctaga 2220
gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc ctttttcccg 2280
agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt tttcgcaacg 2340
ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta 2400
cgggttatgg cccttgcgtg ccttgaatta cttccacgcc cctggctgca gtacgtgatt 2460
cttgatcccg agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga 2520
gccccttcgc ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga 2580
atctggtggc accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat 2640
ttttgatgat atcctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa 2700
gatctgcaca ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc 2760
cagcgcacat gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg 2820
tagtctcaag ctggccggcc tgctctggtg cctggcctcg cgccgccgtg tatcgccccg 2880
ccctgggcgg caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt 2940
cccggccctg ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt 3000
gagtcaccca cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc 3060
acggagtacc gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg 3120
tctttaggtt ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag 3180
actgaagtta ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag 3240
tttggatctt ggttcattct caagcctcag acagtggttc aaagtttttt tcttccattt 3300
caggtgtcgt gaaaactacc cctctagata atacgactca ctatagggcc cgggttggat 3360
ccgccgccac catgggctgc agactgctgt gctgtgtggt gttctgcctg ctgcaagccg 3420
gacctctgga tacagccgtg tctcagaccc ctaagtacct ggtcacccag atgggcaacg 3480
acaagagcat caagtgcgag cagaacctgg gccacgacac catgtactgg tacaagcagg 3540
acagcaagaa attcctgaag atcatgttca gctacaacaa caaagagctg atcatcaacg 3600
agacagtgcc caaccggttc agccctaaga gccctgataa ggcccacctg aacctgcaca 3660
tcaacagcct ggaactgggc gacagcgccg tgtacttttg tgccagctct caaggcaccg 3720
gcagaggcaa taccgaggcc ttttttggcc aaggcacccg gctgaccgtg gtggaagatc 3780
tgaacaaggt gttccctcca gaggtggccg tgttcgagcc ttctaaggcc gagattgccc 3840
acacacagaa agccacactc gtgtgtctgg ccaccggctt ctatcccgat cacgtggaac 3900
tgtcttggtg ggtcaacggc aaagaggtgc acagcggcgt ctgtaccgat cctcagcctc 3960
tgaaagagca gcccgctctg aacgacagca gatactgcct gagcagcaga ctgagagtgt 4020
ccgccacctt ctggcagaac cccagaaacc acttcagatg ccaggtgcag ttctacggcc 4080
tgagcgagaa cgatgagtgg acccaggata gagccaagcc tgtgacacag atcgtgtctg 4140
ccgaagcctg gggcagagcc gattgtggaa ttaccagcgc cagctaccat cagggcgtgc 4200
tgtctgccac aatcctgtac gagatcctgc tgggcaaagc cactctgtac gccgtgctgg 4260
tgtctgccct ggtgctgatg gccatggtca agcggaagga cttcagagcc aagagatccg 4320
gctccggcgc accggtgaaa cagactttga attttgacct tctcaagttg gcaggagacg 4380
ttgagtccaa ccctgggccc atgagacagg tggccagagt gatcgtgttc ctgacactga 4440
gcaccctgag cctggccaag accacacagc ccatcagcat ggacagctac gagggccaag 4500
aagtgaacat cacctgtagc cacaacaata tcgccaccaa cgactacatc acgtggtatc 4560
agcagttccc cagtcaaggc cccagattca tcatccaagg ctacaagacc aaagtgacca 4620
acgaggtggc ctctctgttc atccccgccg acagaaagag cagcaccctg tctctgccta 4680
gagtgtccct gagcgatacc gccgtgtact actgtctcgt gggcccttat tttggcggcg 4740
gaagctacca gctgaccttc ggcaagggca caaagctgag cgtgatcccc aacattcaga 4800
accccgatcc tgccgtgtac cagctgcggg atagcaagag cagcgacaag agcgtgtgcc 4860
tgttcaccga cttcgacagc cagaccaacg tgtcccagag caaggacagc gacgtgtaca 4920
tcaccgataa gtgcgtgctg gacatgcgga gcatggactt caagagcaac agcgccgtgg 4980
cctggtccaa caagagcgat ttcgcctgcg ccaacgcctt caacaacagc attatccccg 5040
aggacacatt cttccccagc tccgatgtgc cctgcgacgt gaagctggtg gaaaagagct 5100
tcgagacaga caccaacctg aacttccaga acctgtccgt gatcggcttc cgcatcctgc 5160
tgctgaaagt ggccggcttc aacctgctga tgaccctgag actgtggtcc agctaatgag 5220
