CN112789054A - 用于预防或治疗癌症的方法的、编码癌症/睾丸抗原的病毒载体 - Google Patents
用于预防或治疗癌症的方法的、编码癌症/睾丸抗原的病毒载体 Download PDFInfo
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Abstract
将含有编码癌抗原的多核苷酸序列的黑猩猩腺病毒(ChAd)和MVA病毒载体在合适的佐剂中循序施用于受试者,以达到初免加强免疫效果。所述多核苷酸在施用后原位表达以提供MAGEA3/接头/NY‑ESO‑1融合蛋白及其变体。还有,hli/MAGEA3/接头/NY‑ESO‑1融合蛋白及其变体。发现了改善的T细胞应答。在特定的协同治疗方法中,ChAdOx和MVA载体与化学治疗剂和检查点抑制剂的三联组合导致髓源抑制性细胞(MDSC)的消耗,并显著提高癌症小鼠模型的存活时间。
Description
技术领域
本发明涉及用于预防或治疗癌症的基于病毒载体的疫苗,更具体地说,涉及复制缺陷型腺病毒(Ad)和改良的牛痘病毒安卡拉(MVA)载体,其包含目的癌症疫苗抗原并用于哺乳动物。因此,本发明涉及病毒颗粒、包含所述病毒颗粒的免疫原性组合物以及包含所述病毒载体的宿主细胞。所述病毒载体疫苗被用于治疗患有癌症的受试者或预防受试者罹患癌症。在优选的方案中,本发明涉及使用Ad载体的初次施用,然后是使用MVA载体的加强施用。本发明进一步提供了包含本发明的新型复制缺陷型腺病毒载体的疫苗组合物。
背景技术
每年有超过160万美国人被诊断出患有癌症,预计在2018年仅在美国就有约60万人死于这种疾病。在过去的数十年中,在癌症的检测、诊断和治疗方面已经取得了重大进展。但是,仍然只有67%的人在治疗开始5年后还活着。(参见Siegel,R.L.等人(2017)Cancer J.Clin.67(1):7–30.)
当前的治疗选择包括外科手术、放射、射频、化疗、单克隆抗体等。这些方法的大多数都与严重的风险、毒性副作用、高成本和令人怀疑的功效相关联。
然而,癌症免疫疗法近年来已显示出一些显著的进展,并且持续作为受关注的发展领域。基于溶细胞性T淋巴细胞(CTL)识别肿瘤相关抗原(TA)的能力,健康正常的人类免疫系统具有先天的能力来识别和排斥肿瘤细胞。癌细胞通常应激活细胞和体液的综合免疫应答。细胞应答涉及参与免疫应答的CD8+和CD4+T细胞。然而,在癌症和恶性肿瘤的起源中,针对肿瘤细胞的正常CTL活性受到损害或丧失。因此,癌症免疫疗法采用各种方法用于恢复或重新唤醒人类免疫系统针对肿瘤细胞的CTL活性。可以利用人类癌症患者的免疫系统来消除表达肿瘤相关抗原(TA)的恶性细胞。
细胞毒性T细胞表达CD8并且可以特异性杀死癌细胞。CD4+ T细胞或T辅助细胞支持细胞毒性应答的发展,产生细胞因子,还有助于B细胞的成熟和增殖。在体液应答过程中,B细胞被激活、复制、分化并产生TA特异性抗体。更多的信息请参见Murphy,K.&Weaver,C.“Janeway’s Immunobiology”第九版(2016):Garland Science/Taylor&Francis:NewYork,NY。
过继性T细胞疗法和免疫检查点调节剂是旨在增强人类免疫系统抵抗肿瘤能力的临床方法。但是,这两种方法都有局限性。过继性T细胞疗法需要扩增和转导所需特异性的效应T细胞(参见Baruch E.N.等人(2017)Cancer 123(S11):2154-62)。目前,这种复杂性限制了该方法的适用性。检查点抑制剂治疗是免疫检查点调节剂的一部分,是基于单克隆抗体的,所述单克隆抗体可在T细胞上释放制动(brake),以改善其效应子功能。尽管检查点抑制剂可能在一部分晚期癌症患者中引起长期临床反应,但是由所有T细胞的这种刺激引起的自身免疫毒性的副作用仍然是一个问题。而且,现有的检查点抑制剂治疗对于未被T细胞浸润的“冷”肿瘤缺乏功效。
代表上述方法的有前景的替代方法的另一种方法是癌症疫苗或更具体地为治疗性癌症疫苗,其用于引发针对肿瘤细胞的免疫应答。这是基于以下概念:肿瘤细胞固有地免疫原性差并且疫苗应有助于克服这一缺陷。已经研究了许多不同类型的癌症疫苗,其中一些已显示出有前景的结果。Sahin U.等人(2017)Nature 547(7662):222–226尝试了个性化的RNA突变组疫苗,该疫苗可动员针对癌症的多特异性治疗性免疫。此外,Ott P.A.等人(2017)Nature 547(7662):217-221尝试了用于黑色素瘤患者的个性化的免疫原性新抗原疫苗。
但是,在几项大规模临床试验(包括葛兰素史克(GSK)进行的两项大型III期试验)失败后,癌症疫苗的潜力变得可疑。这些试验使用了基于结合佐剂的重组肿瘤相关蛋白的疫苗接种方法。与许多其他疫苗平台一样,该疫苗平台已被证明能够诱导良好的抗体和CD4+T辅助应答,但无法产生稳定的CTL应答。鉴于CTL是抗肿瘤免疫应答的关键效应子,这可能解释了这些疫苗的临床失败。因此,技术挑战是提供一种新的癌症疫苗平台,该平台可在人体内诱导良好的CD8应答。
为了达到一定的效果,据信癌症疫苗应该具有以下能力:i)靶向可能在癌细胞上表达或仅在癌细胞上表达的抗原,并能引发综合免疫应答;以及ii)诱导抗原特异性T细胞的强大克隆扩增以及效应子和记忆分化(参见Coulie,P.G.(2014)Nat.Rev.Cancer,14(2):135–146)。
传统上,治疗性癌症疫苗包含肿瘤抗原(TA)蛋白和佐剂。例如,称为Stimuvax的疫苗(以前称为BLP25脂质体疫苗(L-BLP25))是一种脂质体,其包裹了衍生自粘蛋白1(MUC1)抗原的合成肽和佐剂MPL4,对此,US 6,600,012(B1)BIOMIRA INC有所涉及。同样,在MAGE-A3阳性非小细胞肺癌切除患者的3期临床试验中评估的MAGRIT疫苗(参见Vansteenkiste,J.F.et al Lancet Oncol.17(6):822–835)包含AS15佐剂和重组黑素瘤相关抗原MAGE-A3蛋白。但是,如上所述,这些Stimuvax和MAGRIT疫苗在大型III期试验中未显示出功效。
在美国和欧洲,第一个批准的“癌症疫苗”是PROVENGE,这是一种自体细胞疫苗,其中将患者的抗原呈递细胞(APC)与前列腺酸性磷酸酶(PAP)抗原一起孵育。尽管具有激活适当的T细胞应答的功效和能力,但这种疫苗仍需要为每个患者单独制备,从而涉及复杂且昂贵的生产过程。因此,所述疫苗的实际用途有限。(参见US2004/141991(A1)LAUS等人)。
基于载体的癌症疫苗显示出了巨大的前景,并随着临床上测试了数种载体技术、佐剂及组合而引发了强烈的治疗方面的关注。该策略的基础是使用重组病毒载体来递送肿瘤抗原。所述病毒载体本身被改造为复制缺陷的,因此不再对患者有害。所述载体表达TA以及其他病毒抗原,所述其他病毒抗原充当佐剂并增强免疫应答诱导作用。理想的病毒载体应具有以下几个特性:i)安全;ii)可以进行有效的抗原呈递;iii)引发综合免疫应答;以及iv)能够大规模生产(参见Melief,C.J.M.等人(2015)J.Clin.Invest.125(9):3401–3412)。
已经提出了几种病毒载体用于临床用途。例如,已经研究了复制缺陷型腺病毒(Ad)作为用于传染病的疫苗载体,例如在EP 2,130,921 B1GLAXOSMITHKLINE BIOLOGALSSA中公开的用于人类免疫缺陷病毒(HIV)-1或在US2012/082694(A1)CRUCELL中公开的,用于疟疾。
在疫苗接种领域中,通常在疫苗施用之后进行一次或多次加强注射,所述加强注射以与第一次注射相同的方式施用,但是在随后进行的一次或多次施用。在第一次(初免)和随后的(增强)施用之间的间隔期间,免疫系统通过引发细胞和体液应答来进行应答(参见Woodland,D.L.(2004)Trends Immunol.25(2):98–104)。
但是,重复施用相同的载体(同源加强)无法加强肿瘤抗原特异性T细胞应答,因为产生了针对病毒抗原的竞争性免疫原性,导致产生了识别病毒衣壳表面抗原的抗体并阻止重组载体进一步感染抗原呈递细胞。特别地,同源加强不诱导针对插入的肿瘤抗原的CD8 T细胞。规避此问题的一种潜在方法涉及使用不同抗原递送系统(例如两种不同的病毒载体)的疫苗的顺序施用(异源加强)。EP 2,631,290(A1)NATIONAL UNIVERSITY CORPORATION公开了用于初免/加强型疫苗的病毒载体,其包含牛痘病毒载体和仙台病毒载体。Chen,J.-L.等人(2015)Int.J.Cancer 136(6):E590–601描述了以ISCOMATRIX中的NY-ESO-1蛋白进行初免并以重组NY-ESO-1禽痘病毒加强免疫的黑色素瘤患者中的NY-ESO-1特异性抗体和细胞应答。
已经尝试了由DNA疫苗和各种病毒载体组成的许多初免/加强型疫苗。例如,WO2006/057454(A1)JAPAN SCIENCE AND TECHNOLOGY AGENCY公开了针对HIV-1 gag E抗原开发的异源初免/加强型HIV疫苗,通过使用卡介苗芽孢杆菌(Bacillus Calmette–Guérin)(BCG)载体用于初免以及减毒牛痘病毒株DIs用于加强免疫。Odunsi,K.等人(2012)Proc.Natl.Acad.Sci.U.S.A.109(15):5797–5802描述了使用初免-加强免疫方法以两种不同的正痘载体(牛痘和禽痘)和抗原NY-ESO-1进行的有限规模的I期研究,并在黑色素瘤和卵巢癌患者中显示了潜在的临床益处。
人类腺病毒由于其特性(例如复制缺陷、稳定性、高免疫原性、转导多种细胞类型的能力等)而被科学家广泛用于开发癌症疫苗。天然腺病毒感染在人类群体中很普遍,并且大多数人在生命的头五年内会发生血清转化。因此,来源于人类腺病毒的癌症疫苗会遇到预先存在的体液和细胞免疫,这将限制其效力(参见Coughlan,L.(2015)等人J.Pharm.Pharmacol.67(3):382–399以及US 6,140,087ADVEC INC,其标题为“AdenovirusVectors for Gene Therapy”)。
标题为“Simian Adenovirus and hybrid Adenoviral vectors”的US 9,714,435(B2)ISIS INNOVATION以及标题为“Chimpanzee Adenovirus Vaccine Carriers”的EP 2,163,260(A2)ISTITUTO RICHERCHE DI BIOLOGICA MOLECULARE解释了科学家如何开发衍生自非人类灵长类动物的复制缺陷型腺病毒,其可避免人类中任何已有的免疫力。黑猩猩腺病毒(ChAd)具有以下几种特性:i)强大的免疫原性;ii)在人类中的血清阳性率低;iii)生产制造可以标准化。
还已知减毒的非复制型牛痘病毒安卡拉株(MVA)。该病毒载体已显示出可引发免疫应答并具有出色的安全特性。在鸡胚成纤维细胞中,MVA通过超过570次传代而被减毒,结果导致其约15%的基因组丢失。因此,MVA在许多哺乳动物细胞中缺乏使病毒体成熟的能力,并且与强免疫原性和降低的扩增风险有关。Isis Innovation Limited的WO2011/128704描述了一种包括MVA的痘病毒表达系统,其中将转基因插入痘病毒基因组中,因此提供了痘病毒载体,并将其用于将目的基因转移到靶细胞中以用于针对感染的疫苗、癌症治疗和基因治疗的目的。Isis Innovation Limited的EP 2044947 A1也描述了用于诱导免疫应答,特别是针对流感病毒的T细胞免疫应答的MVA病毒载体。
为了治愈传染病,已经开发了异源初免-加强免疫方案的基于病毒载体的疫苗,并对其进行了优化以诱导强烈的CTL应答。这种疫苗策略采用黑猩猩腺病毒(ChAd)用于初免免疫,并以携带相同免疫原的改良的牛痘安卡拉(MVA)进行增强免疫。Coughlan L.等人(2015)J.Pharm.Pharmacol.67(3):382–99和Hui E.P.等人(2013)Cancer Res.73(6):1676–88报道了在传染病背景下的临床前研究和临床研究中对两种病毒载体的单独测试,以及它们如何具有很高的安全特性。
EP 2,044,947(A1)公开了预防流感的疫苗,其以腺病毒载体用于初免免疫,然后MVA用于加强免疫。
Ewer K.J.等人(2013)Nat.Commun.4:2836和Ogwang,C.等人(2015)Sci.Transl.Med.7(286):286re5公开了以ChA作为初免免疫和MVA作为增强免疫的疫苗,其用于疟疾。
在Cappuccini,F.等人(2017)Oncotarget 8(29):47474–47489中描述了在表达5T4抗原的癌症小鼠模型中使用同样的初免-加强免疫方法,在Cappuccini,F.等人(2016)Cancer Immunol.Immunother.CII 65(6):701–713中也进行了描述,其中癌症小鼠模型表达STEAP1,这是一种前列腺癌抗原。在所有这些研究中,异源初免-加强型疫苗诱导了对TA的强烈免疫应答以及抗原特异性CD8+T细胞的激活。
WO2017/120670 A1(Lichty,B.&Bell,J.)也描述了在临床相关的癌症模型中共同施用复制性溶瘤细胞性弹状病毒和免疫检查点抑制剂,其导致抗原特异性T淋巴细胞的激发和显著的存活。溶瘤细胞性弹状病毒特异性感染恶性细胞、在其中复制并将其杀死,而正常组织不受影响。溶瘤细胞性弹状病毒(例如VSVDelt5l或Mamba MG 1)表达肿瘤抗原,受试动物对该肿瘤抗原具有预先存在的免疫力,所述肿瘤抗原选自MAGEA3、人乳头瘤病毒E6/E7融合蛋白、人前列腺六跨膜上皮抗原蛋白或癌睾丸抗原。
成功的治疗性癌症疫苗将需要靶向在肿瘤上表达但在正常组织上不表达的肿瘤抗原。癌症种系抗原是异源蛋白质组,在几种类型的癌症中生理表达,但在分化的正常组织中不表达,除了由于缺乏MHC I分子而无法将抗原呈递给免疫系统的种系细胞。这些抗原由癌症种系基因编码。NY-ESO-1和MAGE-A3是典型的MAGE型抗原,其是如Gnjatic,S.等人(2006)Cancer Res.95:1–30中所述的组中最具代表性的两种抗原。同样,上文的CoulieP.G.等人(2014)也描述了显示在许多患者中发生的应答。
发明内容
根据本发明,提供了将核酸分子衣壳化的黑猩猩腺病毒(ChAd)载体,所述核酸分子包含编码以下的多核苷酸序列:(i)MAGE癌抗原和/或NY-ESO-1癌抗原,或其免疫原性片段;或(ii)MAGE癌抗原和/或LAGE1癌抗原,或其免疫原性片段,所述多核苷酸序列可操作地连接至表达控制序列和腺病毒包装信号序列,所述表达控制序列指导动物细胞中癌抗原或其片段的翻译、转录和/或表达。有利地,这样的ChAd病毒载体是稳定的并且被充分研究的,未被人腺病毒的抗体所中和并且被工程化为复制缺陷的。它们具有高容量用于插入的目标抗原,并且可以在含有腺病毒E1基因的HEK293细胞中产生。
MAGE型抗原是肿瘤特异性共享人类肿瘤抗原,已知其在癌症患者中诱导CD8 T细胞。它们在许多癌症类型中表达,在正常组织(除了不具有MHC-1分子的雄性种系细胞)中不表达。
NY-ESO-1(基因名称CTAG1)在许多癌症患者中诱导强烈的CD8应答,并且许多CD8表位可以被识别,如多种HLA I类特异性所示。
ChAd载体的特定形式可以是(a)如WO2012/172277中所公开的ChAdOx1;优选由WO2012/172277中公开的SEQ ID NO:38的多核苷酸或与其具有至少80%同一性的序列所编码的;或(b)如WO2017/221031中所公开的ChAdOx2;优选由WO2017/221031中公开的SEQ IDNO:10的多核苷酸或与其具有至少80%同一性的序列所编码的。
本发明还提供了将核酸分子衣壳化的改良的牛痘病毒安卡拉(MVA)载体,所述核酸分子包含编码以下的多核苷酸序列:(i)MAGE癌抗原和/或NY-ESO-1癌抗原,或其免疫原性片段;或(ii)MAGE癌抗原和/或LAGE1癌抗原,或其免疫原性片段,所述多核苷酸序列可操作地连接至表达控制序列,所述表达控制序列指导动物细胞中癌抗原或其片段的翻译、转录和/或表达。有利地,这样的MVA载体不能在人类中复制并且作为天花疫苗具有长期的安全追踪记录。用ChAd初免后,MVA可提供出色的增强免疫。MVA没有毒力和免疫系统逃逸因子,具有高免疫原性,很容易在鸡胚成纤维细胞或永生化鸭胚细胞系中产生。
更特定形式的MVA载体可以如WO2011/128704或EP 2044947 A1中所公开的。
对于本文所述的本发明的ChAd和/或MVA载体,MAGE抗原优选是MAGE3A,并且其具有SEQ ID NO:1的氨基酸序列或与其具有至少46%;优选至少69%;更优选至少95%的同一性的序列;或其任何免疫原性片段。
对于本文所述的本发明的ChAd和/或MVA载体,NY-ESO-1癌抗原具有SEQ ID NO:3的氨基酸序列或与其具有至少75%;优选至少76.7%的同一性的序列;或其任何免疫原性片段。
对于本文所述的本发明的ChAd和/或MVA载体,LAGE1抗原具有SEQ ID NO:5的氨基酸序列或与其具有至少78%;优选至少97%的同一性的序列;或其任何免疫原性片段。
在本发明的优选的ChAd和/或MVA载体中,所述多核苷酸序列可以进一步编码人类HLA II类组织相容性抗原γ链(hli或li),并且li可具有SEQ ID NO:6的氨基酸序列或与其具有至少79%的同一性的序列,或其片段,从而使癌抗原在动物细胞中作为与li或其片段的融合体来表达;更优选地,其中所述片段是跨膜结构域;甚至更优选地,其中所述跨膜结构域包含氨基酸残基30-55或30-61。在一个特别优选的实施方案中,所述跨膜结构域具有SEQ ID NO:7的氨基酸序列。
在本发明的另外的优选的ChAd和/或MVA载体中,所述多核苷酸序列可以进一步编码tPA,所述tPA具有SEQ ID NO:8的氨基酸序列或与其具有至少81%的同一性的序列,或其片段,从而使癌抗原在动物细胞中作为与tPA或其片段的融合体来表达;更优选地,其中所述片段包含21个氨基酸的前导序列;甚至更优选地,其中所述21个氨基酸的前导序列是SEQID NO:9。
有利地,包含li或tPA可增加病毒载体产生的抗原的免疫原性。这增加了抗原特异性T细胞应答的幅度、广度和持续时间。
可以构建本发明的ChAd载体,以使其具有编码以下的多核苷酸序列:(i)MAGE癌抗原或其免疫原性片段以及NY-ESO-1癌抗原或其免疫原性片段,其各自如本文所限定;或(ii)MAGE癌抗原或其免疫原性片段以及LAGE1癌抗原或其免疫原性片段,其各自如本文所限定,所述多核苷酸序列在动物细胞中作为融合蛋白表达。
可以构建本发明的MVA载体,以使其具有编码以下的多核苷酸序列:(i)MAGE癌抗原或其免疫原性片段和/或NY-ESO-1癌抗原或其免疫原性片段,其各自如本文所限定;或(ii)MAGE癌抗原或其免疫原性片段和/或LAGE1癌抗原或其免疫原性片段,其各自如本文所限定,所述多核苷酸序列在动物细胞中作为融合蛋白表达,其中所述MAGE癌抗原、NY-ESO-1癌抗原或LAGE1癌抗原中的至少一种是片段。
发明人认为,在人类中,NYESO-1可能比MAGEA3更具免疫原性。同样,在癌症患者中,在其中的某些组中,发现肿瘤更频繁地表达MAGEA3,而不是NY-ESO-1。因此,可能的担忧在于在本发明的初免-加强免疫方案中具有MVA加强载体,其包含MAGEA3和NY-ESO-1抗原两者,从而导致针对NY-ESO-1的免疫优势的免疫应答和针对MAGEA3的无效免疫。因此,至少对于这样的特定患者组或与NY-ESO-1相比具有较高的MAGEA3表达的组,仅包含MAGEA3癌抗原或其免疫原性片段的MVA载体在所述初免-加强免疫方案中是优选的。也就是说,在某些实施方案中,本发明不包括包含任何NY-ESO-1癌抗原或其免疫原性片段的MVA载体。同样地,在某些实施方案中,本发明不包括包含任何LAGE1癌抗原或其免疫原性片段的MVA载体。
在优选的实施方案中,每种MVA载体、每种MAGE癌抗原和NY-ESO-1、或MAGE癌抗原和LAGE1是免疫原性片段。
当构建本发明的ChAd和/或MVA载体以在表达时产生抗原融合体时,所述多核苷酸序列优选还编码5-9个氨基酸的合适的多肽接头;更优选地,所述多肽接头具有氨基酸序列GGGPGGG,当表达时,该序列以任何顺序连接MAGE和NY-ESO-1或LAGE1癌抗原或其片段作为融合蛋白。
因此,本发明还提供了包含以上和本文所述的ChAd或MVA载体的免疫原性组合物。这样的组合物可以进一步包含合适的佐剂。
本发明进一步提供了分离的多核苷酸,其包含编码包含在如本文所述的ChAd载体或MVA载体中的融合蛋白的序列。
优选的多核苷酸包含编码MAGEA3/接头/NY-ESO-1融合蛋白的核酸序列SEQ IDNO:10。其序列与SEQ ID NO:10具有至少70%同一性的多核苷酸也是可能的。翻译的501个氨基酸的蛋白序列如SEQ ID NO:11所示或是与其具有至少70%同一性的序列。
另一优选的多核苷酸具有编码hli/MAGEA3/接头/NY-ESO-1融合蛋白的核酸序列SEQ ID NO:12。其序列与SEQ ID NO:12具有至少70%同一性的多核苷酸也是可能的。翻译的蛋白序列如SEQ ID NO:13所示或是与其具有至少70%同一性的序列。
另一优选的多核苷酸具有编码tPA/MAGEA3/接头/NY-ESO-1融合蛋白的核酸序列SEQ ID NO:14。其序列与SEQ ID NO:12具有至少70%同一性的多核苷酸也是可能的。翻译的蛋白序列如SEQ ID NO:15所示或是与其具有至少70%同一性的序列。
在特定的实施方案中,分离的多核苷酸由上述序列的任一种或其变体组成。
在本发明的所有方面,编码所述抗原的所述多核苷酸优选经密码子优化以用于在人类中表达。本领域技术人员将熟悉许多可用的软件包,包括例如在美国专利号8,326,547或Puigbo,P.等人(2007)OPTIMIZER:A web server for optimizing the codon usage ofDNA sequences:Nucleic Acids Research,35:W126-W131中描述的那些。同样,可商购的服务和软件,例如Integrated DNA Technologies或GenScript提供的那些。
本发明还包括细菌人工染色体(BAC)克隆,其包含如本文所述的多核苷酸。如IsisInnovation Limited的WO2012/172277中所述(该文献通过引用并入本文),可以通过众所周知的方法将病毒基因组的BAC克隆转化到病毒中(“拯救”)。
本发明进一步包括分离的宿主细胞,其包含如本文所述的ChAd和/或MVA载体。
本发明还提供了一种在个体中预防或治疗癌症的方法,所述方法包括施用有效量的如本文所述的ChAd载体,和施用有效量的如本文所述的MVA载体,由此个体的适应性免疫系统被刺激以提供抗癌免疫应答。有利地,本发明的方法产生强烈的T细胞免疫应答,特别是强烈的CD8+免疫应答,从而导致持久的保护性免疫。
在根据本发明的预防或治疗癌症的优选方法中,ChAd和MVA载体的施用分开、循序或同时进行。
在根据本发明的预防或治疗癌症的特定方法中,进一步施用有效量的一种或多种免疫检查点调节剂。这种检查点调节剂可以与ChAd和MVA载体同时、分开或并行施用。
在本发明的预防或治疗癌症的方法方面,被治疗的个体可以是已经接受、正在接受或将要接受化学疗法和/或放射疗法治疗的个体。
在根据本发明的预防或治疗癌症的方法中,优选首先施用ChAd载体。
在本发明的癌症预防或治疗方法中,ChAd和MVA载体可以分别施用一次以上。在优选的方面,当将ChAd用作初次免疫时,则只施用一次,然后进行两次MVA加强免疫。其中ChAd和MVA载体交替施用的癌症治疗或预防方法也是可能的。
本发明的载体的每次施用之间的时间段可以在5天-8周的范围内;尽管,优选地,在初免和随后的一次或多次加强免疫之间使用约1周的时间段。
在本发明的癌症预防或治疗方法中,其中施用检查点调节剂并且也作为治疗方案的一部分,所述检查点调节剂可以是阻断PD-1、CTLA-4或PD-L1的抑制剂。有利地,将本发明的载体和免疫原性组合物与一种或多种检查点调节剂一起使用可用于减少达到同等效果(即,当单独使用时)所需的检查点调节剂的剂量。在本发明的病毒载体治疗方案和检查点调节剂之间,所述效果不是简单的相加,而是协同的。
特别优选的检查点调节剂可以选自纳武利尤单抗(nivolumab)帕博利珠单抗(pembrolizumab)伊匹单抗(ipilimumab)曲美利木单抗(tremelimumab)或阿替利珠单抗(atezolizumab)度伐利尤单抗(durvaliumab)或阿维鲁单抗(avelumab)
根据本发明的预防或治疗癌症的方法涉及表达癌症种系基因,优选编码MAGE型、NYESO和LAGE抗原的基因的癌症:优选涉及特定的癌症类型,例如,其中所述癌症为非小细胞肺癌(NSCLC)、黑色素瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、泌尿道(尿道上皮)癌、食道癌、膀胱癌、小细胞肺癌、肾癌、头颈癌、肉瘤或乳腺癌。
因此,本发明包括用于预防或治疗癌症的本发明的ChAd载体。本发明的MVA载体也可以用于预防或治疗癌症。关于这种用途,本发明的方法的各个方面中的每一个都同样适用。
此外,本发明包括如本文限定的本发明的ChAd载体和如本文限定的本发明的MVA载体,用于分开、循序或同时施用于患者以预防或治疗癌症。
如本文限定的用于预防或治疗癌症的ChAd和MVA载体可以进一步包括一种或多种癌症免疫周期或癌症免疫设定点的调节剂,如Chen,D.S.和Mellman,I.(2013)Immunity 39(1):1-10,以及Chen,D.S.和Mellman,I.(2017)Nature 541(7637):321-330所述;优选地,与用于治疗癌症的ChAd和MVA载体一起施用的检查点抑制剂。
目前,大部分晚期癌症患者对基于检查点调节剂的免疫疗法无应答。例如,在黑色素瘤、肾细胞癌、头颈癌和肺癌中使用抗PD1抑制剂的情况。在一个方面,本发明使用ChAd/MVA疫苗结合抗PD1和化学疗法来诱导针对MAGE-A3和NY-ESO-1的CD8 T细胞。不希望受到任何特定理论的束缚,本发明人预期,原本“冷”的肿瘤会被肿瘤特异性CD8 T细胞浸润,所述CD8T细胞会被抗PD1增强。
发明人还发现,与单独疫苗或疫苗加化学治疗剂或疫苗加检查点抑制剂相比,根据本发明的疫苗,加上化学治疗剂,加上检查点抑制剂的三联组合在小鼠模型中提供了显著改善的抗肿瘤效果以及显著的小鼠存活时间。实际上,所述三联组合的效果是协同的。通过三联组合可实现对髓源抑制性细胞(MDSC)的大量消耗。因此,本发明还提供了这种三联组合治疗方法及相应的医疗用途。本发明还提供了如前限定的ChAd载体、如前限定的MVA载体、化学治疗剂和检查点抑制剂,用于分开、循序或同时施用于患者以预防或治疗癌症。
所述化学治疗剂可以选自(但不限于)(a)卡铂或顺铂以及(b)紫杉醇、多西他赛(docetaxel)、长春瑞滨(vinorelbine)、吉西他滨(gemcitabine)、依托泊苷(etoposide)或培美曲塞(pemetrexed)中的一种。对于检查点抑制剂,它可以是PD-1。这种特定的三联组合可以为非小细胞肺癌(NSCLC)或小细胞肺癌(SCLC)、黑色素瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、泌尿道(尿道上皮)癌、膀胱癌、肾癌、头颈癌、肉瘤或乳腺癌提供有用的治疗。
作为本发明的一部分,还提供了包含如本文所述的ChAd和/或MVA载体的试剂盒,用于预防或治疗或癌症。这样的试剂盒包括至少一个容纳本发明的ChAd和/或MVA载体之一的容器。试剂盒可包含两个或更多个容器,即多重容器,每个容器具有本发明的不同病毒载体。试剂盒可包括使用载体作为疫苗的一组说明,其包括有关所用疫苗方案的基本信息,例如初免-增强免疫,以及多次施用之间的时间间隔。在更复杂的实施方案中,所述试剂盒可以包含根据本文所述的本发明的任何其他治疗元件,例如检查点调节剂。
附图说明
在下文中,将参考附图进一步描述本发明的实施方案,其中:
图1A示意性地示出了制备的编码小鼠P1A抗原的ChAdOx1载体。
图1B示出了对小鼠进行ChAdOx1-P1A/MVA-P1A初免-加强免疫的示意图,从所述小鼠中取得了外周血单个核细胞(PBMC)并测试了其免疫应答。
图2示出了在用如图1所示的编码P1A的ChAdOx1/MVA病毒载体免疫的小鼠中CD8+T细胞应答的结果。
图3示出了对小鼠DBA/2小鼠进行ChAdOx1-P1A/MVA-P1A初免-加强免疫预防性接种以抵御同系表达P1A的癌细胞系P815和15V4T3的攻击的示意图。
图4示出了,对于三种P1A抗原vs.磷酸盐缓冲盐水(PBS)对照,如图3所示对小鼠进行初免-加强免疫接种后P815肿瘤随时间的平均生长。
图5示出了图4所示的疫苗接种小鼠的Kaplan-Meier生存曲线。
图6A示出了如图3所示对小鼠进行ChAdOx1-IiP1A/MVA-P1A的初免-加强免疫接种后,或用细胞系L1210.P1A.B7.1免疫后,15V4T3肿瘤随时间的平均生长,与磷酸盐缓冲盐水(PBS)对照做了比较。
图6B示出了图6A所示的疫苗接种小鼠的Kaplan-Meier生存曲线。
图7示意性地示出了用于在治疗环境中在小鼠中测试初免-加强型PIA疫苗的疫苗接种方案,该方案涉及对确定的肿瘤的排斥。
图8A示出了在针对表达P1A的同系癌细胞系15V4T3的攻击的治疗环境中,在DBA/2小鼠中用不同的ChAdOx1-P1A/MVA-P1A初免-加强免疫接种方案接种后肿瘤体积随时间的增长。
图8B示出了初免加强疫苗接种方案(单次初免-加强,高剂量(108ChadOx/107MVA)后第25天的平均肿瘤生长。
图8C示出了图8所示的疫苗接种小鼠的Kaplan-Meier生存曲线。
图9示出了该实验中使用的疫苗接种方案,以显示在小鼠的治疗环境中,将ChAdOx1-IiP1A/MVA-P1A的初免-加强免疫接种与抗PD1检查点抑制剂治疗组合的效果。
图10示出了DBA/2小鼠中,针对表达P1A的同系癌细胞系15V4T3的攻击,使用ChAdOx1-IiP1A/MVA-P1A初免-加强免疫接种方案结合免疫检查点抑制剂后,肿瘤体积随时间的增长。
图11示出了图10所示的疫苗接种小鼠的Kaplan-Meier生存曲线。
图12示出了实验的示意图,其中用编码MAGE-A3(M)和NY-ESO-1(NY)蛋白的病毒载体对远交CD1小鼠进行疫苗接种,然后确定CD8+T细胞应答。
图13示出了CD8 T细胞的诱导(通过IFNγ产生测量),作为用ChAdOx-MAGEA3/NY-ESO-1融合体免疫远交CD1小鼠的结果,在有和没有恒定链li或tPA的情况下。在免疫后,将分离的PBMC用重叠的MAGEA3或重叠的NY-ESO-1肽进行离体刺激。
图14与图13所示相同,只是加上了在有或没有tPA的情况下用MVA-MAGEA3加强免疫的结果。
图15与图13所示相同,只是加上了在有或没有tPA的情况下用MVA-NY-ESO-1加强免疫的结果。
图16A示出了在用ChAdOx-M-NY、ChAdOx-tPA-M-NY或ChAdOx-Ii-M-NY初免,并用MVA-M、MVA-NY MVA-tPA-M或MVA-tPA-NY载体增强免疫后,PBMC中MAGE-A3和NYESO的特异性应答。
图16B示出了用MVA-M、MVA-NY MVA-tPA-M或MVA-tPA-NY载体第二次加强免疫后,PBMC中MAGE-A3和NYESO的特异性应答。
图17A示出了在用ChAdOx-Ii-MAGEA3/NY-ESO-1融合体免疫并用MVA-M、MVA-NY、MVA-tPA-M或MVA-tPA-NY载体加强免疫后,在远交CD1小鼠中诱导了针对MAGE-A3和NYESO的CD8 T细胞应答。
图17B示出了用MVA-M、MVA-NY MVA-tPA-M或MVA-tPA-NY载体第二次加强免疫后,MAGE-A3和NYESO的特异性应答。
图18示出了向小鼠中注射15V4T3细胞的时间线以及8个实验组小鼠中每组的后续治疗点。
图19显示了图18中所示实验的平均肿瘤生长结果图。结果通过双因素方差分析(2-way ANOVA)来分析。*=p<0.05。**=p<0.01。***=p<0.001。****=p<0.0001。
图20显示了对于8个实验组小鼠中的每一组,肿瘤体积随肿瘤植入后的时间而变化的图。
图21显示了8个实验组小鼠的每一组的Kaplan Meier存活图。数据通过对数秩检验(log-rank test)(Mantel-Cox)进行分析。*=p<0.05。**=p<0.01。
图22是显示8个实验组的小鼠在第27天采血时CD8细胞的IFNγ应答的图。
图23示出了向小鼠中注射15V4T3细胞的重复实验的时间线以及8个实验组小鼠的每组的后续治疗点。
图24示出了CD45+细胞的比例图,它们是(a)CD11b、(b)CD11b+和GR1hi+;或(c)CD11b和GR1int+,用于某些实验治疗和对照。
图25示出了CD45+细胞的比例图,它们是(a)CD11c,以及(b)CD11b+和CD11c+,用于某些实验治疗和对照。
图26示出了PBS对照、仅αPD1和两个小鼠实验组的疫苗接种时间线,所述两个实验组为:(1)低剂量的间隔一周的初免加强免疫(ChAdOx1-Ii-P1A+MVA-tPA-P1A)以及(2)低剂量的间隔一周的初免加强免疫(ChAdOx1-Ii-P1A+MVA-tPA-P1A)+αPD1。
图27示出了图26所示的每个实验小鼠和对照的平均肿瘤体积随时间的变化。
图28是示出了图26所示的每个实验小鼠和对照的肿瘤质量的图。
图29是如图25至28所示的每个对照组和实验组的每只个体动物的肿瘤生长率数据的图。
图30是显示在每个实验组和对照组的小鼠中,肿瘤浸润淋巴细胞(TIL)占肿瘤中总细胞的比例的图。
图31是显示在每个实验组和对照组的小鼠中CD4:CD8 T细胞的比例的图。
图32示出了在每个实验组和对照组的小鼠中肿瘤中CD4+:CD8+ TIL的比例的图(左图);以及T细胞(其是CD8+细胞)的百分比的图(右图)。
图33是显示在每个对照和实验小鼠组中CD3+ CD8+TIL计数的绝对数的图。
图34是显示在每个对照和实验小鼠组中P1A35-43四聚体+H-2Ld CD8+ TIL绝对计数的图。
图35是显示收获时P1A特异的CD8+TIL浸润与肿瘤质量之间的相关性的图。
图36是显示小鼠血液中CD8应答的图。
图38-40是显示小鼠脾脏中CD8应答的数据图。
图41-43是显示T细胞亚群分析的数据条形图。图43的图例适用于图41和42。
图44和45是显示进一步的T细胞亚群分析的数据条形图。图45的图例适用于图44。
图46显示了T细胞亚群分析的进一步的数据。
图47显示了T细胞上PD1表达的数据图。
图48显示了T细胞上PD1表达的进一步的数据。
图49显示了T细胞上PD1表达的进一步的数据。
图50显示了P1A特异的T细胞上PD1表达的数据图。
图51-53显示了P1A特异的T细胞上PD1表达的进一步的数据的图。
具体实施方式
根据本发明使用的合适的黑猩猩腺病毒载体详细描述于WO2012/17277IsisInnovations Limited,或WO 2005/071093 Istituto di Ricerche di BiologiaMolecolare P.Angeletti S.p.A,或Oxford University Innovation Limited的WO2017/221031,所有这些都通过引用并入本文。
特别优选的腺病毒载体是Vaccitech Ltd.,Oxford的黑猩猩腺病毒Oxford 1和2(ChAdOx1和ChAdOx2)。ChAdOx1是来自野生型分离株Y25(物种人类腺病毒E)的复制缺陷型E1/E3缺失的黑猩猩腺病毒载体,在Dicks M.D.等人(2012)PLoS ONE 7:e40385中进行了描述。ChAdOx2是衍生自ChAd68的E1/E3缺失疫苗载体,具有修饰的E4区以提高在HEK293细胞中的病毒产量。
本发明的ChAd载体可以是(a)如WO2012/172277中所公开的ChAdOx1;优选由WO2012/172277中公开的SEQ ID NO:38的多核苷酸或与其具有至少80%同一性的序列所编码的;或(b)如WO2017/221031中所公开的ChAdOx2;优选由WO2017/221031中公开的SEQ IDNO:10的多核苷酸或与其具有至少80%同一性的序列所编码的。技术人员将理解,如本文进一步描述的,本发明中使用的ChAd载体可以包括所有核酸序列的同源物、等同物和衍生物。
根据本发明使用的合适的改良的牛痘安卡拉(MVA)载体具体描述于WO2011/128704或EP 2044947 A1,其各自通过引用并入本文。
由本发明的任何病毒载体编码和表达的癌抗原,其无论是单独的还是彼此融合的形式以及任选地与其他多肽的融合形式,优选是免疫原性的,如本文所限定的,并且包括癌抗原的片段及其彼此之间的融合体以及与其他多肽的融合体。
如本文所用,“抗原”通常等同于蛋白质或多肽的一个或多个表位,包括其融合体、片段和变体。这样的片段和变体可以保留与亲本抗原基本相同的生物学活性或功能。“抗原性”通常是指蛋白质或多肽或片段能够用于产生抗体或T细胞,因此能够在受试者中诱导抗体或T细胞应答。“免疫原性”是指蛋白质或多肽或片段能够在受试者中引发有效的并且优选地保护性免疫应答。因此,在后一种情况下,蛋白质或多肽或片段可能能够产生抗体应答和基于非抗体的免疫应答。
如本文所用,每当提及与参考序列具有同一性的核酸序列时,同一性的程度可选自以下任何一种,其中“至少”适用于此处列出的每个百分比数字:至少46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98.1%、98.2%、98.3%、98.4%、98.5%、98.6%、98.7%、98.8%、98.9%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%。为了确定同源性或同一性程度而比较核酸序列时,可以使用例如BESTFIT和GAP的程序(两者均来自Wisconsin Genetics Computer Group(GCG)软件包)。例如,BESTFIT比较两个序列,并生成最相似片段的最佳比对。GAP使序列能够沿其全长进行比对,并通过在任意一个序列中适当插入间隔来找到最佳比对。适当地,在本发明的上下文中,当讨论核酸序列的同一性时,通过沿序列的全长进行序列比对来进行比较。以上加上必要的变更,适用于本申请中公开的所有核酸序列。
另外,技术人员还将理解,鉴于遗传密码的简并性,与本文示例的特定核酸分子的变异是可能的。优选地,此类变体在其整个长度上与本文所述的核酸序列具有可观的同一性。
考虑到结合本发明描述的任何氨基酸序列,这包括这些氨基酸序列的变体。如本领域技术人员所熟知的,对于本文公开的给定起始或参考序列,一个或多个氨基酸残基可以以任何组合被取代、缺失或添加。优选的改变是沉默取代、添加和缺失,其不改变本发明蛋白质的特性和活性。各种氨基酸具有相似的性质,并且一种或多种这样的氨基酸可以被一种或多种其他这样的氨基酸取代,而不会消除该物质的期望的免疫原性或其他活性。因此,氨基酸甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸通常可以互相取代——它们具有脂肪族侧链。其中,优选使用甘氨酸和丙氨酸互相取代。同样,缬氨酸、亮氨酸和异亮氨酸可用于彼此取代——它们具有较大的疏水性脂族侧链。苯丙氨酸、酪氨酸和色氨酸可以互相取代——它们是具有芳香族侧链的氨基酸。赖氨酸、精氨酸和组氨酸可以互相取代——它们是具有碱性侧链的氨基酸。天冬氨酸和谷氨酸可以互相取代——它们具有酸性侧链。天冬酰胺和谷氨酰胺可以互相取代——它们具有酰胺侧链。半胱氨酸和蛋氨酸可以互相取代——它们具有含硫的侧链。
如本文所述,“变体”包括天然存在的变体或人工变体。人工变体可以使用诱变或基因工程或基因编辑技术来生成,包括应用于核酸分子、细胞或生物体的那些。如本文所用,每当提及与参考序列具有同一性的氨基酸序列时,同一性的程度可选自以下任何一种,其中“至少”适用于此处列出的每个百分比数字:至少46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98.1%、98.2%、98.3%、98.4%、98.5%、98.6%、98.7%、98.8%、98.9%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%。本领域技术人员可以使用例如CLUSTAL程序的程序来比较氨基酸序列。该程序比较氨基酸序列,并通过在任何一个序列中适当插入间隔来找到最佳比对。可以计算氨基酸同一性或相似性(同一性加上氨基酸类型的保守性)以用于最佳比对。如BLASTx的程序将比对最长的相似序列片段,并为拟合指定一个值。因此,可以在发现多个相似区域的情况下进行比较,每个区域具有不同的得分。以上加上必要的变更,适用于本申请中公开的所有氨基酸序列。
特别优选的MVA载体是Anton Mayr在CEF中传代570次后产生的标准MVA,如本领域中最常用的。这是一种高度减毒的牛痘病毒株,是在根除天花的过程中开发的。MVA失去了约10%的牛痘基因组,并因此失去了在灵长类细胞中有效复制的能力。
关于MAGE人类癌抗原,MAGE家族由大约40个成员组成。MAGE-A蛋白共享至少46%的序列同一性、明确的生化结构和特性。MAGE-A3在癌症的主要形式中显著表达并且其表达与阴性结果相关。MAGE-A3氨基酸序列与其他MAGE-A家族成员的比对得出以下同一性百分比值:
上述每种MAGE抗原均可用于本发明,如可以根据与SEQ ID NO:1的MAGEA3参考序列的任何百分比同一性来限定的。
关于NY-ESO-1,这是已知的180个氨基酸的癌抗原。所述序列与LAGE-1具有76.6%的同一性。几项研究试图明确该序列的免疫原性。主要区域的范围从NY-ESO-1的aa 79到173。Gnjatic S,等人(2006)Adv.Cancer Res.vol 95:1–30;Sabbatini P,等人(2012)Clin.Cancer Res.Vol 18(23):6497-508;以及Baumgaertner P,等人(2016)Oncoimmunology vol 9:5(10)报道了黑色素瘤或卵巢癌如何突出了特定的目标片段。这些是在本发明的任何方面中使用的每个选项:
·NY-ESO-1 79-173
·NY-ESO-1 79-108
·NY-ESO-1 100-129
·NY-ESO-1 121-150
·NY-ESO-1 42-173
LAGE1也是一种已知的癌症抗原,并且它或其片段也可以与MAGEA3一起用于本发明的病毒载体以及方法和用途。
佐剂可用于组合物中用于递送本文所述的本发明的AdCh和/或MVA载体。有利地,可以对这些病毒载体进行工程改造,以使其包含编码癌抗原或片段与CD74、MHC II类恒定链(li)之间的融合蛋白的多核苷酸构建体。预期这将导致增强的CD8+ T细胞免疫原性。有关如何制成此类蛋白质融合体以及优选的li序列的更多详细信息在Isis InnovationLimited的WO2015/082922中提供,所述文献通过引用并入本文。
可以设计本发明的病毒载体以将一种或多种抗原基因表达为表位串(epitopestring)。优选地,多个表位的串中的表位在没有插入序列的情况下连接在一起,从而避免了不必要的核酸和/或氨基酸物质。所述表位串的创建优选使用重组DNA构建体来实现,所述重组DNA构建体编码表位串的氨基酸序列,其中DNA在同一阅读框中编码一个或多个表位。或者,所述抗原可以表达为单独的多肽。
抗原的任何片段,无论是分开的还是在所述的表位串中,优选包含来自亲本抗原的序列的至少n个连续氨基酸,其中n优选地为至少或大于7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、57、58、59、60、70、80、90或100个氨基酸。片段优选包括亲本抗原的一个或多个表位。在某些情况下,片段可以包含亲本抗原的单个表位或仅由其组成。通常,所述片段将与亲本区域或表位足够相似,从而保持抗原/免疫原特性。
本发明中使用的一种或多种抗原或抗原基因可以在C末端和/或N末端被截短。这可以促进载体疫苗的克隆和构建和/或增强抗原的免疫原性或抗原性。用于截短的方法是本领域技术人员已知的。例如,可以使用各种众所周知的基因工程技术来选择性地删除抗原基因任一端的编码核酸序列,然后将所需的编码序列插入病毒载体中。例如,使用3'和/或5'核酸外切酶策略选择性地分别侵蚀编码核酸的3'和/或5'端来截短候选蛋白。可以截短野生型基因序列,使得表达的抗原相对于亲本抗原可以被截短1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个或更多个氨基酸。在一些情况下,所述抗原基因(在表达时)相对于野生型抗原在C-末端被截短10-20个氨基酸。在其他情况下,所述抗原基因(在表达时)相对于野生型抗原在C-末端被截短13-18个氨基酸,优选(在表达时)被截短15个氨基酸。
在某些情况下,抗原基因可能包含一个前导序列,这可能会影响初级转录物向mRNA的加工、翻译效率、mRNA稳定性,并可能增强抗原的表达和/或免疫原性。与本发明有关,也可以起佐剂作用的一些优选的前导序列是组织纤溶酶原激活物(tPA)或MHC II伴侣蛋白恒定链(li)。优选地,所述前导序列位于所述一种或多种抗原的N-末端。
本发明包括药物组合物或免疫原性组合物,其包含本发明的一种或多种病毒载体;任选地与一种或多种额外的活性成分、药学上可接受的载体、稀释剂、赋形剂或佐剂组合。优选地,所述组合物是免疫原性组合物和/或抗原性组合物。
合适的佐剂是本领域众所周知的,包括不完全的弗氏佐剂、完全的弗氏佐剂、具有MDP(胞壁酰二肽)的弗氏佐剂、明矾(氢氧化铝)、明矾加上百日咳博德特氏菌(Bordatellapertussis)以及免疫刺激复合物(ISCOM,通常是包含病毒蛋白的Quil A基质)。
本发明的免疫原性组合物和/或抗原性组合物可以是预防性的(其中它们诱导防止癌症形成的免疫应答)或治疗性的(其中它们诱导具有抗癌活性的免疫应答)。
将本发明的载体或组合物以单次免疫或多次免疫的形式施用于个体受试者。优选地,病毒载体或其免疫原性组合物作为单一、双重或三重免疫方案的一部分施用。它们也可以作为同源或异源初免-加强免疫方案的一部分施用。
免疫方案可以包括本发明的病毒载体或免疫原性组合物的第二次或后续施用。所述第二次施用可以在短时间段或长时间段内施用。剂量可以在第一次施用后数小时、数天、数周、数月或数年的时间内施用,例如多达或至少1、2、3、4、5、6、7、8、9或10个或更多周,或0.25、0.5、0.75、1、5、10、15、20、25、30、35或40年或更多年。优选地,所述第二次施用发生在第一次施用之后至少2个月。优选地,所述第二次施用发生在第一次施用之后多达10年。优选地,这些时间间隔,加上必要的变更,适用于任何后续剂量之间的时间段。
就施用而言,本发明的病毒载体可以以如下一种或多种剂量的量施用:10、100、103、104、105、106、107、108、109、1010、1011、1012、1013、1014或更多个病毒颗粒(vp)。
施用可以通过腹膜内、静脉内、动脉内、肌内、皮内、皮下或鼻内施用。在优选的实施方案中,所述病毒载体是全身施用的,特别是通过血管内施用,其包括注射、灌注等。
免疫检查点调节剂(激动剂或抑制剂)是一种用于治疗癌症的免疫疗法。它们调节检查点蛋白,所述检查点蛋白是已知可调节攻击癌细胞的T细胞的蛋白。根据本发明使用的检查点抑制剂是检查点调节剂的一部分,其阻断不同的检查点蛋白,包括CTLA-4(细胞毒性T淋巴细胞相关蛋白4)、PD-1(程序性细胞死亡蛋白1)或PD-L1(程序性死亡配体1)。在T细胞上发现了CTLA-4和PD-1,而在癌细胞上发现了PD-L1。用于阻断PD-1的合适的检查点抑制剂包括纳武利尤单抗帕博利珠单抗并且可以与本发明的疫苗接种方法一起使用,用于治疗患有癌症的患者,所述癌症如黑色素瘤、霍奇金淋巴瘤、非小细胞肺癌、泌尿道(尿道上皮)癌、膀胱癌等。用于阻断CTLA-4的合适的检查点抑制剂包括伊匹单抗并且可以与本发明一起使用,用于治疗黑色素瘤。用于阻断PD-L1的合适的检查点抑制剂包括阿替利珠单抗并且可以与本发明一起使用,用于治疗包括肺癌、乳腺癌和尿路上皮癌的癌症。
在本发明的方法和用途的操作中可用的免疫检查点调节剂的其他合适靶标包括例如选自以下的任何靶标:AMHRII、B7-H3、B7-H4、BTLA、BTNL2、嗜乳脂蛋白家族、CD27、CD28、CD30、CD40、CD40L、CD47、CD48、CD70、CD80、CD86、CD155、CD160、CD226、CD244、CEACAM6、CLDN6、CCR2、CTLA4、CXCR4、GD2、GGG(鸟苷酸环化酶G)、GIRT、GIRT配体、HHLA2、HVEM、ICOS、ICOS配体、IFN、IL1、IL1R、IL1RAP、IL6、IL6R、IL7、IL7R、IL12、IL12R、IL15、IL15R、LAG3、LIGHT、LIF、MUC16、NKG2A家族、OX40、OX40配体、PD1、PDL1、PDL2、Resokine、SEMA4D、Siglec家族、SIRPalpha、STING、TGFβ家族、TIGIT、TIM3、TL1A、TMIGD2、TNFRSF、VISTA、4-1BB和4-1BB配体。
检查点调节剂的更全面的综述由Mahoney,A.M.等人,(2015)Nature ReviewsDrug Discovery vol 14:561–584提供(特别参见图1)。
检查点调节剂的施用可以与本发明的初免或一种或多种加强免疫同时进行。因此,这提供了组合治疗,用于预防或治疗目的。作为同时施用的一种改进,检查点调节剂可以基本上在初免和/或加强施用后施用,实际上是同时施用。或者可能与初免和/或加强施用有时间延迟地按顺序施用。相对于初免和加强免疫施用,延迟可能有所不同,并且可能足够长,使得检查点调节剂在疫苗施用之间要在时间上分开施用。将检查点调节剂与本发明的免疫原性组合物分开施用可导致每次施用之间相等的时间段。在一些情况下,可以在使用本发明的基于ChAd的免疫原性组合物进行初免疫苗接种之前,施用检查点调节剂。
在一种或多种检查点调节剂的背景下的“组合治疗”设想了同时、循序或分开施用组合的成分。例如,同时施用本发明的病毒载体和检查点抑制剂。例如也可以按顺序施用本发明的病毒载体以及一种或多种检查点抑制剂。此外,存在分开施用本发明的病毒载体以及一种或多种检查点抑制剂的实例。在病毒载体和检查点抑制剂循序施用或分开施用的情况下,可以在允许治疗剂显示合作(协同)效应的时间间隔内施用病毒和检查点抑制剂。在优选的实施方案中,本发明的病毒载体和一种或多种检查点抑制剂在彼此的1、2、3、6、12、24、48、72小时内,或在4、5、6或7天内,或在8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天内施用。在一些实施方案中,第一剂本发明的病毒载体在第一剂检查点抑制剂之前施用,反之亦然,并且可以包括用病毒载体和检查点抑制剂重叠治疗的阶段。在其他实施方案中,第一剂本发明的病毒载体可以与第一剂检查点抑制剂同时或大约同时施用。在其他实施方案中,第一剂本发明的病毒载体在第一剂(或第二、第三或后续剂次)检查点抑制剂之后施用,并且可以包括用病毒载体和检查点抑制剂重叠治疗的阶段。
实施例
材料和方法
病毒载体构建
插入病毒载体的基因序列、为了翻译效率优化的密码子由GeneArt(ThermoFisherScientific)合成为DNA串或质粒。为了构建黑猩猩腺病毒载体(ChAdOx),将DNA串插入物和p1990骨架(入门载体)用限制酶KpnI/NotI消化,然后通过过夜孵育连接。将编码目的基因序列的质粒p1990转化到DH5αTM感受态大肠杆菌中,然后通过PCR方法筛选阳性克隆。阳性克隆的DNA通过中量质粒提取(midiprep)扩增,然后使用LR克隆酶(clonase)在含有基因插入物的p1990和p2563[SEQ ID NO:24](ChAdOx目的载体)之间进行(ThermoFisher Scientific)克隆。p2563目的载体DNA通过细菌转化、大量质粒提取(maxiprep)和重力柱纯化进行扩增。将p2563目的载体用Pme1消化以线性化DNA,然后送出以进行病毒生产。
更全面的技术信息,包括用于产生ChAdOx1载体的核酸序列和保藏的生物材料的来源,公开于Isis Innovation Limited的WO2012/172277,其通过引用并入本文。更全面的技术信息,包括用于产生ChAdOx2载体的核酸序列和生物材料的来源,公开于OxfordUniversity Innovation Limited的WO2017/221031,其通过引用并入本文。
通过引用并入本文并提供用于产生本发明的ChAdOx病毒载体的更多材料和方法信息的其他相关公开内容是Dicks,M.D.J.,等人(2012)“A Novel Chimpanzee AdenovirusVector with Low Human Seroprevalence:Improved Systems for Vector Derivationand Comparative Immunogenicity”PlosOne e40385。
