CN101374853B - 用新型腺病毒治疗癌症的方法和组合物 - Google Patents
用新型腺病毒治疗癌症的方法和组合物 Download PDFInfo
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Abstract
本发明包括一种能有效杀死哺乳动物癌细胞的新型病毒。该病毒产生一种可将无毒性前体药物转化成有效的化疗药剂的新型蛋白。这些化疗药剂局部地产生并帮助病毒杀死癌细胞以及使癌细胞对辐射敏感。在临床前研究中已证明，无论单独使用，还是与药物前体治疗和/或放射治疗联合使用，所述病毒都能有效杀死各种哺乳动物癌细胞。本发明可提供一种能安全有效地治疗人类癌症的方法。
Description
相关申请的交叉引用
本申请是2004年7月9日提交的标题为“利用新型腺病毒治疗癌症的组合物和方法”的目前未决的序列号为10/888,492的美国专利申请的部分继续申请，序列号为10/888,492的专利申请要求2003年7月9日提交的美国临时申请60/486,219的优先权，这两篇专利文献均全文引入本文作为参考。
技术领域
概括而言，本发明涉及一种癌症治疗。具体而言，本发明涉及一种基于腺病毒的癌症治疗。
背景技术
在过去的60年中尽管诊断和治疗都有进步，但每年与癌症相关的死亡人数仍没有下降。常规癌症疗法(外科手术，放射疗法，化学疗法)对早期患者的治愈率较高，但许多癌症会复发且大部分晚期癌症患者最终还是死于该疾病。常规癌症疗法的局限性不在于它们不能消除肿瘤，而在于消除肿瘤的同时对患者造成过度损伤。正是这种顾虑限制了外科切除手术的使用范围、放射剂量和照射体积以及化疗药物的剂量和组合使用。若在肿瘤和正常组织之间的反应差异性没有明显提高(即：治疗指数)，则治疗效力的改进是没有临床价值的。
但是，治疗癌症的改进方法和新型药剂已提高了各种癌症患者的存活时间和存活率。例如，改进的手术的和放射疗法的程序可更有效地切除局部的肿瘤。然而，手术方法由于例如肿瘤的位置或转移肿瘤细胞的扩散而受到限制。放射疗法也受其它限制放射剂量的因素的限制。具有一定抗辐射性的肿瘤在此剂量下不能被治愈。
尽管单一的治疗方法如放射疗法，化学疗法，手术或免疫疗法可改善患者的病情，但组合使用这些方法可获得更好的效果。尤其是，可定向于含有肿瘤的局部区域的放射疗法和可提供全身治疗模式的化学疗法或免疫疗法的组合治疗对已发生或可能发生疾病扩散是有效的。不幸的是，放射疗法的治疗效力在肿瘤细胞具有一定抗辐射性时是受限的，因为剂量受到在辐射区域内正常组织的耐受力的限制。因而，需要使癌症肿瘤对放疗的作用敏感化以便能更有效地降低患者体内的肿瘤的严重性。另外，发展一种能更特异地隔离辐射区域的治疗是有效的，从而防止放射治疗对健康细胞的影响。
在有关方式中，为减少某些化学疗法的不需要的效应，使用腺病毒载体以所谓的“化疗基因”转化肿瘤细胞，所述“化疗基因”能将无毒性物质或“前体药物”转化成有毒的、有治疗效果的形式。正在考虑利用几种涉及基因治疗的新方法来改进癌症治疗的治疗指数。
这些方法之一为所谓的“自杀基因疗法”，该方法包括转运和表达非哺乳动物的基因，该基因编码的酶将无毒性前体药物转化成有毒的抗代谢药。目前正处于临床试验评价的两种“自杀基因”是大肠杆菌的胞嘧啶脱氨酶(CD)和I型单纯疱疹病毒的胸腺嘧啶核苷激酶(HSV-1TK)基因，它们分别赋予5-氟胞嘧啶(5-FC)和9-(1，3-二羟-2-丙氧甲基)鸟嘌呤(GCV)的敏感性。这些基因靶向转移至肿瘤后，前体药物5-FC和GCV被局部地转化成可导致大量肿瘤细胞死亡的有效化学治疗药剂(参见下面的参考文献部分的列表中的参考文献1(和它所引用的参考文献))。因而，减轻了与常规化学疗法相关的剂量限制性(dose-limiting)全身毒性。
之前，已将细菌CD和野生型HSV-1TK基因偶联以形成一种新型的CD/HSV-1TK融合基因(参见参考文献部分列表中的参考文献1)。CD/HSV-1TK融合基因可实现组合使用CD/5-FC和HSV-1TK/GCV自杀基因疗法。之前已证明CD/5-FC和HSV-1TK/GCV自杀基因疗法可使恶性肿瘤细胞对特定药剂敏感，重要的是使它们对辐射敏感(参见参考文献1-9)。使用一种含有原型CD/HSV-1TK融合基因(参考文献10)的新型的、溶瘤的和具有复制能力的腺病毒(Ad5-CD/TKrep)，在一些临床前癌症模型中(参考文献10-13)和最近在人前列腺癌患者(参考文献14和15)中已证明了具有复制能力的腺病毒介导的双自杀基因疗法不结合和结合放射疗法的安全性和疗效。