tcgacaatca acctctggat tacaaaattt gtgaaagatt gactggtatt cttaactatg 5280
ttgctccttt tacgctatgt ggatacgctg ctttaatgcc tttgtatcat gctattgctt 5340
cccgtatggc tttcattttc tcctccttgt ataaatcctg gttgctgtct ctttatgagg 5400
agttgtggcc cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct gacgcaaccc 5460
ccactggttg gggcattgcc accacctgtc agctcctttc cgggactttc gctttccccc 5520
tccctattgc cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg acaggggctc 5580
ggctgttggg cactgacaat tccgtggtgt tgtcggggaa gctgacgtcc tttccatggc 5640
tgctcgcctg tgttgccacc tggattctgc gcgggacgtc cttctgctac gtcccttcgg 5700
ccctcaatcc agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg cctcttccgc 5760
gtcttcgcct tcgccctcag acgagtcgga tctccctttg ggccgcctcc ccgcctggaa 5820
ttcgagctcg gtacctttaa gaccaatgac ttacaaggca gctgtagatc ttagccactt 5880
tttaaaagaa aaggggggac tggaagggct aattcactcc caacgaagac aagatctgct 5940
ttttgcttgt actgggtctc tctggttaga ccagatctga gcctgggagc tctctggcta 6000
actagggaac ccactgctta agcctcaata aagcttgcct tgagtgcttc aagtagtgtg 6060
tgcccgtctg ttgtgtgact ctggtaacta gagatccctc agaccctttt agtcagtgtg 6120
gaaaatctct agcagtagta gttcatgtca tcttattatt cagtatttat aacttgcaaa 6180
gaaatgaata tcagagagtg agaggaactt gtttattgca gcttataatg gttacaaata 6240
aagcaatagc atcacaaatt tcacaaataa agcatttttt tcactgcatt ctagttgtgg 6300
tttgtccaaa ctcatcaatg tatcttatca tgtctggctc tagctatccc gcccctaact 6360
ccgcccatcc cgcccctaac tccgcccagt tccgcccatt ctccgcccca tggctgacta 6420
atttttttta tttatgcaga ggccgaggcc gcctcggcct ctgagctatt ccagaagtag 6480
tgaggaggct tttttggagg cctagggacg tacccaattc gccctatagt gagtcgtatt 6540
acgcgcgctc actggccgtc gttttacaac gtcgtgactg ggaaaaccct ggcgttaccc 6600
aacttaatcg ccttgcagca catccccctt tcgccagctg gcgtaatagc gaagaggccc 6660
gcaccgatcg cccttcccaa cagttgcgca gcctgaatgg cgaatgggac gcgccctgta 6720
gcggcgcatt aagcgcggcg ggtgtggtgg ttacgcgcag cgtgaccgct acacttgcca 6780
gcgccctagc gcccgctcct ttcgctttct tcccttcctt tctcgccacg ttcgccggct 6840
ttccccgtca agctctaaat cgggggctcc ctttagggtt ccgatttagt gctttacggc 6900
acctcgaccc caaaaaactt gattagggtg atggttcacg tagtgggcca tcgccctgat 6960
agacggtttt tcgccctttg acgttggagt ccacgttctt taatagtgga ctcttgttcc 7020
aaactggaac aacactcaac cctatctcgg tctattcttt tgatttataa gggattttgc 7080
cgatttcggc ctattggtta aaaaatgagc tgatttaaca aaaatttaac gcgaatttta 7140
acaaaatatt aacgcttaca atttaggtgg cacttttcgg ggaaatgtgc gcggaacccc 7200
tatttgttta tttttctaaa tacattcaaa tatgtatccg ctcatgagac aataaccctg 7260
ataaatgctt caataatatt gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc 7320
ccttattccc ttttttgcgg cattttgcct tcctgttttt gctcacccag aaacgctggt 7380
gaaagtaaaa gatgctgaag atcagttggg tgcacgagtg ggttacatcg aactggatct 7440
caacagcggt aagatccttg agagttttcg ccccgaagaa cgttttccaa tgatgagcac 7500
ttttaaagtt ctgctatgtg gcgcggtatt atcccgtatt gacgccgggc aagagcaact 7560
cggtcgccgc atacactatt ctcagaatga cttggttgag tactcaccag tcacagaaaa 7620
gcatcttacg gatggcatga cagtaagaga attatgcagt gctgccataa ccatgagtga 7680
taacactgcg gccaacttac ttctgacaac gatcggagga ccgaaggagc taaccgcttt 7740
tttgcacaac atgggggatc atgtaactcg ccttgatcgt tgggaaccgg agctgaatga 7800
agccatacca aacgacgagc gtgacaccac gatgcctgta gcaatggcaa caacgttgcg 7860
caaactatta actggcgaac tacttactct agcttcccgg caacaattaa tagactggat 7920
ggaggcggat aaagttgcag gaccacttct gcgctcggcc cttccggctg gctggtttat 7980
tgctgataaa tctggagccg gtgagcgtgg gtctcgcggt atcattgcag cactggggcc 8040
agatggtaag ccctcccgta tcgtagttat ctacacgacg gggagtcagg caactatgga 8100
tgaacgaaat agacagatcg ctgagatagg tgcctcactg attaagcatt ggtaactgtc 8160
agaccaagtt tactcatata tactttagat tgatttaaaa cttcattttt aatttaaaag 8220