为了产生改良的牛痘安卡拉(MVA)载体,使用聚合酶(ThermoFisherScientific)通过PCR扩增GeneArt DNA串或质粒,以确保InFusion反应的正确悬垂。然后将基因插入物和p4719[SEQ ID NO:25](MVA目的载体)用限制酶Ale I消化。然后使用InFusion方法连接扩增的插入物和p4719。将连接的质粒转化到DH5αTM感受态大肠杆菌中。筛选阳性克隆,并通过中量质粒提取扩增DNA。用Xho1+Acc651进行了最终消化以线性化DNA,然后进行病毒生产。
更全面的技术信息,包括用于产生和再生产本发明所需的MVA载体的核酸序列和保藏的生物材料的来源,公开于Isis Innovation Limited的WO2011/128704以及EP2044947 A1,它们中的每一个均通过引用整体并入本文。通过引用并入本文并提供用于产生本发明的MVA病毒载体的更多材料和方法信息的其他相关公开内容是Pavot V.,Sebastian S.,Turner A.V.,Matthews J.,Gilbert S.C.(2017)“Generation andProduction of Modified Vaccinia Virus Ankara(MVA)as a Vaccine Vector”In:Ferran M.,Skuse G.(eds)Recombinant Virus Vaccines,Methods in MolecularBiology,vol 1581Humana Press,New York,NY。
肽生产
覆盖整个P1A、MAGE-A3和NY-ESO-1蛋白的长度为15个氨基酸的短肽重叠库订购并生产于Mimotopes of Mulgrave,Victoria,澳大利亚。
小鼠
六至八周龄的C57BL/6、DBA/2和CD1小鼠购自Envigo,英国,并安置在英国牛津大学功能基因组学研究所。小鼠照管和实验程序根据英国动物科学程序法项目许可证30/2947的条款进行。
体内研究
为了评估疫苗的免疫原性,在全身麻醉下,以图中所示的剂量(总体积50μl)通过肌内(i.m.)注射向小鼠施用生产的ChAdOx1和MVA病毒载体。根据每个实验的详细方案,在多个时间点进行疫苗接种。用活的L1210.P1A.B7-1细胞通过腹膜内注射进行免疫接种。为了获得用于离体试验的PBMC,通过尾静脉抽血对血液进行采样,并用ACK裂解缓冲液处理血液以去除红细胞。
产生了十种不同的重组病毒疫苗(见下表1),并在感染细胞中证实了抗原表达。
表1:
这些表达P1A抗原的病毒载体疫苗的免疫原性在三种不同的小鼠品系(包括DBA/2、C57BL/6和CD1远交小鼠)中进行了测试。
离体肽刺激
将分离的小鼠PBMC或脾细胞悬浮在补充有10%FCS的RPMI 1640培养基中,并将其加至V型底96孔板中。通过将P1A、MAGE-A3或NY-ESO-1肽或DMSO对照(以工作浓度4mg/ml),连同抗CD28抗体(2μg/ml)和DNase(20μg/ml)添加至培养基中来刺激所述细胞。将肽刺激的细胞在5%CO2中于37℃培养5小时,并在1小时后添加Brefaldin A,以促进细胞内细胞因子的积聚。
流式细胞术–细胞内细胞因子染色
肽刺激后,将PBMC用PBS洗涤,并通过与Aqua活/死可固定染料(Invitrogen)和抗CD8/抗CD4抗体在PBS中于4℃孵育20分钟,来进行关于表面标记/生存力的染色。为了评估产生细胞因子的活化细胞的百分比,然后用CytoFix/CytoPerm(BD Biosciences)将细胞固定并透化,并在1x透化缓冲液(perm buffer)(BD Biosciences)中与抗-IFN-γ、抗-TNF-α以及抗-IL-2抗体于4℃孵育20分钟。在BD Fortessa上采集样品,并使用FlowJo软件(TreeStar,Inc.)进行分析。
统计学分析
所有统计学检验和分析均使用GraphPad Prism软件进行。使用Kruskal-Wallis非参数方差分析确定多个组之间的差异,使用Mann-Whitney非参数t检验确定各个组之间的差异。
实施例1:通过用ChAdOx/MVA进行免疫接种,来诱导针对P1A的CD8 T细胞
P1A是鼠类MAGE型抗原,其可被用于确认同系宿主中针对非突变型MAGE型抗原的CD8应答的诱导,并诱导针对表达P1A的肿瘤P815的保护。它是MAGE-A3和NY-ESO-1的替代物。
图1B示出了对小鼠进行初免-加强免疫接种的示意图,从所述小鼠中取得了外周血单个核细胞(PBMC)并测试了其疫苗接种应答。图2示出了以编码P1A的ChAdOx1/MVA病毒载体接种的小鼠中的CD8+ T细胞应答。根据疫苗接种方案的时间线(图1)–用ChAdOx1.P1A或ChAdOx1.P1A-Ii(初免)接种BL/6、DBA/2和CD1小鼠,然后在4周后接种MVA.P1A(加强)。为了测试P1A特异的T细胞应答,用P1A肽库离体刺激PMBC,并通过流式细胞术分析产生I型细胞因子的细胞百分比。测量产生细胞因子IFN-γ(A)和TNF-α(B)的CD8+细胞的百分比(n=6只/组)。如IFN-γ和TNF-α的细胞内染色所示,异源的初免-加强免疫疫苗接种在所有三个小鼠品系中诱导了针对P1A的强CD8应答(图2)。当P1A与MHC II伴侣蛋白恒定链(li)融合时,所述应答会进一步增强。这些结果在DBA/2小鼠中通过IFN-γELISPOT试验和P1A特异性四聚体染色得到了证实(结果未示出)。
总体而言,观察到的是DBA/2、B6和远交CD1小鼠中的非常强的CD8应答。通过在ChAdOx载体中添加li,CD8应答增强。结果发现,当CD8 T细胞被重叠的肽诱导时,它们会分泌IFNγ、IL2和TNFα。CD4对P1A的应答几乎没有(没有CD4表位是已知的)。
实施例2:评估携带P1A的ChAdOx1和MVA病毒载体针对肿瘤形成的保护功效
作为评估针对肿瘤攻击的疫苗保护功效的一部分,向小鼠一侧皮下注射无血清细胞培养基中的肿瘤细胞。出现明显的肿瘤后,记录其生长,并且一旦肿瘤尺寸在任意方向上达到10mm,就将小鼠安乐死。使用公式:长度(mm)x宽度2(mm)x 0.5,测量肿瘤体积。根据Kaplan-Meier方法绘制存活曲线,并使用对数秩检验检验存活上的差异。P值低于0.05被认为是显著的。
更详细地,将DBA/2小鼠用PBS、活L1210.P1A.B7-1细胞免疫或间隔4周给予ChAdOx1-P1A(±Ii)/MVA-P1A初免-加强免疫,然后在一侧用1.5x106个P815细胞或1x106个15V4T3细胞通过皮下注射攻击。P815和15V4T3是同系的P1A阳性肥大细胞瘤细胞系。所述15V4T3细胞被描述于Boon T,Van den Eynde B,Hirsch H,Moroni C,De Plaen E,van derBruggen P,De Smet C,Lurquin C,Szikora JP,De Backer O.(1994)“Genes coding fortumor-specific rejection antigens”Cold Spring Harb Symp Quant Biol.59:617-22。
在P815攻击(图4)和15V4T3(图7A)之后,每个治疗组的平均肿瘤生长。示出了P815(图5)、15V4T3(图7B)的Kaplan-Meier生存曲线,n=10只/组。
如图4和5所示,与PBS对照组相比,用P1A进行的腺病毒初免和MVA加强疫苗接种在接种的小鼠中显著降低了肿瘤的生长并提高了存活率。有趣地,与用L1210.P1A B7.1细胞免疫的阳性对照组相比,接种Ii_P1A的组的肿瘤体积更小、存活率更高。先前已证明此细胞系可诱导非常强的P1A特异性细胞毒活性,并具有针对P1A阳性肿瘤攻击的保护作用(参见Brandle D.等人(1998)Eur.J.Immunol.28(12):4010–4019和Naslund T.I.等人(2007)J.Immunol.178(11):6761-6769)。这表明,由接种疫苗激发的免疫应答在保护小鼠免受P815肿瘤侵袭方面是有效的。图6A和6B显示了使用其他P1A阳性肿瘤细胞系15V4T3观察到的相同结果。
总体而言,所观察到的是,在表达P1A的不同的肿瘤模型P815和15V4T3中(还有V4D6–数据未示出)中,与抗肿瘤攻击的保护和增加的存活率相关的CD8应答。与阳性对照细胞疫苗相比,所述初免-加强免疫方案可提供更好的保护。还观察到恒定链(li)-P1A融合体在载体中的表现如何比单独的P1A更好。任何肿瘤经过长时间的治疗后摆脱了生长降低的影响时,这些肿瘤丧失了P1A表达(数据未示出)。
实施例3:评估携带P1A的ChAdOx1和MVA病毒载体的疫苗治疗功效
进行实验以评估疫苗的治疗功效。建立15V4T3肿瘤后,从5天后开始用ChAdOx载体对小鼠进行初免,然后在第26天用MVA载体进行加强免疫。疫苗接种方案如图7所示。测试了三种不同的疫苗接种方案。通过腹侧皮下注射,用1x106个15V4T3细胞攻击DBA/2小鼠,然后在攻击后5天接受:间隔三周的单次标准剂量的ChAdOx-P1A(108IU)/MVA-P1A(107PFU)初免-加强疫苗接种、间隔三周的单次低剂量初免-加强疫苗接种(ChAdOx–107IU,MVA–106PFU)、每周一次交替的低剂量ChAdOx-P1A/MVA-P1A疫苗接种或每周一次的ChAdOx/MVA疫苗接种,其编码对照抗原DPY。然后监测每个治疗组中15V4T3肿瘤的生长和存活率。
如图8所示,与用表达无关蛋白DPY的病毒载体接种的对照组相比,在接种疫苗的小鼠中肿瘤的生长显著延迟。此外,单次标准剂量的初免-加强免疫显示出针对肿瘤攻击的最佳的保护和存活率。但是,所述接种疫苗的小鼠在后期(第6周)开始失去控制肿瘤生长的能力。
因此在15V4T3模型中观察到了治疗功效。
实施例4:评估ChAdOx1-P1A/MVA-P1A初免-加强疫苗接种方案与免疫检查点抑制
剂组合的治疗功效
为了获得更好的肿瘤保护并提高疫苗功效,将疫苗与检查点抑制剂阻断组合,使用相同的15V4T3肿瘤模型,用表达P1A的同系15V4T3肿瘤细胞接种DBA/2小鼠。通过腹侧皮下注射,用1x106个15V4T3细胞攻击DBA/2小鼠,然后在攻击后第8天根据肿瘤大小随机分为不同的治疗组。小鼠接受PBS(假处理组)疫苗接种,每周一次ChAdOx/MVA疫苗接种——单独或与抗PD1或抗CTLA-4抗体组合(3剂,间隔3天),或仅抗PD1或抗CTLA-4抗体。在整个过程中监测并记录每个治疗组中15V4T3肿瘤的生长(图10)和存活(图11)。出现明显的肿瘤后,测量肿瘤大小并将小鼠随机分为不同的组。如图10(左图)所示,与对照组和单一疗法组的小鼠相比,接受组合疗法的小鼠的肿瘤生长被大大延迟了。此外,接受抗PD1和疫苗组合疗法的小鼠中有100%存活到肿瘤攻击后第36天,在抗CTLA4和疫苗治疗组中有50%的小鼠存活,而其他小鼠的存活均较差。
在15V4T3模型的治疗环境中观察到了疫苗+抗PD1的协同作用。
实施例5:评估CD1远交小鼠中MAGE-A3和NY-ESO-1的免疫原性
确立了来自编码小鼠P1A基因的载体的应答后,产生并测试了编码人MAGE型抗原的载体构建体。在CD1远交小鼠中测试了不同形式的人类MAGE型抗原、MAGE-A3和NY-ESO-1的免疫原性。将MAGE-A3和NY-ESO-1作为融合蛋白在黑猩猩腺病毒载体中克隆,而将它们在MVA中单独克隆。这是由于两个主要原因。首先,腺病毒载体疫苗的生产要比MVA昂贵。为了制备用于临床环境,仅包括一种表达MAGE-A3和NY-ESO-1的融合体的单一腺病毒载体疫苗的目的是将成本最小化。其次,某些人类肿瘤表达MAGE-A3或NY-ESO-1。为了诱导针对肿瘤的更特异性的应答,靶向由肿瘤表达的特定抗原以用于加强免疫。更详细地,按照时间线对小鼠进行疫苗接种(图12)——用编码MAGE-A3-NY-ESO-1±Ii或tPA的ChAdOx1进行初免,然后用编码MAGE-A3或NY-ESO-1、±tPA的MVA进行两次加强免疫(第二次MVA加强免疫包含第一次MVA加强免疫的替代抗原)。每次疫苗接种后在指定的时间点评估抗原特异性T细胞应答——收获PBMC并用MAGE-A3(蓝色圆圈)或NY-ESO-1(红色方块)肽离体刺激,并通过流式细胞术分析IFN-γ+应答细胞的百分比。
图13示出了在向远交CD1小鼠初次注射ChAdOx1-MAGE-A3/NY-ESO-1融合体(M-NY)、具有tPA的ChAdOx1-MAGE-A3/NY-ESO-1融合体(tPA-M-NY)以及具有恒定链的ChAdOx1-MAGE-A3/NY-ESO-1融合体(li-M-NY)后,针对MAGE-A3/NY-ESO-1的CD8 T细胞的诱导。两周后,将PBMC分离,并通过离体细胞内细胞因子染色测试了对MAGE-A3重叠肽(红色圆圈)和NY-ESO-1重叠肽(蓝色方块)的应答。初免后的CD8 IFNγ应答表明,含有融合蛋白的ChAdOx初免可引发针对这两种抗原的特异性CD8 T细胞。
然后,使用以下对ChAdOx初免的小鼠进行加强注射:(i)包含MAGEA3的MVA,有或没有与tPA融合;以及(ii)含有NY-ESO-1的MVA,有或没有与tPA融合。然后从这些小鼠中再次分离出PBMC,并在用重叠肽刺激后,使用离体细胞内细胞因子染色测试了MAGEA3和NY-ESO-1应答。图14显示了MVA-MAGEA3±tPA加强免疫的效果,图15显示了MVA-NY-ESO-1±tPA加强免疫的效果。在图14和15的每一个中,将图13作为左手部分包括在内,是为了方便将加强免疫效果与仅初免的效果做比较。由此可见,使用MVA,针对所选择的两种抗原的任一种的最初的初免应答都被加强到高得多的水平。
作为初免的ChAdOx-恒定链(li)和MVA-tPA似乎是最具免疫原性的方案,取决于样本量和具有一定程度变异性的远交小鼠的使用。
在双重加强免疫中,最初的初免应答同时增加到更高的水平(数据未示出)。观察到的应答与其他I型细胞因子广泛匹配(数据未示出)。
考虑到抗原特异性T细胞似乎被加强到高得多的水平的频率以及针对所选抗原的应答,本发明可以允许采用更具个性化的方法根据所关注的个体肿瘤的特定表达模式来预防或治疗。
图16A示出了用MVA-M、MVA-NY、MVA-tPA-M或MVA-tPA-NY载体加强免疫后,CD8+细胞中IFN-γ+细胞的百分比。图16B示出了用MVA-M、MVA-NY、MVA-tPA-M或MVA-tPA-NY载体的任一个第二次加强免疫后,CD8+细胞中IFN-γ+细胞的百分比。
当用表达融合体MAGE-A3和NY-ESO-1的腺病毒对小鼠进行初免,并用表达MAGE-A3或NY-ESO-1的MVA加强免疫时,增加的CD8应答针对由MVA表达的抗原(图14和15)。同样,用两种MVA(MVA_MAGEA3和MVA_NYESO)对小鼠进行加强免疫可诱导相似水平的针对这两种抗原的CD8应答。
如Bolhassani A.等人(2011)Mol.Cancer.10:3中所述,抗原的免疫原性可以通过将基因与某些分子佐剂融合来增强。其中,人类组织纤溶酶原激活物(tPA)信号肽(参见Delogu G.等人(2002)Infect.Immun.70(1):292-302)可能会增加受感染细胞内的蛋白质表达,从而增强T细胞应答(例如Biswas S.等人(2011)PLoS One 6(6):e20977)。同样,将抗原融合至与MHC II相关的Ii可以增强CD8应答(Mikkelsen M.等人(2011)Journal ofImmunology 186(4):2355-2364;和Sorensen M.R.等人(2009)European Journal ofImmunology 39(10):2725-2736)。
综上所述,从上面的各个实施例中可以看出,将抗原融合至li时,CD8对P1A的应答会增强(图2)。还显示了被更好地刺激的CD8应答如何在小鼠中转化为更好的肿瘤保护(图4和5)。迄今为止,尚未在病毒载体疫苗中研究tPA融合的作用。所述实施例表明,与li不同,tPA与MAGE抗原的融合不能在腺病毒的单次疫苗接种中增强CD8+ T细胞应答。而且,在单次初免加强疫苗接种中,当小鼠用表达与li融合的抗原的腺病毒进行初次免疫,并用编码与tPA融合的抗原的MVA进行加强免疫时,观察到CD8应答增加(参见图16A和16B)。然而,进一步的分析表明,在MVA增强免疫中tPA与MAGE抗原融合不能增强CD8应答。
实施例6:疫苗、检查点抑制剂和化学疗法的三联组合对DBA/2小鼠中的15V4T3肿
瘤有作用
图18示出了对试验小鼠进行疫苗接种,以及化学疗法和检查点抑制剂治疗以及相关的对照治疗的实验时间表。简要地,将100万个15V4T3细胞皮下注射到每只DBA/2小鼠中。在第6天,根据肿瘤大小将所述小鼠随机分组。肿瘤植入后第8天开始进行包括小鼠的任何疫苗接种在内的治疗。施用时,在第8天通过腹膜内(I.P.)给予小鼠20mg/kg紫杉醇和40mg/kg卡铂,并且在第9天通过腹膜内给予20mg/kg紫杉醇。施用时,在第18、第21和第24天通过腹膜内给予3剂100μg的aPD1。每组的小鼠数量为6或7或8。
图19示出了对于每种实验和对照治疗,小鼠中平均肿瘤体积的时间进程。
图20显示了每个实验组或对照组中的单个小鼠的肿瘤体积的时间进程。示出了治疗(无论是疫苗接种和/或化学疗法和/或检查点抑制剂)时间。还指出了每组中发现是无肿瘤的小鼠的48天终点数目。疫苗、化学疗法和检查点抑制剂的三联组合显然可以在各种治疗中最有效地抑制肿瘤的形成。
图21显示了每个实验组和对照组中小鼠随时间的存活。与其他治疗和对照相比,疫苗接种、化学疗法和检查点抑制剂的三联组合显然提供了小鼠的最佳存活。
与其他组相比,疫苗与aPD1和化学疗法的三联组合显著抑制了肿瘤的生长。注射肿瘤后第23天,每8只小鼠中就有6只无肿瘤,这些小鼠直到第48天仍保持无肿瘤状态。同样如图22所示,三联组合组在肿瘤注射后第27天也具有最高的外周P1A特异性CD8应答。
实施例7:疫苗、检查点抑制剂和化学疗法的三联组合对DBA/2小鼠中的15V4T3肿
瘤有作用
图23显示了每个实验组的小鼠和对照的时间线。将100万个15V4T3细胞(早期传代)同时注射到DBA/2小鼠中。根据肿瘤大小在第11天将小鼠随机分组,并在肿瘤植入后第11天开始对小鼠进行疫苗接种。施用时,在第11天通过腹膜内(I.P.)给予20mg/kg紫杉醇和40mg/kg卡铂,并且在第12天通过腹膜内给予20mg/kg紫杉醇。施用时,在第21、第24和第27天通过腹膜内给予3剂100μg的aPD1。n=6或7只/组。该实验还包括一个没有肿瘤攻击的天然组(group)。在第14天进行采血,并将样本用于检查骨髓来源的抑制细胞(MDSC)的消耗。
图24和25显示了仅用化学疗法或用化学疗法加疫苗治疗的小鼠如何具有较低的MDSC频率。
实施例8:DBA/2小鼠中的15V4T3肿瘤–CPI疫苗接种会增加肿瘤T细胞浸润
将100万个15V4T3细胞皮下注射到DBA/2小鼠中。图26示出了PBS对照、仅αPD1和两个小鼠实验组的疫苗接种时间线,所述两个实验组为:(1)低剂量的间隔一周的初免加强免疫(ChAdOx1-Ii-P1A+MVA-tPA-P1A)以及(2)低剂量的间隔一周的初免加强免疫(ChAdOx1-Ii-P1A+MVA-tPA-P1A)+αPD1。在肿瘤植入后的第10天开始给小鼠接种疫苗。初免后第3天给予CPI(αPD1),在肿瘤注射后第13、16和19天使用3剂100μg。在第20天对所有小鼠采血并在第21天牺牲小鼠。通过FACS研究了肿瘤微环境的免疫特性。所述结果示于图27-53。
更详细地,图27显示了牺牲时所有组小鼠中肿瘤大小的均匀分布。图28显示了疫苗+抗PD-1组合组中的小鼠亚群中肿瘤质量的减少,这表明了这些小鼠中肿瘤清除的开始。
图29显示了每组中每只小鼠的个体肿瘤生长曲线。
图30显示了疫苗和对照组小鼠的肿瘤中CD8+肿瘤浸润淋巴细胞(TIL)的百分比。疫苗接种会增加CD3+CD8+ TIL在肿瘤总细胞中所占的比例。
图33和34显示了计算的并且相对于细胞数和肿瘤重量标准化的绝对TIL数。
图36和37显示了在ChAdOx初免后第11天的较早时间点进行评估时,添加αPD1治疗如何似乎增强由ChAdOx/MVA疫苗接种初免的P1A特异性应答。
图46显示了肿瘤中P1A特异性TEM CD8+的浸润如何遵循与P1A特异性CD8相同的模式。
总体而言,图27-53的结果显示了疫苗如何增加肿瘤的T细胞浸润,其中,与对照组相比,在小鼠疫苗组中CD3+CD8+ TIL增加并且P1A特异性TIL增加。
此外,所述CD3+CD8+ TIL主要是效应记忆细胞TEM(CD62L-CD44+)和TCM(CD62L+CD44+)。
此外,P1A特异的TIL在疫苗组中表达PD-1,但随着αPD1的阻滞,表达降低。
本文所引用的核苷酸序列和氨基酸序列
本文引用某些蛋白质或多肽,并且在作为本说明书一部分提交的随附序列表中提供了这些的参考核苷酸和/或氨基酸序列。注释了一些序列以提供如下进一步的信息:
人类HLAII类组织相容性抗原γ链(li)UniProtKB/Swiss-Prot:P04233.3。带下划
线的序列部分代表载体中使用的跨膜结构域:
MHRRRSRSCR EDQKPVMDDQ RDLISNNEQL PMLGRRPGAP ESKCSRGALY TGFSILVTLL LAGQATTAYF LYQQQGRLDK LTVTSQNLQL ENLRMKLPKP PKPVSKMRMA TPLLMQALPM GALPQGPMQNATKYGNMTED HVMHLLQNAD PLKVYPPLKG SFPENLRHLK NTMETIDWKV FESWMHHWLL FEMSRHSLEQKPTDAPPKVL TKCQEEVSHI PAVHPGSFRP KCDENGNYLP LQCYGSIGYC WCVFPNGTEV PNTRSRGHHNCSESLELEDP SSGLGVTKQD LGPVPM[SEQ ID NO:6]
人类组织型纤溶酶原激活剂(tPA)。所示带下划线的序列部分是载体中使用的前
导序列。
MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRGARSYQVICRDEKTQMIYQQHQSWLRPVLRSNRVEYCWCNSGRAQCHSVPVKSCSEPRCFNGGTCQQALYFSDFVCQCPEGFAGKCCEIDTRATCYEDQGISYRGTWSTAESGAECTNWNSSALAQKPYSGRRPDAIRLGLGNHNYCRNPDRDSKPWCYVFKAGKYSSEFCSTPACSEGNSDCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQALGLGKHNYCRNPDGDAKPWCHVLKNRRLTWEYCDVPSCSTCGLRQYSQPQFRIKGGLFADIASHPWQAAIFAKHRRSPGERFLCGGILISSCWILSAAHCFQERFPPHHLTVILGRTYRVVPGEEEQKFEVEKYIVHKEFDDDTYDNDIALLQLKSDSSRCAQESSVVRTVCLPPADLQLPDWTECELSGYGKHEALSPFYSERLKEAHVRLYPSSRCTSQHLLNRTVTDNMLCAGDTRSGGPQANLHDACQGDSGGPLVCLNDGRMTLVGIISWGLGCGQKDVPGVYTKVTNYLDWIRDNMRP[SEQ ID NO:8]
载体ChAdOx1_MAGE_NYESO的多核苷酸构建体。带下划线的为MAGEA3。接头为粗体。
NY-ESO-1以斜体显示。
ChAdOx1_MAGE_NYESO的翻译蛋白。带下划线的为MAGEA3。接头为粗体。NY-ESO-1以
斜体显示:
载体ChAdOx1_hIi_MAGE_NY-ESO-1的多核苷酸构建体。li序列以粗体和斜体显示。
带下划线的为MAGEA3。序列接头为粗体。NY-ESO-1以斜体显示:
ChAdOx1_hIi_MAGE_NY-ESO-1的翻译蛋白质序列。li序列以粗体和斜体显示。带下
划线的为MAGEA3。接头为粗体。NY-ESO-1以斜体显示:
载体ChAdOx1_tPA_MAGE_NY-ESO-1的多核苷酸构建体。tPA序列以粗体和斜体显
示。带下划线的为MAGEA3。接头为粗体。NY-ESO-1以斜体显示:
ChAdOx1_tPA_MAGE_NY-ESO-1的翻译蛋白。tPA序列以粗体和斜体显示。带下划线
的为MAGEA3。接头为粗体。NY-ESO-1以斜体显示:
载体MVA_tPA_MAGEA3的多核苷酸构建体。tPA以下划线表示:
ATGGACGCCATGAAGCGGGGCCTGTGCTGCGTGCTGCTGCTGTGTGGCGCTGTGTTCGTGTCCCCCCCACTGGAACAGAGAAGCCAGCACTGCAAGCCCGAGGAAGGCCTGGAAGCCAGAGGCGAAGCTCTGGGACTCGTGGGAGCACAGGCTCCAGCCACCGAAGAACAGGAAGCCGCCAGCAGCTCTAGCACCCTGGTGGAAGTGACACTGGGCGAAGTGCCTGCCGCCGAGTCTCCTGATCCTCCTCAGTCTCCTCAGGGCGCCAGCTCTCTGCCCACCACCATGAACTACCCCCTGTGGTCCCAGTCCTACGAGGACAGCAGCAACCAGGAAGAAGAGGGCCCCAGCACCTTCCCCGACCTGGAATCTGAATTCCAGGCCGCCCTGAGCCGGAAGGTGGCCGAACTGGTGCACTTCCTGCTGCTGAAGTACCGGGCCAGAGAACCCGTGACCAAGGCCGAGATGCTGGGCAGCGTCGTGGGCAACTGGCAGTACTTCTTCCCCGTGATCTTCTCCAAGGCCAGCTCCAGCCTGCAGCTGGTGTTCGGCATCGAGCTGATGGAAGTGGACCCCATCGGACACCTGTACATCTTCGCCACCTGTCTGGGCCTGAGCTACGATGGCCTGCTGGGCGACAACCAGATCATGCCCAAAGCCGGCCTGCTGATCATCGTGCTGGCCATCATTGCCCGCGAGGGCGATTGTGCCCCCGAGGAAAAGATCTGGGAGGAACTGAGCGTGCTGGAAGTGTTCGAGGGAAGAGAGGACTCCATCCTGGGCGACCCCAAGAAGCTGCTGACCCAGCACTTCGTGCAGGAAAACTACCTGGAGTATAGACAGGTGCCCGGCAGCGACCCTGCCTGCTACGAATTTCTGTGGGGCCCTAGAGCACTGGTGGAAACCAGCTACGTGAAAGTGCTGCACCACATGGTCAAGATCAGCGGCGGACCCCACATCAGCTACCCACCTCTGCACGAATGGGTGCTGCGGGAAGGCGAAGAGTGA[SEQ ID NO:20]
MVA_tPA_MAGEA3的翻译蛋白。tPA以下划线表示:
MDAMKRGLCCVLLLCGAVFVSPPLEQRSQHCKPEEGLEARGEALGLVGAQAPATEEQEAASSSSTLVEVTLGEVPAAESPDPPQSPQGASSLPTTMNYPLWSQSYEDSSNQEEEGPSTFPDLESEFQAALSRKVAELVHFLLLKYRAREPVTKAEMLGSVVGNWQYFFPVIFSKASSSLQLVFGIELMEVDPIGHLYIFATCLGLSYDGLLGDNQIMPKAGLLIIVLAIIAREGDCAPEEKIWEELSVLEVFEGREDSILGDPKKLLTQHFVQENYLEYRQVPGSDPACYEFLWGPRALVETSYVKVLHHMVKISGGPHISYPPLHEWVLREGEE[SEQ ID NO:21]
载体MVA_tPA_NYESO的多核苷酸构建体。tPA以下划线表示:
ATGGACGCCATGAAGCGGGGCCTGTGCTGCGTGCTGCTGCTGTGTGGCGCTGTGTTCGTGAGCCCTCAGGCCGAGGGAAGAGGCACAGGCGGATCTACAGGCGACGCTGATGGACCTGGCGGCCCTGGAATTCCTGATGGCCCAGGCGGAAATGCTGGCGGACCAGGCGAAGCTGGCGCTACAGGCGGAAGAGGACCTAGAGGCGCTGGCGCCGCTAGAGCTTCTGGACCTGGGGGAGGCGCTCCTAGAGGACCTCATGGCGGAGCTGCCTCTGGCCTGAATGGCTGCTGTAGATGTGGCGCCAGAGGCCCCGAAAGCCGGCTGCTGGAATTCTACCTGGCCATGCCCTTCGCCACCCCCATGGAAGCTGAGCTGGCCAGAAGAAGCCTGGCCCAGGACGCTCCTCCACTGCCTGTGCCAGGGGTGCTGCTGAAAGAATTCACCGTGTCCGGCAACATCCTGACCATCCGGCTGACAGCCGCCGACCACAGACAGCTGCAGCTGAGCATCAGCAGCTGCCTGCAGCAGCTGTCCCTGCTGATGTGGATCACCCAGTGCTTTCTGCCCGTGTTTCTGGCCCAGCCTCCTAGCGGCCAGCGGCGCTAA[SEQ ID NO:22]
MVA_tPA_NYESO的翻译蛋白。tPA以下划线表示:
MDAMKRGLCCVLLLCGAVFVSPQAEGRGTGGSTGDADGPGGPGIPDGPGGNAGGPGEAGATGGRGPRGAGAARASGPGGGAPRGPHGGAASGLNGCCRCGARGPESRLLEFYLAMPFATPMEAELARRSLAQDAPPLPVPGVLLKEFTVSGNILTIRLTAADHRQLQLSISSCLQQLSLLMWITQCFLPVFLAQPPSGQRR[SEQ ID NO:23]
载体ChAdOx1_mli_P1A的多核苷酸构建体。li序列以下划线表示:
ATGGGCGCTCTGTATACTGGCGTGTCCGTGCTGGTGGCCCTGCTGCTGGCTGGACAGGCTACAACCGC CTACTTCCTGTACAGCGACAACAAGAAGCCCGACAAGGCCCACTCTGGCAGCGGCGGAGATGGCGACGGCAACAGATGTAACCTGCTGCACAGATACAGCCTGGAAGAGATCCTGCCCTACCTGGGCTGGCTGGTGTTCGCCGTCGTGACAACAAGCTTCCTGGCCCTGCAGATGTTCATCGACGCCCTGTACGAGGAACAGTACGAGAGGGACGTGGCCTGGATCGCCAGACAGAGCAAGAGAATGAGCAGCGTGGACGAGGACGAGGATGATGAGGACGACGAAGATGACTACTACGACGATGAGGATGACGACGACGACGCCTTCTACGATGACGAGGACGATGAAGAGGAAGAACTGGAAAACCTGATGGACGACGAGTCCGAGGATGAGGCCGAGGAAGAGATGAGCGTGGAAATGGGCGCTGGCGCCGAAGAGATGGGAGCCGGCGCTAACTGTGCTTGCGTGCCAGGACACCACCTGAGAAAGAACGAAGTGAAGTGCCGGATGATCTACTTCTTCCACGACCCCAACTTTCTGGTGTCCATCCCCGTGAACCCCAAAGAACAGATGGAATGCAGATGCGAGAACGCCGACGAAGAGGTGGCCATGGAAGAAGAAGAGGAAGAGGAAGAAGAAGAAGAAGAGGAAGAAATGGGCAACCCCGACGGCTTCAGCCCCTGA[SEQ ID NO:28]
ChAdOx1_mli_P1A的翻译蛋白。li序列以下划线表示:
MGALYTGVSVLVALLLAGQATTAYFLYSDNKKPDKAHSGSGGDGDGNRCNLLHRYSLEEILPYLGWLVFAVVTTSFLALQMFIDALYEEQYERDVAWIARQSKRMSSVDEDEDDEDDEDDYYDDEDDDDDAFYDDEDDEEEELENLMDDESEDEAEEEMSVEMGAGAEEMGAGANCACVPGHHLRKNEVKCRMIYFFHDPNFLVSIPVNPKEQMECRCENADEEVAMEEEEEEEEEEEEEEMGNPDGFSP[SEQ ID NO:29]
在本说明书的整个描述和权利要求书中,词语“包括”和“包含”及其变体表示“包括但不限于”,并且它们并不旨在(并且不)排除其他部分、添加剂、组分、整数或步骤。在本说明书的整个描述和权利要求书中,单数形式包括复数形式,除非上下文另有要求。特别地,在使用不定冠词的地方,本发明应被理解为既包含复数也包含单数,除非上下文有其他要求。
结合本发明的特定方面、实施方案或实施例描述的特征、整数、特性、化合物、化学部分或基团应理解为适用于本文所述的任何其他方面、实施方案或实施例,除非与其不相容。本说明书中公开的所有特征(包括任何随附的权利要求书、摘要和附图)和/或如此公开的任何方法或过程的所有步骤可以任意组合进行组合,除了这些特征和/或步骤中的至少一些是互斥的组合之外。本发明不限于任何前述实施方案的细节。本发明扩展到本说明书(包括任何所附权利要求、摘要和附图)中公开的特征的任何新颖的一个或任何新颖的组合,或者扩展到如此公开的任何方法或过程的步骤的任何新颖的一个或任何新颖的组合。
读者应注意与本申请相关的与本说明书同时提交或在本说明书之前提交的所有论文和文献,这些论文和文献与本说明书一起公开供公众查阅,并且所有这些论文和文献的内容通过引用并入本文。
序列表
<110> 路德维格癌症研究所有限公司
<120> 用于预防或治疗癌症的方法的、编码癌症/睾丸抗原的病毒载体
<130> P257619WO
<150> 1812647.4
<151> 2018-08-03
<160> 31
<170> PatentIn版本3.5
<210> 1
<211> 314
<212> PRT
<213> 智人
<400> 1
Met Pro Leu Glu Gln Arg Ser Gln His Cys Lys Pro Glu Glu Gly Leu
1 5 10 15
Glu Ala Arg Gly Glu Ala Leu Gly Leu Val Gly Ala Gln Ala Pro Ala
20 25 30
Thr Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser Thr Leu Val Glu Val
35 40 45
Thr Leu Gly Glu Val Pro Ala Ala Glu Ser Pro Asp Pro Pro Gln Ser
50 55 60
Pro Gln Gly Ala Ser Ser Leu Pro Thr Thr Met Asn Tyr Pro Leu Trp
65 70 75 80
Ser Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu Glu Glu Gly Pro Ser
85 90 95
Thr Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala Ala Leu Ser Arg Lys
100 105 110
Val Ala Glu Leu Val His Phe Leu Leu Leu Lys Tyr Arg Ala Arg Glu
115 120 125
Pro Val Thr Lys Ala Glu Met Leu Gly Ser Val Val Gly Asn Trp Gln
130 135 140
Tyr Phe Phe Pro Val Ile Phe Ser Lys Ala Ser Ser Ser Leu Gln Leu
145 150 155 160
Val Phe Gly Ile Glu Leu Met Glu Val Asp Pro Ile Gly His Leu Tyr
165 170 175
Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu Leu Gly Asp
180 185 190
Asn Gln Ile Met Pro Lys Ala Gly Leu Leu Ile Ile Val Leu Ala Ile
195 200 205
Ile Ala Arg Glu Gly Asp Cys Ala Pro Glu Glu Lys Ile Trp Glu Glu
210 215 220
Leu Ser Val Leu Glu Val Phe Glu Gly Arg Glu Asp Ser Ile Leu Gly
225 230 235 240
Asp Pro Lys Lys Leu Leu Thr Gln His Phe Val Gln Glu Asn Tyr Leu
245 250 255
Glu Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala Cys Tyr Glu Phe Leu
260 265 270
Trp Gly Pro Arg Ala Leu Val Glu Thr Ser Tyr Val Lys Val Leu His
275 280 285
His Met Val Lys Ile Ser Gly Gly Pro His Ile Ser Tyr Pro Pro Leu
290 295 300
His Glu Trp Val Leu Arg Glu Gly Glu Glu
305 310
<210> 2
<211> 1753
<212> PRT
<213> 智人
<400> 2
Gly Ala Gly Ala Thr Thr Cys Thr Cys Gly Cys Cys Cys Thr Gly Ala
1 5 10 15
Gly Cys Ala Ala Cys Gly Ala Gly Cys Gly Ala Cys Gly Gly Cys Cys
20 25 30
Thr Gly Ala Cys Gly Thr Cys Gly Gly Cys Gly Gly Ala Gly Gly Gly
35 40 45
Ala Ala Gly Cys Cys Gly Gly Cys Cys Cys Ala Gly Gly Cys Thr Cys
50 55 60
Gly Gly Thr Gly Ala Gly Gly Ala Gly Gly Cys Ala Ala Gly Gly Thr
65 70 75 80
Thr Cys Thr Gly Ala Gly Gly Gly Gly Ala Cys Ala Gly Gly Cys Thr
85 90 95
Gly Ala Cys Cys Thr Gly Gly Ala Gly Gly Ala Cys Cys Ala Gly Ala
100 105 110
Gly Gly Cys Cys Cys Cys Cys Gly Gly Ala Gly Gly Ala Gly Cys Ala
115 120 125
Cys Thr Gly Ala Ala Gly Gly Ala Gly Ala Ala Gly Ala Thr Cys Thr
130 135 140
Gly Cys Cys Ala Gly Thr Gly Gly Gly Thr Cys Thr Cys Cys Ala Thr
145 150 155 160
Thr Gly Cys Cys Cys Ala Gly Cys Thr Cys Cys Thr Gly Cys Cys Cys
165 170 175
Ala Cys Ala Cys Thr Cys Cys Cys Gly Cys Cys Thr Gly Thr Thr Gly
180 185 190
Cys Cys Cys Thr Gly Ala Cys Cys Ala Gly Ala Gly Thr Cys Ala Thr
195 200 205
Cys Ala Thr Gly Cys Cys Thr Cys Thr Thr Gly Ala Gly Cys Ala Gly
210 215 220
Ala Gly Gly Ala Gly Thr Cys Ala Gly Cys Ala Cys Thr Gly Cys Ala
225 230 235 240
Ala Gly Cys Cys Thr Gly Ala Ala Gly Ala Ala Gly Gly Cys Cys Thr
245 250 255
Thr Gly Ala Gly Gly Cys Cys Cys Gly Ala Gly Gly Ala Gly Ala Gly
260 265 270
Gly Cys Cys Cys Thr Gly Gly Gly Cys Cys Thr Gly Gly Thr Gly Gly
275 280 285
Gly Thr Gly Cys Gly Cys Ala Gly Gly Cys Thr Cys Cys Thr Gly Cys
290 295 300
Thr Ala Cys Thr Gly Ala Gly Gly Ala Gly Cys Ala Gly Gly Ala Gly
305 310 315 320
Gly Cys Thr Gly Cys Cys Thr Cys Cys Thr Cys Cys Thr Cys Thr Thr
325 330 335
Cys Thr Ala Cys Thr Cys Thr Ala Gly Thr Thr Gly Ala Ala Gly Thr
340 345 350
Cys Ala Cys Cys Cys Thr Gly Gly Gly Gly Gly Ala Gly Gly Thr Gly
355 360 365
Cys Cys Thr Gly Cys Thr Gly Cys Cys Gly Ala Gly Thr Cys Ala Cys
370 375 380
Cys Ala Gly Ala Thr Cys Cys Thr Cys Cys Cys Cys Ala Gly Ala Gly
385 390 395 400
Thr Cys Cys Thr Cys Ala Gly Gly Gly Ala Gly Cys Cys Thr Cys Cys
405 410 415
Ala Gly Cys Cys Thr Cys Cys Cys Cys Ala Cys Thr Ala Cys Cys Ala
420 425 430
Thr Gly Ala Ala Cys Thr Ala Cys Cys Cys Thr Cys Thr Cys Thr Gly
435 440 445
Gly Ala Gly Cys Cys Ala Ala Thr Cys Cys Thr Ala Thr Gly Ala Gly
450 455 460
Gly Ala Cys Thr Cys Cys Ala Gly Cys Ala Ala Cys Cys Ala Ala Gly
465 470 475 480
Ala Ala Gly Ala Gly Gly Ala Gly Gly Gly Gly Cys Cys Ala Ala Gly
485 490 495
Cys Ala Cys Cys Thr Thr Cys Cys Cys Thr Gly Ala Cys Cys Thr Gly
500 505 510
Gly Ala Gly Thr Cys Cys Gly Ala Gly Thr Thr Cys Cys Ala Ala Gly
515 520 525
Cys Ala Gly Cys Ala Cys Thr Cys Ala Gly Thr Ala Gly Gly Ala Ala
530 535 540
Gly Gly Thr Gly Gly Cys Cys Gly Ala Gly Thr Thr Gly Gly Thr Thr
545 550 555 560
Cys Ala Thr Thr Thr Thr Cys Thr Gly Cys Thr Cys Cys Thr Cys Ala
565 570 575
Ala Gly Thr Ala Thr Cys Gly Ala Gly Cys Cys Ala Gly Gly Gly Ala
580 585 590
Gly Cys Cys Gly Gly Thr Cys Ala Cys Ala Ala Ala Gly Gly Cys Ala
595 600 605
Gly Ala Ala Ala Thr Gly Cys Thr Gly Gly Gly Gly Ala Gly Thr Gly
610 615 620
Thr Cys Gly Thr Cys Gly Gly Ala Ala Ala Thr Thr Gly Gly Cys Ala
625 630 635 640
Gly Thr Ala Thr Thr Thr Cys Thr Thr Thr Cys Cys Thr Gly Thr Gly
645 650 655
Ala Thr Cys Thr Thr Cys Ala Gly Cys Ala Ala Ala Gly Cys Thr Thr
660 665 670
Cys Cys Ala Gly Thr Thr Cys Cys Thr Thr Gly Cys Ala Gly Cys Thr
675 680 685
Gly Gly Thr Cys Thr Thr Thr Gly Gly Cys Ala Thr Cys Gly Ala Gly
690 695 700
Cys Thr Gly Ala Thr Gly Gly Ala Ala Gly Thr Gly Gly Ala Cys Cys
705 710 715 720
Cys Cys Ala Thr Cys Gly Gly Cys Cys Ala Cys Thr Thr Gly Thr Ala
725 730 735
Cys Ala Thr Cys Thr Thr Thr Gly Cys Cys Ala Cys Cys Thr Gly Cys
740 745 750
Cys Thr Gly Gly Gly Cys Cys Thr Cys Thr Cys Cys Thr Ala Cys Gly
755 760 765
Ala Thr Gly Gly Cys Cys Thr Gly Cys Thr Gly Gly Gly Thr Gly Ala
770 775 780
Cys Ala Ala Thr Cys Ala Gly Ala Thr Cys Ala Thr Gly Cys Cys Cys
785 790 795 800
Ala Ala Gly Gly Cys Ala Gly Gly Cys Cys Thr Cys Cys Thr Gly Ala
805 810 815
Thr Ala Ala Thr Cys Gly Thr Cys Cys Thr Gly Gly Cys Cys Ala Thr
820 825 830
Ala Ala Thr Cys Gly Cys Ala Ala Gly Ala Gly Ala Gly Gly Gly Cys
835 840 845
Gly Ala Cys Thr Gly Thr Gly Cys Cys Cys Cys Thr Gly Ala Gly Gly
850 855 860
Ala Gly Ala Ala Ala Ala Thr Cys Thr Gly Gly Gly Ala Gly Gly Ala
865 870 875 880
Gly Cys Thr Gly Ala Gly Thr Gly Thr Gly Thr Thr Ala Gly Ala Gly
885 890 895
Gly Thr Gly Thr Thr Thr Gly Ala Gly Gly Gly Gly Ala Gly Gly Gly
900 905 910
Ala Ala Gly Ala Cys Ala Gly Thr Ala Thr Cys Thr Thr Gly Gly Gly
915 920 925
Gly Gly Ala Thr Cys Cys Cys Ala Ala Gly Ala Ala Gly Cys Thr Gly
930 935 940
Cys Thr Cys Ala Cys Cys Cys Ala Ala Cys Ala Thr Thr Thr Cys Gly
945 950 955 960
Thr Gly Cys Ala Gly Gly Ala Ala Ala Ala Cys Thr Ala Cys Cys Thr
965 970 975
Gly Gly Ala Gly Thr Ala Cys Cys Gly Gly Cys Ala Gly Gly Thr Cys
980 985 990
Cys Cys Cys Gly Gly Cys Ala Gly Thr Gly Ala Thr Cys Cys Thr Gly
995 1000 1005
Cys Ala Thr Gly Thr Thr Ala Thr Gly Ala Ala Thr Thr Cys Cys
1010 1015 1020
Thr Gly Thr Gly Gly Gly Gly Thr Cys Cys Ala Ala Gly Gly Gly
1025 1030 1035
Cys Cys Cys Thr Cys Gly Thr Thr Gly Ala Ala Ala Cys Cys Ala
1040 1045 1050
Gly Cys Thr Ala Thr Gly Thr Gly Ala Ala Ala Gly Thr Cys Cys
1055 1060 1065
Thr Gly Cys Ala Cys Cys Ala Thr Ala Thr Gly Gly Thr Ala Ala
1070 1075 1080
Ala Gly Ala Thr Cys Ala Gly Thr Gly Gly Ala Gly Gly Ala Cys
1085 1090 1095
Cys Thr Cys Ala Cys Ala Thr Thr Thr Cys Cys Thr Ala Cys Cys
1100 1105 1110
Cys Ala Cys Cys Cys Cys Thr Gly Cys Ala Thr Gly Ala Gly Thr
1115 1120 1125
Gly Gly Gly Thr Thr Thr Thr Gly Ala Gly Ala Gly Ala Gly Gly
1130 1135 1140
Gly Gly Gly Ala Ala Gly Ala Gly Thr Gly Ala Gly Thr Cys Thr
1145 1150 1155
Gly Ala Gly Cys Ala Cys Gly Ala Gly Thr Thr Gly Cys Ala Gly
1160 1165 1170
Cys Cys Ala Gly Gly Gly Cys Cys Ala Gly Thr Gly Gly Gly Ala
1175 1180 1185
Gly Gly Gly Gly Gly Thr Cys Thr Gly Gly Gly Cys Cys Ala Gly
1190 1195 1200
Thr Gly Cys Ala Cys Cys Thr Thr Cys Cys Gly Gly Gly Gly Cys
1205 1210 1215
Cys Gly Cys Ala Thr Cys Cys Cys Thr Thr Ala Gly Thr Thr Thr
1220 1225 1230
Cys Cys Ala Cys Thr Gly Cys Cys Thr Cys Cys Thr Gly Thr Gly
1235 1240 1245
Ala Cys Gly Thr Gly Ala Gly Gly Cys Cys Cys Ala Thr Thr Cys
1250 1255 1260
Thr Thr Cys Ala Cys Thr Cys Thr Thr Thr Gly Ala Ala Gly Cys
1265 1270 1275
Gly Ala Gly Cys Ala Gly Thr Cys Ala Gly Cys Ala Thr Thr Cys
1280 1285 1290
Thr Thr Ala Gly Thr Ala Gly Thr Gly Gly Gly Thr Thr Thr Cys
1295 1300 1305
Thr Gly Thr Thr Cys Thr Gly Thr Thr Gly Gly Ala Thr Gly Ala
1310 1315 1320
Cys Thr Thr Thr Gly Ala Gly Ala Thr Thr Ala Thr Thr Cys Thr
1325 1330 1335
Thr Thr Gly Thr Thr Thr Cys Cys Thr Gly Thr Thr Gly Gly Ala
1340 1345 1350
Gly Thr Thr Gly Thr Thr Cys Ala Ala Ala Thr Gly Thr Thr Cys