gatctaggtg aagatccttt ttgataatct catgaccaaa atcccttaac gtgagttttc 8280
gttccactga gcgtcagacc ccgtagaaaa gatcaaagga tcttcttgag atcctttttt 8340
tctgcgcgta atctgctgct tgcaaacaaa aaaaccaccg ctaccagcgg tggtttgttt 8400
gccggatcaa gagctaccaa ctctttttcc gaaggtaact ggcttcagca gagcgcagat 8460
accaaatact gttcttctag tgtagccgta gttaggccac cacttcaaga actctgtagc 8520
accgcctaca tacctcgctc tgctaatcct gttaccagtg gctgctgcca gtggcgataa 8580
gtcgtgtctt accgggttgg actcaagacg atagttaccg gataaggcgc agcggtcggg 8640
ctgaacgggg ggttcgtgca cacagcccag cttggagcga acgacctaca ccgaactgag 8700
atacctacag cgtgagctat gagaaagcgc cacgcttccc gaagggagaa aggcggacag 8760
gtatccggta agcggcaggg tcggaacagg agagcgcacg agggagcttc cagggggaaa 8820
cgcctggtat ctttatagtc ctgtcgggtt tcgccacctc tgacttgagc gtcgattttt 8880
gtgatgctcg tcaggggggc ggagcctatg gaaaaacgcc agcaacgcgg cctttttacg 8940
gttcctggcc ttttgctggc cttttgctca catgttcttt cctgcgttat cccctgattc 9000
tgtggataac cgtattaccg cctttgagtg agctgatacc gctcgccgca gccgaacgac 9060
cgagcgcagc gagtcagtga gcgaggaagc ggaagagcgc ccaatacgca aaccgcctct 9120
ccccgcgcgt tggccgattc attaatgcag ctggcacgac aggtttcccg actggaaagc 9180
gggcagtgag cgcaacgcaa ttaatgtgag ttagctcact cattaggcac cccaggcttt 9240
acactttatg cttccggctc gtatgttgtg tggaattgtg agcggataac aatttcacac 9300
aggaaacagc tatgaccatg attacgccaa gcgcgcaatt aaccctcact aaagggaaca 9360
aaagctggag ctgc 9374
<210> 228
<211> 9419
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多核苷酸
<400> 228
aagcttaatg tagtcttatg caatactctt gtagtcttgc aacatggtaa cgatgagtta 60
gcaacatgcc ttacaaggag agaaaaagca ccgtgcatgc cgattggtgg aagtaaggtg 120
gtacgatcgt gccttattag gaaggcaaca gacgggtctg acatggattg gacgaaccac 180
tgaattgccg cattgcagag atattgtatt taagtgccta gctcgataca taaacgggtc 240
tctctggtta gaccagatct gagcctggga gctctctggc taactaggga acccactgct 300
taagcctcaa taaagcttgc cttgagtgct tcaagtagtg tgtgcccgtc tgttgtgtga 360
ctctggtaac tagagatccc tcagaccctt ttagtcagtg tggaaaatct ctagcagtgg 420
cgcccgaaca gggacttgaa agcgaaaggg aaaccagagg agctctctcg acgcaggact 480
cggcttgctg aagcgcgcac ggcaagaggc gaggggcggc gactggtgag tacgccaaaa 540
attttgacta gcggaggcta gaaggagaga gatgggtgcg agagcgtcag tattaagcgg 600
gggagaatta gatcgcgatg ggaaaaaatt cggttaaggc cagggggaaa gaaaaaatat 660
aaattaaaac atatagtatg ggcaagcagg gagctagaac gattcgcagt taatcctggc 720
ctgttagaaa catcagaagg ctgtagacaa atactgggac agctacaacc atcccttcag 780
acaggatcag aagaacttag atcattatat aatacagtag caaccctcta ttgtgtgcat 840
caaaggatag agataaaaga caccaaggaa gctttagaca agatagagga agagcaaaac 900
aaaagtaaga ccaccgcaca gcaagcggcc gctgatcttc agacctggag gaggagatat 960
gagggacaat tggagaagtg aattatataa atataaagta gtaaaaattg aaccattagg 1020
agtagcaccc accaaggcaa agagaagagt ggtgcagaga gaaaaaagag cagtgggaat 1080
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 1140
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 1200
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 1260
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcctggggat 1320
ttggggttgc tctggaaaac tcatttgcac cactgctgtg ccttggaatg ctagttggag 1380
taataaatct ctggaacaga tttggaatca cacgacctgg atggagtggg acagagaaat 1440
taacaattac acaagcttaa tacactcctt aattgaagaa tcgcaaaacc agcaagaaaa 1500
gaatgaacaa gaattattgg aattagataa atgggcaagt ttgtggaatt ggtttaacat 1560
aacaaattgg ctgtggtata taaaattatt cataatgata gtaggaggct tggtaggttt 1620
aagaatagtt tttgctgtac tttctatagt gaatagagtt aggcagggat attcaccatt 1680
atcgtttcag acccacctcc caaccccgag gggacccgac aggcccgaag gaatagaaga 1740
agaaggtgga gagagagaca gagacagatc cattcgatta gtgaacggat ctcgacggta 1800
tcggttaact tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 1860