1355 1360 1365
Cys Thr Thr Thr Thr Ala Ala Cys Gly Gly Ala Thr Gly Gly Thr
1370 1375 1380
Thr Gly Ala Ala Thr Gly Ala Gly Cys Gly Thr Cys Ala Gly Cys
1385 1390 1395
Ala Thr Cys Cys Ala Gly Gly Thr Thr Thr Ala Thr Gly Ala Ala
1400 1405 1410
Thr Gly Ala Cys Ala Gly Thr Ala Gly Thr Cys Ala Cys Ala Cys
1415 1420 1425
Ala Thr Ala Gly Thr Gly Cys Thr Gly Thr Thr Thr Ala Thr Ala
1430 1435 1440
Thr Ala Gly Thr Thr Thr Ala Gly Gly Ala Gly Thr Ala Ala Gly
1445 1450 1455
Ala Gly Thr Cys Thr Thr Gly Thr Thr Thr Thr Thr Thr Ala Cys
1460 1465 1470
Thr Cys Ala Ala Ala Thr Thr Gly Gly Gly Ala Ala Ala Thr Cys
1475 1480 1485
Cys Ala Thr Thr Cys Cys Ala Thr Thr Thr Thr Gly Thr Gly Ala
1490 1495 1500
Ala Thr Thr Gly Thr Gly Ala Cys Ala Thr Ala Ala Thr Ala Ala
1505 1510 1515
Thr Ala Gly Cys Ala Gly Thr Gly Gly Thr Ala Ala Ala Ala Gly
1520 1525 1530
Thr Ala Thr Thr Thr Gly Cys Thr Thr Ala Ala Ala Ala Thr Thr
1535 1540 1545
Gly Thr Gly Ala Gly Cys Gly Ala Ala Thr Thr Ala Gly Cys Ala
1550 1555 1560
Ala Thr Ala Ala Cys Ala Thr Ala Cys Ala Thr Gly Ala Gly Ala
1565 1570 1575
Thr Ala Ala Cys Thr Cys Ala Ala Gly Ala Ala Ala Thr Cys Ala
1580 1585 1590
Ala Ala Ala Gly Ala Thr Ala Gly Thr Thr Gly Ala Thr Thr Cys
1595 1600 1605
Thr Thr Gly Cys Cys Thr Thr Gly Thr Ala Cys Cys Thr Cys Ala
1610 1615 1620
Ala Thr Cys Thr Ala Thr Thr Cys Thr Gly Thr Ala Ala Ala Ala
1625 1630 1635
Thr Thr Ala Ala Ala Cys Ala Ala Ala Thr Ala Thr Gly Cys Ala
1640 1645 1650
Ala Ala Cys Cys Ala Gly Gly Ala Thr Thr Thr Cys Cys Thr Thr
1655 1660 1665
Gly Ala Cys Thr Thr Cys Thr Thr Thr Gly Ala Gly Ala Ala Thr
1670 1675 1680
Gly Cys Ala Ala Gly Cys Gly Ala Ala Ala Thr Thr Ala Ala Ala
1685 1690 1695
Thr Cys Thr Gly Ala Ala Thr Ala Ala Ala Thr Ala Ala Thr Thr
1700 1705 1710
Cys Thr Thr Cys Cys Thr Cys Thr Thr Cys Ala Ala Ala Ala Ala
1715 1720 1725
Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala
1730 1735 1740
Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala
1745 1750
<210> 3
<211> 180
<212> PRT
<213> 智人
<400> 3
Met Gln Ala Glu Gly Arg Gly Thr Gly Gly Ser Thr Gly Asp Ala Asp
1 5 10 15
Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly Pro Gly Gly Asn Ala Gly
20 25 30
Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly Arg Gly Pro Arg Gly Ala
35 40 45
Gly Ala Ala Arg Ala Ser Gly Pro Gly Gly Gly Ala Pro Arg Gly Pro
50 55 60
His Gly Gly Ala Ala Ser Gly Leu Asn Gly Cys Cys Arg Cys Gly Ala
65 70 75 80
Arg Gly Pro Glu Ser Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro Phe
85 90 95
Ala Thr Pro Met Glu Ala Glu Leu Ala Arg Arg Ser Leu Ala Gln Asp
100 105 110
Ala Pro Pro Leu Pro Val Pro Gly Val Leu Leu Lys Glu Phe Thr Val
115 120 125
Ser Gly Asn Ile Leu Thr Ile Arg Leu Thr Ala Ala Asp His Arg Gln
130 135 140
Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln Gln Leu Ser Leu Leu Met
145 150 155 160
Trp Ile Thr Gln Cys Phe Leu Pro Val Phe Leu Ala Gln Pro Pro Ser
165 170 175
Gly Gln Arg Arg
180
<210> 4
<211> 752
<212> DNA
<213> 智人
<400> 4
atcctcgtgg gccctgacct tctctctgag agccgggcag aggctccgga gccatgcagg 60
ccgaaggccg gggcacaggg ggttcgacgg gcgatgctga tggcccagga ggccctggca 120
ttcctgatgg cccagggggc aatgctggcg gcccaggaga ggcgggtgcc acgggcggca 180
gaggtccccg gggcgcaggg gcagcaaggg cctcggggcc gggaggaggc gccccgcggg 240
gtccgcatgg cggcgcggct tcagggctga atggatgctg cagatgcggg gccagggggc 300
cggagagccg cctgcttgag ttctacctcg ccatgccttt cgcgacaccc atggaagcag 360
agctggcccg caggagcctg gcccaggatg ccccaccgct tcccgtgcca ggggtgcttc 420
tgaaggagtt cactgtgtcc ggcaacatac tgactatccg actgactgct gcagaccacc 480
gccaactgca gctctccatc agctcctgtc tccagcagct ttccctgttg atgtggatca 540
cgcagtgctt tctgcccgtg tttttggctc agcctccctc agggcagagg cgctaagccc 600
agcctggcgc cccttcctag gtcatgcctc ctcccctagg gaatggtccc agcacgagtg 660
gccagttcat tgtgggggcc tgattgtttg tcgctggagg aggacggctt acatgtttgt 720
ttctgtagaa aataaaactg agctacgaaa aa 752
<210> 5
<211> 180
<212> PRT
<213> 智人
<400> 5
Met Gln Ala Glu Gly Gln Gly Thr Gly Gly Ser Thr Gly Asp Ala Asp
1 5 10 15
Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly Pro Gly Gly Asn Ala Gly
20 25 30
Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly Arg Gly Pro Arg Gly Ala
35 40 45
Gly Ala Ala Arg Ala Ser Gly Pro Arg Gly Gly Ala Pro Arg Gly Pro
50 55 60
His Gly Gly Ala Ala Ser Ala Gln Asp Gly Arg Cys Pro Cys Gly Ala
65 70 75 80
Arg Arg Pro Asp Ser Arg Leu Leu Gln Leu His Ile Thr Met Pro Phe
85 90 95
Ser Ser Pro Met Glu Ala Glu Leu Val Arg Arg Ile Leu Ser Arg Asp
100 105 110
Ala Ala Pro Leu Pro Arg Pro Gly Ala Val Leu Lys Asp Phe Thr Val
115 120 125
Ser Gly Asn Leu Leu Phe Ile Arg Leu Thr Ala Ala Asp His Arg Gln
130 135 140
Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln Gln Leu Ser Leu Leu Met
145 150 155 160
Trp Ile Thr Gln Cys Phe Leu Pro Val Phe Leu Ala Gln Ala Pro Ser
165 170 175
Gly Gln Arg Arg
180
<210> 6
<211> 296
<212> PRT
<213> 智人
<400> 6
Met His Arg Arg Arg Ser Arg Ser Cys Arg Glu Asp Gln Lys Pro Val
1 5 10 15
Met Asp Asp Gln Arg Asp Leu Ile Ser Asn Asn Glu Gln Leu Pro Met
20 25 30
Leu Gly Arg Arg Pro Gly Ala Pro Glu Ser Lys Cys Ser Arg Gly Ala
35 40 45
Leu Tyr Thr Gly Phe Ser Ile Leu Val Thr Leu Leu Leu Ala Gly Gln
50 55 60
Ala Thr Thr Ala Tyr Phe Leu Tyr Gln Gln Gln Gly Arg Leu Asp Lys
65 70 75 80
Leu Thr Val Thr Ser Gln Asn Leu Gln Leu Glu Asn Leu Arg Met Lys
85 90 95
Leu Pro Lys Pro Pro Lys Pro Val Ser Lys Met Arg Met Ala Thr Pro
100 105 110
Leu Leu Met Gln Ala Leu Pro Met Gly Ala Leu Pro Gln Gly Pro Met
115 120 125
Gln Asn Ala Thr Lys Tyr Gly Asn Met Thr Glu Asp His Val Met His
130 135 140
Leu Leu Gln Asn Ala Asp Pro Leu Lys Val Tyr Pro Pro Leu Lys Gly
145 150 155 160
Ser Phe Pro Glu Asn Leu Arg His Leu Lys Asn Thr Met Glu Thr Ile
165 170 175
Asp Trp Lys Val Phe Glu Ser Trp Met His His Trp Leu Leu Phe Glu
180 185 190
Met Ser Arg His Ser Leu Glu Gln Lys Pro Thr Asp Ala Pro Pro Lys
195 200 205
Val Leu Thr Lys Cys Gln Glu Glu Val Ser His Ile Pro Ala Val His
210 215 220
Pro Gly Ser Phe Arg Pro Lys Cys Asp Glu Asn Gly Asn Tyr Leu Pro
225 230 235 240
Leu Gln Cys Tyr Gly Ser Ile Gly Tyr Cys Trp Cys Val Phe Pro Asn
245 250 255
Gly Thr Glu Val Pro Asn Thr Arg Ser Arg Gly His His Asn Cys Ser
260 265 270
Glu Ser Leu Glu Leu Glu Asp Pro Ser Ser Gly Leu Gly Val Thr Lys
275 280 285
Gln Asp Leu Gly Pro Val Pro Met
290 295
<210> 7
<211> 26
<212> PRT
<213> 智人
<400> 7
Gly Ala Leu Tyr Thr Gly Phe Ser Ile Leu Val Thr Leu Leu Leu Ala
1 5 10 15
Gly Gln Ala Thr Thr Ala Tyr Phe Leu Tyr
20 25
<210> 8
<211> 562
<212> PRT
<213> 智人
<400> 8
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Gln Glu Ile His Ala Arg Phe Arg Arg
20 25 30
Gly Ala Arg Ser Tyr Gln Val Ile Cys Arg Asp Glu Lys Thr Gln Met
35 40 45
Ile Tyr Gln Gln His Gln Ser Trp Leu Arg Pro Val Leu Arg Ser Asn
50 55 60
Arg Val Glu Tyr Cys Trp Cys Asn Ser Gly Arg Ala Gln Cys His Ser
65 70 75 80
Val Pro Val Lys Ser Cys Ser Glu Pro Arg Cys Phe Asn Gly Gly Thr
85 90 95
Cys Gln Gln Ala Leu Tyr Phe Ser Asp Phe Val Cys Gln Cys Pro Glu
100 105 110
Gly Phe Ala Gly Lys Cys Cys Glu Ile Asp Thr Arg Ala Thr Cys Tyr
115 120 125
Glu Asp Gln Gly Ile Ser Tyr Arg Gly Thr Trp Ser Thr Ala Glu Ser
130 135 140
Gly Ala Glu Cys Thr Asn Trp Asn Ser Ser Ala Leu Ala Gln Lys Pro
145 150 155 160
Tyr Ser Gly Arg Arg Pro Asp Ala Ile Arg Leu Gly Leu Gly Asn His
165 170 175
Asn Tyr Cys Arg Asn Pro Asp Arg Asp Ser Lys Pro Trp Cys Tyr Val
180 185 190
Phe Lys Ala Gly Lys Tyr Ser Ser Glu Phe Cys Ser Thr Pro Ala Cys
195 200 205
Ser Glu Gly Asn Ser Asp Cys Tyr Phe Gly Asn Gly Ser Ala Tyr Arg
210 215 220
Gly Thr His Ser Leu Thr Glu Ser Gly Ala Ser Cys Leu Pro Trp Asn
225 230 235 240
Ser Met Ile Leu Ile Gly Lys Val Tyr Thr Ala Gln Asn Pro Ser Ala
245 250 255
Gln Ala Leu Gly Leu Gly Lys His Asn Tyr Cys Arg Asn Pro Asp Gly
260 265 270
Asp Ala Lys Pro Trp Cys His Val Leu Lys Asn Arg Arg Leu Thr Trp
275 280 285
Glu Tyr Cys Asp Val Pro Ser Cys Ser Thr Cys Gly Leu Arg Gln Tyr
290 295 300
Ser Gln Pro Gln Phe Arg Ile Lys Gly Gly Leu Phe Ala Asp Ile Ala
305 310 315 320
Ser His Pro Trp Gln Ala Ala Ile Phe Ala Lys His Arg Arg Ser Pro
325 330 335
Gly Glu Arg Phe Leu Cys Gly Gly Ile Leu Ile Ser Ser Cys Trp Ile
340 345 350
Leu Ser Ala Ala His Cys Phe Gln Glu Arg Phe Pro Pro His His Leu
355 360 365
Thr Val Ile Leu Gly Arg Thr Tyr Arg Val Val Pro Gly Glu Glu Glu
370 375 380
Gln Lys Phe Glu Val Glu Lys Tyr Ile Val His Lys Glu Phe Asp Asp
385 390 395 400
Asp Thr Tyr Asp Asn Asp Ile Ala Leu Leu Gln Leu Lys Ser Asp Ser
405 410 415
Ser Arg Cys Ala Gln Glu Ser Ser Val Val Arg Thr Val Cys Leu Pro
420 425 430
Pro Ala Asp Leu Gln Leu Pro Asp Trp Thr Glu Cys Glu Leu Ser Gly
435 440 445
Tyr Gly Lys His Glu Ala Leu Ser Pro Phe Tyr Ser Glu Arg Leu Lys
450 455 460
Glu Ala His Val Arg Leu Tyr Pro Ser Ser Arg Cys Thr Ser Gln His
465 470 475 480
Leu Leu Asn Arg Thr Val Thr Asp Asn Met Leu Cys Ala Gly Asp Thr
485 490 495
Arg Ser Gly Gly Pro Gln Ala Asn Leu His Asp Ala Cys Gln Gly Asp
500 505 510
Ser Gly Gly Pro Leu Val Cys Leu Asn Asp Gly Arg Met Thr Leu Val
515 520 525
Gly Ile Ile Ser Trp Gly Leu Gly Cys Gly Gln Lys Asp Val Pro Gly
530 535 540
Val Tyr Thr Lys Val Thr Asn Tyr Leu Asp Trp Ile Arg Asp Asn Met
545 550 555 560
Arg Pro
<210> 9
<211> 21
<212> PRT
<213> 智人
<400> 9
Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly Ala
1 5 10 15
Val Phe Val Ser Pro
20
<210> 10
<211> 1506
<212> DNA
<213> 人工序列
<220>
<223> Polynucleotide construct for vector ChAdOx1_MAGE_NYESO
<400> 10
atgcccctgg aacagcggag ccagcactgc aagcctgagg aaggcctgga agccagaggc 60
gaagctctgg gactcgtggg agcacaggct ccagccaccg aagaacagga agccgccagc 120
agcagctcca ccctggtgga agtgacactg ggcgaagtgc ctgccgccga gtctcctgat 180
cctcctcagt ctcctcaggg cgccagctct ctgcccacca ccatgaacta ccccctgtgg 240
tcccagtcct acgaggacag cagcaaccag gaagaagagg gccccagcac cttccccgac 300
ctggaatctg aattccaggc cgccctgagc cggaaggtgg ccgaactggt gcacttcctg 360
ctgctgaagt accgggccag agaacccgtg accaaggccg agatgctggg cagcgtcgtg 420
ggcaactggc agtacttctt ccccgtgatc ttctccaagg ccagctccag cctgcagctg 480
gtgttcggca tcgagctgat ggaagtggac cccatcggac acctgtacat cttcgccacc 540
tgtctgggcc tgagctacga tggcctgctg ggcgacaacc agatcatgcc caaagccggc 600
ctgctgatca tcgtgctggc catcattgcc cgcgagggcg attgtgcccc cgaggaaaag 660
atctgggagg aactgagcgt gctggaagtg ttcgagggaa gagaggactc catcctgggc 720
gaccccaaga agctgctgac ccagcacttc gtgcaggaaa actacctgga gtatagacag 780
gtgcccggca gcgaccctgc ctgctacgaa tttctgtggg gccctagagc actggtggaa 840
accagctacg tgaaagtgct gcaccacatg gtcaagatca gcggcggacc ccacatcagc 900
tacccccctc tgcatgaatg ggtgctgaga gagggcgagg aaggcggagg acctggcgga 960
ggaatgcagg ctgaaggcag aggcacaggc ggctctacag gcgacgctga tggaccaggc 1020
ggacccggaa ttccagatgg ccctggcgga aatgctggcg ggcctggcga agctggcgct 1080
acaggcggaa gaggacctag aggcgctggc gccgctagag cttctggacc agggggaggc 1140
gctcctagag gacctcatgg cggagctgcc tctggcctga acggctgctg tagatgtggc 1200
gccagaggcc ccgaaagcag actgctggaa ttctacctgg ccatgccttt cgccaccccc 1260
atggaagctg agctggccag aagaagcctg gcccaggacg ctcctccact gcctgtgcca 1320
ggcgtgctgc tgaaagaatt caccgtgtcc ggcaacatcc tgaccatccg gctgacagcc 1380
gccgaccaca gacagctgca gctgagcatc agcagctgcc tgcagcagct gtccctgctg 1440
atgtggatca cccagtgctt tctgcccgtg tttctggccc agcctcctag cggacagcgg 1500
agatga 1506
<210> 11
<211> 501
<212> PRT
<213> 人工序列
<220>
<223> ChAdOx1_MAGE_NYESO的翻译蛋白
<400> 11
Met Pro Leu Glu Gln Arg Ser Gln His Cys Lys Pro Glu Glu Gly Leu
1 5 10 15
Glu Ala Arg Gly Glu Ala Leu Gly Leu Val Gly Ala Gln Ala Pro Ala
20 25 30
Thr Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser Thr Leu Val Glu Val
35 40 45
Thr Leu Gly Glu Val Pro Ala Ala Glu Ser Pro Asp Pro Pro Gln Ser
50 55 60
Pro Gln Gly Ala Ser Ser Leu Pro Thr Thr Met Asn Tyr Pro Leu Trp
65 70 75 80
Ser Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu Glu Glu Gly Pro Ser
85 90 95
Thr Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala Ala Leu Ser Arg Lys
100 105 110
Val Ala Glu Leu Val His Phe Leu Leu Leu Lys Tyr Arg Ala Arg Glu
115 120 125
Pro Val Thr Lys Ala Glu Met Leu Gly Ser Val Val Gly Asn Trp Gln
130 135 140
Tyr Phe Phe Pro Val Ile Phe Ser Lys Ala Ser Ser Ser Leu Gln Leu
145 150 155 160
Val Phe Gly Ile Glu Leu Met Glu Val Asp Pro Ile Gly His Leu Tyr
165 170 175
Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu Leu Gly Asp
180 185 190
Asn Gln Ile Met Pro Lys Ala Gly Leu Leu Ile Ile Val Leu Ala Ile
195 200 205
Ile Ala Arg Glu Gly Asp Cys Ala Pro Glu Glu Lys Ile Trp Glu Glu
210 215 220
Leu Ser Val Leu Glu Val Phe Glu Gly Arg Glu Asp Ser Ile Leu Gly
225 230 235 240
Asp Pro Lys Lys Leu Leu Thr Gln His Phe Val Gln Glu Asn Tyr Leu
245 250 255
Glu Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala Cys Tyr Glu Phe Leu
260 265 270
Trp Gly Pro Arg Ala Leu Val Glu Thr Ser Tyr Val Lys Val Leu His
275 280 285
His Met Val Lys Ile Ser Gly Gly Pro His Ile Ser Tyr Pro Pro Leu
290 295 300
His Glu Trp Val Leu Arg Glu Gly Glu Glu Gly Gly Gly Pro Gly Gly
305 310 315 320
Gly Met Gln Ala Glu Gly Arg Gly Thr Gly Gly Ser Thr Gly Asp Ala
325 330 335
Asp Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly Pro Gly Gly Asn Ala
340 345 350
Gly Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly Arg Gly Pro Arg Gly
355 360 365
Ala Gly Ala Ala Arg Ala Ser Gly Pro Gly Gly Gly Ala Pro Arg Gly
370 375 380
Pro His Gly Gly Ala Ala Ser Gly Leu Asn Gly Cys Cys Arg Cys Gly
385 390 395 400
Ala Arg Gly Pro Glu Ser Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro
405 410 415
Phe Ala Thr Pro Met Glu Ala Glu Leu Ala Arg Arg Ser Leu Ala Gln
420 425 430
Asp Ala Pro Pro Leu Pro Val Pro Gly Val Leu Leu Lys Glu Phe Thr
435 440 445
Val Ser Gly Asn Ile Leu Thr Ile Arg Leu Thr Ala Ala Asp His Arg
450 455 460
Gln Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln Gln Leu Ser Leu Leu
465 470 475 480
Met Trp Ile Thr Gln Cys Phe Leu Pro Val Phe Leu Ala Gln Pro Pro
485 490 495
Ser Gly Gln Arg Arg
500
<210> 12
<211> 1584
<212> DNA
<213> 人工序列
<220>
<223> 载体ChAdOx1_hIi_MAGE_NY-ESO-1的多核苷酸构建体
<400> 12
atgggcgccc tgtacaccgg ctttagcatc ctcgtgaccc tgctgctggc cggacaggct 60
accaccgcct actttctgta ccccctggaa cagcggagcc agcactgcaa gcctgaggaa 120
ggcctggaag ccagaggcga agctctggga ctcgtgggag cacaggctcc agccaccgaa 180
gaacaggaag ccgccagcag ctctagcacc ctggtggaag tgacactggg cgaagtgcct 240
gccgccgagt ctcctgatcc tcctcagtct cctcagggcg ccagctctct gcccaccacc 300
atgaactacc ccctgtggtc ccagtcctac gaggacagca gcaaccagga agaagagggc 360
cccagcacct tccccgacct ggaatctgaa ttccaggccg ccctgagccg gaaggtggcc 420
gaactggtgc actttctgct gctgaagtac cgggccagag aacccgtgac caaggccgag 480
atgctgggca gcgtcgtggg caactggcag tacttcttcc ccgtgatctt ctccaaggcc 540
agctccagcc tgcagctggt gttcggcatc gagctgatgg aagtggaccc catcggacac 600
ctgtacatct tcgccacctg tctgggcctg agctacgatg gcctgctggg cgacaaccag 660
atcatgccca aagccggcct gctgatcatc gtgctggcca tcattgcccg cgagggcgat 720
tgtgcccccg aggaaaagat ctgggaggaa ctgagcgtgc tggaagtgtt cgagggaaga 780
gaggactcca tcctgggcga ccccaagaag ctgctgaccc agcacttcgt gcaggaaaac 840
tacctggagt atagacaggt gcccggcagc gaccctgcct gctacgaatt tctgtggggc 900
cctagagcac tggtggaaac cagctacgtg aaagtgctgc accacatggt caagatcagc 960
ggcggacccc acatcagcta cccccctctg catgaatggg tgctgagaga gggcgaggaa 1020
ggcggaggac ctggcggagg aatgcaggct gaaggcagag gcacaggcgg ctctacaggc 1080
gacgctgatg gaccaggcgg acccggaatt ccagatggcc ctggcggaaa tgctggcggg 1140
cctggcgaag ctggcgctac aggcggaaga ggacctagag gcgctggcgc cgctagagca 1200
tctggaccag ggggaggcgc tcctagagga cctcatggcg gagctgcctc tggcctgaac 1260
ggctgctgta gatgtggcgc cagaggcccc gaaagcagac tgctggaatt ctacctggcc 1320
atgcctttcg ccacccccat ggaagctgag ctggccagaa gaagcctggc ccaggacgct 1380
cctccactgc ctgtgccagg cgtgctgctg aaagaattca ccgtgtccgg caacatcctg 1440
accatccggc tgacagccgc cgaccacaga cagctgcagc tgagcatcag cagctgcctg 1500
cagcagctgt ccctgctgat gtggatcacc cagtgctttc tgcccgtgtt tctggcccag 1560
cctcctagcg gacagcggag atga 1584
<210> 13
<211> 527
<212> PRT
<213> 人工序列
<220>
<223> ChAdOx1_hIi_MAGE_NY-ESO-1的翻译蛋白序列
<400> 13
Met Gly Ala Leu Tyr Thr Gly Phe Ser Ile Leu Val Thr Leu Leu Leu
1 5 10 15
Ala Gly Gln Ala Thr Thr Ala Tyr Phe Leu Tyr Pro Leu Glu Gln Arg
20 25 30
Ser Gln His Cys Lys Pro Glu Glu Gly Leu Glu Ala Arg Gly Glu Ala
35 40 45
Leu Gly Leu Val Gly Ala Gln Ala Pro Ala Thr Glu Glu Gln Glu Ala
50 55 60
Ala Ser Ser Ser Ser Thr Leu Val Glu Val Thr Leu Gly Glu Val Pro
65 70 75 80
Ala Ala Glu Ser Pro Asp Pro Pro Gln Ser Pro Gln Gly Ala Ser Ser
85 90 95
Leu Pro Thr Thr Met Asn Tyr Pro Leu Trp Ser Gln Ser Tyr Glu Asp
100 105 110
Ser Ser Asn Gln Glu Glu Glu Gly Pro Ser Thr Phe Pro Asp Leu Glu
115 120 125
Ser Glu Phe Gln Ala Ala Leu Ser Arg Lys Val Ala Glu Leu Val His
130 135 140
Phe Leu Leu Leu Lys Tyr Arg Ala Arg Glu Pro Val Thr Lys Ala Glu
145 150 155 160
Met Leu Gly Ser Val Val Gly Asn Trp Gln Tyr Phe Phe Pro Val Ile
165 170 175
Phe Ser Lys Ala Ser Ser Ser Leu Gln Leu Val Phe Gly Ile Glu Leu
180 185 190
Met Glu Val Asp Pro Ile Gly His Leu Tyr Ile Phe Ala Thr Cys Leu
195 200 205
Gly Leu Ser Tyr Asp Gly Leu Leu Gly Asp Asn Gln Ile Met Pro Lys
210 215 220
Ala Gly Leu Leu Ile Ile Val Leu Ala Ile Ile Ala Arg Glu Gly Asp
225 230 235 240
Cys Ala Pro Glu Glu Lys Ile Trp Glu Glu Leu Ser Val Leu Glu Val
245 250 255
Phe Glu Gly Arg Glu Asp Ser Ile Leu Gly Asp Pro Lys Lys Leu Leu
260 265 270
Thr Gln His Phe Val Gln Glu Asn Tyr Leu Glu Tyr Arg Gln Val Pro
275 280 285
Gly Ser Asp Pro Ala Cys Tyr Glu Phe Leu Trp Gly Pro Arg Ala Leu
290 295 300
Val Glu Thr Ser Tyr Val Lys Val Leu His His Met Val Lys Ile Ser
305 310 315 320
Gly Gly Pro His Ile Ser Tyr Pro Pro Leu His Glu Trp Val Leu Arg
325 330 335
Glu Gly Glu Glu Gly Gly Gly Pro Gly Gly Gly Met Gln Ala Glu Gly
340 345 350
Arg Gly Thr Gly Gly Ser Thr Gly Asp Ala Asp Gly Pro Gly Gly Pro
355 360 365
Gly Ile Pro Asp Gly Pro Gly Gly Asn Ala Gly Gly Pro Gly Glu Ala
370 375 380
Gly Ala Thr Gly Gly Arg Gly Pro Arg Gly Ala Gly Ala Ala Arg Ala
385 390 395 400
Ser Gly Pro Gly Gly Gly Ala Pro Arg Gly Pro His Gly Gly Ala Ala
405 410 415
Ser Gly Leu Asn Gly Cys Cys Arg Cys Gly Ala Arg Gly Pro Glu Ser
420 425 430
Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro Phe Ala Thr Pro Met Glu
435 440 445
Ala Glu Leu Ala Arg Arg Ser Leu Ala Gln Asp Ala Pro Pro Leu Pro
450 455 460
Val Pro Gly Val Leu Leu Lys Glu Phe Thr Val Ser Gly Asn Ile Leu
465 470 475 480
Thr Ile Arg Leu Thr Ala Ala Asp His Arg Gln Leu Gln Leu Ser Ile
485 490 495
Ser Ser Cys Leu Gln Gln Leu Ser Leu Leu Met Trp Ile Thr Gln Cys
500 505 510
Phe Leu Pro Val Phe Leu Ala Gln Pro Pro Ser Gly Gln Arg Arg
515 520 525
<210> 14
<211> 1569
<212> DNA
<213> 人工序列
<220>
<223> 载体ChAdOx1_tPA_MAGE_NY-ESO-1的多核苷酸构建体
<400> 14
atggacgcca tgaagcgggg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tcccccccac tggaacagag aagccagcac tgcaagcccg aggaaggcct ggaagccaga 120
ggcgaagctc tgggactcgt gggagcacag gctccagcca ccgaagaaca ggaagccgcc 180
agcagctcta gcaccctggt ggaagtgaca ctgggcgaag tgcctgccgc cgagtctcct 240
gatcctcctc agtctcctca gggcgccagc tctctgccca ccaccatgaa ctaccccctg 300
tggtcccagt cctacgagga cagcagcaac caggaagaag agggccccag caccttcccc 360
gacctggaat ctgaattcca ggccgccctg agccggaagg tggccgaact ggtgcacttc 420
ctgctgctga agtaccgggc cagagaaccc gtgaccaagg ccgagatgct gggcagcgtc 480
gtgggcaact ggcagtactt cttccccgtg atcttctcca aggccagctc cagcctgcag 540
ctggtgttcg gcatcgagct gatggaagtg gaccccatcg gacacctgta catcttcgcc 600
acctgtctgg gcctgagcta cgatggcctg ctgggcgaca accagatcat gcccaaagcc 660
ggcctgctga tcatcgtgct ggccatcatt gcccgcgagg gcgattgtgc ccccgaggaa 720
aagatctggg aggaactgag cgtgctggaa gtgttcgagg gaagagagga ctccatcctg 780
ggcgacccca agaagctgct gacccagcac ttcgtgcagg aaaactacct ggagtataga 840
caggtgcccg gcagcgaccc tgcctgctac gaatttctgt ggggccctag agcactggtg 900
gaaaccagct acgtgaaagt gctgcaccac atggtcaaga tcagcggcgg accccacatc 960
agctacccac ctctgcacga atgggtgctg agagagggcg aagaaggcgg aggacctggc 1020
ggaggaatgc aggctgaagg cagaggcaca ggcggctcta caggcgacgc tgatggacca 1080
ggcggacccg gaattccaga tggccctggc ggaaatgctg gcgggcctgg cgaagctggc 1140
gctacaggcg gaagaggacc tagaggcgct ggcgccgcta gagcatctgg accaggggga 1200
ggcgctccta gaggacctca tggcggagct gcctctggcc tgaatggctg ctgtagatgt 1260
ggcgccagag gccccgaaag cagactgctg gaattctacc tggccatgcc tttcgccacc 1320
cccatggaag ctgagctggc cagaagaagc ctggcccagg acgctcctcc actgcctgtg 1380
ccaggggtgc tgctgaaaga attcaccgtg tccggcaaca tcctgaccat ccggctgaca 1440
gccgccgacc acagacagct gcagctgagc atcagcagct gcctgcagca gctgtccctg 1500
ctgatgtgga tcacccagtg ctttctgccc gtgtttctgg cccagcctcc tagcggacag 1560
cggagatga 1569
<210> 15
<211> 522
<212> PRT
<213> 人工序列
<220>
<223> ChAdOx1_tPA_MAGE_NY-ESO-1的翻译蛋白
<400> 15
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Pro Leu Glu Gln Arg Ser Gln His Cys Lys
20 25 30
Pro Glu Glu Gly Leu Glu Ala Arg Gly Glu Ala Leu Gly Leu Val Gly
35 40 45
Ala Gln Ala Pro Ala Thr Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser
50 55 60
Thr Leu Val Glu Val Thr Leu Gly Glu Val Pro Ala Ala Glu Ser Pro
65 70 75 80
Asp Pro Pro Gln Ser Pro Gln Gly Ala Ser Ser Leu Pro Thr Thr Met
85 90 95
Asn Tyr Pro Leu Trp Ser Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu
100 105 110
Glu Glu Gly Pro Ser Thr Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala
115 120 125
Ala Leu Ser Arg Lys Val Ala Glu Leu Val His Phe Leu Leu Leu Lys
130 135 140
Tyr Arg Ala Arg Glu Pro Val Thr Lys Ala Glu Met Leu Gly Ser Val
145 150 155 160
Val Gly Asn Trp Gln Tyr Phe Phe Pro Val Ile Phe Ser Lys Ala Ser
165 170 175
Ser Ser Leu Gln Leu Val Phe Gly Ile Glu Leu Met Glu Val Asp Pro
180 185 190
Ile Gly His Leu Tyr Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp
195 200 205
Gly Leu Leu Gly Asp Asn Gln Ile Met Pro Lys Ala Gly Leu Leu Ile
210 215 220
Ile Val Leu Ala Ile Ile Ala Arg Glu Gly Asp Cys Ala Pro Glu Glu
225 230 235 240
Lys Ile Trp Glu Glu Leu Ser Val Leu Glu Val Phe Glu Gly Arg Glu
245 250 255
Asp Ser Ile Leu Gly Asp Pro Lys Lys Leu Leu Thr Gln His Phe Val
260 265 270
Gln Glu Asn Tyr Leu Glu Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala
275 280 285
Cys Tyr Glu Phe Leu Trp Gly Pro Arg Ala Leu Val Glu Thr Ser Tyr
290 295 300
Val Lys Val Leu His His Met Val Lys Ile Ser Gly Gly Pro His Ile
305 310 315 320
Ser Tyr Pro Pro Leu His Glu Trp Val Leu Arg Glu Gly Glu Glu Gly
325 330 335
Gly Gly Pro Gly Gly Gly Met Gln Ala Glu Gly Arg Gly Thr Gly Gly
340 345 350
Ser Thr Gly Asp Ala Asp Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly
355 360 365
Pro Gly Gly Asn Ala Gly Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly
370 375 380
Arg Gly Pro Arg Gly Ala Gly Ala Ala Arg Ala Ser Gly Pro Gly Gly
385 390 395 400
Gly Ala Pro Arg Gly Pro His Gly Gly Ala Ala Ser Gly Leu Asn Gly
405 410 415
Cys Cys Arg Cys Gly Ala Arg Gly Pro Glu Ser Arg Leu Leu Glu Phe
420 425 430
Tyr Leu Ala Met Pro Phe Ala Thr Pro Met Glu Ala Glu Leu Ala Arg
435 440 445
Arg Ser Leu Ala Gln Asp Ala Pro Pro Leu Pro Val Pro Gly Val Leu
450 455 460
Leu Lys Glu Phe Thr Val Ser Gly Asn Ile Leu Thr Ile Arg Leu Thr
465 470 475 480
Ala Ala Asp His Arg Gln Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln
485 490 495
Gln Leu Ser Leu Leu Met Trp Ile Thr Gln Cys Phe Leu Pro Val Phe
500 505 510
Leu Ala Gln Pro Pro Ser Gly Gln Arg Arg
515 520
<210> 16
<211> 945
<212> DNA
<213> 人工序列
<220>
<223> 载体MVA_MAGEA3的多核苷酸构建体
<400> 16
atgcccctgg aacagcggag ccagcactgc aagcctgagg aaggcctgga agccagaggc 60