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaattcaa 1920
aattttatcg atgcctcccc gtcaccaccc cccccaaccc gccccgaccg gagctgagag 1980
taattcatac aaaaggactc gcccctgcct tggggaatcc cagggaccgt cgttaaactc 2040
ccactaacgt agaacccaga gatcgctgcg ttcccgcccc ctcacccgcc cgctctcgtc 2100
atcactgagg tggagaagag catgcgtgag gctccggtgc ccgtcagtgg gcagagcgca 2160
catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc ggtgcctaga 2220
gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc ctttttcccg 2280
agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt tttcgcaacg 2340
ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta 2400
cgggttatgg cccttgcgtg ccttgaatta cttccacgcc cctggctgca gtacgtgatt 2460
cttgatcccg agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga 2520
gccccttcgc ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga 2580
atctggtggc accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat 2640
ttttgatgat atcctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa 2700
gatctgcaca ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc 2760
cagcgcacat gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg 2820
tagtctcaag ctggccggcc tgctctggtg cctggcctcg cgccgccgtg tatcgccccg 2880
ccctgggcgg caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt 2940
cccggccctg ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt 3000
gagtcaccca cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc 3060
acggagtacc gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg 3120
tctttaggtt ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag 3180
actgaagtta ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag 3240
tttggatctt ggttcattct caagcctcag acagtggttc aaagtttttt tcttccattt 3300
caggtgtcgt gaaaactacc cctctagata atacgactca ctatagggcc cgggttggat 3360
ccgccgccac catgggcacc agactgctgt tctgggtcgc cttttgtctg ctgggcgccg 3420
atcatacagg tgccggtgtt tctcagagcc ccagcaacaa agtgaccgag aagggcaaag 3480
acgtggaact gagatgcgac cccatcagcg gacacacagc cctgtactgg tacagacagt 3540
ctctcggcca gggcctcgag ttcctgatct acttccaagg caacagcgcc cctgacaaga 3600
gcggcctgcc tagcgataga ttcagcgccg aaagaacagg cggcagcgtg tccacactga 3660
ccatccagag aacccagcaa gaggacagcg ccgtgtacct gtgtgccagc tctcttggac 3720
aaggcgccgt gggcacagac acccagtatt ttggccctgg caccaggctg accgtgctgg 3780
aagatagaaa gaccctgaag aacgtgttcc cacctgaggt ggccgtgttc gagccttcta 3840
aggccgagat tgcccacaca cagaaagcca cactcgtgtg tctggccacc ggcttctatc 3900
ccgaccatgt ggaactgtct tggtgggtca acggcaaaga ggtgcacagc ggcgtctgta 3960
ccgatcctca gcctctgaaa gagcagcccg ctctgaacga cagcagatac tgcctgagca 4020
gcagactgag agtgtccgcc accttctggc agaaccccag aaaccacttc agatgccagg 4080
tgcagttcta cggcctgagc gagaacgatg agtggaccca ggatagagcc aagcctgtga 4140
cacagatcgt gtctgccgaa gcctggggca gagccgattg tggaattacc agcgccagct 4200
accatcaggg cgtgctgtct gccacaatcc tgtacgagat cctgctgggc aaagccactc 4260
tgtacgccgt gctggtgtct gccctggtgc tgatggccat ggtcaagcgg aaggatagca 4320
gaggcagagc caagagatcc ggctccggcg caccggtgaa acagactttg aattttgacc 4380
ttctcaagtt ggcaggagac gttgagtcca accctgggcc catgaccaga gtgtctctgc 4440
tgtgggccgt cgtggtgtcc acatgtctgg aatctggcat ggcccagacc gtgacacaga 4500
gccagcctga gatgtctgtg caagaggccg agacagtgac cctgagctgc acctacgata 4560
ccagcgagaa caactactac ctgttctggt acaagcagcc tcctagccgg cagatgatcc 4620
tggtcatcag acaagaggcc tataagcagc agaacgccac cgagaacaga ttcagcgtga 4680
acttccagaa ggccgccaag agcttcagcc tgaagatcag cgatagccag ctgggcgaca 4740
ccgccatgta cttttgcgcc tttatgaagc ccgacggcag cggcaatacc ggcaagctga 4800
tttttggcca gggcaccaca ctgcaagtga agcccaacat tcagaacccc gatcctgccg 4860
tgtaccagct gagagacagc aagagcagcg acaagagcgt gtgcctgttc accgacttcg 4920
acagccagac caacgtgtcc cagagcaagg acagcgacgt gtacatcacc gataagtgcg 4980
tgctggacat gcggagcatg gacttcaaga gcaacagcgc cgtggcctgg tccaacaaga 5040
gcgatttcgc ctgcgccaac gccttcaaca acagcattat ccccgaggac acattcttcc 5100
ccagctccga tgtgccctgc gacgtgaagc tggtggaaaa gagcttcgag acagacacca 5160
acctgaattt ccagaacctg agcgtgatcg gcttccgcat cctgctgctg aaagtggccg 5220
gcttcaacct gctgatgacc ctgcgacttt ggagcagcta atgagtcgac aatcaacctc 5280
tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct ccttttacgc 5340
tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt atggctttca 5400
ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg tggcccgttg 5460
tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact ggttggggca 5520
ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct attgccacgg 5580
cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg ttgggcactg 5640
acaattccgt ggtgttgtcg gggaagctga cgtcctttcc atggctgctc gcctgtgttg 5700
ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc aatccagcgg 5760
accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt cgccttcgcc 5820
ctcagacgag tcggatctcc ctttgggccg cctccccgcc tggaattcga gctcggtacc 5880
tttaagacca atgacttaca aggcagctgt agatcttagc cactttttaa aagaaaaggg 5940
gggactggaa gggctaattc actcccaacg aagacaagat ctgctttttg cttgtactgg 6000
gtctctctgg ttagaccaga tctgagcctg ggagctctct ggctaactag ggaacccact 6060
gcttaagcct caataaagct tgccttgagt gcttcaagta gtgtgtgccc gtctgttgtg 6120
tgactctggt aactagagat ccctcagacc cttttagtca gtgtggaaaa tctctagcag 6180
tagtagttca tgtcatctta ttattcagta tttataactt gcaaagaaat gaatatcaga 6240
gagtgagagg aacttgttta ttgcagctta taatggttac aaataaagca atagcatcac 6300
aaatttcaca aataaagcat ttttttcact gcattctagt tgtggtttgt ccaaactcat 6360
caatgtatct tatcatgtct ggctctagct atcccgcccc taactccgcc catcccgccc 6420
ctaactccgc ccagttccgc ccattctccg ccccatggct gactaatttt ttttatttat 6480
gcagaggccg aggccgcctc ggcctctgag ctattccaga agtagtgagg aggctttttt 6540
ggaggcctag ggacgtaccc aattcgccct atagtgagtc gtattacgcg cgctcactgg 6600
ccgtcgtttt acaacgtcgt gactgggaaa accctggcgt tacccaactt aatcgccttg 6660
cagcacatcc ccctttcgcc agctggcgta atagcgaaga ggcccgcacc gatcgccctt 6720
cccaacagtt gcgcagcctg aatggcgaat gggacgcgcc ctgtagcggc gcattaagcg 6780
cggcgggtgt ggtggttacg cgcagcgtga ccgctacact tgccagcgcc ctagcgcccg 6840
ctcctttcgc tttcttccct tcctttctcg ccacgttcgc cggctttccc cgtcaagctc 6900
taaatcgggg gctcccttta gggttccgat ttagtgcttt acggcacctc gaccccaaaa 6960
aacttgatta gggtgatggt tcacgtagtg ggccatcgcc ctgatagacg gtttttcgcc 7020
ctttgacgtt ggagtccacg ttctttaata gtggactctt gttccaaact ggaacaacac 7080
tcaaccctat ctcggtctat tcttttgatt tataagggat tttgccgatt tcggcctatt 7140
ggttaaaaaa tgagctgatt taacaaaaat ttaacgcgaa ttttaacaaa atattaacgc 7200
ttacaattta ggtggcactt ttcggggaaa tgtgcgcgga acccctattt gtttattttt 7260
ctaaatacat tcaaatatgt atccgctcat gagacaataa ccctgataaa tgcttcaata 7320
atattgaaaa aggaagagta tgagtattca acatttccgt gtcgccctta ttcccttttt 7380
tgcggcattt tgccttcctg tttttgctca cccagaaacg ctggtgaaag taaaagatgc 7440
tgaagatcag ttgggtgcac gagtgggtta catcgaactg gatctcaaca gcggtaagat 7500
ccttgagagt tttcgccccg aagaacgttt tccaatgatg agcactttta aagttctgct 7560
atgtggcgcg gtattatccc gtattgacgc cgggcaagag caactcggtc gccgcataca 7620
ctattctcag aatgacttgg ttgagtactc accagtcaca gaaaagcatc ttacggatgg 7680
catgacagta agagaattat gcagtgctgc cataaccatg agtgataaca ctgcggccaa 7740
cttacttctg acaacgatcg gaggaccgaa ggagctaacc gcttttttgc acaacatggg 7800
ggatcatgta actcgccttg atcgttggga accggagctg aatgaagcca taccaaacga 7860
cgagcgtgac accacgatgc ctgtagcaat ggcaacaacg ttgcgcaaac tattaactgg 7920
cgaactactt actctagctt cccggcaaca attaatagac tggatggagg cggataaagt 7980