gaagctctgg gactcgtggg agcacaggct ccagccaccg aagaacagga agccgccagc 120
agcagctcca ccctggtgga agtgacactg ggcgaagtgc ctgccgccga gtctcctgat 180
cctcctcagt ctcctcaggg cgccagctct ctgcccacca ccatgaacta ccccctgtgg 240
tcccagtcct acgaggacag cagcaaccag gaagaagagg gccccagcac cttccccgac 300
ctggaatctg aattccaggc cgccctgagc cggaaggtgg ccgaactggt gcacttcctg 360
ctgctgaagt accgggccag agaacccgtg accaaggccg agatgctggg cagcgtcgtg 420
ggcaactggc agtacttctt ccccgtgatc ttctccaagg ccagctccag cctgcagctg 480
gtgttcggca tcgagctgat ggaagtggac cccatcggac acctgtacat cttcgccacc 540
tgtctgggcc tgagctacga tggcctgctg ggcgacaacc agatcatgcc caaagccggc 600
ctgctgatca tcgtgctggc catcattgcc cgcgagggcg attgtgcccc cgaggaaaag 660
atctgggagg aactgagcgt gctggaagtg ttcgagggaa gagaggactc catcctgggc 720
gaccccaaga agctgctgac ccagcacttc gtgcaggaaa actacctgga gtatagacag 780
gtgcccggca gcgaccctgc ctgctacgaa tttctgtggg gccctagagc actggtggaa 840
accagctacg tgaaagtgct gcaccacatg gtcaagatca gcggcggacc ccacatcagc 900
tacccccctc tgcatgaatg ggtgctgcgg gaaggcgaag agtga 945
<210> 17
<211> 314
<212> PRT
<213> 人工序列
<220>
<223> MVA_MAGEA3的翻译蛋白
<400> 17
Met Pro Leu Glu Gln Arg Ser Gln His Cys Lys Pro Glu Glu Gly Leu
1 5 10 15
Glu Ala Arg Gly Glu Ala Leu Gly Leu Val Gly Ala Gln Ala Pro Ala
20 25 30
Thr Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser Thr Leu Val Glu Val
35 40 45
Thr Leu Gly Glu Val Pro Ala Ala Glu Ser Pro Asp Pro Pro Gln Ser
50 55 60
Pro Gln Gly Ala Ser Ser Leu Pro Thr Thr Met Asn Tyr Pro Leu Trp
65 70 75 80
Ser Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu Glu Glu Gly Pro Ser
85 90 95
Thr Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala Ala Leu Ser Arg Lys
100 105 110
Val Ala Glu Leu Val His Phe Leu Leu Leu Lys Tyr Arg Ala Arg Glu
115 120 125
Pro Val Thr Lys Ala Glu Met Leu Gly Ser Val Val Gly Asn Trp Gln
130 135 140
Tyr Phe Phe Pro Val Ile Phe Ser Lys Ala Ser Ser Ser Leu Gln Leu
145 150 155 160
Val Phe Gly Ile Glu Leu Met Glu Val Asp Pro Ile Gly His Leu Tyr
165 170 175
Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu Leu Gly Asp
180 185 190
Asn Gln Ile Met Pro Lys Ala Gly Leu Leu Ile Ile Val Leu Ala Ile
195 200 205
Ile Ala Arg Glu Gly Asp Cys Ala Pro Glu Glu Lys Ile Trp Glu Glu
210 215 220
Leu Ser Val Leu Glu Val Phe Glu Gly Arg Glu Asp Ser Ile Leu Gly
225 230 235 240
Asp Pro Lys Lys Leu Leu Thr Gln His Phe Val Gln Glu Asn Tyr Leu
245 250 255
Glu Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala Cys Tyr Glu Phe Leu
260 265 270
Trp Gly Pro Arg Ala Leu Val Glu Thr Ser Tyr Val Lys Val Leu His
275 280 285
His Met Val Lys Ile Ser Gly Gly Pro His Ile Ser Tyr Pro Pro Leu
290 295 300
His Glu Trp Val Leu Arg Glu Gly Glu Glu
305 310
<210> 18
<211> 543
<212> DNA
<213> 人工序列
<220>
<223> 载体MVA_NYESO的多核苷酸构建体
<400> 18
atgcaggccg agggcagagg caccggcgga tctactgggg atgctgatgg acctggcggc 60
cctggcattc cagatggccc aggcggaaat gctggcggac caggcgaagc tggcgctaca 120
ggcggaagag gacctagagg cgctggcgcc gctagagctt ctggacctgg gggaggcgct 180
cctagaggac ctcatggcgg agctgcctct ggcctgaatg gctgctgtag atgtggcgcc 240
agaggccccg aaagccggct gctggaattc tacctggcca tgcccttcgc cacccccatg 300
gaagctgagc tggccagaag aagcctggcc caggacgctc ctcctctgcc tgtgcctggc 360
gtgctgctga aagaattcac cgtgtccggc aacatcctga ccatccggct gacagccgcc 420
gaccacagac agctgcagct gagcatcagc agctgcctgc agcagctgtc cctgctgatg 480
tggatcaccc agtgctttct gcccgtgttt ctggcccagc ctcctagcgg ccagcggcgc 540
taa 543
<210> 19
<211> 180
<212> PRT
<213> 人工序列
<220>
<223> MVA_NYESO的翻译蛋白
<400> 19
Met Gln Ala Glu Gly Arg Gly Thr Gly Gly Ser Thr Gly Asp Ala Asp
1 5 10 15
Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly Pro Gly Gly Asn Ala Gly
20 25 30
Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly Arg Gly Pro Arg Gly Ala
35 40 45
Gly Ala Ala Arg Ala Ser Gly Pro Gly Gly Gly Ala Pro Arg Gly Pro
50 55 60
His Gly Gly Ala Ala Ser Gly Leu Asn Gly Cys Cys Arg Cys Gly Ala
65 70 75 80
Arg Gly Pro Glu Ser Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro Phe
85 90 95
Ala Thr Pro Met Glu Ala Glu Leu Ala Arg Arg Ser Leu Ala Gln Asp
100 105 110
Ala Pro Pro Leu Pro Val Pro Gly Val Leu Leu Lys Glu Phe Thr Val
115 120 125
Ser Gly Asn Ile Leu Thr Ile Arg Leu Thr Ala Ala Asp His Arg Gln
130 135 140
Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln Gln Leu Ser Leu Leu Met
145 150 155 160
Trp Ile Thr Gln Cys Phe Leu Pro Val Phe Leu Ala Gln Pro Pro Ser
165 170 175
Gly Gln Arg Arg
180
<210> 20
<211> 1008
<212> DNA
<213> 人工序列
<220>
<223> 载体MVA_tPA_MAGEA3的多核苷酸构建体
<400> 20
atggacgcca tgaagcgggg cctgtgctgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tcccccccac tggaacagag aagccagcac tgcaagcccg aggaaggcct ggaagccaga 120
ggcgaagctc tgggactcgt gggagcacag gctccagcca ccgaagaaca ggaagccgcc 180
agcagctcta gcaccctggt ggaagtgaca ctgggcgaag tgcctgccgc cgagtctcct 240
gatcctcctc agtctcctca gggcgccagc tctctgccca ccaccatgaa ctaccccctg 300
tggtcccagt cctacgagga cagcagcaac caggaagaag agggccccag caccttcccc 360
gacctggaat ctgaattcca ggccgccctg agccggaagg tggccgaact ggtgcacttc 420
ctgctgctga agtaccgggc cagagaaccc gtgaccaagg ccgagatgct gggcagcgtc 480
gtgggcaact ggcagtactt cttccccgtg atcttctcca aggccagctc cagcctgcag 540
ctggtgttcg gcatcgagct gatggaagtg gaccccatcg gacacctgta catcttcgcc 600
acctgtctgg gcctgagcta cgatggcctg ctgggcgaca accagatcat gcccaaagcc 660
ggcctgctga tcatcgtgct ggccatcatt gcccgcgagg gcgattgtgc ccccgaggaa 720
aagatctggg aggaactgag cgtgctggaa gtgttcgagg gaagagagga ctccatcctg 780
ggcgacccca agaagctgct gacccagcac ttcgtgcagg aaaactacct ggagtataga 840
caggtgcccg gcagcgaccc tgcctgctac gaatttctgt ggggccctag agcactggtg 900
gaaaccagct acgtgaaagt gctgcaccac atggtcaaga tcagcggcgg accccacatc 960
agctacccac ctctgcacga atgggtgctg cgggaaggcg aagagtga 1008
<210> 21
<211> 335
<212> PRT
<213> 人工序列
<220>
<223> MVA_tPA_MAGEA3的翻译蛋白
<400> 21
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Pro Leu Glu Gln Arg Ser Gln His Cys Lys
20 25 30
Pro Glu Glu Gly Leu Glu Ala Arg Gly Glu Ala Leu Gly Leu Val Gly
35 40 45
Ala Gln Ala Pro Ala Thr Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser
50 55 60
Thr Leu Val Glu Val Thr Leu Gly Glu Val Pro Ala Ala Glu Ser Pro
65 70 75 80
Asp Pro Pro Gln Ser Pro Gln Gly Ala Ser Ser Leu Pro Thr Thr Met
85 90 95
Asn Tyr Pro Leu Trp Ser Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu
100 105 110
Glu Glu Gly Pro Ser Thr Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala
115 120 125
Ala Leu Ser Arg Lys Val Ala Glu Leu Val His Phe Leu Leu Leu Lys
130 135 140
Tyr Arg Ala Arg Glu Pro Val Thr Lys Ala Glu Met Leu Gly Ser Val
145 150 155 160
Val Gly Asn Trp Gln Tyr Phe Phe Pro Val Ile Phe Ser Lys Ala Ser
165 170 175
Ser Ser Leu Gln Leu Val Phe Gly Ile Glu Leu Met Glu Val Asp Pro
180 185 190
Ile Gly His Leu Tyr Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp
195 200 205
Gly Leu Leu Gly Asp Asn Gln Ile Met Pro Lys Ala Gly Leu Leu Ile
210 215 220
Ile Val Leu Ala Ile Ile Ala Arg Glu Gly Asp Cys Ala Pro Glu Glu
225 230 235 240
Lys Ile Trp Glu Glu Leu Ser Val Leu Glu Val Phe Glu Gly Arg Glu
245 250 255
Asp Ser Ile Leu Gly Asp Pro Lys Lys Leu Leu Thr Gln His Phe Val
260 265 270
Gln Glu Asn Tyr Leu Glu Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala
275 280 285
Cys Tyr Glu Phe Leu Trp Gly Pro Arg Ala Leu Val Glu Thr Ser Tyr
290 295 300
Val Lys Val Leu His His Met Val Lys Ile Ser Gly Gly Pro His Ile
305 310 315 320
Ser Tyr Pro Pro Leu His Glu Trp Val Leu Arg Glu Gly Glu Glu
325 330 335
<210> 22
<211> 606
<212> DNA
<213> 人工序列
<220>
<223> 载体MVA_tPA_NYESO的多核苷酸构建体
<400> 22
atggacgcca tgaagcgggg cctgtgctgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
agccctcagg ccgagggaag aggcacaggc ggatctacag gcgacgctga tggacctggc 120
ggccctggaa ttcctgatgg cccaggcgga aatgctggcg gaccaggcga agctggcgct 180
acaggcggaa gaggacctag aggcgctggc gccgctagag cttctggacc tgggggaggc 240
gctcctagag gacctcatgg cggagctgcc tctggcctga atggctgctg tagatgtggc 300
gccagaggcc ccgaaagccg gctgctggaa ttctacctgg ccatgccctt cgccaccccc 360
atggaagctg agctggccag aagaagcctg gcccaggacg ctcctccact gcctgtgcca 420
ggggtgctgc tgaaagaatt caccgtgtcc ggcaacatcc tgaccatccg gctgacagcc 480
gccgaccaca gacagctgca gctgagcatc agcagctgcc tgcagcagct gtccctgctg 540
atgtggatca cccagtgctt tctgcccgtg tttctggccc agcctcctag cggccagcgg 600
cgctaa 606
<210> 23
<211> 201
<212> PRT
<213> 人工序列
<220>
<223> MVA_tPA_NYESO的翻译蛋白
<400> 23
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Gln Ala Glu Gly Arg Gly Thr Gly Gly Ser
20 25 30
Thr Gly Asp Ala Asp Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly Pro
35 40 45
Gly Gly Asn Ala Gly Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly Arg
50 55 60
Gly Pro Arg Gly Ala Gly Ala Ala Arg Ala Ser Gly Pro Gly Gly Gly
65 70 75 80
Ala Pro Arg Gly Pro His Gly Gly Ala Ala Ser Gly Leu Asn Gly Cys
85 90 95
Cys Arg Cys Gly Ala Arg Gly Pro Glu Ser Arg Leu Leu Glu Phe Tyr
100 105 110
Leu Ala Met Pro Phe Ala Thr Pro Met Glu Ala Glu Leu Ala Arg Arg
115 120 125
Ser Leu Ala Gln Asp Ala Pro Pro Leu Pro Val Pro Gly Val Leu Leu
130 135 140
Lys Glu Phe Thr Val Ser Gly Asn Ile Leu Thr Ile Arg Leu Thr Ala
145 150 155 160
Ala Asp His Arg Gln Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln Gln
165 170 175
Leu Ser Leu Leu Met Trp Ile Thr Gln Cys Phe Leu Pro Val Phe Leu
180 185 190
Ala Gln Pro Pro Ser Gly Gln Arg Arg
195 200
<210> 24
<211> 39593
<212> DNA
<213> 人工序列
<220>
<223> ChAdOx1穿梭载体p2563
<400> 24
gtttaaacgc ggccgccagg cctacccact agtcaattcg ggaggatcga aacggcagat 60
cgcaaaaaac agtacataca gaaggagaca tgaacatgaa catcaaaaaa attgtaaaac 120
aagccacagt tctgactttt acgactgcac ttctggcagg aggagcgact caagccttcg 180
cgaaagaaaa taaccaaaaa gcatacaaag aaacgtacgg cgtctctcat attacacgcc 240
atgatatgct gcagatccct aaacagcagc aaaacgaaaa ataccaagtg cctcaattcg 300
atcaatcaac gattaaaaat attgagtctg caaaaggact tgatgtgtgg gacagctggc 360
cgctgcaaaa cgctgacgga acagtagctg aatacaacgg ctatcacgtt gtgtttgctc 420
ttgcgggaag cccgaaagac gctgatgaca catcaatcta catgttttat caaaaggtcg 480
gcgacaactc aatcgacagc tggaaaaacg cgggccgtgt ctttaaagac agcgataagt 540
tcgacgccaa cgatccgatc ctgaaagatc agacgcaaga atggtccggt tctgcaacct 600
ttacatctga cggaaaaatc cgtttattct acactgacta ttccggtaaa cattacggca 660
aacaaagcct gacaacagcg caggtaaatg tgtcaaaatc tgatgacaca ctcaaaatca 720
acggagtgga agatcacaaa acgatttttg acggagacgg aaaaacatat cagaacgttc 780
agcagtttat cgatgaaggc aattatacat ccggcgacaa ccatacgctg agagaccctc 840
actacgttga agacaaaggc cataaatacc ttgtattcga agccaacacg ggaacagaaa 900
acggatacca aggcgaagaa tctttattta acaaagcgta ctacggcggc ggcacgaact 960
tcttccgtaa agaaagccag aagcttcagc agagcgctaa aaaacgcgat gctgagttag 1020
cgaacggcgc cctcggtatc atagagttaa ataatgatta cacattgaaa aaagtaatga 1080
agccgctgat cacttcaaac acggtaactg atgaaatcga gcgcgcgaat gttttcaaaa 1140
tgaacggcaa atggtacttg ttcactgatt cacgcggttc aaaaatgacg atcgatggta 1200
ttaactcaaa cgatatttac atgcttggtt atgtatcaaa ctctttaacc ggcccttaca 1260
agccgctgaa caaaacaggg cttgtgctgc aaatgggtct tgatccaaac gatgtgacat 1320
tcacttactc tcacttcgca gtgccgcaag ccaaaggcaa caatgtggtt atcacaagct 1380
acatgacaaa cagaggcttc ttcgaggata aaaaggcaac atttgcgcca agcttcttaa 1440
tgaacatcaa aggcaataaa acatccgttg tcaaaaacag catcctggag caaggacagc 1500
tgacagtcaa ctaataacag caaaaagaaa atgccgatac ttcattggca ttttctttta 1560
tttctcaaca agatggtgaa ttgactagtg ggtagatcca caggacgggt gtggtcgcca 1620
tgatcgcgta gtcgatagtg gctccaagta gcgaagcgag caggactggg cggcggccaa 1680
agcggtcgga cagtgctccg agaacgggtg cgcatagaaa ttgcatcaac gcatatagcg 1740
ctagcagcac gccatagtga ctggcgatgc tgtcggaatg gacgatatcc cgcaagaggc 1800
ccggcagtac cggcataacc aagcctatgc ctacagcatc cagggtgacg gtgccgagga 1860
tgacgatgag cgcattgtta gatttcatac acggtgcctg actgcgttag caatttaact 1920
gtgataaact accgcattaa agcttatcga tgataagctg tcaaacatga gaattgatcc 1980
ggaaccctta atataacttc gtataatgta tgctatacga agttattagg tccctcgact 2040
atagggtcac cgtcgacagc gacacacttg catcggatgc agcccggtta acgtgccggc 2100
acggcctggg taaccaggta ttttgtccac ataaccgtgc gcaaaatgtt gtggataagc 2160
aggacacagc agcaatccac agcaggcata caaccgcaca ccgaggttac tccgttctac 2220
aggttacgac gacatgtcaa tacttgccct tgacaggcat tgatggaatc gtagtctcac 2280
gctgatagtc tgatcgacaa tacaagtggg accgtggtcc cagaccgata atcagaccga 2340
crayacgagt gggaycgtgg tcccagacta ataatcagac cgacgatacg agtgggaccg 2400
tggtcccaga ctaataatca gaccgacgat acgagtggga ccgtggtycc agwctratwa 2460
tcagaccgac gatacragtg gracmgtggk cccagasaka atawtcagrc cgagwtaygc 2520
wktckggcct gtaacaaagg acattaagta aagacagata mrmgtgrgac taaaacgtgg 2580
tcccagtctg attatcagac cgacgatacg agtgggaccg tggtcccaga ctaataatca 2640
gaccgacgat acgagtggga ccgtggtccc agactaataa tcagaccgac gatacgagtg 2700
ggaccgtggt cccagtctga ttatcagacc gacgatacaa gtggaacagt gggcccagag 2760
agaatattca ggccagttat gctttctggc ctgtaacaaa ggacattaag taaagacaga 2820
taaacgtaga ctaaaacgtg gtcgcatcag ggtgctggct tttcaagttc cttaagaatg 2880
gcctcaattt tctctataca ctcagttgga acacgagacc tgtccaggtt aagcaccatt 2940
ttatcgccct tatacaatac tgtcgctcca ggagcaaact gatgtcgtga gcttaaacta 3000
gttcttgatg cagatgacgt tttaagcaca gaagttaaaa gagtgataac ttcttcagct 3060
tcaaatatca ccccagcttt tttctgctca tgaaggttag atgcctgctg cttaagtaat 3120
tcctctttat ctgtaaaggc tttttgaagt gcatcacctg accgggcaga tagttcaccg 3180
gggtgagaaa aaagagcaac aactgattta ggcaatttgg cggtgttgat acagcgggta 3240
ataatcttac gtgaaatatt ttccgcatca gccagcgcag aaatatttcc agcaaattca 3300
ttctgcaatc ggcttgcata acgctgacca cgttcataag cacttgttgg gcgataatcg 3360
ttacccaatc tggataatgc agccatctgc tcatcatcca gctcgccaac cagaacacga 3420
taatcacttt cggtaagtgc agcagcttta cgacggcgac tcccatcggc aatttctatg 3480
acaccagata ctcttcgacc gaacgccggt gtctgttgac cagtcagtag aaaagaaggg 3540
atgagatcat ccagtgcgtc ctcagtaagc agctcctggt cacgttcatt acctgaccat 3600
acccgagagg tcttctcaac actatcaccc cggagcactt caagagtaaa cttcacatcc 3660
cgaccacata caggcaaagt aatggcatta ccgcgagcca ttactcctac gcgcgcaatt 3720
aacgaatcca ccatcggggc agctggtgtc gataacgaag tatcttcaac cggttgagta 3780
ttgagcgtat gttttggaat aacaggcgca cgcttcatta tctaatctcc cagcgtggtt 3840
taatcagacg atcgaaaatt tcattgcaga caggttccca aatagaaaga gcatttctcc 3900
aggcaccagt tgaagagcgt tgatcaatgg cctgttcaaa aacagttctc atccggatct 3960
gacctttacc aacttcatcc gtttcacgta caacattttt tagaaccatg cttccccagg 4020
catcccgaat ttgctcctcc atccacgggg actgagagcc attactattg ctgtatttgg 4080
taagcaaaat acgtacatca ggctcgaacc ctttaagatc aacgttcttg agcagatcac 4140
gaagcatatc gaaaaactgc agtgcggagg tgtagtcaaa caactcagca ggcgtgggaa 4200
caatcagcac atcagcagca catacgacat taatcgtgcc gatacccagg ttaggcgcgc 4260
tgtcaataac tatgacatca tagtcatgag caacagtttc aatggccagt cggagcatca 4320
ggtgtggatc ggtgggcagt ttaccttcat caaatttgcc cattaactca gtttcaatac 4380
ggtgcagagc cagacaggaa ggaataatgt caagccccgg ccagcaagtg ggctttattg 4440
cataagtgac atcgtccttt tccccaagat agaaaggcag gagagtgtct tctgcatgaa 4500
tatgaagatc tggtacccat ccgtgataca ttgaggctgt tccctggggg tcgttacctt 4560
ccacgagcaa aacacgtagc cccttcagag ccagatcctg agcaagatga acagaaactg 4620
aggttttgta aacgccacct ttatgggcag caaccccgat caccggtgga aatacgtctt 4680
cagcacgtcg caatcgcgta ccaaacacat cacgcatatg attaatttgt tcaattgtat 4740
aaccaacacg ttgctcaacc cgtcctcgaa tttccatatc cgggtgcggt agtcgccctg 4800
ctttctcggc atctctgata gcctgagaag aaaccccaac taaatccgct gcttcaccta 4860
ttctccagcg ccgggttatt ttcctcgctt ccgggctgtc atcattaaac tgtgcaatgg 4920
cgatagcctt cgtcatttca tgaccagcgt ttatgcactg gttaagtgtt tccatgagtt 4980
tcattctgaa catcctttaa tcattgcttt gcgttttttt attaaatctt gcaatttact 5040
gcaaagcaac aacaaaatcg caaagtcatc aaaaaaccgc aaagttgttt aaaataagag 5100
caacactaca aaaggagata agaagagcac atacctcagt cacttattat cactagcgct 5160
cgccgcagcc gtgtaaccga gcatagcgag cgaactggcg aggaagcaaa gaagaactgt 5220
tctgtcagat agctcttacg ctcagcgcaa gaagaaatat ccaccgtggg aaaaactcca 5280
ggtagaggta cacacgcgga tagccaattc agagtaataa actgtgataa tcaaccctca 5340
tcaatgatga cgaactaacc cccgatatca ggtcacatga cgaagggaaa gagaaggaaa 5400
tcaactgtga caaactgccc tcaaatttgg cttccttaaa aattacagtt caaaaagtat 5460
gagaaaatcc atgcaggctg aaggaaacag caaaactgtg acaaattacc ctcagtaggt 5520
cagaacaaat gtgacgaacc accctcaaat ctgtgacaga taaccctcag actatcctgt 5580
cgtcatggaa gtgatatcgc ggaaggaaaa tacgatatga gtcgtctggc ggcctttctt 5640
tttctcaatg tatgagaggc gcattggagt tctgctgttg atctcattaa cacagacctg 5700
caggaagcgg cggcggaagt caggcatacg ctggtaactt tgaggcagct ggtaacgctc 5760
tatgatccag tcgattttca gagagacgat gcctgagcca tccggcttac gatactgaca 5820
cagggattcg tataaacgca tggcatacgg attggtgatt tcttttgttt cactaagccg 5880
aaactgcgta aaccggttct gtaacccgat aaagaaggga atgagatatg ggttgatatg 5940
tacactgtaa agccctctgg atggactgtg cgcacgtttg ataaaccaag gaaaagattc 6000
atagcctttt tcatcgccgg catcctcttc agggcgataa aaaaccactt ccttccccgc 6060
gaaactcttc aatgcctgcc gtatatcctt actggcttcc gcagaggtca atccgaatat 6120
ttcagcatat ttagcaacat ggatctcgca gataccgtca tgttcctgta gggtgccatc 6180
agattttctg atctggtcaa cgaacagata cagcatacgt ttttgatccc gggagagact 6240
atatgccgcc tcagtgaggt cgtttgactg gacgattcgc gggctatttt tacgtttctt 6300
gtgattgata accgctgttt ccgccatgac agatccatgt gaagtgtgac aagtttttag 6360
attgtcacac taaataaaaa agagtcaata agcagggata actttgtgaa aaaacagctt 6420
cttctgaggg caatttgtca cagggttaag ggcaatttgt cacagacagg actgtcattt 6480
gagggtgatt tgtcacactg aaagggcaat ttgtcacaac accttctcta gaaccagcat 6540
ggataaaggc ctacaaggcg ctctaaaaaa gaagatctaa aaactataaa aaaaataatt 6600
ataaaaatat ccccgtggat aagtggataa ccccaaggga agttttttca ggcatcgtgt 6660
gtaagcagaa tatataagtg ctgttccctg gtgcttcctc gctcactcga gggcttcgcc 6720
ctgtcgctca actgcggcga gcactactgg ctgtaaaagg acagaccaca tcatggttct 6780
gtgttcatta ggttgttctg tccattgctg acataatccg ctccacttca acgtaacacc 6840
gcacgaagat ttctattgtt cctgaaggca tattcaaatc gttttcgtta ccgcttgcag 6900
gcatcatgac agaacactac ttcctataaa cgctacacag gctcctgaga ttaataatgc 6960
ggatctctac gataatggga gattttcccg actgtttcgt tcgcttctca gtggataaca 7020
gccagcttct ctgtttaaca gacaaaaaca gcatatccac tcagttccac atttccatat 7080
aaaggccaag gcatttattc tcaggataat tgtttcagca tcgcaaccgc atcagactcc 7140
ggcatcgcaa actgcacccg gtgccgggca gccacatcca gcgcaaaaac cttcgtgtag 7200
acttccgttg aactgatgga cttatgtccc atcaggcttt gcagaacttt cagcggtata 7260
ccggcataca gcatgtgcat cgcataggaa tggcggaacg tatgtggtgt gaccggaaca 7320
gagaacgtca caccgtcagc agcagcggcg gcaaccgcct ccccaatcca ggtcctgacc 7380
gttctgtccg tcacttccca gatccgcgct ttctctgtcc ttcctgtgcg acggttacgc 7440
cgctccatga gcttatcgcg aataaatacc tgtgacggaa gatcacttcg cagaataaat 7500
aaatcctggt gtccctgttg ataccgggaa gccctgggcc aacttttggc gaaaatgaga 7560
cgttgatcgg cacgtaagag gttccaactt tcaccataat gaaataagat cactaccggg 7620
cgtatttttt gagttatcga gattttcagg agctaaggaa gctaaaatgg agaaaaaaat 7680
cactggatat accaccgttg atatatccca atggcatcgt aaagaacatt ttgaggcatt 7740
tcagtcagtt gctcaatgta cctataacca gaccgttcag ctggatatta cggccttttt 7800
aaagaccgta aagaaaaata agcacaagtt ttatccggcc tttattcaca ttcttgcccg 7860
cctgatgaat gctcatccgg agttccgtat ggcaatgaaa gacggtgagc tggtgatatg 7920
ggatagtgtt cacccttgtt acaccgtttt ccatgagcaa actgaaacgt tttcatcgct 7980
ctggagtgaa taccacgacg atttccggca gtttctacac atatattcgc aagatgtggc 8040
gtgttacggt gaaaacctgg cctatttccc taaagggttt attgagaata tgtttttcgt 8100
ctcagccaat ccctgggtga gtttcaccag ttttgattta aacgtggcca atatggacaa 8160
cttcttcgcc cccgttttca ccatgggcaa atattatacg caaggcgaca aggtgctgat 8220
gccgctggcg attcaggttc atcatgccgt ttgtgatggc ttccatgtcg gcagaatgct 8280
taatgaatta caacagtact gcgatgagtg gcagggcggg gcgtaatttt tttaaggcag 8340
ttattggtgc ccttaaacgc ctggttgcta cgcctgaata agtgataata agcggatgaa 8400
tggcagaaat tcgatgataa gctgtcaaac atgagaattg gtcgacggcg cgccaaagct 8460
tgcatgcctg cagccgcgta acctggcaaa atcggttacg gttgagtaat aaatggatgc 8520
cctgcgtaag cggggcacat ttcattacct ctttctccgc acccgacata gataataact 8580
tcgtatagta tacattatac gaagttatct agtagactta atcgcgttta aacccatcat 8640
caataatata cctcaaactt tttgtgcgcg ttaatatgca aatgaggcgt ttgaatttgg 8700
gaagggagga aggtgattgg ccgagagaag ggcgaccgtt aggggcgggg cgagtgacgt 8760
tttgatgacg tgaccgcgag gaggagccag tttgcaagtt ctcgtgggaa aagtgacgtc 8820
aaacgaggtg tggtttgaac acggaaatac tcaattttcc cgcgctctct gacaggaaat 8880
gaggtgtttc taggcggatg caagtgaaaa cgggccattt tcgcgcgaaa actgaatgag 8940
gaagtgaaaa tctgagtaat ttcgcgttta tgacagggag gagtatttgc cgagggccga 9000
gtagactttg accgattacg tgggggtttc gattaccgtg tttttcacct aaatttccgc 9060
gtacggtgtc aaagtccggt gtttttacgt aggtgtcagc tgatcgccag ggtatttaaa 9120
cctgcgctct ccagtcaaga ggccactctt gagtgccagc gagaagagtt ttctcctccg 9180
cgcgcgagtc agatctacac tttgaaaggc gatcgctagc gacatcgatc acaagtttgt 9240
acaaaaaagc tgaacgagaa acgtaaaatg atataaatat caatatatta aattagattt 9300
tgcataaaaa acagactaca taatactgta aaacacaaca tatccagtca ctatggcggc 9360
cgccgattta ttcaacaaag ccacgttgtg tctcaaaatc tctgatgtta cattgcacaa 9420
gataaaaata tatcatcatg aacaataaaa ctgtctgctt acataaacag taatacaagg 9480
ggtgttatga gccatattca acgggaaacg tcttgctcga ggccgcgatt aaattccaac 9540
atggatgctg atttatatgg gtataaatgg gctcgtgata atgtcgggca atcaggtgcg 9600
acaatctatc gattgtatgg gaagcccgat gcgccagagt tgtttctgaa acatggcaaa 9660
ggtagcgttg ccaatgatgt tacagatgag atggtcagac taaactggct gacggaattt 9720
atgcctcttc cgaccatcaa gcattttatc cgtactcctg atgatgcatg gttactcacc 9780
actgcgatcc ccgggaaaac agcattccag gtattagaag aatatcctga ttcaggtgaa 9840
aatattgttg atgcgctggc agtgttcctg cgccggttgc attcgattcc tgtttgtaat 9900
tgtcctttta acagcgatcg cgtatttcgt ctcgctcagg cgcaatcacg aatgaataac 9960
ggtttggttg atgcgagtga ttttgatgac gagcgtaatg gctggcctgt tgaacaagtc 10020
tggaaagaaa tgcataagct tttgccattc tcaccggatt cagtcgtcac tcatggtgat 10080
ttctcacttg ataaccttat ttttgacgag gggaaattaa taggttgtat tgatgttgga 10140
cgagtcggaa tcgcagaccg ataccaggat cttgccatcc tatggaactg cctcggtgag 10200
ttttctcctt cattacagaa acggcttttt caaaaatatg gtattgataa tcctgatatg 10260
aataaattgc agtttcattt gatgctcgat gagtttttct aatcagaatt ggttaattgg 10320
ttgtaacact ggcacgcgtg gatccggctt actaaaagcc agataacagt atgcgtattt 10380
gcgcgctgat ttttgcggta taagaatata tactgatatg tatacccgaa gtatgtcaaa 10440
aagaggtatg ctatgaagca gcgtattaca gtgacagttg acagcgacag ctatcagttg 10500
ctcaaggcat atatgatgtc aatatctccg gtctggtaag cacaaccatg cagaatgaag 10560
cccgtcgtct gcgtgccgaa cgctggaaag cggaaaatca ggaagggatg gctgaggtcg 10620
cccggtttat tgaaatgaac ggctcttttg ctgacgagaa caggggctgg tgaaatgcag 10680
tttaaggttt acacctataa aagagagagc cgttatcgtc tgtttgtgga tgtacagagt 10740
gatattattg acacgcccgg gcgacggatg gtgatccccc tggccagtgc acgtctgctg 10800
tcagataaag tctcccgtga actttacccg gtggtgcata tcggggatga aagctggcgc 10860
atgatgacca ccgatatggc cagtgtgccg gtctccgtta tcggggaaga agtggctgat 10920
ctcagccacc gcgaaaatga catcaaaaac gccattaacc tgatgttctg gggaatataa 10980
atgtcaggct cccttataca cagccagtct gcaggtcgac catagtgact ggatatgttg 11040
tgttttacag tattatgtag tctgtttttt atgcaaaatc taatttaata tattgatatt 11100
tatatcattt tacgtttctc gttcagcttt cttgtacaaa gtggtgatcg attcgacaga 11160
tcgcgatcgc agtgagtagt gttctggggc gggggaggac ctgcatgagg gccagaatga 11220
ctgaaatctg tgcttttctg tgtgttgcag catcatgagc ggaagcggct cctttgaggg 11280
aggggtattc agcccttatc tgacggggcg tctcccctcc tgggcgggag tgcgtcagaa 11340
tgtgatggga tccacggtgg acggccggcc cgtgcagccc gcgaactctt caaccctgac 11400
ctatgcaacc ctgagctctt cgtcggtgga cgcagctgcc gccgcagctg ctgcatccgc 11460
cgccagcgcc gtgcgcggaa tggccatggg cgccggctac tacggcactc tggtggccaa 11520
ctcgagttcc accaataatc ccgccagcct gaacgaggag aagctgctgc tgctgatggc 11580