tgcaggacca cttctgcgct cggcccttcc ggctggctgg tttattgctg ataaatctgg 8040
agccggtgag cgtgggtctc gcggtatcat tgcagcactg gggccagatg gtaagccctc 8100
ccgtatcgta gttatctaca cgacggggag tcaggcaact atggatgaac gaaatagaca 8160
gatcgctgag ataggtgcct cactgattaa gcattggtaa ctgtcagacc aagtttactc 8220
atatatactt tagattgatt taaaacttca tttttaattt aaaaggatct aggtgaagat 8280
cctttttgat aatctcatga ccaaaatccc ttaacgtgag ttttcgttcc actgagcgtc 8340
agaccccgta gaaaagatca aaggatcttc ttgagatcct ttttttctgc gcgtaatctg 8400
ctgcttgcaa acaaaaaaac caccgctacc agcggtggtt tgtttgccgg atcaagagct 8460
accaactctt tttccgaagg taactggctt cagcagagcg cagataccaa atactgttct 8520
tctagtgtag ccgtagttag gccaccactt caagaactct gtagcaccgc ctacatacct 8580
cgctctgcta atcctgttac cagtggctgc tgccagtggc gataagtcgt gtcttaccgg 8640
gttggactca agacgatagt taccggataa ggcgcagcgg tcgggctgaa cggggggttc 8700
gtgcacacag cccagcttgg agcgaacgac ctacaccgaa ctgagatacc tacagcgtga 8760
gctatgagaa agcgccacgc ttcccgaagg gagaaaggcg gacaggtatc cggtaagcgg 8820
cagggtcgga acaggagagc gcacgaggga gcttccaggg ggaaacgcct ggtatcttta 8880
tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg 8940
ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg 9000
ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg ataaccgtat 9060
taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc gcagcgagtc 9120
agtgagcgag gaagcggaag agcgcccaat acgcaaaccg cctctccccg cgcgttggcc 9180
gattcattaa tgcagctggc acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa 9240
cgcaattaat gtgagttagc tcactcatta ggcaccccag gctttacact ttatgcttcc 9300
ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt cacacaggaa acagctatga 9360
ccatgattac gccaagcgcg caattaaccc tcactaaagg gaacaaaagc tggagctgc 9419
<210> 229
<211> 292
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 229
Asp Thr Ala Val Ser Gln Thr Pro Lys Tyr Leu Val Thr Gln Met Gly
1 5 10 15
Asn Asp Lys Ser Ile Lys Cys Glu Gln Asn Leu Gly His Asp Thr Met
20 25 30
Tyr Trp Tyr Lys Gln Asp Ser Lys Lys Phe Leu Lys Ile Met Phe Ser
35 40 45
Tyr Asn Asn Lys Glu Leu Ile Ile Asn Glu Thr Val Pro Asn Arg Phe
50 55 60
Ser Pro Lys Ser Pro Asp Lys Ala His Leu Asn Leu His Ile Asn Ser
65 70 75 80
Leu Glu Leu Gly Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Gln Gly
85 90 95
Thr Gly Arg Gly Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu
100 105 110
Thr Val Val Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val
115 120 125
Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala Thr Leu
130 135 140
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
145 150 155 160
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
165 170 175
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
180 185 190
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
195 200 205
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
210 215 220
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
225 230 235 240
Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly
245 250 255
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
260 265 270
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
275 280 285
Arg Lys Asp Phe
290
<210> 230
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 230
Leu Ala Lys Thr Thr Gln Pro Ile Ser Met Asp Ser Tyr Glu Gly Gln
1 5 10 15
Glu Val Asn Ile Thr Cys Ser His Asn Asn Ile Ala Thr Asn Asp Tyr
20 25 30
Ile Thr Trp Tyr Gln Gln Phe Pro Ser Gln Gly Pro Arg Phe Ile Ile
35 40 45
Gln Gly Tyr Lys Thr Lys Val Thr Asn Glu Val Ala Ser Leu Phe Ile
50 55 60
Pro Ala Asp Arg Lys Ser Ser Thr Leu Ser Leu Pro Arg Val Ser Leu
65 70 75 80
Ser Asp Thr Ala Val Tyr Tyr Cys Leu Val Gly Pro Tyr Phe Gly Gly
85 90 95
Gly Ser Tyr Gln Leu Thr Phe Gly Lys Gly Thr Lys Leu Ser Val Ile
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Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
115 120 125
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
130 135 140
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
145 150 155 160
Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
165 170 175
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
180 185 190
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys
195 200 205
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
210 215 220
Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val
225 230 235 240
Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
245 250
<210> 231
<211> 299
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 231
Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr Glu Lys Gly
1 5 10 15
Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu
20 25 30
Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe Leu Ile Tyr
35 40 45
Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro Ser Asp Arg
50 55 60
Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu Thr Ile Gln
65 70 75 80
Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu
85 90 95
Gly Gln Gly Ala Val Gly Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr
100 105 110
Arg Leu Thr Val Leu Glu Asp Arg Lys Thr Leu Lys Asn Val Phe Pro
115 120 125
Pro Glu Val Ala Val Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr
130 135 140
Gln Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His
145 150 155 160
Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val
165 170 175
Cys Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser
180 185 190
Arg Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln
195 200 205
Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser
210 215 220
Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile
225 230 235 240
Val Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala
245 250 255
Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu
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Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu
275 280 285
Met Ala Met Val Lys Arg Lys Asp Ser Arg Gly
290 295
<210> 232
<211> 259
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 232
Ala Gln Thr Val Thr Gln Ser Gln Pro Glu Met Ser Val Gln Glu Ala
1 5 10 15
Glu Thr Val Thr Leu Ser Cys Thr Tyr Asp Thr Ser Glu Asn Asn Tyr
20 25 30
Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Arg Gln Met Ile Leu Val
35 40 45
Ile Arg Gln Glu Ala Tyr Lys Gln Gln Asn Ala Thr Glu Asn Arg Phe
50 55 60
Ser Val Asn Phe Gln Lys Ala Ala Lys Ser Phe Ser Leu Lys Ile Ser
65 70 75 80
Asp Ser Gln Leu Gly Asp Thr Ala Met Tyr Phe Cys Ala Phe Met Lys
85 90 95
Pro Asp Gly Ser Gly Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
100 105 110
Thr Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr
115 120 125
Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr
130 135 140
Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val
145 150 155 160
Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys
165 170 175
Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala
180 185 190
Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser
195 200 205
Ser Asp Val Pro Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr
210 215 220
Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile
225 230 235 240
Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu
245 250 255
Trp Ser Ser
<210> 233
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 233
Ser Gly Ser Gly