ccagcttgag gccttgaccc agcgcctggg cgagctgacc cagcaggtgg ctcagctgca 11640
ggagcagacg cgggccgcgg ttgccacggt gaaatccaaa taaaaaatga atcaataaat 11700
aaacggagac ggttgttgat tttaacacag agtctgaatc tttatttgat ttttcgcgcg 11760
cggtaggccc tggaccaccg gtctcgatca ttgagcaccc ggtggatctt ttccaggacc 11820
cggtagaggt gggcttggat gttgaggtac atgggcatga gcccgtcccg ggggtggagg 11880
tagctccatt gcagggcctc gtgctcgggg gtggtgttgt aaatcaccca gtcatagcag 11940
gggcgcaggg cgtggtgttg cacaatatct ttgaggagga gactgatggc cacgggcagc 12000
cctttggtgt aggtgtttac aaatctgttg agctgggagg gatgcatgcg gggggagatg 12060
aggtgcatct tggcctggat cttgagattg gcgatgttac cgcccagatc ccgcctgggg 12120
ttcatgttgt gcaggaccac cagcacggtg tatccggtgc acttggggaa tttatcatgc 12180
aacttggaag ggaaggcgtg aaagaatttg gcgacgccct tgtgtccgcc caggttttcc 12240
atgcactcat ccatgatgat ggcaatgggc ccgtgggcgg cggcctgggc aaagacgttt 12300
cgggggtcgg acacatcata gttgtggtcc tgggtgaggt catcataggc cattttaatg 12360
aatttggggc ggagggtgcc ggactggggg acaaaggtac cctcgatccc gggggcgtag 12420
ttcccctcac agatctgcat ctcccaggct ttgagctcag agggggggat catgtccacc 12480
tgcggggcga taaagaacac ggtttccggg gcgggggaga tgagctgggc cgaaagcaag 12540
ttccggagca gctgggactt gccgcagccg gtggggccgt aaatgacccc gatgaccggc 12600
tgcaggtggt agttgaggga gagacagctg ccgtcctccc ggaggagggg ggccacctcg 12660
ttcatcatct cgcgcacgtg catgttctcg cgcaccagtt ccgccaggag gcgctctccc 12720
cccagagata ggagctcctg gagcgaggcg aagtttttca gcggcttgag tccgtcggcc 12780
atgggcattt tggagagggt ctgttgcaag agttccaagc ggtcccagag ctcggtgatg 12840
tgctctacgg catctcgatc cagcagacct cctcgtttcg cgggttggga cgactgcggg 12900
agtagggcac cagacgatgg gcgtccagcg cagccagggt ccggtccttc cagggccgca 12960
gcgtccgcgt cagggtggtc tccgtcacgg tgaaggggtg cgcgccgggc tgggcgcttg 13020
cgagggtgcg cttcaggctc atccggctgg tcgaaaaccg ctcccgatcg gcgccctgcg 13080
cgtcggccag gtagcaattg accatgagtt cgtagttgag cgcctcggcc gcgtggcctt 13140
tggcgcggag cttacctttg gaagtctgcc cgcaggcggg acagaggagg gacttgaggg 13200
cgtagagctt gggggcgagg aagacggaat cgggggcgta ggcgtccgcg ccgcagtggg 13260
cgcagacggt ctcgcactcc acgagccagg tgaggtcggg ctggtcgggg tcaaaaacca 13320
gtttcccgcc gttctttttg atgcgtttct tacctttggt ctccatgagc tcgtgtcccc 13380
gctgggtgac aaagaggctg tccgtgtccc cgtagaccga ctttatgggc cggtcctcga 13440
gcggtgtgcc gcggtcctcc tcgtagagga accccgccca ctccgagacg aaagcccggg 13500
tccaggccag cacgaaggag gccacgtggg acgggtagcg gtcgttgtcc accagcgggt 13560
ccactttttc cagggtatgc aaacacatgt ccccctcgtc cacatccagg aaggtgattg 13620
gcttgtaagt gtaggccacg tgaccggggg tcccggccgg gggggtataa aagggggcgg 13680
gcccctgctc gtcctcactg tcttccggat cgctgtccag gagcgccagc tgttggggta 13740
ggtattccct ctcgaaggcg ggcatgacct cggcactcag gttgtcagtt tctagaaacg 13800
aggaggattt gatattgacg gtgccagcgg agatgccttt caagagcccc tcgtccatct 13860
ggtcagaaaa gacgattttt ttgttgtcga gcttggtggc gaaggagccg tagagggcgt 13920
tggaaaggag cttggcgatg gagcgcatgg tctggttttt ttccttgtcg gcgcgctcct 13980
tggccgcgat gttgagctgc acgtactcgc gcgccacgca cttccattcg gggaagacgg 14040
tggtcatctc gtcgggcacg attctgacct gccaacctcg attatgcagg gtgatgaggt 14100
ccacactggt ggccacctcg ccgcgcaggg gctcgttggt ccagcagagg cggccgccct 14160
tgcgcgagca gaaggggggc agagggtcca gcatgacctc gtcggggggg tcggcatcga 14220
tggtgaagat gccgggcagg agatcggggt cgaagtagct gatggaagtg gccagatcgt 14280
ccagggaagc ttgccattcg cgcacggcca gcgcgcgctc gtagggactg aggggcgtgc 14340
cccagggcat ggggtgggtg agcgcggagg cgtacatgcc gcagatgtcg tagacgtaga 14400
ggggctcctc gaggatgccg atgtaggtgg ggtagcagcg ccccccgcgg atgctggcgc 14460
gcacgtagtc atacagctcg tgcgagggcg cgaggagccc cgggcccagg ttggtgcgac 14520
tgggcttttc ggcgcggtag acgatctggc gaaagatggc atgcgagttg gaggagatgg 14580
tgggcctttg gaagatgttg aagtgggcgt gggggaggcc gaccgagtcg cggatgaagt 14640
gggcgtagga gtcttgcagt ttggcgacga gctcggcggt gacgaggacg tccagagcgc 14700
agtagtcgag ggtctcctgg atgatgtcat acttgagctg gcccttttgt ttccacagct 14760
cgcggttgag aaggaactct tcgcggtcct tccagtactc ttcgaggggg aacccgtcct 14820
gatctgcacg gtaagagcct agcatgtaga actggttgac ggccttgtag gcgcagcagc 14880
ccttctccac ggggagggcg taggcctggg cggccttgcg cagggaggtg tgcgtgaggg 14940
cgaaggtgtc cctgaccatg accttgagga actggtgctt gaaatcgata tcgtcgcagc 15000
ccccctgctc ccagagctgg aagtccgtgc gcttcttgta ggcggggttg ggcaaagcga 15060
aagtaacatc gttgaaaagg atcttgcccg cgcggggcat aaagttgcga gtgatgcgga 15120
aaggctgggg cacctcggcc cggttgttga tgacctgggc ggcgagcacg atctcgtcga 15180
aaccgttgat gttgtggccc acgatgtaga gttccacgaa tcgcgggcgg cccttgacgt 15240
ggggcagctt cttgagctcc tcgtaggtga gctcgtcggg gtcgctgaga ccgtgctgct 15300
cgagcgccca gtcggcgaga tgggggttgg cgcggaggaa ggaagtccag agatccacgg 15360
ccagggcggt ttgcagacgg tcccggtact gacggaactg ctgcccgacg gccatttttt 15420
cgggggtgac gcagtagaag gtgcgggggt ccccgtgcca gcggtcccat ttgagctgga 15480
gggcgagatc gagggcgagc tcgacgaggc ggtcgtcccc tgagagtttc atgaccagca 15540
tgaaggggac gagctgcttg ccgaaggacc ccatccaggt gtaggtttcc acatcgtagg 15600
tgaggaagag cctttcggtg cgaggatgcg agccgatggg gaagaactgg atctcctgcc 15660
accaattgga ggaatggctg ttgatgtgat ggaagtagaa atgccgacgg cgcgccgaac 15720
actcgtgctt gtgtttatac aagcggccac agtgctcgca acgctgcacg ggatgcacgt 15780
gctgcacgag ctgtacctga gttcctttga cgaggaattt cagtgggaag tggagtcgtg 15840
gcgcctgcat ctcgtgctgt actacgtcgt ggtggtcggc ctggccctct tctgcctcga 15900
tggtggtcat gctgacgagc ccgcgcggga ggcaggtcca gacctcggcg cgagcgggtc 15960
ggagagcgag gacgagggcg cgcaggccgg agctgtccag ggtcctgaga cgctgcggag 16020
tcaggtcagt gggcagcggc ggcgcgcggt tgacttgcag gagtttttcc agggcgcgcg 16080
ggaggtccag atggtacttg atctccaccg cgccgttggt ggcgacgtcg atggcttgca 16140
gggtcccgtg cccctggggt gtgaccaccg tcccccgttt cttcttgggc ggctggggcg 16200
acgggggcgg tgcctcttcc atggttagaa gcggcggcga ggacgcgcgc cgggcggcag 16260
aggcggctcg gggcccggag gcaggggcgg caggggcacg tcggcgccgc gcgcgggtag 16320
gttctggtac tgcgcccgga gaagactggc gtgagcgacg acgcgacggt tgacgtcctg 16380
gatctgacgc ctctgggtga aggccacggg acccgtgagt ttgaacctga aagagagttc 16440
gacagaatca atctcggtat cgttgacggc ggcctgccgc aggatctctt gcacgtcgcc 16500
cgagttgtcc tggtaggcga tctcggtcat gaactgctcg atctcctcct cctgaaggtc 16560
tccgcgaccg gcgcgctcca cggtggccgc gaggtcgttg gagatgcggc ccatgagctg 16620
cgagaaggcg ttcatgcccg cctcgttcca gacgcggctg tagaccacga cgccctcggg 16680
atcgcgggcg cgcatgacca cctgggcgag gttgagctcc acgtggcgcg tgaagaccgc 16740
gtagttgcag aggcgctggt agaggtagtt gagcgtggtg gcgatgtgct cggtgacgaa 16800
gaaatacatg atccagcggc ggagcggcat ctcgctgacg tcgcccagcg cctccaagcg 16860
ttccatggcc tcgtaaaagt ccacggcgaa gttgaaaaac tgggagttgc gcgccgagac 16920
ggtcaactcc tcctccagaa gacggatgag ctcggcgatg gtggcgcgca cctcgcgctc 16980
gaaggccccc gggagttcct ccacttcctc ctcttcttcc tcctccacta acatctcttc 17040
tacttcctcc tcaggcggtg gtggtggcgg gggagggggc ctgcgtcgcc ggcggcgcac 17100
gggcagacgg tcgatgaagc gctcgatggt ctcgccgcgc cggcgtcgca tggtctcggt 17160
gacggcgcgc ccgtcctcgc ggggccgcag cgtgaagacg ccgccgcgca tctccaggtg 17220
gccggggggg tccccgttgg gcagggagag ggcgctgacg atgcatctta tcaattgccc 17280
cgtagggact ccgcgcaagg acctgagcgt ctcgagatcc acgggatctg aaaaccgttg 17340
aacgaaggct tcgagccagt cgcagtcgca aggtaggctg agcacggttt cttctgccgg 17400
gtcatgttgg ggagcggggc gggcgatgct gctggtgatg aagttgaaat aggcggttct 17460
gagacggcgg atggtggcga ggagcaccag gtctttgggc ccggcttgct ggatgcgcag 17520
acggtcggcc atgccccagg cgtggtcctg acacctggcc aggtccttgt agtagtcctg 17580
catgagccgc tccacgggca cctcctcctc gcccgcgcgg ccgtgcatgc gcgtgagccc 17640
gaagccgcgc tggggctgga cgagcgccag gtcggcgacg acgcgctcgg cgaggatggc 17700
ctgctggatc tgggtgaggg tggtctggaa gtcgtcaaag tcgacgaagc ggtggtaggc 17760
tccggtgttg atggtgtagg agcagttggc catgacggac cagttgacgg tctggtggcc 17820
cggacgcacg agctcgtggt acttgaggcg cgagtaggcg cgcgtgtcga agatgtagtc 17880
gttgcaggtg cgcaccaggt actggtagcc gatgaggaag tgcggcggcg gctggcggta 17940
gagcggccat cgctcggtgg cgggggcgcc gggcgcgagg tcctcgagca tggtgcggtg 18000
gtagccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 18060
gaactcgcgg acgcggttcc agatgttgcg cagcggcagg aagtagttca tggtgggcac 18120
ggtctggccc gtgaggcgcg cgcagtcgtg gatgctctat acgggcaaaa acgaaagcgg 18180
tcagcggctc gactccgtgg cctggaggct aagcgaacgg gttgggctgc gcgtgtaccc 18240
cggttcgaat ctcgaatcag gctggagccg cagctaacgt ggtactggca ctcccgtctc 18300
gacccaagcc tgcaccaacc ctccaggata cggaggcggg tcgttttgca actttttttg 18360
gaggccggaa atgaaactag taagcgcgga aagcggccga ccgcgatggc tcgctgccgt 18420
agtctggaga agaatcgcca gggttgcgtt gcggtgtgcc ccggttcgag gccggccgga 18480
ttccgcggct aacgagggcg tggctgcccc gtcgtttcca agaccccata gccagccgac 18540
ttctccagtt acggagcgag cccctctttt gttttgtttg tttttgccag atgcatcccg 18600
tactgcggca gatgcgcccc caccaccctc caccgcaaca acagccccct cctccacagc 18660
cggcgcttct gcccccgccc cagcagcagc agcaacttcc agccacgacc gccgcggccg 18720
ccgtgagcgg ggctggacag acttctcagt atgatcacct ggccttggaa gagggcgagg 18780
ggctggcgcg cctgggggcg tcgtcgccgg agcggcaccc gcgcgtgcag atgaaaaggg 18840
acgctcgcga ggcctacgtg cccaagcaga acctgttcag agacaggagc ggcgaggagc 18900
ccgaggagat gcgcgcggcc cggttccacg cggggcggga gctgcggcgc ggcctggacc 18960
gaaagagggt gctgagggac gaggatttcg aggcggacga gctgacgggg atcagccccg 19020
cgcgcgcgca cgtggccgcg gccaacctgg tcacggcgta cgagcagacc gtgaaggagg 19080
agagcaactt ccaaaaatcc ttcaacaacc acgtgcgcac cctgatcgcg cgcgaggagg 19140
tgaccctggg cctgatgcac ctgtgggacc tgctggaggc catcgtgcag aaccccacca 19200
gcaagccgct gacggcgcag ctgttcctgg tggtgcagca tagtcgggac aacgaggcgt 19260
tcagggaggc gctgctgaat atcaccgagc ccgagggccg ctggctcctg gacctggtga 19320
acattctgca gagcatcgtg gtgcaggagc gcgggctgcc gctgtccgag aagctggcgg 19380
ccatcaactt ctcggtgctg agtctgggca agtactacgc taggaagatc tacaagaccc 19440
cgtacgtgcc catagacaag gaggtgaaga tcgacgggtt ttacatgcgc atgaccctga 19500
aagtgctgac cctgagcgac gatctggggg tgtaccgcaa cgacaggatg caccgcgcgg 19560
tgagcgccag caggcggcgc gagctgagcg accaggagct gatgcacagc ctgcagcggg 19620
ccctgaccgg ggccgggacc gagggggaga gctactttga catgggcgcg gacctgcact 19680
ggcagcccag ccgccgggcc ttggaggcgg caggcggtcc cccctacata gaagaggtgg 19740
acgatgaggt ggacgaggag ggcgagtacc tggaagactg atggcgcgac cgtatttttg 19800
ctagatgcaa caacagccac ctcctgatcc cgcgatgcgg gcggcgctgc agagccagcc 19860
gtccggcatt aactcctcgg acgattggac ccaggccatg caacgcatca tggcgctgac 19920
gacccgcaac cccgaagcct ttagacagca gccccaggcc aaccggctct cggccatcct 19980
ggaggccgtg gtgccctcgc gctccaaccc cacgcacgag aaggtcctgg ccatcgtgaa 20040
cgcgctggtg gagaacaagg ccatccgcgg cgacgaggcc ggcctggtgt acaacgcgct 20100
gctggagcgc gtggcccgct acaacagcac caacgtgcag accaacctgg accgcatggt 20160
gaccgacgtg cgcgaggccg tggcccagcg cgagcggttc caccgcgagt ccaacctggg 20220
atccatggtg gcgctgaacg ccttcctcag cacccagccc gccaacgtgc cccggggcca 20280
ggaggactac accaacttca tcagcgccct gcgcctgatg gtgaccgagg tgccccagag 20340
cgaggtgtac cagtccgggc cggactactt cttccagacc agtcgccagg gcttgcagac 20400
cgtgaacctg agccaggcgt tcaagaactt gcagggcctg tggggcgtgc aggccccggt 20460
cggggaccgc gcgacggtgt cgagcctgct gacgccgaac tcgcgcctgc tgctgctgct 20520
ggtggccccc ttcacggaca gcggcagcat caaccgcaac tcgtacctgg gctacctgat 20580
taacctgtac cgcgaggcca tcggccaggc gcacgtggac gagcagacct accaggagat 20640
cacccacgtg agccgcgccc tgggccagga cgacccgggc aatctggaag ccaccctgaa 20700
ctttttgctg accaaccggt cgcagaagat cccgccccag tacacgctca gcgccgagga 20760
ggagcgcatc ctgcgatacg tgcagcagag cgtgggcctg ttcctgatgc aggagggggc 20820
cacccccagc gccgcgctcg acatgaccgc gcgcaacatg gagcccagca tgtacgccag 20880
caaccgcccg ttcatcaata aactgatgga ctacttgcat cgggcggccg ccatgaactc 20940
tgactatttc accaacgcca tcctgaatcc ccactggctc ccgccgccgg ggttctacac 21000
gggcgagtac gacatgcccg accccaatga cgggttcctg tgggacgatg tggacagcag 21060
cgtgttctcc ccccgaccgg gtgctaacga gcgccccttg tggaagaagg aaggcagcga 21120
ccgacgcccg tcctcggcgc tgtccggccg cgagggtgct gccgcggcgg tgcccgaggc 21180
cgccagtcct ttcccgagct tgcccttctc gctgaacagt attcgcagca gcgagctggg 21240
caggatcacg cgcccgcgct tgctgggcga ggaggagtac ttgaatgact cgctgttgag 21300
acccgagcgg gagaagaact tccccaataa cgggatagag agcctggtgg acaagatgag 21360
ccgctggaag acgtatgcgc aggagcacag ggacgatccg tcgcaggggg ccacgagccg 21420
gggcagcgcc gcccgtaaac gccggtggca cgacaggcag cggggactga tgtgggacga 21480
tgaggattcc gccgacgaca gcagcgtgtt ggacttgggt gggagtggta acccgttcgc 21540
tcacctgcgc ccccgcatcg ggcgcatgat gtaagagaaa ccgaaaataa atgatactca 21600
ccaaggccat ggcgaccagc gtgcgttcgt ttcttctctg ttgttgtatc tagtatgatg 21660
aggcgtgcgt acccggaggg tcctcctccc tcgtacgaga gcgtgatgca gcaggcgatg 21720
gcggcggcgg cggcgatgca gcccccgctg gaggctcctt acgtgccccc gcggtacctg 21780
gcgcctacgg aggggcggaa cagcattcgt tactcggagc tggcaccctt gtacgatacc 21840
acccggttgt acctggtgga caacaagtcg gcggacatcg cctcgctgaa ctaccagaac 21900
gaccacagca acttcctgac caccgtggtg cagaacaatg acttcacccc cacggaggcc 21960
agcacccaga ccatcaactt tgacgagcgc tcgcggtggg gcggtcagct gaaaaccatc 22020
atgcacacca acatgcccaa cgtgaacgag ttcatgtaca gcaacaagtt caaggcgcgg 22080
gtgatggtct cccgcaagac ccccaacggg gtgacagtga cagatggtag tcaggatatc 22140
ttggagtatg aatgggtgga gtttgagctg cccgaaggca acttctcggt gaccatgacc 22200
atcgacctga tgaacaacgc catcatcgac aattacttgg cggtggggcg gcagaacggg 22260
gtcctggaga gcgatatcgg cgtgaagttc gacactagga acttcaggct gggctgggac 22320
cccgtgaccg agctggtcat gcccggggtg tacaccaacg aggccttcca ccccgatatt 22380
gtcttgctgc ccggctgcgg ggtggacttc accgagagcc gcctcagcaa cctgctgggc 22440
attcgcaaga ggcagccctt ccaggagggc ttccagatca tgtacgagga tctggagggg 22500
ggcaacatcc ccgcgctcct ggatgtcgac gcctatgaga aaagcaagga ggagagcgcc 22560
gccgcggcga ctgcagctgt agccaccgcc tctaccgagg tcaggggcga taattttgcc 22620
agccctgcag cagtggcagc ggccgaggcg gctgaaaccg aaagtaagat agtcattcag 22680
ccggtggaga aggatagcaa ggacaggagc tacaacgtgc tgccggacaa gataaacacc 22740
gcctaccgca gctggtacct ggcctacaac tatggcgacc ccgagaaggg cgtgcgctcc 22800
tggacgctgc tcaccacctc ggacgtcacc tgcggcgtgg agcaagtcta ctggtcgctg 22860
cccgacatga tgcaagaccc ggtcaccttc cgctccacgc gtcaagttag caactacccg 22920
gtggtgggcg ccgagctcct gcccgtctac tccaagagct tcttcaacga gcaggccgtc 22980
tactcgcagc agctgcgcgc cttcacctcg ctcacgcacg tcttcaaccg cttccccgag 23040
aaccagatcc tcgtccgccc gcccgcgccc accattacca ccgtcagtga aaacgttcct 23100
gctctcacag atcacgggac cctgccgctg cgcagcagta tccggggagt ccagcgcgtg 23160
accgttactg acgccagacg ccgcacctgc ccctacgtct acaaggccct gggcatagtc 23220
gcgccgcgcg tcctctcgag ccgcaccttc taaaaaatgt ccattctcat ctcgcccagt 23280
aataacaccg gttggggcct gcgcgcgccc agcaagatgt acggaggcgc tcgccaacgc 23340
tccacgcaac accccgtgcg cgtgcgcggg cacttccgcg ctccctgggg cgccctcaag 23400
ggccgcgtgc ggtcgcgcac caccgtcgac gacgtgatcg accaggtggt ggccgacgcg 23460
cgcaactaca cccccgccgc cgcgcccgtc tccaccgtgg acgccgtcat cgacagcgtg 23520
gtggccgacg cgcgccggta cgcccgcgcc aagagccggc ggcggcgcat cgcccggcgg 23580
caccggagca cccccgccat gcgcgcggcg cgagccttgc tgcgcagggc caggcgcacg 23640
ggacgcaggg ccatgctcag ggcggccaga cgcgcggctt caggcgccag cgccggcagg 23700
acccggagac gcgcggccac ggcggcggca gcggccatcg ccagcatgtc ccgcccgcgg 23760
cgagggaacg tgtactgggt gcgcgacgcc gccaccggtg tgcgcgtgcc cgtgcgcacc 23820
cgcccccctc gcacttgaag atgttcactt cgcgatgttg atgtgtccca gcggcgagga 23880
ggatgtccaa gcgcaaattc aaggaagaga tgctccaggt catcgcgcct gagatctacg 23940
gccccgcggt ggtgaaggag gaaagaaagc cccgcaaaat caagcgggtc aaaaaggaca 24000
aaaaggaaga agatgacgat ctggtggagt ttgtgcgcga gttcgccccc cggcggcgcg 24060
tgcagtggcg cgggcggaaa gtgcacccgg tgctgagacc cggcaccacc gtggtcttca 24120
cgcccggcga gcgctccggc agcgcttcca agcgctccta cgacgaggtg tacggggacg 24180
aggacatcct cgagcaggcg gccgagcgcc tgggcgagtt tgcttacggc aagcgcagcc 24240
gccccgccct gaaggaagag gcggtgtcca tcccgctgga ccacggcaac cccacgccga 24300
gcctcaagcc cgtgaccctg cagcaggtgc tgccgagcgc agcgccgcgc cgggggttca 24360
agcgcgaggg cgaggatctg taccccacca tgcagctgat ggtgcccaag cgccagaagc 24420
tggaagacgt gctggagacc atgaaggtgg acccggacgt gcagcccgag gtcaaggtgc 24480
ggcccatcaa gcaggtggcc ccgggcctgg gcgtgcagac cgtggacatc aagatcccca 24540
cggagcccat ggaaacgcag accgagccca tgatcaagcc cagcaccagc accatggagg 24600
tgcagacgga tccctggatg ccatcggctc ctagccgaag accccggcgc aagtacggcg 24660
cggccagcct gctgatgccc aactacgcgc tgcatccttc catcatcccc acgccgggct 24720
accgcggcac gcgcttctac cgcggtcata caaccagccg ccgccgcaag accaccaccc 24780
gccgccgccg tcgccgcaca gccgctgcat ctacccctgc cgccctggtg cggagagtgt 24840
accgccgcgg ccgcgcgcct ctgaccctac cgcgcgcgcg ctaccacccg agcatcgcca 24900
tttaaacttt cgcctgcttt gcagatggcc ctcacatgcc gcctccgcgt tcccattacg 24960
ggctaccgag gaagaaaacc gcgccgtaga aggctggcgg ggaacgggat gcgtcgccac 25020
caccatcggc ggcggcgcgc catcagcaag cggttggggg gaggcttcct gcccgcgctg 25080
atccccatca tcgccgcggc gatcggggcg atccccggca ttgcttccgt ggcggtgcag 25140
gcctctcagc gccactgaga cacttggaaa acatcttgta ataaaccaat ggactctgac 25200
gctcctggtc ctgtgatgtg ttttcgtaga cagatggaag acatcaattt ttcgtccctg 25260
gctccgcgac acggcacgcg gccgttcatg ggcacctgga gcgacatcgg caccagccaa 25320
ctgaacgggg gcgccttcaa ttggagcagt ctctggagcg ggcttaagaa tttcgggtcc 25380
acgcttaaaa cctatggcag caaggcgtgg aacagcacca cagggcaggc gctgagggat 25440
aagctgaaag agcagaactt ccagcagaag gtggtcgatg ggctcgcctc gggcatcaac 25500
ggggtggtgg acctggccaa ccaggccgtg cagcggcaga tcaacagccg cctggacccg 25560
gtgccgcccg ccggctccgt ggagatgccg caggtggagg aggagctgcc tcccctggac 25620
aagcggggcg agaagcgacc ccgccccgac gcggaggaga cgctgctgac gcacacggac 25680
gagccgcccc cgtacgagga ggcggtgaaa ctgggtctgc ccaccacgcg gcccatcgcg 25740
cccctggcca ccggggtgct gaaacccgaa agtaataagc ccgcgaccct ggacttgcct 25800
cctcccgctt cccgcccctc tacagtggct aagcccctgc cgccggtggc cgtggcccgc 25860
gcgcgacccg ggggctccgc ccgccctcat gcgaactggc agagcactct gaacagcatc 25920
gtgggtctgg gagtgcagag tgtgaagcgc cgccgctgct attaaaccta ccgtagcgct 25980
taacttgctt gtctgtgtgt gtatgtatta tgtcgccgct gtccgccaga aggaggagtg 26040
aagaggcgcg tcgccgagtt gcaagatggc caccccatcg atgctgcccc agtgggcgta 26100
catgcacatc gccggacagg acgcttcgga gtacctgagt ccgggtctgg tgcagttcgc 26160
ccgcgccaca gacacctact tcagtctggg gaacaagttt aggaacccca cggtggcgcc 26220
cacgcacgat gtgaccaccg accgcagcca gcggctgacg ctgcgcttcg tgcccgtgga 26280
ccgcgaggac aacacctact cgtacaaagt gcgctacacg ctggccgtgg gcgacaaccg 26340
cgtgctggac atggccagca cctactttga catccgcggc gtgctggatc ggggccctag 26400
cttcaaaccc tactccggca ccgcctacaa cagcctggct cccaagggag cgcccaattc 26460
cagccagtgg gagcaaaaaa aggcaggcaa tggtgacact atggaaacac acacatttgg 26520
tgtggcccca atgggcggtg agaatattac aatcgacgga ttacaaattg gaactgacgc 26580
tacagctgat caggataaac caatttatgc tgacaaaaca ttccagcctg aacctcaagt 26640
aggagaagaa aattggcaag aaactgaaag cttttatggc ggtagggctc ttaaaaaaga 26700
cacaagcatg aaaccttgct atggctccta tgctagaccc accaatgtaa agggaggtca 26760
agctaaactt aaagttggag ctgatggagt tcctaccaaa gaatttgaca tagacctggc 26820
tttctttgat actcccggtg gcacagtgaa tggacaagat gagtataaag cagacattgt 26880
catgtatacc gaaaacacgt atctggaaac tccagacacg catgtggtat acaaaccagg 26940
caaggatgat gcaagttctg aaattaacct ggttcagcag tccatgccca atagacccaa 27000
ctatattggg ttcagagaca actttattgg gctcatgtat tacaacagta ctggcaatat 27060
gggggtgctg gctggtcagg cctcacagct gaatgctgtg gtcgacttgc aagacagaaa 27120
caccgagctg tcataccagc tcttgcttga ctctttgggt gacagaaccc ggtatttcag 27180
tatgtggaat caggcggtgg acagttatga tcctgatgtg cgcattattg aaaaccatgg 27240
tgtggaagac gaacttccca actattgctt ccccctggat gggtctggca ctaatgccgc 27300
ttaccaaggt gtgaaagtaa aaaatggtaa cgatggtgat gttgagagcg aatgggaaaa 27360
tgatgatact gtcgcagctc gaaatcaatt atgcaagggc aacatttttg ccatggaaat 27420
taacctccaa gccaacctgt ggagaagttt cctctactcg aacgtggccc tgtacctgcc 27480
cgactcttac aagtacacgc cagccaacat caccctgccc accaacacca acacttatga 27540
ttacatgaac gggagagtgg tgcctccctc gctggtggac gcctacatca acatcggggc 27600
gcgctggtcg ctggacccca tggacaacgt caatcccttc aaccaccacc gcaacgcggg 27660
cctgcgctac cgctccatgc tcctgggcaa cgggcgctac gtgcccttcc acatccaggt 27720
gccccagaaa tttttcgcca tcaagagcct cctgctcctg cccgggtcct acacctacga 27780
gtggaacttc cgcaaggacg tcaacatgat cctgcagagc tccctcggca acgacctgcg 27840
cacggacggg gcctccatct ccttcaccag catcaacctc tacgccacct tcttccccat 27900
ggcgcacaac acggcctcca cgctcgaggc catgctgcgc aacgacacca acgaccagtc 27960
cttcaacgac tacctctcgg cggccaacat gctctacccc atcccggcca acgccaccaa 28020
cgtgcccatc tccatcccct cgcgcaactg ggccgccttc cgcggctggt ccttcacgcg 28080
cctcaagacc aaggagacgc cctcgctggg ctccgggttc gacccctact tcgtctactc 28140
gggctccatc ccctacctcg acggcacctt ctacctcaac cacaccttca agaaggtctc 28200
catcaccttc gactcctccg tcagctggcc cggcaacgac cggctcctga cgcccaacga 28260
gttcgaaatc aagcgcaccg tcgacggcga gggatacaac gtggcccagt gcaacatgac 28320
caaggactgg ttcctggtcc agatgctggc ccactacaac atcggctacc agggcttcta 28380
cgtgcccgag ggctacaagg accgcatgta ctccttcttc cgcaacttcc agcccatgag 28440
ccgccaggtg gtggacgagg tcaactacaa ggactaccag gccgtcaccc tggcctacca 28500
gcacaacaac tcgggcttcg tcggctacct cgcgcccacc atgcgccagg gccagcccta 28560
ccccgccaac tacccgtacc cgctcatcgg caagagcgcc gtcaccagcg tcacccagaa 28620
aaagttcctc tgcgacaggg tcatgtggcg catccccttc tccagcaact tcatgtccat 28680
gggcgcgctc accgacctcg gccagaacat gctctatgcc aactccgccc acgcgctaga 28740
catgaatttc gaagtcgacc ccatggatga gtccaccctt ctctatgttg tcttcgaagt 28800
cttcgacgtc gtccgagtgc accagcccca ccgcggcgtc atcgaggccg tctacctgcg 28860
cacccccttc tcggccggta acgccaccac ctaaattgct acttgcatga tggctgagcc 28920
cacaggctcc ggcgagcagg agctcagggc catcatccgc gacctgggct gcgggcccta 28980
cttcctgggc accttcgata agcgcttccc gggattcatg gccccgcaca agctggcctg 29040
cgccatcgtc aacacggccg gccgcgagac cgggggcgag cactggctgg ccttcgcctg 29100
gaacccgcgc tcgaacacct gctacctctt cgaccccttc gggttctcgg acgagcgcct 29160
caagcagatc taccagttcg agtacgaggg cctgctgcgc cgtagcgccc tggccaccga 29220
ggaccgctgc gtcaccctgg aaaagtccac ccagaccgtg cagggtccgc gctcggccgc 29280
ctgcgggctc ttctgctgca tgttcctgca cgccttcgtg cactggcccg accgccccat 29340
ggacaagaac cccaccatga acttgctgac gggggtgccc aacggcatgc tccagtcgcc 29400
ccaggtggaa cccaccctgc gccgcaacca ggaggcgctc taccgcttcc tcaactccca 29460
ctccgcctac tttcgctccc accgcgcgcg catcgagaag gccaccgcct tcgaccgcat 29520
gaacaatcaa gacatgtaaa ccgtgtgtgt atgtttaaaa tatcttttaa taaacagcac 29580
tttaatgtta cacatgcatc tgagatgatt ttattttaga aatcgaaagg gttctgccgg 29640
gtctcggcat ggcccgcggg cagggacacg ttgcggaact ggtacttggc cagccacttg 29700
aactcgggga tcagcagttt gggcagcggg gtgtcgggga aggagtcggt ccacagcttc 29760
cgcgtcagct gcagggcgcc cagcaggtcg ggcgcggaga tcttgaaatc gcagttggga 29820
cccgcgttct gcgcgcgaga gttgcggtac acggggttgc agcactggaa caccatcagg 29880
gccgggtgct tcacgctcgc cagcaccgcc gcgtcggtga tgctctccac gtcgaggtcc 29940
tcggcgttgg ccatcccgaa gggggtcatc ttgcaggtct gccttcccat ggtgggcacg 30000
cacccgggct tgtggttgca atcgcagtgc agggggatca gcatcatctg ggcctggtcg 30060
gcgttcatcc ccgggtacat ggccttcatg aaagcctcca attgcctgaa cgcctgctgg 30120
gccttggctc cctcggtgaa gaagaccccg caggacttgc tagagaactg gttggtggca 30180
cagccggcat cgtgcacgca gcagcgcgcg tcgttgttgg ccagctgcac cacgctgcgc 30240
ccccagcggt tctgggtgat cttggcccgg tcggggttct ccttcagcgc gcgctgcccg 30300
ttctcgctcg ccacatccat ctcgatcatg tgctccttct ggatcatggt ggtcccgtgc 30360
aggcaccgca gtttgccctc ggcctcggtg cacccgtgca gccacagcgc gcacccggtg 30420
cactcccagt tcttgtgggc gatctgggaa tgcgcgtgca cgaacccttg caggaagcgg 30480
cccatcatgg tcgtcagggt cttgttgcta gtgaaggtca acgggatgcc gcggtgctcc 30540
tcgttgatgt acaggtggca gatgcggcgg tacacctcgc cctgctcggg catcagttgg 30600
aagttggctt tcaggtcggt ctccacgcgg tagcggtcca tcagcatagt catgatttcc 30660
atgcccttct cccaggccga gacgatgggc aggctcatag ggttcttcac catcatctta 30720
gcactagcag ccgcggccag ggggtcgctc tcatccaggg tctcaaagct ccgcttgccg 30780