1
Claims (49)
1.一种对人乳头瘤病毒(HPV)16具有抗原特异性的T细胞受体(TCR)多肽,其中所述TCR包含选自SEQ ID NO.13至52、或219-226中所列氨基酸序列的至少一个互补决定区3α(CDR3α)氨基酸序列和至少一个CDR3β氨基酸序列。
2.一种对HPV16具有抗原特异性的TCR多肽,其中所述TCR对包含至少一个表位的抗原具有特异性,所述表位具有选自SEQ ID NO:1-12、217或218中所列氨基酸序列的氨基酸序列。
3.根据权利要求1或2所述的TCR多肽,其中所述TCR对E6和E7之外的HPV16肽具有抗原特异性。
4.根据权利要求1至3中任一项所述的TCR多肽,其中所述TCR对HPV16肽E1、E2、E4或E5中的任一具有抗原特异性。
5.根据权利要求1至4中任一项所述的TCR多肽,其中所述TCR对包含至少一个表位的抗原具有抗原特异性,所述表位具有选自SEQ ID NO:1-7中所列氨基酸序列的氨基酸序列。
6.根据权利要求4所述的TCR多肽,其中所述TCR包含在SEQ ID NO.13和14,SEQ IDNO.25和26,或SEQ ID NO.51和52中列出的CDR3α氨基酸序列和CDR3β氨基酸。
7.根据权利要求4所述的TCR多肽,其中所述TCR包含在SEQ ID NO.59和60,或SEQ IDNO.61和62中列出的TCRβ氨基酸序列和TCRα链氨基酸。
8.一种核酸,其编码权利要求1至7中任一项所述的TCR多肽。
9.根据权利要求8所述的核酸,其包含在SEQ ID NO.53至58、227、228中列出的任何一种核酸序列,和/或其片段。
10.一种分离的核酸,其包含编码一种或多种多肽的核苷酸序列,所述多肽包含TCR,所述TCR包含选自SEQ ID NO.59至70、229-232、或209至216的氨基酸序列。
11.根据权利要求8至10中任一项所述的核酸,其中所述核酸是表达载体。
12.根据权利要求11所述的核酸,其中所述表达载体是病毒载体。
13.根据权利要求12所述的核酸,其中所述病毒载体是慢病毒表达载体。
14.一种免疫细胞,其包含权利要求8至13中任一项所述的核酸。
15.一种免疫细胞,其表达权利要求1至6中任一项所述的TCR多肽。
16.根据权利要求14或15所述的免疫细胞,其中所述免疫细胞是白细胞。
17.根据权利要求14至16中任一项所述的免疫细胞,其中所述免疫细胞是淋巴细胞、单核细胞、巨噬细胞、树突状细胞、肥大细胞、嗜中性粒细胞、嗜碱性粒细胞或嗜酸性粒细胞。
18.根据权利要求14至17中任一项所述的免疫细胞,其中所述免疫细胞是淋巴细胞,其选自αβT细胞、γδT细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、B细胞、先天性淋巴细胞(ILC)、细胞因子诱导的杀伤(CIK)细胞、细胞毒性T淋巴细胞(CTL)、淋巴因子活化的杀伤(LAK)细胞、调节性T细胞或其任意组合。
19.根据权利要求18所述的免疫细胞,其中所述免疫细胞是细胞毒性T淋巴细胞(CTL)。
20.根据权利要求18或19所述的免疫细胞,其中所述免疫细胞是病毒抗原致敏的CTL。
21.根据权利要求18至20中任一项所述的免疫细胞,其中所述免疫细胞是对病毒抗原致敏的CTL,所述病毒抗原来自人乳头瘤病毒(HPV)、爱泼斯坦-巴尔病毒(EBV)、巨细胞病毒(CMV)、B.K.病毒(BKV)、约翰坎宁安病毒(JCV)、小核糖核酸病毒(例如,甲型肝炎病毒)、嗜肝DNA病毒(例如,乙型肝炎病毒)、肝炎病毒(例如,丙型肝炎病毒)、delta病毒(例如,丁型肝炎病毒)、肝炎病毒(例如,戊型肝炎病毒)中的任一、或其任何组合。
22.根据权利要求18至21中任一项所述的免疫细胞,其中所述免疫细胞是HPV致敏的CTL。
23.根据权利要求15至22中任一项所述的表达TCR的细胞,其中所述表达TCR的细胞被遗传修饰以不再表达一种或多种免疫检查点分子。
24.根据权利要求15至22中任一项所述的表达TCR的细胞,其中所述细胞还表达一种或多种免疫检查点分子的显性失活形式。
25.根据权利要求15至22中任一项所述的表达TCR的细胞,其中所述细胞还表达对一种或多种免疫检查点分子特异的开关受体。
26.根据权利要求15至22中任一项所述的表达TCR的细胞,其中所述细胞还表达能够阻断一种或多种检查点分子的信号传导的抗体或其功能片段。
27.根据权利要求21至26中任一项所述的表达TCR的细胞,其中所述免疫检查点分子选自程序性死亡1(PD-1)、程序性死亡配体1(PD-L1)、程序性死亡配体2(PD-L2)、细胞毒性T淋巴细胞抗原4(CTLA-4)、B和T淋巴细胞减毒剂(BTLA)、T细胞免疫球蛋白粘蛋白3(TIM-3)、淋巴细胞活化蛋白3(LAG-3)、具有Ig和ITIM结构域的T细胞免疫受体(TIGIT)、白细胞相关免疫球蛋白样受体1(LAIR1)、自然杀伤细胞受体2B4(2B4)、CD160、和转化生长因子β(TGF-β)受体。
28.根据权利要求23至27中任一项所述的免疫细胞,其中所述免疫检查点分子为PD-1和/或CTLA-4。
29.一种治疗受试者中HPV相关癌症或癌前病变的方法,所述方法包括施用有效量的包含权利要求14至28中任一项所述的表达TCR的细胞的过继免疫疗法组合物。
30.根据权利要求29所述的方法,其中所述HPV相关癌症是鳞状细胞癌。
31.根据权利要求29或30所述的方法,其中所述HPV相关癌症选自头颈癌(例如,HNSCC等)和宫颈癌、肛门癌、阴道癌、外阴癌、阴茎癌、舌根癌、喉癌和扁桃体癌。
32.根据权利要求28所述的方法,其中所述HPV相关癌前病变包括选自以下的异常细胞改变和/或癌前细胞改变:宫颈上皮内瘤变(CIN)、鳞状上皮内病变(SIL)或宫颈疣。
33.根据权利要求29至32中任一项所述的方法,其中所述受试者已经接受、正在接受或将接受额外的抗癌疗法。
34.根据权利要求33所述的方法,其中所述额外的抗癌疗法包括手术、放射、化疗、免疫疗法或激素疗法。
35.根据权利要求34所述的方法,其中所述受试者在施用所述过继免疫疗法组合物之前已经接受了IFNγ。
36.根据权利要求29至35中任一项所述的方法,其中所述过继免疫疗法组合物通过胸膜内、静脉内、皮下、结内、瘤内、鞘内、腹膜内、颅内或通过直接给药至器官来给药。
37.根据权利要求29至36中任一项所述的方法,其中所述受试者是人。
38.根据权利要求37所述的方法,其中所述过继免疫疗法组合物的表达TCR的细胞来源于受试者。
39.根据权利要求37所述的方法,其中所述过继免疫疗法组合物的表达TCR的细胞来源于供体样品,或来源于供体样品的库或文库。
40.根据权利要求29至39中任一项所述的方法,还包括施用至少一种免疫检查点抑制剂。
41.根据权利要求40所述的方法,其中所述免疫检查点抑制剂包括抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、抗CTLA-4抗体或其组合。
42.根据权利要求40所述的方法,其中所述免疫检查点抑制剂包括RNAi分子,例如反义RNA分子(asRNA)、micro RNA分子(miRNA)、短发夹RNA分子(shRNA)或小干扰RNA分子(siRNA)。
43.根据权利要求40所述的方法,其中所述免疫检查点抑制剂包括CRISPR RNA(crRNA)分子。
44.根据权利要求40所述的方法,其中所述免疫检查点抑制剂包括免疫检查点分子的显性失活形式。
45.根据权利要求40所述的方法,其中所述免疫检查点抑制剂包括重组的开关受体。
46.根据权利要求40至45中任一项所述的方法,其中所述免疫检查点抑制剂由包含编码所述免疫检查点抑制剂的核酸分子的载体表达,其中所述载体选自DNA载体、RNA载体、质粒或病毒载体。
47.根据权利要求46的方法,其中包含编码免疫检查点抑制剂的核酸分子的载体在过继免疫疗法组合物的表达TCR的细胞中表达。
48.一种包含用于过继免疫疗法的细胞的细胞库,其中所述细胞是权利要求14至28中任一项所述的表达TCR的细胞,其中所述表达TCR的细胞的HLA限制性是已知的。
49.一种治疗受试者中HPV相关癌症或癌前病变的方法,所述方法包括施用有效量的过继免疫疗法组合物,所述组合物包含选自权利要求48的细胞库的表达TCR的细胞。
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