tccttctcgg tgatccgcac cggggggtag ctgaagccca cggccgccag ctcctcctcg 30840
gcctgtcttt cgtcctcgct gtcctggctg acgtcctgca tgaccacatg cttggtcttg 30900
cggggtttct tcttgggcgg cagtggcggc ggagatgctt gtggcgaggg ggagcgcgag 30960
ttctcgctca ccactactat ctcttcctct tcttggtccg aggccacgcg gcggtaggta 31020
tgtctcttcg ggggcagagg cggaggcgac gggctctcgc cgccgcgact tggcggatgg 31080
ctggcagagc cccttccgcg ttcgggggtg cgctcccggc ggcgctctga ctgacttcct 31140
ccgcggccgg ccattgtgtt ctcctaggga ggaacaacaa gcatggagac tcagccatcg 31200
ccaacctcgc catctgcccc caccgccggc gacgagaagc agcagcagca gaatgaaagc 31260
ttaaccgccc cgccgcccag ccccgcctcc gacgcagccg cggtcccaga catgcaagag 31320
atggaggaat ccatcgagat tgacctgggc tatgtgacgc ccgcggagca tgaggaggag 31380
ctggcagtgc gctttcaatc gtcaagccag gaagataaag aacagccaga gcaggaagca 31440
gagaacgagc agagtcaggc tgggctcgag catggcgact acctccacct gagcggggag 31500
gaggacgcgc tcatcaagca tctggcccgg caggccacca tcgtcaagga cgcgctgctc 31560
gaccgcaccg aggtgcccct cagcgtggag gagctcagcc gcgcctacga gctcaacctc 31620
ttctcgccgc gcgtgccccc caagcgccag cccaacggca cctgcgagcc caacccccgc 31680
ctcaacttct acccggtctt cgcggtgccc gaggccctgg ccacctacca catctttttc 31740
aagaaccaaa agatccccgt ctcctgccgc gccaaccgca cccgcgccga cgccctcttc 31800
aacctgggtc ccggcgcccg cctacctgat atcgcctcct tggaagaggt tcccaagatc 31860
ttcgagggtc tgggcagcga cgagactcgg gccgcgaacg ctctgcaagg agaaggagga 31920
ggagagcatg agcaccacag cgccctggtc gagttggaag gcgacaacgc gcggctggcg 31980
gtgctcaaac gcacggtcga gctgacccat ttcgcctacc cggctctgaa cctgcccccg 32040
aaagtcatga gcgcggtcat ggaccaggtg ctcatcaagc gcgcgtcgcc catctccgag 32100
gacgagggca tgcaagactc cgaggagggc aagcccgtgg tcagcgacga gcagctggcc 32160
cggtggctgg gtcctaatgc tacccctcaa agtttggaag agcggcgcaa gctcatgatg 32220
gccgtggtcc tggtgaccgt ggagctggag tgcctgcgcc gcttcttcgc cgacgcggag 32280
accctgcgca aggtcgagga gaacctgcac tacctcttca ggcacgggtt cgtgcgccag 32340
gcctgcaaga tctccaacgt ggagctgacc aacctggtct cctacatggg catcttgcac 32400
gagaaccgcc tggggcagaa cgtgctgcac accaccctgc gcggggaggc ccgccgcgac 32460
tacatccgcg actgcgtcta cctctacctc tgccacacct ggcagacggg catgggcgtg 32520
tggcagcagt gtctggagga gcagaacctg aaagagctct gcaagctcct gcaaaagaac 32580
ctcaagggtc tgtggaccgg gttcgacgag cggaccaccg cctcggacct ggccgacctc 32640
atcttccccg agcgcctcag gctgacgctg cgcaacggcc tgcccgactt tatgagccaa 32700
agcatgttgc aaaactttcg ctctttcatc ctcgaacgct ccggaatcct gcccgccacc 32760
tgctccgcgc tgccctcgga cttcgtgccg ctgaccttcc gcgagtgccc cccgccgctg 32820
tggagccact gctacctgct gcgcctggcc aactacctgg cctaccactc ggacgtgatc 32880
gaggacgtca gcggcgaggg cctgctcgag tgccactgcc gctgcaacct ctgcacgccg 32940
caccgctccc tggcctgcaa cccccagctg ctgagcgaga cccagatcat cggcaccttc 33000
gagttgcaag ggcccagcga gggcgaggga gccaaggggg gtctgaaact caccccgggg 33060
ctgtggacct cggcctactt gcgcaagttc gtgcccgagg attaccatcc cttcgagatc 33120
aggttctacg aggaccaatc ccagccgccc aaggccgagc tgtcggcctg cgtcatcacc 33180
cagggggcga tcctggccca attgcaagcc atccagaaat cccgccaaga attcttgctg 33240
aaaaagggcc gcggggtcta cctcgacccc cagaccggtg aggagctcaa ccccggcttc 33300
ccccaggatg ccccgaggaa acaagaagct gaaagtggag ctgccgcccg tggaggattt 33360
ggaggaagac tgggagaaca gcagtcaggc agaggagatg gaggaagact gggacagcac 33420
tcaggcagag gaggacagcc tgcaagacag tctggaggaa gacgaggagg aggcagagga 33480
ggaggtggaa gaagcagccg ccgccagacc gtcgtcctcg gcgggggaga aagcaagcag 33540
cacggatacc atctccgctc cgggtcgggg tcccgctcgg ccccacagta gatgggacga 33600
gaccgggcga ttcccgaacc ccaccaccca gaccggtaag aaggagcggc agggatacaa 33660
gtcctggcgg gggcacaaaa acgccatcgt ctcctgcttg caggcctgcg ggggcaacat 33720
ctccttcacc cggcgctacc tgctcttcca ccgcggggtg aacttccccc gcaacatctt 33780
gcattactac cgtcacctcc acagccccta ctacttccaa gaagaggcag cagcagcaga 33840
aaaagaccag aaaaccagct agaaaatcca cagcggcggc agcggcaggt ggactgagga 33900
tcgcggcgaa cgagccggcg cagacccggg agctgaggaa ccggatcttt cccaccctct 33960
atgccatctt ccagcagagt cgggggcagg agcaggaact gaaagtcaag aaccgttctc 34020
tgcgctcgct cacccgcagt tgtctgtatc acaagagcga agaccaactt cagcgcactc 34080
tcgaggacgc cgaggctctc ttcaacaagt actgcgcgct cactcttaaa gagtagcccg 34140
cgcccgccca gtcgcagaaa aaggcgggaa ttacgtcacc tgtgcccttc gccctagccg 34200
cctccaccca gcaccgccat gagcaaagag attcccacgc cttacatgtg gagctaccag 34260
ccccagatgg gcctggccgc cggcgccgcc caggactact ccacccgcat gaattggctc 34320
agcgccgggc ccgcgatgat ctcacgggtg aatgacatcc gcgcccaccg aaaccagata 34380
ctcctagaac agtcagcgct caccgccacg ccccgcaatc acctcaatcc gcgtaattgg 34440
cccgccgccc tggtgtacca ggaaattccc cagcccacga ccgtactact tccgcgagac 34500
gcccaggccg aagtccagct gactaactca ggtgtccagc tggcgggcgg cgccaccctg 34560
tgtcgtcacc gccccgctca gggtataaag cggctggtga tccggggcag aggcacacag 34620
ctcaacgacg aggtggtgag ctcttcgctg ggtctgcgac ctgacggagt cttccaactc 34680
gccggatcgg ggagatcttc cttcacgcct cgtcaggcgg tcctgacttt ggagagttcg 34740
tcctcgcagc cccgctcggg cggcatcggc actctccagt tcgtggagga gttcactccc 34800
tcggtctact tcaacccctt ctccggctcc cccggccact acccggacga gttcatcccg 34860
aactttgacg ccatcagcga gtcggtggac ggctacgatt gattaattaa tcaactaacc 34920
ccttacccct ttaccctcca gtaaaaataa agattaaaaa tgattgaatt gatcaataaa 34980
gaatcactta cttgaaatct gaaaccaggt ctctgtccat gttttctgtc agcagcactt 35040
cactcccctc ttcccaactc tggtactgca ggccccggcg ggctgcaaac ttcctccaca 35100
ctctgaaggg gatgtcaaat tcctcctgtc cctcaatctt catttttatc ttctatcaga 35160
tgtccaaaaa gcgcgcgcgg gtggatgatg gcttcgaccc cgtgtacccc tacgatgcag 35220
acaacgcacc gactgtgccc ttcatcaacc ctcccttcgt ctcttcagat ggattccaag 35280
aaaagcccct gggggtgttg tccctgcgac tggccgaccc cgtcaccacc aagaatgggg 35340
ctgtcaccct caagctgggg gagggggtgg acctcgacga ctcgggaaaa ctcatctcca 35400
aaaatgccac caaggccact gcccctctca gtatttccaa cggcaccatt tcccttaaca 35460
tggctgcccc tttttacaac aacaatggaa cgttaagtct caatgtttct acaccattag 35520
cagtatttcc cacttttaac actttaggta tcagtcttgg aaacggtctt caaacttcta 35580
ataagttgct gactgtacag ttaactcatc ctcttacatt cagctcaaat agcatcacag 35640
taaaaacaga caaaggactc tatattaatt ctagtggaaa cagagggctt gaggctaaca 35700
taagcctaaa aagaggactg atttttgatg gtaatgctat tgcaacatac cttggaagtg 35760
gtttagacta tggatcctat gatagcgatg ggaaaacaag acccatcatc accaaaattg 35820
gagcaggttt gaattttgat gctaataatg ccatggctgt gaagctaggc acaggtttaa 35880
gttttgactc tgccggtgcc ttaacagctg gaaacaaaga ggatgacaag ctaacacttt 35940
ggactacacc tgacccaagc cctaattgtc aattactttc agacagagat gccaaattta 36000
ccctatgtct tacaaaatgc ggtagtcaaa tactaggcac tgttgcagta gctgctgtta 36060
ctgtaggttc agcactaaat ccaattaatg acacagtaaa aagcgccata gtattcctta 36120
gatttgactc tgacggtgtg ctcatgtcaa actcatcaat ggtaggtgat tactggaact 36180
ttagggaagg acagaccacc caaagtgtgg cctatacaaa tgctgtggga ttcatgccca 36240
atctaggtgc atatcctaaa acccaaagca aaacaccaaa aaatagtata gtaagtcagg 36300
tatatttaaa tggagaaact actatgccaa tgacactgac aataactttc aatggcactg 36360
atgaaaaaga cacaacacct gtgagcactt actccatgac ttttacatgg cagtggactg 36420
gagactataa ggacaagaat attacctttg ctaccaactc ctttactttc tcctacatgg 36480
cccaagaata aaccctgcat gccaacccca ttgttcccac cactatggaa aactctgaag 36540
cagaaaaaaa taaagttcaa gtgttttatt gattcaacag ttttctcaca gaaccctagt 36600
attcaacctg ccacctccct cccaacacac agagtacaca gtcctttctc cccggctggc 36660
cttaaaaagc atcatatcat gggtaacaga catattctta ggtgttatat tccacacggt 36720
ttcctgtcga gccaaacgct catcagtgat attaataaac tccccgggca gctcacttaa 36780
gttcatgtcg ctgtccagct gctgagccac aggctgctgt ccaacttgcg gttgcttaac 36840
gggcggcgaa ggagaagtcc acgcctacat gggggtagag tcataatcgt gcatcaggat 36900
agggcggtgg tgctgcagca gcgcgcgaat aaactgctgc cgccgccgct ccgtcctgca 36960
ggaatacaac atggcagtgg tctcctcagc gatgattcgc accgcccgca gcataaggcg 37020
ccttgtcctc cgggcacagc agcgcaccct gatctcactt aaatcagcac agtaactgca 37080
gcacagcacc acaatattgt tcaaaatccc acagtgcaag gcgctgtatc caaagctcat 37140
ggcggggacc acagaaccca cgtggccatc ataccacaag cgcaggtaga ttaagtggcg 37200
acccctcata aacacgctgg acataaacat tacctctttt ggcatgttgt aattcaccac 37260
ctcccggtac catataaacc tctgattaaa catggcgcca tccaccacca tcctaaacca 37320
gctggccaaa acctgcccgc cggctataca ctgcagggaa ccgggactgg aacaatgaca 37380
gtggagagcc caggactcgt aaccatggat catcatgctc gtcatgatat caatgttggc 37440
acaacacagg cacacgtgca tacacttcct caggattaca agctcctccc gcgttagaac 37500
catatcccag ggaacaaccc attcctgaat cagcgtaaat cccacactgc agggaagacc 37560
tcgcacgtaa ctcacgttgt gcattgtcaa agtgttacat tcgggcagca gcggatgatc 37620
ctccagtatg gtagcgcggg tttctgtctc aaaaggaggt agacgatccc tactgtacgg 37680
agtgcgccga gacaaccgag atcgtgttgg tcgtagtgtc atgccaaatg gaacgccgga 37740
cgtagtcata tttcctgaag caaaaccagg tgcgggcgtg acaaacagat ctgcgtctcc 37800
ggtctcgccg cttagatcgc tctgtgtagt agttgtagta tatccactct ctcaaagcat 37860
ccaggcgccc cctggcttcg ggttctatgt aaactccttc atgcgccgct gccctgataa 37920
catccaccac cgcagaataa gccacaccca gccaacctac acattcgttc tgcgagtcac 37980
acacgggagg agcgggaaga gctggaagaa ccatgattaa ctttattcca aacggtctcg 38040
gagcacttca aaatgcaggt cccggaggtg gcacctctcg cccccactgt gttggtggaa 38100
aataacagcc aggtcaaagg tgacacggtt ctcgagatgt tccacggtgg cttccagcaa 38160
agcctccacg cgcacatcca gaaacaagag gacagcgaaa gcgggagcgt tttctaattc 38220
ctcaatcatc atattacact cctgcaccat ccccagataa ttttcatttt tccagccttg 38280
aatgattcgt attagttcct gaggtaaatc caagccagcc atgataaaaa gctcgcgcag 38340
agcgccctcc accggcattc ttaagcacac cctcataatt ccaagagatt ctgctcctgg 38400
ttcacctgca gcagattaac aatgggaata tcaaaatctc tgccgcgatc cctaagctcc 38460
tccctcaaca ataactgtat gtaatctttc atatcatctc cgaaattttt agccataggg 38520
ccgccaggaa taagagcagg gcaagccaca ttacagataa agcgaagtcc tccccagtgw 38580
gcattgccaa atgtaagatt gaaataagca tgctggctag accctgtgat atcttccaga 38640
taactggaca gaaaatcagg caagcaattt ttaagaaaat caacaaaaga aaagtcgtcc 38700
aggtgcaggt ttagagcctc aggaacaacg atggaataag tgcaaggagt gcgttccagc 38760
atggttagtg tttttttggt gatctgtaga acaaaaaata aacatgcaat attaaaccat 38820
gctagcctgg cgaacaggtg ggtaaatcac tctttccagc accaggcagg ctacggggtc 38880
tccggcgcga ccctcgtaga agctgtcgcc atgattgaaa agcatcaccg agagaccttc 38940
ccggtggccg gcatggatga ttcgagaaga agcatacact ccgggaacat tggcatccgt 39000
gagtgaaaaa aagcgaccta taaagcctcg gggcactaca atgctcaatc tcaattccag 39060
caaagccacc ccatgcggat ggagcacaaa attggcaggt gcgtaaaaaa tgtaattact 39120
cccctcctgc acaggcagca aagcccccgc tccctccaga aacacataca aagcctcagc 39180
gtccatagct taccgagcac ggcaggcgca agagtcagag aaaaggctga gctctaacct 39240
gactgcccgc tcctgtgctc aatatatagc cctaacctac actgacgtaa aggccaaagt 39300
ctaaaaatac ccgccaaaat gacacacacg cccagcacac gcccagaaac cggtgacaca 39360
ctcaaaaaaa tacgtgcgct tcctcaaacg cccaaaccgg cgtcatttcc gggttcccac 39420
gctacgtcac cgctcagcga ctttcaaatt ccgtcgaccg ttaaaaacgt cactcgcccc 39480
gcccctaacg gtcgcccttc tctcggccaa tcaccttcct cccttcccaa attcaaacgc 39540
ctcatttgca tattaacgcg cacaaaaagt ttgaggtata tatttgaatg atg 39593
<210> 25
<211> 39593
<212> DNA
<213> 人工序列
<220>
<223> MVA穿梭载体p4719
<400> 25
gtttaaacgc ggccgccagg cctacccact agtcaattcg ggaggatcga aacggcagat 60
cgcaaaaaac agtacataca gaaggagaca tgaacatgaa catcaaaaaa attgtaaaac 120
aagccacagt tctgactttt acgactgcac ttctggcagg aggagcgact caagccttcg 180
cgaaagaaaa taaccaaaaa gcatacaaag aaacgtacgg cgtctctcat attacacgcc 240
atgatatgct gcagatccct aaacagcagc aaaacgaaaa ataccaagtg cctcaattcg 300
atcaatcaac gattaaaaat attgagtctg caaaaggact tgatgtgtgg gacagctggc 360
cgctgcaaaa cgctgacgga acagtagctg aatacaacgg ctatcacgtt gtgtttgctc 420
ttgcgggaag cccgaaagac gctgatgaca catcaatcta catgttttat caaaaggtcg 480
gcgacaactc aatcgacagc tggaaaaacg cgggccgtgt ctttaaagac agcgataagt 540
tcgacgccaa cgatccgatc ctgaaagatc agacgcaaga atggtccggt tctgcaacct 600
ttacatctga cggaaaaatc cgtttattct acactgacta ttccggtaaa cattacggca 660
aacaaagcct gacaacagcg caggtaaatg tgtcaaaatc tgatgacaca ctcaaaatca 720
acggagtgga agatcacaaa acgatttttg acggagacgg aaaaacatat cagaacgttc 780
agcagtttat cgatgaaggc aattatacat ccggcgacaa ccatacgctg agagaccctc 840
actacgttga agacaaaggc cataaatacc ttgtattcga agccaacacg ggaacagaaa 900
acggatacca aggcgaagaa tctttattta acaaagcgta ctacggcggc ggcacgaact 960
tcttccgtaa agaaagccag aagcttcagc agagcgctaa aaaacgcgat gctgagttag 1020
cgaacggcgc cctcggtatc atagagttaa ataatgatta cacattgaaa aaagtaatga 1080
agccgctgat cacttcaaac acggtaactg atgaaatcga gcgcgcgaat gttttcaaaa 1140
tgaacggcaa atggtacttg ttcactgatt cacgcggttc aaaaatgacg atcgatggta 1200
ttaactcaaa cgatatttac atgcttggtt atgtatcaaa ctctttaacc ggcccttaca 1260
agccgctgaa caaaacaggg cttgtgctgc aaatgggtct tgatccaaac gatgtgacat 1320
tcacttactc tcacttcgca gtgccgcaag ccaaaggcaa caatgtggtt atcacaagct 1380
acatgacaaa cagaggcttc ttcgaggata aaaaggcaac atttgcgcca agcttcttaa 1440
tgaacatcaa aggcaataaa acatccgttg tcaaaaacag catcctggag caaggacagc 1500
tgacagtcaa ctaataacag caaaaagaaa atgccgatac ttcattggca ttttctttta 1560
tttctcaaca agatggtgaa ttgactagtg ggtagatcca caggacgggt gtggtcgcca 1620
tgatcgcgta gtcgatagtg gctccaagta gcgaagcgag caggactggg cggcggccaa 1680
agcggtcgga cagtgctccg agaacgggtg cgcatagaaa ttgcatcaac gcatatagcg 1740
ctagcagcac gccatagtga ctggcgatgc tgtcggaatg gacgatatcc cgcaagaggc 1800
ccggcagtac cggcataacc aagcctatgc ctacagcatc cagggtgacg gtgccgagga 1860
tgacgatgag cgcattgtta gatttcatac acggtgcctg actgcgttag caatttaact 1920
gtgataaact accgcattaa agcttatcga tgataagctg tcaaacatga gaattgatcc 1980
ggaaccctta atataacttc gtataatgta tgctatacga agttattagg tccctcgact 2040
atagggtcac cgtcgacagc gacacacttg catcggatgc agcccggtta acgtgccggc 2100
acggcctggg taaccaggta ttttgtccac ataaccgtgc gcaaaatgtt gtggataagc 2160
aggacacagc agcaatccac agcaggcata caaccgcaca ccgaggttac tccgttctac 2220
aggttacgac gacatgtcaa tacttgccct tgacaggcat tgatggaatc gtagtctcac 2280
gctgatagtc tgatcgacaa tacaagtggg accgtggtcc cagaccgata atcagaccga 2340
crayacgagt gggaycgtgg tcccagacta ataatcagac cgacgatacg agtgggaccg 2400
tggtcccaga ctaataatca gaccgacgat acgagtggga ccgtggtycc agwctratwa 2460
tcagaccgac gatacragtg gracmgtggk cccagasaka atawtcagrc cgagwtaygc 2520
wktckggcct gtaacaaagg acattaagta aagacagata mrmgtgrgac taaaacgtgg 2580
tcccagtctg attatcagac cgacgatacg agtgggaccg tggtcccaga ctaataatca 2640
gaccgacgat acgagtggga ccgtggtccc agactaataa tcagaccgac gatacgagtg 2700
ggaccgtggt cccagtctga ttatcagacc gacgatacaa gtggaacagt gggcccagag 2760
agaatattca ggccagttat gctttctggc ctgtaacaaa ggacattaag taaagacaga 2820
taaacgtaga ctaaaacgtg gtcgcatcag ggtgctggct tttcaagttc cttaagaatg 2880
gcctcaattt tctctataca ctcagttgga acacgagacc tgtccaggtt aagcaccatt 2940
ttatcgccct tatacaatac tgtcgctcca ggagcaaact gatgtcgtga gcttaaacta 3000
gttcttgatg cagatgacgt tttaagcaca gaagttaaaa gagtgataac ttcttcagct 3060
tcaaatatca ccccagcttt tttctgctca tgaaggttag atgcctgctg cttaagtaat 3120
tcctctttat ctgtaaaggc tttttgaagt gcatcacctg accgggcaga tagttcaccg 3180
gggtgagaaa aaagagcaac aactgattta ggcaatttgg cggtgttgat acagcgggta 3240
ataatcttac gtgaaatatt ttccgcatca gccagcgcag aaatatttcc agcaaattca 3300
ttctgcaatc ggcttgcata acgctgacca cgttcataag cacttgttgg gcgataatcg 3360
ttacccaatc tggataatgc agccatctgc tcatcatcca gctcgccaac cagaacacga 3420
taatcacttt cggtaagtgc agcagcttta cgacggcgac tcccatcggc aatttctatg 3480
acaccagata ctcttcgacc gaacgccggt gtctgttgac cagtcagtag aaaagaaggg 3540
atgagatcat ccagtgcgtc ctcagtaagc agctcctggt cacgttcatt acctgaccat 3600
acccgagagg tcttctcaac actatcaccc cggagcactt caagagtaaa cttcacatcc 3660
cgaccacata caggcaaagt aatggcatta ccgcgagcca ttactcctac gcgcgcaatt 3720
aacgaatcca ccatcggggc agctggtgtc gataacgaag tatcttcaac cggttgagta 3780
ttgagcgtat gttttggaat aacaggcgca cgcttcatta tctaatctcc cagcgtggtt 3840
taatcagacg atcgaaaatt tcattgcaga caggttccca aatagaaaga gcatttctcc 3900
aggcaccagt tgaagagcgt tgatcaatgg cctgttcaaa aacagttctc atccggatct 3960
gacctttacc aacttcatcc gtttcacgta caacattttt tagaaccatg cttccccagg 4020
catcccgaat ttgctcctcc atccacgggg actgagagcc attactattg ctgtatttgg 4080
taagcaaaat acgtacatca ggctcgaacc ctttaagatc aacgttcttg agcagatcac 4140
gaagcatatc gaaaaactgc agtgcggagg tgtagtcaaa caactcagca ggcgtgggaa 4200
caatcagcac atcagcagca catacgacat taatcgtgcc gatacccagg ttaggcgcgc 4260
tgtcaataac tatgacatca tagtcatgag caacagtttc aatggccagt cggagcatca 4320
ggtgtggatc ggtgggcagt ttaccttcat caaatttgcc cattaactca gtttcaatac 4380
ggtgcagagc cagacaggaa ggaataatgt caagccccgg ccagcaagtg ggctttattg 4440
cataagtgac atcgtccttt tccccaagat agaaaggcag gagagtgtct tctgcatgaa 4500
tatgaagatc tggtacccat ccgtgataca ttgaggctgt tccctggggg tcgttacctt 4560
ccacgagcaa aacacgtagc cccttcagag ccagatcctg agcaagatga acagaaactg 4620
aggttttgta aacgccacct ttatgggcag caaccccgat caccggtgga aatacgtctt 4680
cagcacgtcg caatcgcgta ccaaacacat cacgcatatg attaatttgt tcaattgtat 4740
aaccaacacg ttgctcaacc cgtcctcgaa tttccatatc cgggtgcggt agtcgccctg 4800
ctttctcggc atctctgata gcctgagaag aaaccccaac taaatccgct gcttcaccta 4860
ttctccagcg ccgggttatt ttcctcgctt ccgggctgtc atcattaaac tgtgcaatgg 4920
cgatagcctt cgtcatttca tgaccagcgt ttatgcactg gttaagtgtt tccatgagtt 4980
tcattctgaa catcctttaa tcattgcttt gcgttttttt attaaatctt gcaatttact 5040
gcaaagcaac aacaaaatcg caaagtcatc aaaaaaccgc aaagttgttt aaaataagag 5100
caacactaca aaaggagata agaagagcac atacctcagt cacttattat cactagcgct 5160
cgccgcagcc gtgtaaccga gcatagcgag cgaactggcg aggaagcaaa gaagaactgt 5220
tctgtcagat agctcttacg ctcagcgcaa gaagaaatat ccaccgtggg aaaaactcca 5280
ggtagaggta cacacgcgga tagccaattc agagtaataa actgtgataa tcaaccctca 5340
tcaatgatga cgaactaacc cccgatatca ggtcacatga cgaagggaaa gagaaggaaa 5400
tcaactgtga caaactgccc tcaaatttgg cttccttaaa aattacagtt caaaaagtat 5460
gagaaaatcc atgcaggctg aaggaaacag caaaactgtg acaaattacc ctcagtaggt 5520
cagaacaaat gtgacgaacc accctcaaat ctgtgacaga taaccctcag actatcctgt 5580
cgtcatggaa gtgatatcgc ggaaggaaaa tacgatatga gtcgtctggc ggcctttctt 5640
tttctcaatg tatgagaggc gcattggagt tctgctgttg atctcattaa cacagacctg 5700
caggaagcgg cggcggaagt caggcatacg ctggtaactt tgaggcagct ggtaacgctc 5760
tatgatccag tcgattttca gagagacgat gcctgagcca tccggcttac gatactgaca 5820
cagggattcg tataaacgca tggcatacgg attggtgatt tcttttgttt cactaagccg 5880
aaactgcgta aaccggttct gtaacccgat aaagaaggga atgagatatg ggttgatatg 5940
tacactgtaa agccctctgg atggactgtg cgcacgtttg ataaaccaag gaaaagattc 6000
atagcctttt tcatcgccgg catcctcttc agggcgataa aaaaccactt ccttccccgc 6060
gaaactcttc aatgcctgcc gtatatcctt actggcttcc gcagaggtca atccgaatat 6120
ttcagcatat ttagcaacat ggatctcgca gataccgtca tgttcctgta gggtgccatc 6180
agattttctg atctggtcaa cgaacagata cagcatacgt ttttgatccc gggagagact 6240
atatgccgcc tcagtgaggt cgtttgactg gacgattcgc gggctatttt tacgtttctt 6300
gtgattgata accgctgttt ccgccatgac agatccatgt gaagtgtgac aagtttttag 6360
attgtcacac taaataaaaa agagtcaata agcagggata actttgtgaa aaaacagctt 6420
cttctgaggg caatttgtca cagggttaag ggcaatttgt cacagacagg actgtcattt 6480
gagggtgatt tgtcacactg aaagggcaat ttgtcacaac accttctcta gaaccagcat 6540
ggataaaggc ctacaaggcg ctctaaaaaa gaagatctaa aaactataaa aaaaataatt 6600
ataaaaatat ccccgtggat aagtggataa ccccaaggga agttttttca ggcatcgtgt 6660
gtaagcagaa tatataagtg ctgttccctg gtgcttcctc gctcactcga gggcttcgcc 6720
ctgtcgctca actgcggcga gcactactgg ctgtaaaagg acagaccaca tcatggttct 6780
gtgttcatta ggttgttctg tccattgctg acataatccg ctccacttca acgtaacacc 6840
gcacgaagat ttctattgtt cctgaaggca tattcaaatc gttttcgtta ccgcttgcag 6900
gcatcatgac agaacactac ttcctataaa cgctacacag gctcctgaga ttaataatgc 6960
ggatctctac gataatggga gattttcccg actgtttcgt tcgcttctca gtggataaca 7020
gccagcttct ctgtttaaca gacaaaaaca gcatatccac tcagttccac atttccatat 7080
aaaggccaag gcatttattc tcaggataat tgtttcagca tcgcaaccgc atcagactcc 7140
ggcatcgcaa actgcacccg gtgccgggca gccacatcca gcgcaaaaac cttcgtgtag 7200
acttccgttg aactgatgga cttatgtccc atcaggcttt gcagaacttt cagcggtata 7260
ccggcataca gcatgtgcat cgcataggaa tggcggaacg tatgtggtgt gaccggaaca 7320
gagaacgtca caccgtcagc agcagcggcg gcaaccgcct ccccaatcca ggtcctgacc 7380
gttctgtccg tcacttccca gatccgcgct ttctctgtcc ttcctgtgcg acggttacgc 7440
cgctccatga gcttatcgcg aataaatacc tgtgacggaa gatcacttcg cagaataaat 7500
aaatcctggt gtccctgttg ataccgggaa gccctgggcc aacttttggc gaaaatgaga 7560
cgttgatcgg cacgtaagag gttccaactt tcaccataat gaaataagat cactaccggg 7620
cgtatttttt gagttatcga gattttcagg agctaaggaa gctaaaatgg agaaaaaaat 7680
cactggatat accaccgttg atatatccca atggcatcgt aaagaacatt ttgaggcatt 7740
tcagtcagtt gctcaatgta cctataacca gaccgttcag ctggatatta cggccttttt 7800
aaagaccgta aagaaaaata agcacaagtt ttatccggcc tttattcaca ttcttgcccg 7860
cctgatgaat gctcatccgg agttccgtat ggcaatgaaa gacggtgagc tggtgatatg 7920
ggatagtgtt cacccttgtt acaccgtttt ccatgagcaa actgaaacgt tttcatcgct 7980
ctggagtgaa taccacgacg atttccggca gtttctacac atatattcgc aagatgtggc 8040
gtgttacggt gaaaacctgg cctatttccc taaagggttt attgagaata tgtttttcgt 8100
ctcagccaat ccctgggtga gtttcaccag ttttgattta aacgtggcca atatggacaa 8160
cttcttcgcc cccgttttca ccatgggcaa atattatacg caaggcgaca aggtgctgat 8220
gccgctggcg attcaggttc atcatgccgt ttgtgatggc ttccatgtcg gcagaatgct 8280
taatgaatta caacagtact gcgatgagtg gcagggcggg gcgtaatttt tttaaggcag 8340
ttattggtgc ccttaaacgc ctggttgcta cgcctgaata agtgataata agcggatgaa 8400
tggcagaaat tcgatgataa gctgtcaaac atgagaattg gtcgacggcg cgccaaagct 8460
tgcatgcctg cagccgcgta acctggcaaa atcggttacg gttgagtaat aaatggatgc 8520
cctgcgtaag cggggcacat ttcattacct ctttctccgc acccgacata gataataact 8580
tcgtatagta tacattatac gaagttatct agtagactta atcgcgttta aacccatcat 8640
caataatata cctcaaactt tttgtgcgcg ttaatatgca aatgaggcgt ttgaatttgg 8700
gaagggagga aggtgattgg ccgagagaag ggcgaccgtt aggggcgggg cgagtgacgt 8760
tttgatgacg tgaccgcgag gaggagccag tttgcaagtt ctcgtgggaa aagtgacgtc 8820
aaacgaggtg tggtttgaac acggaaatac tcaattttcc cgcgctctct gacaggaaat 8880
gaggtgtttc taggcggatg caagtgaaaa cgggccattt tcgcgcgaaa actgaatgag 8940
gaagtgaaaa tctgagtaat ttcgcgttta tgacagggag gagtatttgc cgagggccga 9000
gtagactttg accgattacg tgggggtttc gattaccgtg tttttcacct aaatttccgc 9060
gtacggtgtc aaagtccggt gtttttacgt aggtgtcagc tgatcgccag ggtatttaaa 9120
cctgcgctct ccagtcaaga ggccactctt gagtgccagc gagaagagtt ttctcctccg 9180
cgcgcgagtc agatctacac tttgaaaggc gatcgctagc gacatcgatc acaagtttgt 9240
acaaaaaagc tgaacgagaa acgtaaaatg atataaatat caatatatta aattagattt 9300
tgcataaaaa acagactaca taatactgta aaacacaaca tatccagtca ctatggcggc 9360
cgccgattta ttcaacaaag ccacgttgtg tctcaaaatc tctgatgtta cattgcacaa 9420
gataaaaata tatcatcatg aacaataaaa ctgtctgctt acataaacag taatacaagg 9480
ggtgttatga gccatattca acgggaaacg tcttgctcga ggccgcgatt aaattccaac 9540
atggatgctg atttatatgg gtataaatgg gctcgtgata atgtcgggca atcaggtgcg 9600
acaatctatc gattgtatgg gaagcccgat gcgccagagt tgtttctgaa acatggcaaa 9660
ggtagcgttg ccaatgatgt tacagatgag atggtcagac taaactggct gacggaattt 9720
atgcctcttc cgaccatcaa gcattttatc cgtactcctg atgatgcatg gttactcacc 9780
actgcgatcc ccgggaaaac agcattccag gtattagaag aatatcctga ttcaggtgaa 9840
aatattgttg atgcgctggc agtgttcctg cgccggttgc attcgattcc tgtttgtaat 9900
tgtcctttta acagcgatcg cgtatttcgt ctcgctcagg cgcaatcacg aatgaataac 9960
ggtttggttg atgcgagtga ttttgatgac gagcgtaatg gctggcctgt tgaacaagtc 10020
tggaaagaaa tgcataagct tttgccattc tcaccggatt cagtcgtcac tcatggtgat 10080
ttctcacttg ataaccttat ttttgacgag gggaaattaa taggttgtat tgatgttgga 10140
cgagtcggaa tcgcagaccg ataccaggat cttgccatcc tatggaactg cctcggtgag 10200
ttttctcctt cattacagaa acggcttttt caaaaatatg gtattgataa tcctgatatg 10260
aataaattgc agtttcattt gatgctcgat gagtttttct aatcagaatt ggttaattgg 10320
ttgtaacact ggcacgcgtg gatccggctt actaaaagcc agataacagt atgcgtattt 10380
gcgcgctgat ttttgcggta taagaatata tactgatatg tatacccgaa gtatgtcaaa 10440
aagaggtatg ctatgaagca gcgtattaca gtgacagttg acagcgacag ctatcagttg 10500
ctcaaggcat atatgatgtc aatatctccg gtctggtaag cacaaccatg cagaatgaag 10560
cccgtcgtct gcgtgccgaa cgctggaaag cggaaaatca ggaagggatg gctgaggtcg 10620
cccggtttat tgaaatgaac ggctcttttg ctgacgagaa caggggctgg tgaaatgcag 10680
tttaaggttt acacctataa aagagagagc cgttatcgtc tgtttgtgga tgtacagagt 10740
gatattattg acacgcccgg gcgacggatg gtgatccccc tggccagtgc acgtctgctg 10800
tcagataaag tctcccgtga actttacccg gtggtgcata tcggggatga aagctggcgc 10860
atgatgacca ccgatatggc cagtgtgccg gtctccgtta tcggggaaga agtggctgat 10920
ctcagccacc gcgaaaatga catcaaaaac gccattaacc tgatgttctg gggaatataa 10980
atgtcaggct cccttataca cagccagtct gcaggtcgac catagtgact ggatatgttg 11040
tgttttacag tattatgtag tctgtttttt atgcaaaatc taatttaata tattgatatt 11100
tatatcattt tacgtttctc gttcagcttt cttgtacaaa gtggtgatcg attcgacaga 11160
tcgcgatcgc agtgagtagt gttctggggc gggggaggac ctgcatgagg gccagaatga 11220
ctgaaatctg tgcttttctg tgtgttgcag catcatgagc ggaagcggct cctttgaggg 11280
aggggtattc agcccttatc tgacggggcg tctcccctcc tgggcgggag tgcgtcagaa 11340
tgtgatggga tccacggtgg acggccggcc cgtgcagccc gcgaactctt caaccctgac 11400
ctatgcaacc ctgagctctt cgtcggtgga cgcagctgcc gccgcagctg ctgcatccgc 11460
cgccagcgcc gtgcgcggaa tggccatggg cgccggctac tacggcactc tggtggccaa 11520
ctcgagttcc accaataatc ccgccagcct gaacgaggag aagctgctgc tgctgatggc 11580
ccagcttgag gccttgaccc agcgcctggg cgagctgacc cagcaggtgg ctcagctgca 11640
ggagcagacg cgggccgcgg ttgccacggt gaaatccaaa taaaaaatga atcaataaat 11700
aaacggagac ggttgttgat tttaacacag agtctgaatc tttatttgat ttttcgcgcg 11760
cggtaggccc tggaccaccg gtctcgatca ttgagcaccc ggtggatctt ttccaggacc 11820
cggtagaggt gggcttggat gttgaggtac atgggcatga gcccgtcccg ggggtggagg 11880
tagctccatt gcagggcctc gtgctcgggg gtggtgttgt aaatcaccca gtcatagcag 11940
gggcgcaggg cgtggtgttg cacaatatct ttgaggagga gactgatggc cacgggcagc 12000
cctttggtgt aggtgtttac aaatctgttg agctgggagg gatgcatgcg gggggagatg 12060
aggtgcatct tggcctggat cttgagattg gcgatgttac cgcccagatc ccgcctgggg 12120
ttcatgttgt gcaggaccac cagcacggtg tatccggtgc acttggggaa tttatcatgc 12180
aacttggaag ggaaggcgtg aaagaatttg gcgacgccct tgtgtccgcc caggttttcc 12240
atgcactcat ccatgatgat ggcaatgggc ccgtgggcgg cggcctgggc aaagacgttt 12300
cgggggtcgg acacatcata gttgtggtcc tgggtgaggt catcataggc cattttaatg 12360
aatttggggc ggagggtgcc ggactggggg acaaaggtac cctcgatccc gggggcgtag 12420
ttcccctcac agatctgcat ctcccaggct ttgagctcag agggggggat catgtccacc 12480
tgcggggcga taaagaacac ggtttccggg gcgggggaga tgagctgggc cgaaagcaag 12540
ttccggagca gctgggactt gccgcagccg gtggggccgt aaatgacccc gatgaccggc 12600
tgcaggtggt agttgaggga gagacagctg ccgtcctccc ggaggagggg ggccacctcg 12660
ttcatcatct cgcgcacgtg catgttctcg cgcaccagtt ccgccaggag gcgctctccc 12720
cccagagata ggagctcctg gagcgaggcg aagtttttca gcggcttgag tccgtcggcc 12780
atgggcattt tggagagggt ctgttgcaag agttccaagc ggtcccagag ctcggtgatg 12840
tgctctacgg catctcgatc cagcagacct cctcgtttcg cgggttggga cgactgcggg 12900
agtagggcac cagacgatgg gcgtccagcg cagccagggt ccggtccttc cagggccgca 12960
gcgtccgcgt cagggtggtc tccgtcacgg tgaaggggtg cgcgccgggc tgggcgcttg 13020
cgagggtgcg cttcaggctc atccggctgg tcgaaaaccg ctcccgatcg gcgccctgcg 13080
cgtcggccag gtagcaattg accatgagtt cgtagttgag cgcctcggcc gcgtggcctt 13140
tggcgcggag cttacctttg gaagtctgcc cgcaggcggg acagaggagg gacttgaggg 13200
cgtagagctt gggggcgagg aagacggaat cgggggcgta ggcgtccgcg ccgcagtggg 13260
cgcagacggt ctcgcactcc acgagccagg tgaggtcggg ctggtcgggg tcaaaaacca 13320
gtttcccgcc gttctttttg atgcgtttct tacctttggt ctccatgagc tcgtgtcccc 13380
gctgggtgac aaagaggctg tccgtgtccc cgtagaccga ctttatgggc cggtcctcga 13440
gcggtgtgcc gcggtcctcc tcgtagagga accccgccca ctccgagacg aaagcccggg 13500
tccaggccag cacgaaggag gccacgtggg acgggtagcg gtcgttgtcc accagcgggt 13560
ccactttttc cagggtatgc aaacacatgt ccccctcgtc cacatccagg aaggtgattg 13620
gcttgtaagt gtaggccacg tgaccggggg tcccggccgg gggggtataa aagggggcgg 13680
gcccctgctc gtcctcactg tcttccggat cgctgtccag gagcgccagc tgttggggta 13740
ggtattccct ctcgaaggcg ggcatgacct cggcactcag gttgtcagtt tctagaaacg 13800
aggaggattt gatattgacg gtgccagcgg agatgccttt caagagcccc tcgtccatct 13860
ggtcagaaaa gacgattttt ttgttgtcga gcttggtggc gaaggagccg tagagggcgt 13920
tggaaaggag cttggcgatg gagcgcatgg tctggttttt ttccttgtcg gcgcgctcct 13980
tggccgcgat gttgagctgc acgtactcgc gcgccacgca cttccattcg gggaagacgg 14040
tggtcatctc gtcgggcacg attctgacct gccaacctcg attatgcagg gtgatgaggt 14100
ccacactggt ggccacctcg ccgcgcaggg gctcgttggt ccagcagagg cggccgccct 14160
tgcgcgagca gaaggggggc agagggtcca gcatgacctc gtcggggggg tcggcatcga 14220
tggtgaagat gccgggcagg agatcggggt cgaagtagct gatggaagtg gccagatcgt 14280
ccagggaagc ttgccattcg cgcacggcca gcgcgcgctc gtagggactg aggggcgtgc 14340
cccagggcat ggggtgggtg agcgcggagg cgtacatgcc gcagatgtcg tagacgtaga 14400
ggggctcctc gaggatgccg atgtaggtgg ggtagcagcg ccccccgcgg atgctggcgc 14460
gcacgtagtc atacagctcg tgcgagggcg cgaggagccc cgggcccagg ttggtgcgac 14520
tgggcttttc ggcgcggtag acgatctggc gaaagatggc atgcgagttg gaggagatgg 14580
tgggcctttg gaagatgttg aagtgggcgt gggggaggcc gaccgagtcg cggatgaagt 14640
gggcgtagga gtcttgcagt ttggcgacga gctcggcggt gacgaggacg tccagagcgc 14700
agtagtcgag ggtctcctgg atgatgtcat acttgagctg gcccttttgt ttccacagct 14760
cgcggttgag aaggaactct tcgcggtcct tccagtactc ttcgaggggg aacccgtcct 14820
gatctgcacg gtaagagcct agcatgtaga actggttgac ggccttgtag gcgcagcagc 14880
ccttctccac ggggagggcg taggcctggg cggccttgcg cagggaggtg tgcgtgaggg 14940
cgaaggtgtc cctgaccatg accttgagga actggtgctt gaaatcgata tcgtcgcagc 15000
ccccctgctc ccagagctgg aagtccgtgc gcttcttgta ggcggggttg ggcaaagcga 15060
aagtaacatc gttgaaaagg atcttgcccg cgcggggcat aaagttgcga gtgatgcgga 15120
aaggctgggg cacctcggcc cggttgttga tgacctgggc ggcgagcacg atctcgtcga 15180
aaccgttgat gttgtggccc acgatgtaga gttccacgaa tcgcgggcgg cccttgacgt 15240
ggggcagctt cttgagctcc tcgtaggtga gctcgtcggg gtcgctgaga ccgtgctgct 15300
cgagcgccca gtcggcgaga tgggggttgg cgcggaggaa ggaagtccag agatccacgg 15360
ccagggcggt ttgcagacgg tcccggtact gacggaactg ctgcccgacg gccatttttt 15420
cgggggtgac gcagtagaag gtgcgggggt ccccgtgcca gcggtcccat ttgagctgga 15480
gggcgagatc gagggcgagc tcgacgaggc ggtcgtcccc tgagagtttc atgaccagca 15540
tgaaggggac gagctgcttg ccgaaggacc ccatccaggt gtaggtttcc acatcgtagg 15600
tgaggaagag cctttcggtg cgaggatgcg agccgatggg gaagaactgg atctcctgcc 15660
accaattgga ggaatggctg ttgatgtgat ggaagtagaa atgccgacgg cgcgccgaac 15720
actcgtgctt gtgtttatac aagcggccac agtgctcgca acgctgcacg ggatgcacgt 15780
gctgcacgag ctgtacctga gttcctttga cgaggaattt cagtgggaag tggagtcgtg 15840
gcgcctgcat ctcgtgctgt actacgtcgt ggtggtcggc ctggccctct tctgcctcga 15900
tggtggtcat gctgacgagc ccgcgcggga ggcaggtcca gacctcggcg cgagcgggtc 15960
ggagagcgag gacgagggcg cgcaggccgg agctgtccag ggtcctgaga cgctgcggag 16020
tcaggtcagt gggcagcggc ggcgcgcggt tgacttgcag gagtttttcc agggcgcgcg 16080
ggaggtccag atggtacttg atctccaccg cgccgttggt ggcgacgtcg atggcttgca 16140
gggtcccgtg cccctggggt gtgaccaccg tcccccgttt cttcttgggc ggctggggcg 16200
acgggggcgg tgcctcttcc atggttagaa gcggcggcga ggacgcgcgc cgggcggcag 16260
aggcggctcg gggcccggag gcaggggcgg caggggcacg tcggcgccgc gcgcgggtag 16320
gttctggtac tgcgcccgga gaagactggc gtgagcgacg acgcgacggt tgacgtcctg 16380
gatctgacgc ctctgggtga aggccacggg acccgtgagt ttgaacctga aagagagttc 16440
gacagaatca atctcggtat cgttgacggc ggcctgccgc aggatctctt gcacgtcgcc 16500
cgagttgtcc tggtaggcga tctcggtcat gaactgctcg atctcctcct cctgaaggtc 16560
tccgcgaccg gcgcgctcca cggtggccgc gaggtcgttg gagatgcggc ccatgagctg 16620
cgagaaggcg ttcatgcccg cctcgttcca gacgcggctg tagaccacga cgccctcggg 16680
atcgcgggcg cgcatgacca cctgggcgag gttgagctcc acgtggcgcg tgaagaccgc 16740
gtagttgcag aggcgctggt agaggtagtt gagcgtggtg gcgatgtgct cggtgacgaa 16800
gaaatacatg atccagcggc ggagcggcat ctcgctgacg tcgcccagcg cctccaagcg 16860
ttccatggcc tcgtaaaagt ccacggcgaa gttgaaaaac tgggagttgc gcgccgagac 16920
ggtcaactcc tcctccagaa gacggatgag ctcggcgatg gtggcgcgca cctcgcgctc 16980
gaaggccccc gggagttcct ccacttcctc ctcttcttcc tcctccacta acatctcttc 17040
tacttcctcc tcaggcggtg gtggtggcgg gggagggggc ctgcgtcgcc ggcggcgcac 17100
gggcagacgg tcgatgaagc gctcgatggt ctcgccgcgc cggcgtcgca tggtctcggt 17160
gacggcgcgc ccgtcctcgc ggggccgcag cgtgaagacg ccgccgcgca tctccaggtg 17220
gccggggggg tccccgttgg gcagggagag ggcgctgacg atgcatctta tcaattgccc 17280
cgtagggact ccgcgcaagg acctgagcgt ctcgagatcc acgggatctg aaaaccgttg 17340
aacgaaggct tcgagccagt cgcagtcgca aggtaggctg agcacggttt cttctgccgg 17400
gtcatgttgg ggagcggggc gggcgatgct gctggtgatg aagttgaaat aggcggttct 17460
gagacggcgg atggtggcga ggagcaccag gtctttgggc ccggcttgct ggatgcgcag 17520
acggtcggcc atgccccagg cgtggtcctg acacctggcc aggtccttgt agtagtcctg 17580
catgagccgc tccacgggca cctcctcctc gcccgcgcgg ccgtgcatgc gcgtgagccc 17640
gaagccgcgc tggggctgga cgagcgccag gtcggcgacg acgcgctcgg cgaggatggc 17700
ctgctggatc tgggtgaggg tggtctggaa gtcgtcaaag tcgacgaagc ggtggtaggc 17760
tccggtgttg atggtgtagg agcagttggc catgacggac cagttgacgg tctggtggcc 17820
cggacgcacg agctcgtggt acttgaggcg cgagtaggcg cgcgtgtcga agatgtagtc 17880
gttgcaggtg cgcaccaggt actggtagcc gatgaggaag tgcggcggcg gctggcggta 17940
gagcggccat cgctcggtgg cgggggcgcc gggcgcgagg tcctcgagca tggtgcggtg 18000
gtagccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 18060
gaactcgcgg acgcggttcc agatgttgcg cagcggcagg aagtagttca tggtgggcac 18120
ggtctggccc gtgaggcgcg cgcagtcgtg gatgctctat acgggcaaaa acgaaagcgg 18180
tcagcggctc gactccgtgg cctggaggct aagcgaacgg gttgggctgc gcgtgtaccc 18240
cggttcgaat ctcgaatcag gctggagccg cagctaacgt ggtactggca ctcccgtctc 18300
gacccaagcc tgcaccaacc ctccaggata cggaggcggg tcgttttgca actttttttg 18360
gaggccggaa atgaaactag taagcgcgga aagcggccga ccgcgatggc tcgctgccgt 18420
agtctggaga agaatcgcca gggttgcgtt gcggtgtgcc ccggttcgag gccggccgga 18480
ttccgcggct aacgagggcg tggctgcccc gtcgtttcca agaccccata gccagccgac 18540
ttctccagtt acggagcgag cccctctttt gttttgtttg tttttgccag atgcatcccg 18600
tactgcggca gatgcgcccc caccaccctc caccgcaaca acagccccct cctccacagc 18660
cggcgcttct gcccccgccc cagcagcagc agcaacttcc agccacgacc gccgcggccg 18720
ccgtgagcgg ggctggacag acttctcagt atgatcacct ggccttggaa gagggcgagg 18780
ggctggcgcg cctgggggcg tcgtcgccgg agcggcaccc gcgcgtgcag atgaaaaggg 18840
acgctcgcga ggcctacgtg cccaagcaga acctgttcag agacaggagc ggcgaggagc 18900
ccgaggagat gcgcgcggcc cggttccacg cggggcggga gctgcggcgc ggcctggacc 18960
gaaagagggt gctgagggac gaggatttcg aggcggacga gctgacgggg atcagccccg 19020
cgcgcgcgca cgtggccgcg gccaacctgg tcacggcgta cgagcagacc gtgaaggagg 19080
agagcaactt ccaaaaatcc ttcaacaacc acgtgcgcac cctgatcgcg cgcgaggagg 19140
tgaccctggg cctgatgcac ctgtgggacc tgctggaggc catcgtgcag aaccccacca 19200
gcaagccgct gacggcgcag ctgttcctgg tggtgcagca tagtcgggac aacgaggcgt 19260
tcagggaggc gctgctgaat atcaccgagc ccgagggccg ctggctcctg gacctggtga 19320
acattctgca gagcatcgtg gtgcaggagc gcgggctgcc gctgtccgag aagctggcgg 19380
ccatcaactt ctcggtgctg agtctgggca agtactacgc taggaagatc tacaagaccc 19440
cgtacgtgcc catagacaag gaggtgaaga tcgacgggtt ttacatgcgc atgaccctga 19500
aagtgctgac cctgagcgac gatctggggg tgtaccgcaa cgacaggatg caccgcgcgg 19560
tgagcgccag caggcggcgc gagctgagcg accaggagct gatgcacagc ctgcagcggg 19620
ccctgaccgg ggccgggacc gagggggaga gctactttga catgggcgcg gacctgcact 19680
ggcagcccag ccgccgggcc ttggaggcgg caggcggtcc cccctacata gaagaggtgg 19740
acgatgaggt ggacgaggag ggcgagtacc tggaagactg atggcgcgac cgtatttttg 19800
ctagatgcaa caacagccac ctcctgatcc cgcgatgcgg gcggcgctgc agagccagcc 19860
gtccggcatt aactcctcgg acgattggac ccaggccatg caacgcatca tggcgctgac 19920
gacccgcaac cccgaagcct ttagacagca gccccaggcc aaccggctct cggccatcct 19980
ggaggccgtg gtgccctcgc gctccaaccc cacgcacgag aaggtcctgg ccatcgtgaa 20040
cgcgctggtg gagaacaagg ccatccgcgg cgacgaggcc ggcctggtgt acaacgcgct 20100
gctggagcgc gtggcccgct acaacagcac caacgtgcag accaacctgg accgcatggt 20160
gaccgacgtg cgcgaggccg tggcccagcg cgagcggttc caccgcgagt ccaacctggg 20220
atccatggtg gcgctgaacg ccttcctcag cacccagccc gccaacgtgc cccggggcca 20280
ggaggactac accaacttca tcagcgccct gcgcctgatg gtgaccgagg tgccccagag 20340
cgaggtgtac cagtccgggc cggactactt cttccagacc agtcgccagg gcttgcagac 20400
cgtgaacctg agccaggcgt tcaagaactt gcagggcctg tggggcgtgc aggccccggt 20460
cggggaccgc gcgacggtgt cgagcctgct gacgccgaac tcgcgcctgc tgctgctgct 20520
ggtggccccc ttcacggaca gcggcagcat caaccgcaac tcgtacctgg gctacctgat 20580
taacctgtac cgcgaggcca tcggccaggc gcacgtggac gagcagacct accaggagat 20640
cacccacgtg agccgcgccc tgggccagga cgacccgggc aatctggaag ccaccctgaa 20700
ctttttgctg accaaccggt cgcagaagat cccgccccag tacacgctca gcgccgagga 20760
ggagcgcatc ctgcgatacg tgcagcagag cgtgggcctg ttcctgatgc aggagggggc 20820
cacccccagc gccgcgctcg acatgaccgc gcgcaacatg gagcccagca tgtacgccag 20880
caaccgcccg ttcatcaata aactgatgga ctacttgcat cgggcggccg ccatgaactc 20940
tgactatttc accaacgcca tcctgaatcc ccactggctc ccgccgccgg ggttctacac 21000
gggcgagtac gacatgcccg accccaatga cgggttcctg tgggacgatg tggacagcag 21060
cgtgttctcc ccccgaccgg gtgctaacga gcgccccttg tggaagaagg aaggcagcga 21120
ccgacgcccg tcctcggcgc tgtccggccg cgagggtgct gccgcggcgg tgcccgaggc 21180
cgccagtcct ttcccgagct tgcccttctc gctgaacagt attcgcagca gcgagctggg 21240
caggatcacg cgcccgcgct tgctgggcga ggaggagtac ttgaatgact cgctgttgag 21300
acccgagcgg gagaagaact tccccaataa cgggatagag agcctggtgg acaagatgag 21360
ccgctggaag acgtatgcgc aggagcacag ggacgatccg tcgcaggggg ccacgagccg 21420
gggcagcgcc gcccgtaaac gccggtggca cgacaggcag cggggactga tgtgggacga 21480
tgaggattcc gccgacgaca gcagcgtgtt ggacttgggt gggagtggta acccgttcgc 21540
tcacctgcgc ccccgcatcg ggcgcatgat gtaagagaaa ccgaaaataa atgatactca 21600
ccaaggccat ggcgaccagc gtgcgttcgt ttcttctctg ttgttgtatc tagtatgatg 21660
aggcgtgcgt acccggaggg tcctcctccc tcgtacgaga gcgtgatgca gcaggcgatg 21720
gcggcggcgg cggcgatgca gcccccgctg gaggctcctt acgtgccccc gcggtacctg 21780
gcgcctacgg aggggcggaa cagcattcgt tactcggagc tggcaccctt gtacgatacc 21840
acccggttgt acctggtgga caacaagtcg gcggacatcg cctcgctgaa ctaccagaac 21900
gaccacagca acttcctgac caccgtggtg cagaacaatg acttcacccc cacggaggcc 21960
agcacccaga ccatcaactt tgacgagcgc tcgcggtggg gcggtcagct gaaaaccatc 22020
atgcacacca acatgcccaa cgtgaacgag ttcatgtaca gcaacaagtt caaggcgcgg 22080
gtgatggtct cccgcaagac ccccaacggg gtgacagtga cagatggtag tcaggatatc 22140
ttggagtatg aatgggtgga gtttgagctg cccgaaggca acttctcggt gaccatgacc 22200
atcgacctga tgaacaacgc catcatcgac aattacttgg cggtggggcg gcagaacggg 22260
gtcctggaga gcgatatcgg cgtgaagttc gacactagga acttcaggct gggctgggac 22320
cccgtgaccg agctggtcat gcccggggtg tacaccaacg aggccttcca ccccgatatt 22380
gtcttgctgc ccggctgcgg ggtggacttc accgagagcc gcctcagcaa cctgctgggc 22440
attcgcaaga ggcagccctt ccaggagggc ttccagatca tgtacgagga tctggagggg 22500
ggcaacatcc ccgcgctcct ggatgtcgac gcctatgaga aaagcaagga ggagagcgcc 22560
gccgcggcga ctgcagctgt agccaccgcc tctaccgagg tcaggggcga taattttgcc 22620
agccctgcag cagtggcagc ggccgaggcg gctgaaaccg aaagtaagat agtcattcag 22680
ccggtggaga aggatagcaa ggacaggagc tacaacgtgc tgccggacaa gataaacacc 22740
gcctaccgca gctggtacct ggcctacaac tatggcgacc ccgagaaggg cgtgcgctcc 22800
tggacgctgc tcaccacctc ggacgtcacc tgcggcgtgg agcaagtcta ctggtcgctg 22860
cccgacatga tgcaagaccc ggtcaccttc cgctccacgc gtcaagttag caactacccg 22920
gtggtgggcg ccgagctcct gcccgtctac tccaagagct tcttcaacga gcaggccgtc 22980
tactcgcagc agctgcgcgc cttcacctcg ctcacgcacg tcttcaaccg cttccccgag 23040
aaccagatcc tcgtccgccc gcccgcgccc accattacca ccgtcagtga aaacgttcct 23100
gctctcacag atcacgggac cctgccgctg cgcagcagta tccggggagt ccagcgcgtg 23160
accgttactg acgccagacg ccgcacctgc ccctacgtct acaaggccct gggcatagtc 23220
gcgccgcgcg tcctctcgag ccgcaccttc taaaaaatgt ccattctcat ctcgcccagt 23280
aataacaccg gttggggcct gcgcgcgccc agcaagatgt acggaggcgc tcgccaacgc 23340
tccacgcaac accccgtgcg cgtgcgcggg cacttccgcg ctccctgggg cgccctcaag 23400
ggccgcgtgc ggtcgcgcac caccgtcgac gacgtgatcg accaggtggt ggccgacgcg 23460
cgcaactaca cccccgccgc cgcgcccgtc tccaccgtgg acgccgtcat cgacagcgtg 23520
gtggccgacg cgcgccggta cgcccgcgcc aagagccggc ggcggcgcat cgcccggcgg 23580
caccggagca cccccgccat gcgcgcggcg cgagccttgc tgcgcagggc caggcgcacg 23640
ggacgcaggg ccatgctcag ggcggccaga cgcgcggctt caggcgccag cgccggcagg 23700
acccggagac gcgcggccac ggcggcggca gcggccatcg ccagcatgtc ccgcccgcgg 23760
cgagggaacg tgtactgggt gcgcgacgcc gccaccggtg tgcgcgtgcc cgtgcgcacc 23820
cgcccccctc gcacttgaag atgttcactt cgcgatgttg atgtgtccca gcggcgagga 23880
ggatgtccaa gcgcaaattc aaggaagaga tgctccaggt catcgcgcct gagatctacg 23940
gccccgcggt ggtgaaggag gaaagaaagc cccgcaaaat caagcgggtc aaaaaggaca 24000
aaaaggaaga agatgacgat ctggtggagt ttgtgcgcga gttcgccccc cggcggcgcg 24060
tgcagtggcg cgggcggaaa gtgcacccgg tgctgagacc cggcaccacc gtggtcttca 24120
cgcccggcga gcgctccggc agcgcttcca agcgctccta cgacgaggtg tacggggacg 24180
aggacatcct cgagcaggcg gccgagcgcc tgggcgagtt tgcttacggc aagcgcagcc 24240
gccccgccct gaaggaagag gcggtgtcca tcccgctgga ccacggcaac cccacgccga 24300
gcctcaagcc cgtgaccctg cagcaggtgc tgccgagcgc agcgccgcgc cgggggttca 24360
agcgcgaggg cgaggatctg taccccacca tgcagctgat ggtgcccaag cgccagaagc 24420
tggaagacgt gctggagacc atgaaggtgg acccggacgt gcagcccgag gtcaaggtgc 24480
ggcccatcaa gcaggtggcc ccgggcctgg gcgtgcagac cgtggacatc aagatcccca 24540
cggagcccat ggaaacgcag accgagccca tgatcaagcc cagcaccagc accatggagg 24600
tgcagacgga tccctggatg ccatcggctc ctagccgaag accccggcgc aagtacggcg 24660
cggccagcct gctgatgccc aactacgcgc tgcatccttc catcatcccc acgccgggct 24720
accgcggcac gcgcttctac cgcggtcata caaccagccg ccgccgcaag accaccaccc 24780
gccgccgccg tcgccgcaca gccgctgcat ctacccctgc cgccctggtg cggagagtgt 24840
accgccgcgg ccgcgcgcct ctgaccctac cgcgcgcgcg ctaccacccg agcatcgcca 24900
tttaaacttt cgcctgcttt gcagatggcc ctcacatgcc gcctccgcgt tcccattacg 24960
ggctaccgag gaagaaaacc gcgccgtaga aggctggcgg ggaacgggat gcgtcgccac 25020
caccatcggc ggcggcgcgc catcagcaag cggttggggg gaggcttcct gcccgcgctg 25080
atccccatca tcgccgcggc gatcggggcg atccccggca ttgcttccgt ggcggtgcag 25140
gcctctcagc gccactgaga cacttggaaa acatcttgta ataaaccaat ggactctgac 25200
gctcctggtc ctgtgatgtg ttttcgtaga cagatggaag acatcaattt ttcgtccctg 25260
gctccgcgac acggcacgcg gccgttcatg ggcacctgga gcgacatcgg caccagccaa 25320
ctgaacgggg gcgccttcaa ttggagcagt ctctggagcg ggcttaagaa tttcgggtcc 25380
acgcttaaaa cctatggcag caaggcgtgg aacagcacca cagggcaggc gctgagggat 25440
aagctgaaag agcagaactt ccagcagaag gtggtcgatg ggctcgcctc gggcatcaac 25500
ggggtggtgg acctggccaa ccaggccgtg cagcggcaga tcaacagccg cctggacccg 25560
gtgccgcccg ccggctccgt ggagatgccg caggtggagg aggagctgcc tcccctggac 25620
aagcggggcg agaagcgacc ccgccccgac gcggaggaga cgctgctgac gcacacggac 25680
gagccgcccc cgtacgagga ggcggtgaaa ctgggtctgc ccaccacgcg gcccatcgcg 25740
cccctggcca ccggggtgct gaaacccgaa agtaataagc ccgcgaccct ggacttgcct 25800
cctcccgctt cccgcccctc tacagtggct aagcccctgc cgccggtggc cgtggcccgc 25860
gcgcgacccg ggggctccgc ccgccctcat gcgaactggc agagcactct gaacagcatc 25920
gtgggtctgg gagtgcagag tgtgaagcgc cgccgctgct attaaaccta ccgtagcgct 25980
taacttgctt gtctgtgtgt gtatgtatta tgtcgccgct gtccgccaga aggaggagtg 26040
aagaggcgcg tcgccgagtt gcaagatggc caccccatcg atgctgcccc agtgggcgta 26100
catgcacatc gccggacagg acgcttcgga gtacctgagt ccgggtctgg tgcagttcgc 26160
ccgcgccaca gacacctact tcagtctggg gaacaagttt aggaacccca cggtggcgcc 26220
cacgcacgat gtgaccaccg accgcagcca gcggctgacg ctgcgcttcg tgcccgtgga 26280
ccgcgaggac aacacctact cgtacaaagt gcgctacacg ctggccgtgg gcgacaaccg 26340
cgtgctggac atggccagca cctactttga catccgcggc gtgctggatc ggggccctag 26400
cttcaaaccc tactccggca ccgcctacaa cagcctggct cccaagggag cgcccaattc 26460
cagccagtgg gagcaaaaaa aggcaggcaa tggtgacact atggaaacac acacatttgg 26520
tgtggcccca atgggcggtg agaatattac aatcgacgga ttacaaattg gaactgacgc 26580
tacagctgat caggataaac caatttatgc tgacaaaaca ttccagcctg aacctcaagt 26640
aggagaagaa aattggcaag aaactgaaag cttttatggc ggtagggctc ttaaaaaaga 26700
cacaagcatg aaaccttgct atggctccta tgctagaccc accaatgtaa agggaggtca 26760
agctaaactt aaagttggag ctgatggagt tcctaccaaa gaatttgaca tagacctggc 26820
tttctttgat actcccggtg gcacagtgaa tggacaagat gagtataaag cagacattgt 26880
catgtatacc gaaaacacgt atctggaaac tccagacacg catgtggtat acaaaccagg 26940
caaggatgat gcaagttctg aaattaacct ggttcagcag tccatgccca atagacccaa 27000
ctatattggg ttcagagaca actttattgg gctcatgtat tacaacagta ctggcaatat 27060
gggggtgctg gctggtcagg cctcacagct gaatgctgtg gtcgacttgc aagacagaaa 27120
caccgagctg tcataccagc tcttgcttga ctctttgggt gacagaaccc ggtatttcag 27180
tatgtggaat caggcggtgg acagttatga tcctgatgtg cgcattattg aaaaccatgg 27240
tgtggaagac gaacttccca actattgctt ccccctggat gggtctggca ctaatgccgc 27300
ttaccaaggt gtgaaagtaa aaaatggtaa cgatggtgat gttgagagcg aatgggaaaa 27360
tgatgatact gtcgcagctc gaaatcaatt atgcaagggc aacatttttg ccatggaaat 27420
taacctccaa gccaacctgt ggagaagttt cctctactcg aacgtggccc tgtacctgcc 27480
cgactcttac aagtacacgc cagccaacat caccctgccc accaacacca acacttatga 27540
ttacatgaac gggagagtgg tgcctccctc gctggtggac gcctacatca acatcggggc 27600
gcgctggtcg ctggacccca tggacaacgt caatcccttc aaccaccacc gcaacgcggg 27660
cctgcgctac cgctccatgc tcctgggcaa cgggcgctac gtgcccttcc acatccaggt 27720
gccccagaaa tttttcgcca tcaagagcct cctgctcctg cccgggtcct acacctacga 27780
gtggaacttc cgcaaggacg tcaacatgat cctgcagagc tccctcggca acgacctgcg 27840
cacggacggg gcctccatct ccttcaccag catcaacctc tacgccacct tcttccccat 27900
ggcgcacaac acggcctcca cgctcgaggc catgctgcgc aacgacacca acgaccagtc 27960
cttcaacgac tacctctcgg cggccaacat gctctacccc atcccggcca acgccaccaa 28020
cgtgcccatc tccatcccct cgcgcaactg ggccgccttc cgcggctggt ccttcacgcg 28080
cctcaagacc aaggagacgc cctcgctggg ctccgggttc gacccctact tcgtctactc 28140
gggctccatc ccctacctcg acggcacctt ctacctcaac cacaccttca agaaggtctc 28200
catcaccttc gactcctccg tcagctggcc cggcaacgac cggctcctga cgcccaacga 28260
gttcgaaatc aagcgcaccg tcgacggcga gggatacaac gtggcccagt gcaacatgac 28320
caaggactgg ttcctggtcc agatgctggc ccactacaac atcggctacc agggcttcta 28380
cgtgcccgag ggctacaagg accgcatgta ctccttcttc cgcaacttcc agcccatgag 28440
ccgccaggtg gtggacgagg tcaactacaa ggactaccag gccgtcaccc tggcctacca 28500
gcacaacaac tcgggcttcg tcggctacct cgcgcccacc atgcgccagg gccagcccta 28560
ccccgccaac tacccgtacc cgctcatcgg caagagcgcc gtcaccagcg tcacccagaa 28620
aaagttcctc tgcgacaggg tcatgtggcg catccccttc tccagcaact tcatgtccat 28680
gggcgcgctc accgacctcg gccagaacat gctctatgcc aactccgccc acgcgctaga 28740
catgaatttc gaagtcgacc ccatggatga gtccaccctt ctctatgttg tcttcgaagt 28800
cttcgacgtc gtccgagtgc accagcccca ccgcggcgtc atcgaggccg tctacctgcg 28860
cacccccttc tcggccggta acgccaccac ctaaattgct acttgcatga tggctgagcc 28920
cacaggctcc ggcgagcagg agctcagggc catcatccgc gacctgggct gcgggcccta 28980
cttcctgggc accttcgata agcgcttccc gggattcatg gccccgcaca agctggcctg 29040
cgccatcgtc aacacggccg gccgcgagac cgggggcgag cactggctgg ccttcgcctg 29100
gaacccgcgc tcgaacacct gctacctctt cgaccccttc gggttctcgg acgagcgcct 29160
caagcagatc taccagttcg agtacgaggg cctgctgcgc cgtagcgccc tggccaccga 29220
ggaccgctgc gtcaccctgg aaaagtccac ccagaccgtg cagggtccgc gctcggccgc 29280
ctgcgggctc ttctgctgca tgttcctgca cgccttcgtg cactggcccg accgccccat 29340
ggacaagaac cccaccatga acttgctgac gggggtgccc aacggcatgc tccagtcgcc 29400
ccaggtggaa cccaccctgc gccgcaacca ggaggcgctc taccgcttcc tcaactccca 29460
ctccgcctac tttcgctccc accgcgcgcg catcgagaag gccaccgcct tcgaccgcat 29520
gaacaatcaa gacatgtaaa ccgtgtgtgt atgtttaaaa tatcttttaa taaacagcac 29580
tttaatgtta cacatgcatc tgagatgatt ttattttaga aatcgaaagg gttctgccgg 29640
gtctcggcat ggcccgcggg cagggacacg ttgcggaact ggtacttggc cagccacttg 29700
aactcgggga tcagcagttt gggcagcggg gtgtcgggga aggagtcggt ccacagcttc 29760
cgcgtcagct gcagggcgcc cagcaggtcg ggcgcggaga tcttgaaatc gcagttggga 29820
cccgcgttct gcgcgcgaga gttgcggtac acggggttgc agcactggaa caccatcagg 29880
gccgggtgct tcacgctcgc cagcaccgcc gcgtcggtga tgctctccac gtcgaggtcc 29940
tcggcgttgg ccatcccgaa gggggtcatc ttgcaggtct gccttcccat ggtgggcacg 30000
cacccgggct tgtggttgca atcgcagtgc agggggatca gcatcatctg ggcctggtcg 30060
gcgttcatcc ccgggtacat ggccttcatg aaagcctcca attgcctgaa cgcctgctgg 30120
gccttggctc cctcggtgaa gaagaccccg caggacttgc tagagaactg gttggtggca 30180
cagccggcat cgtgcacgca gcagcgcgcg tcgttgttgg ccagctgcac cacgctgcgc 30240
ccccagcggt tctgggtgat cttggcccgg tcggggttct ccttcagcgc gcgctgcccg 30300
ttctcgctcg ccacatccat ctcgatcatg tgctccttct ggatcatggt ggtcccgtgc 30360
aggcaccgca gtttgccctc ggcctcggtg cacccgtgca gccacagcgc gcacccggtg 30420
cactcccagt tcttgtgggc gatctgggaa tgcgcgtgca cgaacccttg caggaagcgg 30480
cccatcatgg tcgtcagggt cttgttgcta gtgaaggtca acgggatgcc gcggtgctcc 30540
tcgttgatgt acaggtggca gatgcggcgg tacacctcgc cctgctcggg catcagttgg 30600
aagttggctt tcaggtcggt ctccacgcgg tagcggtcca tcagcatagt catgatttcc 30660
atgcccttct cccaggccga gacgatgggc aggctcatag ggttcttcac catcatctta 30720
gcactagcag ccgcggccag ggggtcgctc tcatccaggg tctcaaagct ccgcttgccg 30780
tccttctcgg tgatccgcac cggggggtag ctgaagccca cggccgccag ctcctcctcg 30840
gcctgtcttt cgtcctcgct gtcctggctg acgtcctgca tgaccacatg cttggtcttg 30900
cggggtttct tcttgggcgg cagtggcggc ggagatgctt gtggcgaggg ggagcgcgag 30960
ttctcgctca ccactactat ctcttcctct tcttggtccg aggccacgcg gcggtaggta 31020
tgtctcttcg ggggcagagg cggaggcgac gggctctcgc cgccgcgact tggcggatgg 31080
ctggcagagc cccttccgcg ttcgggggtg cgctcccggc ggcgctctga ctgacttcct 31140
ccgcggccgg ccattgtgtt ctcctaggga ggaacaacaa gcatggagac tcagccatcg 31200
ccaacctcgc catctgcccc caccgccggc gacgagaagc agcagcagca gaatgaaagc 31260
ttaaccgccc cgccgcccag ccccgcctcc gacgcagccg cggtcccaga catgcaagag 31320
atggaggaat ccatcgagat tgacctgggc tatgtgacgc ccgcggagca tgaggaggag 31380
ctggcagtgc gctttcaatc gtcaagccag gaagataaag aacagccaga gcaggaagca 31440
gagaacgagc agagtcaggc tgggctcgag catggcgact acctccacct gagcggggag 31500
gaggacgcgc tcatcaagca tctggcccgg caggccacca tcgtcaagga cgcgctgctc 31560
gaccgcaccg aggtgcccct cagcgtggag gagctcagcc gcgcctacga gctcaacctc 31620
ttctcgccgc gcgtgccccc caagcgccag cccaacggca cctgcgagcc caacccccgc 31680
ctcaacttct acccggtctt cgcggtgccc gaggccctgg ccacctacca catctttttc 31740
aagaaccaaa agatccccgt ctcctgccgc gccaaccgca cccgcgccga cgccctcttc 31800
aacctgggtc ccggcgcccg cctacctgat atcgcctcct tggaagaggt tcccaagatc 31860
ttcgagggtc tgggcagcga cgagactcgg gccgcgaacg ctctgcaagg agaaggagga 31920
ggagagcatg agcaccacag cgccctggtc gagttggaag gcgacaacgc gcggctggcg 31980
gtgctcaaac gcacggtcga gctgacccat ttcgcctacc cggctctgaa cctgcccccg 32040
aaagtcatga gcgcggtcat ggaccaggtg ctcatcaagc gcgcgtcgcc catctccgag 32100
gacgagggca tgcaagactc cgaggagggc aagcccgtgg tcagcgacga gcagctggcc 32160
cggtggctgg gtcctaatgc tacccctcaa agtttggaag agcggcgcaa gctcatgatg 32220
gccgtggtcc tggtgaccgt ggagctggag tgcctgcgcc gcttcttcgc cgacgcggag 32280
accctgcgca aggtcgagga gaacctgcac tacctcttca ggcacgggtt cgtgcgccag 32340
gcctgcaaga tctccaacgt ggagctgacc aacctggtct cctacatggg catcttgcac 32400
gagaaccgcc tggggcagaa cgtgctgcac accaccctgc gcggggaggc ccgccgcgac 32460
tacatccgcg actgcgtcta cctctacctc tgccacacct ggcagacggg catgggcgtg 32520
tggcagcagt gtctggagga gcagaacctg aaagagctct gcaagctcct gcaaaagaac 32580
ctcaagggtc tgtggaccgg gttcgacgag cggaccaccg cctcggacct ggccgacctc 32640
atcttccccg agcgcctcag gctgacgctg cgcaacggcc tgcccgactt tatgagccaa 32700
agcatgttgc aaaactttcg ctctttcatc ctcgaacgct ccggaatcct gcccgccacc 32760
tgctccgcgc tgccctcgga cttcgtgccg ctgaccttcc gcgagtgccc cccgccgctg 32820
tggagccact gctacctgct gcgcctggcc aactacctgg cctaccactc ggacgtgatc 32880
gaggacgtca gcggcgaggg cctgctcgag tgccactgcc gctgcaacct ctgcacgccg 32940
caccgctccc tggcctgcaa cccccagctg ctgagcgaga cccagatcat cggcaccttc 33000
gagttgcaag ggcccagcga gggcgaggga gccaaggggg gtctgaaact caccccgggg 33060
ctgtggacct cggcctactt gcgcaagttc gtgcccgagg attaccatcc cttcgagatc 33120
aggttctacg aggaccaatc ccagccgccc aaggccgagc tgtcggcctg cgtcatcacc 33180
cagggggcga tcctggccca attgcaagcc atccagaaat cccgccaaga attcttgctg 33240
aaaaagggcc gcggggtcta cctcgacccc cagaccggtg aggagctcaa ccccggcttc 33300
ccccaggatg ccccgaggaa acaagaagct gaaagtggag ctgccgcccg tggaggattt 33360
ggaggaagac tgggagaaca gcagtcaggc agaggagatg gaggaagact gggacagcac 33420
tcaggcagag gaggacagcc tgcaagacag tctggaggaa gacgaggagg aggcagagga 33480
ggaggtggaa gaagcagccg ccgccagacc gtcgtcctcg gcgggggaga aagcaagcag 33540
cacggatacc atctccgctc cgggtcgggg tcccgctcgg ccccacagta gatgggacga 33600
gaccgggcga ttcccgaacc ccaccaccca gaccggtaag aaggagcggc agggatacaa 33660
gtcctggcgg gggcacaaaa acgccatcgt ctcctgcttg caggcctgcg ggggcaacat 33720
ctccttcacc cggcgctacc tgctcttcca ccgcggggtg aacttccccc gcaacatctt 33780
gcattactac cgtcacctcc acagccccta ctacttccaa gaagaggcag cagcagcaga 33840
aaaagaccag aaaaccagct agaaaatcca cagcggcggc agcggcaggt ggactgagga 33900
tcgcggcgaa cgagccggcg cagacccggg agctgaggaa ccggatcttt cccaccctct 33960
atgccatctt ccagcagagt cgggggcagg agcaggaact gaaagtcaag aaccgttctc 34020
tgcgctcgct cacccgcagt tgtctgtatc acaagagcga agaccaactt cagcgcactc 34080
tcgaggacgc cgaggctctc ttcaacaagt actgcgcgct cactcttaaa gagtagcccg 34140
cgcccgccca gtcgcagaaa aaggcgggaa ttacgtcacc tgtgcccttc gccctagccg 34200
cctccaccca gcaccgccat gagcaaagag attcccacgc cttacatgtg gagctaccag 34260
ccccagatgg gcctggccgc cggcgccgcc caggactact ccacccgcat gaattggctc 34320
agcgccgggc ccgcgatgat ctcacgggtg aatgacatcc gcgcccaccg aaaccagata 34380
ctcctagaac agtcagcgct caccgccacg ccccgcaatc acctcaatcc gcgtaattgg 34440
cccgccgccc tggtgtacca ggaaattccc cagcccacga ccgtactact tccgcgagac 34500
gcccaggccg aagtccagct gactaactca ggtgtccagc tggcgggcgg cgccaccctg 34560
tgtcgtcacc gccccgctca gggtataaag cggctggtga tccggggcag aggcacacag 34620
ctcaacgacg aggtggtgag ctcttcgctg ggtctgcgac ctgacggagt cttccaactc 34680
gccggatcgg ggagatcttc cttcacgcct cgtcaggcgg tcctgacttt ggagagttcg 34740
tcctcgcagc cccgctcggg cggcatcggc actctccagt tcgtggagga gttcactccc 34800
tcggtctact tcaacccctt ctccggctcc cccggccact acccggacga gttcatcccg 34860
aactttgacg ccatcagcga gtcggtggac ggctacgatt gattaattaa tcaactaacc 34920
ccttacccct ttaccctcca gtaaaaataa agattaaaaa tgattgaatt gatcaataaa 34980
gaatcactta cttgaaatct gaaaccaggt ctctgtccat gttttctgtc agcagcactt 35040
cactcccctc ttcccaactc tggtactgca ggccccggcg ggctgcaaac ttcctccaca 35100
ctctgaaggg gatgtcaaat tcctcctgtc cctcaatctt catttttatc ttctatcaga 35160
tgtccaaaaa gcgcgcgcgg gtggatgatg gcttcgaccc cgtgtacccc tacgatgcag 35220
acaacgcacc gactgtgccc ttcatcaacc ctcccttcgt ctcttcagat ggattccaag 35280
aaaagcccct gggggtgttg tccctgcgac tggccgaccc cgtcaccacc aagaatgggg 35340
ctgtcaccct caagctgggg gagggggtgg acctcgacga ctcgggaaaa ctcatctcca 35400
aaaatgccac caaggccact gcccctctca gtatttccaa cggcaccatt tcccttaaca 35460
tggctgcccc tttttacaac aacaatggaa cgttaagtct caatgtttct acaccattag 35520
cagtatttcc cacttttaac actttaggta tcagtcttgg aaacggtctt caaacttcta 35580
ataagttgct gactgtacag ttaactcatc ctcttacatt cagctcaaat agcatcacag 35640
taaaaacaga caaaggactc tatattaatt ctagtggaaa cagagggctt gaggctaaca 35700
taagcctaaa aagaggactg atttttgatg gtaatgctat tgcaacatac cttggaagtg 35760
gtttagacta tggatcctat gatagcgatg ggaaaacaag acccatcatc accaaaattg 35820
gagcaggttt gaattttgat gctaataatg ccatggctgt gaagctaggc acaggtttaa 35880
gttttgactc tgccggtgcc ttaacagctg gaaacaaaga ggatgacaag ctaacacttt 35940
ggactacacc tgacccaagc cctaattgtc aattactttc agacagagat gccaaattta 36000
ccctatgtct tacaaaatgc ggtagtcaaa tactaggcac tgttgcagta gctgctgtta 36060
ctgtaggttc agcactaaat ccaattaatg acacagtaaa aagcgccata gtattcctta 36120
gatttgactc tgacggtgtg ctcatgtcaa actcatcaat ggtaggtgat tactggaact 36180
ttagggaagg acagaccacc caaagtgtgg cctatacaaa tgctgtggga ttcatgccca 36240
atctaggtgc atatcctaaa acccaaagca aaacaccaaa aaatagtata gtaagtcagg 36300
tatatttaaa tggagaaact actatgccaa tgacactgac aataactttc aatggcactg 36360
atgaaaaaga cacaacacct gtgagcactt actccatgac ttttacatgg cagtggactg 36420
gagactataa ggacaagaat attacctttg ctaccaactc ctttactttc tcctacatgg 36480
cccaagaata aaccctgcat gccaacccca ttgttcccac cactatggaa aactctgaag 36540
cagaaaaaaa taaagttcaa gtgttttatt gattcaacag ttttctcaca gaaccctagt 36600
attcaacctg ccacctccct cccaacacac agagtacaca gtcctttctc cccggctggc 36660
cttaaaaagc atcatatcat gggtaacaga catattctta ggtgttatat tccacacggt 36720
ttcctgtcga gccaaacgct catcagtgat attaataaac tccccgggca gctcacttaa 36780
gttcatgtcg ctgtccagct gctgagccac aggctgctgt ccaacttgcg gttgcttaac 36840
gggcggcgaa ggagaagtcc acgcctacat gggggtagag tcataatcgt gcatcaggat 36900
agggcggtgg tgctgcagca gcgcgcgaat aaactgctgc cgccgccgct ccgtcctgca 36960
ggaatacaac atggcagtgg tctcctcagc gatgattcgc accgcccgca gcataaggcg 37020
ccttgtcctc cgggcacagc agcgcaccct gatctcactt aaatcagcac agtaactgca 37080
gcacagcacc acaatattgt tcaaaatccc acagtgcaag gcgctgtatc caaagctcat 37140
ggcggggacc acagaaccca cgtggccatc ataccacaag cgcaggtaga ttaagtggcg 37200
acccctcata aacacgctgg acataaacat tacctctttt ggcatgttgt aattcaccac 37260
ctcccggtac catataaacc tctgattaaa catggcgcca tccaccacca tcctaaacca 37320
gctggccaaa acctgcccgc cggctataca ctgcagggaa ccgggactgg aacaatgaca 37380
gtggagagcc caggactcgt aaccatggat catcatgctc gtcatgatat caatgttggc 37440
acaacacagg cacacgtgca tacacttcct caggattaca agctcctccc gcgttagaac 37500
catatcccag ggaacaaccc attcctgaat cagcgtaaat cccacactgc agggaagacc 37560
tcgcacgtaa ctcacgttgt gcattgtcaa agtgttacat tcgggcagca gcggatgatc 37620
ctccagtatg gtagcgcggg tttctgtctc aaaaggaggt agacgatccc tactgtacgg 37680
agtgcgccga gacaaccgag atcgtgttgg tcgtagtgtc atgccaaatg gaacgccgga 37740
cgtagtcata tttcctgaag caaaaccagg tgcgggcgtg acaaacagat ctgcgtctcc 37800
ggtctcgccg cttagatcgc tctgtgtagt agttgtagta tatccactct ctcaaagcat 37860
ccaggcgccc cctggcttcg ggttctatgt aaactccttc atgcgccgct gccctgataa 37920
catccaccac cgcagaataa gccacaccca gccaacctac acattcgttc tgcgagtcac 37980
acacgggagg agcgggaaga gctggaagaa ccatgattaa ctttattcca aacggtctcg 38040
gagcacttca aaatgcaggt cccggaggtg gcacctctcg cccccactgt gttggtggaa 38100
aataacagcc aggtcaaagg tgacacggtt ctcgagatgt tccacggtgg cttccagcaa 38160
agcctccacg cgcacatcca gaaacaagag gacagcgaaa gcgggagcgt tttctaattc 38220
ctcaatcatc atattacact cctgcaccat ccccagataa ttttcatttt tccagccttg 38280
aatgattcgt attagttcct gaggtaaatc caagccagcc atgataaaaa gctcgcgcag 38340
agcgccctcc accggcattc ttaagcacac cctcataatt ccaagagatt ctgctcctgg 38400
ttcacctgca gcagattaac aatgggaata tcaaaatctc tgccgcgatc cctaagctcc 38460
tccctcaaca ataactgtat gtaatctttc atatcatctc cgaaattttt agccataggg 38520
ccgccaggaa taagagcagg gcaagccaca ttacagataa agcgaagtcc tccccagtgw 38580
gcattgccaa atgtaagatt gaaataagca tgctggctag accctgtgat atcttccaga 38640
taactggaca gaaaatcagg caagcaattt ttaagaaaat caacaaaaga aaagtcgtcc 38700
aggtgcaggt ttagagcctc aggaacaacg atggaataag tgcaaggagt gcgttccagc 38760
atggttagtg tttttttggt gatctgtaga acaaaaaata aacatgcaat attaaaccat 38820
gctagcctgg cgaacaggtg ggtaaatcac tctttccagc accaggcagg ctacggggtc 38880
tccggcgcga ccctcgtaga agctgtcgcc atgattgaaa agcatcaccg agagaccttc 38940
ccggtggccg gcatggatga ttcgagaaga agcatacact ccgggaacat tggcatccgt 39000
gagtgaaaaa aagcgaccta taaagcctcg gggcactaca atgctcaatc tcaattccag 39060
caaagccacc ccatgcggat ggagcacaaa attggcaggt gcgtaaaaaa tgtaattact 39120
cccctcctgc acaggcagca aagcccccgc tccctccaga aacacataca aagcctcagc 39180
gtccatagct taccgagcac ggcaggcgca agagtcagag aaaaggctga gctctaacct 39240
gactgcccgc tcctgtgctc aatatatagc cctaacctac actgacgtaa aggccaaagt 39300
ctaaaaatac ccgccaaaat gacacacacg cccagcacac gcccagaaac cggtgacaca 39360
ctcaaaaaaa tacgtgcgct tcctcaaacg cccaaaccgg cgtcatttcc gggttcccac 39420
gctacgtcac cgctcagcga ctttcaaatt ccgtcgaccg ttaaaaacgt cactcgcccc 39480
gcccctaacg gtcgcccttc tctcggccaa tcaccttcct cccttcccaa attcaaacgc 39540
ctcatttgca tattaacgcg cacaaaaagt ttgaggtata tatttgaatg atg 39593
<210> 26
<211> 675
<212> DNA
<213> 人工序列
<220>
<223> 载体ChAdOx1_P1A的多核苷酸构建体
<400> 26
atgagcgaca acaagaagcc cgacaaggcc cactctggca gcggcggaga tggcgacggc 60
aacagatgta acctgctgca cagatacagc ctggaagaga tcctgcccta cctgggctgg 120
ctggtgttcg ccgtcgtgac aacaagcttc ctggccctgc agatgttcat cgacgccctg 180
tacgaggaac agtacgagag ggacgtggcc tggatcgcca gacagagcaa gagaatgagc 240
agcgtggacg aggacgagga tgatgaggac gacgaagatg actactacga cgatgaggat 300
gacgacgacg acgccttcta cgatgacgag gacgatgaag aggaagaact ggaaaacctg 360
atggacgacg agtccgagga tgaggccgag gaagagatga gcgtggaaat gggcgctggc 420
gccgaagaga tgggagccgg cgctaactgt gcttgcgtgc caggacacca cctgagaaag 480
aacgaagtga agtgccggat gatctacttc ttccacgacc ccaactttct ggtgtccatc 540
cccgtgaacc ccaaagaaca gatggaatgc agatgcgaga acgccgacga agaggtggcc 600
atggaagaag aagaggaaga ggaagaagaa gaagaagagg aagaaatggg caaccccgac 660
ggcttcagcc cctga 675
<210> 27
<211> 224
<212> PRT
<213> 人工序列
<220>
<223> ChAdOx1_P1A的翻译蛋白
<400> 27
Met Ser Asp Asn Lys Lys Pro Asp Lys Ala His Ser Gly Ser Gly Gly
1 5 10 15
Asp Gly Asp Gly Asn Arg Cys Asn Leu Leu His Arg Tyr Ser Leu Glu
20 25 30
Glu Ile Leu Pro Tyr Leu Gly Trp Leu Val Phe Ala Val Val Thr Thr
35 40 45
Ser Phe Leu Ala Leu Gln Met Phe Ile Asp Ala Leu Tyr Glu Glu Gln
50 55 60
Tyr Glu Arg Asp Val Ala Trp Ile Ala Arg Gln Ser Lys Arg Met Ser
65 70 75 80
Ser Val Asp Glu Asp Glu Asp Asp Glu Asp Asp Glu Asp Asp Tyr Tyr
85 90 95
Asp Asp Glu Asp Asp Asp Asp Asp Ala Phe Tyr Asp Asp Glu Asp Asp
100 105 110
Glu Glu Glu Glu Leu Glu Asn Leu Met Asp Asp Glu Ser Glu Asp Glu
115 120 125
Ala Glu Glu Glu Met Ser Val Glu Met Gly Ala Gly Ala Glu Glu Met
130 135 140
Gly Ala Gly Ala Asn Cys Ala Cys Val Pro Gly His His Leu Arg Lys
145 150 155 160
Asn Glu Val Lys Cys Arg Met Ile Tyr Phe Phe His Asp Pro Asn Phe
165 170 175
Leu Val Ser Ile Pro Val Asn Pro Lys Glu Gln Met Glu Cys Arg Cys
180 185 190
Glu Asn Ala Asp Glu Glu Val Ala Met Glu Glu Glu Glu Glu Glu Glu
195 200 205
Glu Glu Glu Glu Glu Glu Glu Met Gly Asn Pro Asp Gly Phe Ser Pro
210 215 220
<210> 28
<211> 753
<212> DNA
<213> 人工序列
<220>
<223> 载体ChAdOx1_mIi_P1A的多核苷酸构建体
<400> 28
atgggcgctc tgtatactgg cgtgtccgtg ctggtggccc tgctgctggc tggacaggct 60
acaaccgcct acttcctgta cagcgacaac aagaagcccg acaaggccca ctctggcagc 120
ggcggagatg gcgacggcaa cagatgtaac ctgctgcaca gatacagcct ggaagagatc 180
ctgccctacc tgggctggct ggtgttcgcc gtcgtgacaa caagcttcct ggccctgcag 240
atgttcatcg acgccctgta cgaggaacag tacgagaggg acgtggcctg gatcgccaga 300
cagagcaaga gaatgagcag cgtggacgag gacgaggatg atgaggacga cgaagatgac 360
tactacgacg atgaggatga cgacgacgac gccttctacg atgacgagga cgatgaagag 420
gaagaactgg aaaacctgat ggacgacgag tccgaggatg aggccgagga agagatgagc 480
gtggaaatgg gcgctggcgc cgaagagatg ggagccggcg ctaactgtgc ttgcgtgcca 540
ggacaccacc tgagaaagaa cgaagtgaag tgccggatga tctacttctt ccacgacccc 600
aactttctgg tgtccatccc cgtgaacccc aaagaacaga tggaatgcag atgcgagaac 660
gccgacgaag aggtggccat ggaagaagaa gaggaagagg aagaagaaga agaagaggaa 720
gaaatgggca accccgacgg cttcagcccc tga 753
<210> 29
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> ChAdOx1_mIi_P1A翻译蛋白
<400> 29
Met Gly Ala Leu Tyr Thr Gly Val Ser Val Leu Val Ala Leu Leu Leu
1 5 10 15
Ala Gly Gln Ala Thr Thr Ala Tyr Phe Leu Tyr Ser Asp Asn Lys Lys
20 25 30
Pro Asp Lys Ala His Ser Gly Ser Gly Gly Asp Gly Asp Gly Asn Arg
35 40 45
Cys Asn Leu Leu His Arg Tyr Ser Leu Glu Glu Ile Leu Pro Tyr Leu
50 55 60
Gly Trp Leu Val Phe Ala Val Val Thr Thr Ser Phe Leu Ala Leu Gln
65 70 75 80
Met Phe Ile Asp Ala Leu Tyr Glu Glu Gln Tyr Glu Arg Asp Val Ala
85 90 95
Trp Ile Ala Arg Gln Ser Lys Arg Met Ser Ser Val Asp Glu Asp Glu
100 105 110
Asp Asp Glu Asp Asp Glu Asp Asp Tyr Tyr Asp Asp Glu Asp Asp Asp
115 120 125
Asp Asp Ala Phe Tyr Asp Asp Glu Asp Asp Glu Glu Glu Glu Leu Glu
130 135 140
Asn Leu Met Asp Asp Glu Ser Glu Asp Glu Ala Glu Glu Glu Met Ser
145 150 155 160
Val Glu Met Gly Ala Gly Ala Glu Glu Met Gly Ala Gly Ala Asn Cys
165 170 175
Ala Cys Val Pro Gly His His Leu Arg Lys Asn Glu Val Lys Cys Arg
180 185 190
Met Ile Tyr Phe Phe His Asp Pro Asn Phe Leu Val Ser Ile Pro Val
195 200 205
Asn Pro Lys Glu Gln Met Glu Cys Arg Cys Glu Asn Ala Asp Glu Glu
210 215 220
Val Ala Met Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu
225 230 235 240
Glu Met Gly Asn Pro Asp Gly Phe Ser Pro
245 250
<210> 30
<211> 675
<212> DNA
<213> 人工序列
<220>
<223> 载体MVA_P1A的多核苷酸构建体
<400> 30
atgagcgaca acaagaagcc cgacaaggcc cactctggca gcggcggaga tggcgacggc 60
aacagatgta acctgctgca cagatacagc ctggaagaga tcctgcccta cctgggctgg 120
ctggtgttcg ccgtcgtgac aacaagcttc ctggccctgc agatgttcat cgacgccctg 180
tacgaggaac agtacgagag ggacgtggcc tggatcgcca gacagagcaa gagaatgagc 240
agcgtggacg aggacgagga tgatgaggac gacgaagatg actactacga cgatgaggat 300
gacgacgacg acgccttcta cgatgacgag gacgatgaag aggaagaact ggaaaacctg 360
atggacgacg agtccgagga tgaggccgag gaagagatga gcgtggaaat gggcgctggc 420
gccgaagaga tgggagccgg cgctaactgt gcttgcgtgc caggacacca cctgagaaag 480
aacgaagtga agtgccggat gatctacttc ttccacgacc ccaactttct ggtgtccatc 540
cccgtgaacc ccaaagaaca gatggaatgc agatgcgaga acgccgacga agaggtggcc 600
atggaagaag aagaggaaga ggaagaagaa gaagaagagg aagaaatggg caaccccgac 660
ggcttcagcc cctga 675
<210> 31
<211> 224
<212> PRT
<213> 人工序列
<220>
<223> MVA_P1A的翻译蛋白
<400> 31
Met Ser Asp Asn Lys Lys Pro Asp Lys Ala His Ser Gly Ser Gly Gly
1 5 10 15
Asp Gly Asp Gly Asn Arg Cys Asn Leu Leu His Arg Tyr Ser Leu Glu
20 25 30
Glu Ile Leu Pro Tyr Leu Gly Trp Leu Val Phe Ala Val Val Thr Thr
35 40 45
Ser Phe Leu Ala Leu Gln Met Phe Ile Asp Ala Leu Tyr Glu Glu Gln
50 55 60
Tyr Glu Arg Asp Val Ala Trp Ile Ala Arg Gln Ser Lys Arg Met Ser
65 70 75 80
Ser Val Asp Glu Asp Glu Asp Asp Glu Asp Asp Glu Asp Asp Tyr Tyr
85 90 95
Asp Asp Glu Asp Asp Asp Asp Asp Ala Phe Tyr Asp Asp Glu Asp Asp
100 105 110
Glu Glu Glu Glu Leu Glu Asn Leu Met Asp Asp Glu Ser Glu Asp Glu
115 120 125
Ala Glu Glu Glu Met Ser Val Glu Met Gly Ala Gly Ala Glu Glu Met
130 135 140
Gly Ala Gly Ala Asn Cys Ala Cys Val Pro Gly His His Leu Arg Lys
145 150 155 160
Asn Glu Val Lys Cys Arg Met Ile Tyr Phe Phe His Asp Pro Asn Phe
165 170 175
Leu Val Ser Ile Pro Val Asn Pro Lys Glu Gln Met Glu Cys Arg Cys
180 185 190
Glu Asn Ala Asp Glu Glu Val Ala Met Glu Glu Glu Glu Glu Glu Glu
195 200 205
Glu Glu Glu Glu Glu Glu Glu Met Gly Asn Pro Asp Gly Phe Ser Pro
210 215 220
Claims (48)
1.一种将核酸分子衣壳化的黑猩猩腺病毒(ChAd)载体,所述核酸分子包含编码以下的多核苷酸序列:(i)MAGE癌抗原和/或NY-ESO-1癌抗原,或其免疫原性片段;或(ii)MAGE癌抗原和/或LAGE1癌抗原,或其免疫原性片段,所述多核苷酸序列可操作地连接至表达控制序列和腺病毒包装信号序列,所述表达控制序列指导所述癌抗原或其片段在动物细胞中的翻译、转录和/或表达。
2.根据权利要求1所述的ChAd载体,其中所述ChAd载体是(a)如WO2012/172277中所公开的ChAdOx1;优选由WO2012/172277中公开的SEQ ID NO:38的多核苷酸或与其具有至少80%同一性的序列所编码的;或(b)如WO2017/221031中所公开的ChAdOx2;优选由WO2017/221031中公开的SEQ ID NO:10的多核苷酸或与其具有至少80%同一性的序列所编码的。
3.一种将核酸分子衣壳化的改良的牛痘病毒安卡拉(MVA)载体,所述核酸分子包含编码以下的多核苷酸序列:(i)MAGE癌抗原和/或NY-ESO-1癌抗原,或其免疫原性片段;或(ii)MAGE癌抗原和/或LAGE1癌抗原,或其免疫原性片段,所述多核苷酸序列可操作地连接至表达控制序列,所述表达控制序列指导所述癌抗原或其片段在动物细胞中的翻译、转录和/或表达。
4.根据权利要求3所述的MVA载体,其中所述MVA载体是如WO2011/128704或EP2044947A1中所公开的。
5.根据权利要求1-4的任一项所述的ChAd或MVA载体,其中所述MAGE抗原是MAGE 3A,其具有SEQ ID NO:1的氨基酸序列或与其具有至少46%;优选至少69%;更优选至少95%的同一性的序列;或其任何免疫原性片段。
6.根据权利要求1-5的任一项所述的ChAd或MVA载体,其中所述NY-ESO-1癌抗原具有SEQ ID NO:3的氨基酸序列或与其具有至少75%;优选至少76.7%的同一性的序列;或其任何免疫原性片段。
7.根据权利要求1-5的任一项所述的ChAd或MVA载体,其中所述LAGE1癌抗原具有SEQID NO:5的氨基酸序列或与其具有至少78%;优选至少97%的同一性的序列;或其任何免疫原性片段。
8.根据任意一项前述权利要求所述的ChAd或MVA载体,其中所述多核苷酸序列还编码人类HLA II类组织相容性抗原γ链(li),其具有SEQ ID NO:6的氨基酸序列或与其具有至少79%的同一性的序列,或其片段,从而使所述癌抗原在动物细胞中作为与li或其片段的融合体来表达;优选地,其中所述片段是跨膜结构域;更优选地,其中所述跨膜结构域包含氨基酸残基30-55或30-61,甚至更优选地,其中所述跨膜结构域具有SEQ ID NO:7的氨基酸序列。
9.根据任意一项前述权利要求所述的ChAd或MVA载体,其中所述多核苷酸序列还编码tPA,所述tPA具有SEQ ID NO:8的氨基酸序列或与其具有至少81%的同一性的序列,或其片段;从而使癌抗原在动物细胞中作为与tPA或其片段的融合体来表达;优选地,其中所述片段包含21个氨基酸的前导序列;更优选地,其中所述21个氨基酸的前导序列是SEQ ID NO:9。
10.根据任意一项前述权利要求所述的ChAd载体,其中所述多核苷酸序列编码:(i)MAGE癌抗原或其免疫原性片段以及NY-ESO-1癌抗原或其免疫原性片段;或(ii)MAGE癌抗原或其免疫原性片段以及LAGE1癌抗原或其免疫原性片段,其在动物细胞中作为融合蛋白表达。
11.根据权利要求1-9中的任一项所述的MVA载体,其中所述多核苷酸序列编码:(i)MAGE癌抗原或其免疫原性片段和/或NY-ESO-1癌抗原或其免疫原性片段;或(ii)MAGE癌抗原或其免疫原性片段和/或LAGE1癌抗原或其免疫原性片段,其在动物细胞中作为融合蛋白表达,其中所述MAGE癌抗原、NY-ESO-1癌抗原或LAGE1癌抗原中的至少一种是片段。
12.根据权利要求11所述的MVA载体,其中所述MAGE癌抗原和NY-ESO-1或MAGE癌抗原和LAGE1是免疫原性片段。
13.根据权利要求10-12的任一项所述的ChAd或MVA载体,其中所述多核苷酸序列编码5-9个氨基酸的接头;其优选具有氨基酸序列GGGPGGG,当表达时,所述序列将MAGE和NY-ESO-1或LAGE1癌抗原或其片段以任何顺序连接,作为融合蛋白。
14.一种免疫原性组合物,其包含根据任意一项前述权利要求所述的ChAd或MVA载体。
15.根据权利要求14所述的组合物,其进一步包含佐剂。
16.一种分离的多核苷酸,其包含编码权利要求1-10或13中任一项所述的ChAd载体或权利要求3-9或11-13中任一项所述的MVA载体的序列。
17.根据权利要求16所述的分离的多核苷酸,其密码子被优化以用于人类密码子使用。
18.一种细菌人工染色体(BAC)克隆,其包含权利要求16或权利要求17所述的多核苷酸。
19.一种分离的宿主细胞,其包含如权利要求1-13的任一项所述的ChAd和/或MVA载体。
20.一种在个体中预防或治疗癌症的方法,所述方法包括施用有效量的如权利要求1-10或13的任一项所述的ChAd载体,和施用有效量的如权利要求3-9或11-13的任一项所述的MVA载体,由此个体的适应性免疫系统被刺激以提供抗癌免疫应答。
21.根据权利要求20所述的预防或治疗癌症的方法,其中所述ChAd和MVA载体的施用分开、循序或同时进行。
22.根据权利要求20或权利要求21所述的方法,所述方法进一步包括施用有效量的一种或多种检查点抑制剂。
23.根据权利要求20-22的任一项所述的方法,其中所述检查点抑制剂与所述ChAd和MVA载体同时、分开或并行施用。
24.根据权利要求20-23的任一项所述的方法,其中所述个体已经接受、正在接受或将要接受化学疗法和/或放射疗法治疗。
25.根据权利要求20-24的任一项所述的方法,其中首先施用所述ChAd载体。
26.根据权利要求20-25的任一项所述的方法,其中所述ChAd和MVA载体分别施用一次以上。
27.根据权利要求20-26的任一项所述的方法,其中所述ChAd和MVA载体交替施用。
28.根据权利要求20-27的任一项所述的方法,其中每次施用载体之间的时间段为5天至8周;优选为1周。
29.根据权利要求22-28的任一项所述的方法,其中所述检查点抑制剂阻断PD-1、CTLA-4或PD-L1。
30.根据权利要求22-28的任一项所述的方法,其中所述检查点抑制剂选自纳武利尤单抗、帕博利珠单抗、伊匹单抗、曲美利木单抗或阿替利珠单抗、度伐利尤单抗或阿维鲁单抗。
31.根据权利要求22-28的任一项所述的方法,其中所述癌症是非小细胞肺癌(NSCLC)、黑色素瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、泌尿道(尿道上皮)癌、膀胱癌、小细胞肺癌、肾癌、头颈癌、肉瘤或乳腺癌。
32.根据权利要求1、2、5-10或13的任一项所述的ChAd载体,其用于预防或治疗癌症。
33.根据权利要求3-9或11-13的任一项所述MVA载体,其用于预防或治疗癌症。
34.根据权利要求1、2、5-10或13的任一项所述的ChAd载体和权利要求3-9或11-13的任一项所述MVA载体,其用于分开、循序或同时向患者施用用于预防或治疗癌症。
35.根据权利要求34所述的用于预防或治疗癌症的ChAd和MVA载体,其进一步包括与所述ChAd和MVA载体一起施用的一种或多种检查点抑制剂,用于治疗癌症。
36.根据权利要求35所述的用于预防或治疗癌症的ChAd和MVA载体,其中所述检查点抑制剂与载体同时、分开或并行施用。
37.根据权利要求31-33的任一项所述的用于预防或治疗癌症的ChAd和MVA载体,其中所述患者已经接受、正在接受或将要接受化学疗法。
38.根据权利要求34-36的任一项所述的用于预防或治疗癌症的ChAd和MVA载体,其中首先施用所述ChAd载体。
39.根据权利要求34-38的任一项所述的用于预防或治疗癌症的ChAd和MVA载体,其中所述ChAd和MVA载体分别施用一次以上。
40.根据权利要求34-39的任一项所述的用于预防或治疗癌症的ChAd和MVA载体,其中ChAd和MVA载体交替施用。
41.根据权利要求34-40的任一项所述的用于预防或治疗癌症的ChAd和MVA载体,其中每次施用载体之间的时间段为5天至8周;优选为1周。
42.根据权利要求35-41的任一项所述的用于预防或治疗癌症的ChAd和MVA载体,其中所述检查点抑制剂阻断PD-1、CTLA-4或PD-L1。
43.根据权利要求35-41的任一项所述的用于预防或治疗癌症的ChAd和MVA载体,其中所述检查点抑制剂选自纳武利尤单抗、帕博利珠单抗、伊匹单抗、曲美利木单抗或阿替利珠单抗、度伐利尤单抗或阿维鲁单抗。
44.根据权利要求35-41的任一项所述的用于预防或治疗癌症的ChAd和MVA载体,其中所述癌症是非小细胞肺癌(NSCLC)、黑色素瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、泌尿道(尿道上皮)癌、膀胱癌、小细胞肺癌、肾癌、头颈癌、肉瘤或乳腺癌。
45.根据权利要求1、2、5-10或13的任一项所述的ChAd载体、权利要求3-9或11-13的任一项所述MVA载体、化学治疗剂以及检查点抑制剂,其用于分开、循序或同时向患者施用用于预防或治疗癌症。
46.根据权利要求45所述的ChAd载体、MVA载体、化学治疗剂以及检查点抑制剂,其中所述化学治疗剂选自(a)卡铂或顺铂以及(b)紫杉醇、多西他赛、长春瑞滨、吉西他滨、依托泊苷或培美曲塞。
47.根据权利要求45或权利要求46所述的ChAd载体、MVA载体、化学治疗剂以及检查点抑制剂,其中所述检查点抑制剂是PD-1。
48.根据权利要求45-47的任一项所述的ChAd载体、MVA载体、化学治疗剂以及检查点抑制剂,其中所述癌症选自非小细胞肺癌(NSCLC)或小细胞肺癌(SCLC)、黑色素瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、泌尿道(尿道上皮)癌、膀胱癌、小细胞肺癌、肾癌、头颈癌、肉瘤或乳腺癌。
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PCT/EP2019/070555 WO2020025642A1 (en) | 2018-08-03 | 2019-07-30 | Viral vectors encoding cancer/testis antigens for use in a method of prevention or treatment of cancer |
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WO2022099543A1 (zh) * | 2020-11-12 | 2022-05-19 | 深圳先进技术研究院 | Ny-eso-1基因抑制剂作为抗肿瘤化疗药物增敏剂的应用 |
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