在这些以人前列腺癌为对象的临床试验中，当与长达三周的5-FC和GCV(vGCV)前体药物治疗结合，同时不结合(参考文献14)和结合(参考文献15)常规剂量(70Gy)的三维适形放射治疗(three dimensionalconformal radiation therapy，3DCRT)时，所述Ad5-CD/TKrep病毒的安全剂量高达1012病毒颗粒(Vp)。而且，这类治疗方案已表现出具有临床效果的迹象(参考文献14和15)。
但是，尽管有这些进步，仍强烈需要包括用于癌症治疗的有效方法和组合物的发明。鉴于这些和其它不足开发了本发明。
发明内容
本发明包括用于癌症治疗的、新型的和改进的方法和组合物，该方法和组合物包括一种能有效杀死哺乳动物癌细胞的新型病毒。该病毒产生一种可将无毒性前体药物转化成有效的化疗药剂的新型蛋白。这类化疗药剂局部地产生并帮助病毒杀死癌细胞以及使癌细胞对辐射敏感。临床前研究证明，无论单独使用，还是与前体药物疗法和/或放射治疗组合使用，所述病毒都能有效杀死各种人癌细胞。
本发明包括一种新型的、“第二代”腺病毒(设计为“Ad5-yCD/mutTKSR39rep-ADP”)，该病毒相对于之前已公开的原型Ad5-CD/Tkrep病毒具有至少两种重要改进。Ad5-yCD/mutTKSR39rep-ADP含有一种改进的yCD/mutTKSR39融合基因，该基因的产物可更有效地将5-FC和GCV前体药物转化成它们的活性化疗药剂。此外，Ad5-yCD/mutTKSR39rep-ADP表达Ad5ADP蛋白，该蛋白明显地提高了具有复制能力的腺病毒的溶瘤活性。相对于原型Ad5-CDITKrep病毒，Ad5-yCD/mutTKSR39rep-ADP已被证实在临床前癌症模型中有更高的病毒溶瘤和化学疗法的活性。数据表明了含有Ad5-yCD/mutTKSR39rep-ADP病毒的本发明在与5-FC和GCV前体药物治疗和放射疗法结合使用时表现出低毒性和明显的抗肿瘤活性。
在仔细研究以下的附图和详细描述后，本发明的其它方面对于本领域技术人员是显而易见的。
附图说明
现在将以举例的方式参照附图描述本发明，其中：
图1是本发明Ad5-yCD/mutTKSR39rep-ADP病毒的示意图。
图2是显示本发明ADP基因的优势的图。
图3A和3B是显示本发明的改进的yCD/mutTKSR39基因的优势的图。
图4是显示本发明ADP基因的优势的图。
图5是Ad5-yCD/mutTKSR39rep-ADP在前列腺内LNCaP C4-2小鼠模型中的开普莱-米耳(Kaplan-Meier)生存曲线图。
具体实施方式
概括而言，本发明包括用于治疗癌症的方法和组合物。具体而言，本发明提供了一种当给予前体药物时能杀死癌细胞并使残余的癌细胞对辐射更敏感的治疗方法。
本发明的实施方式包括一种能产生可将无毒性前体药物转化成化疗药剂的蛋白的新型病毒。前体药物可被局部地生成或与所述治疗联合被给药。优选地，病毒是一种溶瘤的并具有复制能力的病毒，例如但不限于Ad5-yCD/mutTKSR39rep-ADP。当被给予需要这种治疗的患者时，所述腺病毒将至少两种前体药物转化成化疗药剂。这些前体药物包括但不限于5-氟胞嘧啶(5-FC)和9-(1，3-二羟-2-丙氧甲基)鸟嘌呤(GCV及其衍生物)。
除了能将前体药物转化成化疗药剂之外，本发明的实施方式可使细胞对辐射敏感。通过敏化细胞，可采用更低剂量的辐射且不限制辐射的优势。而且，放射疗法会更有效，因为癌细胞对辐射更敏感，而正常细胞不会更敏感，所以减少了癌症治疗的副作用。本发明的疗法可与其它疗法如外科手术，化学疗法，激素疗法和免疫疗法联合使用。
在优选的实施方式中，本发明包括了一种新型的、溶瘤的和具有复制能力的腺病毒(Ad5-yCD/mutTKSR39rep-ADP)，该腺病毒含有酵母胞嘧啶脱氨酶(yCD)/突变的SR39I型单纯疱疹病毒的胸腺嘧啶核苷激酶(mutTKSR39)融合基因和5型腺病毒(Ad5)腺病毒死亡蛋白(ADP)基因。Ad5-yCD/mutTKSR39rep-ADP在人癌细胞中复制并有效杀死人癌细胞。Ad5-yCD/mutTKSR39rep-ADP可产生一种能将两种前体药物5-氟胞嘧啶(5-FC)和9-(1，3-二羟-2-丙氧甲基)鸟嘌呤(GCV和GCV衍生物)转化成有效的化疗药剂的yCD/mutTKSR39融合蛋白(是指双自杀基因疗法)。yCD/5-FC和HSV-1TKSR39自杀基因疗法都显示出有效的化疗活性并使肿瘤细胞对离子辐射敏感。
仅通过举例方式，临床前研究表明Ad5-yCD/mutTKSR39rep-ADP病毒单独地使用或与双自杀基因疗法和/或放射疗法联合使用时可有效杀死各种人癌细胞。在临床应用中，Ad5-yCD/mutTKSR39rep-ADP病毒可作为单一疗法获得它的病毒介导溶瘤效果，它可与yCD/5-FC和HSV-1 Ad5-TKSR39/GCV自杀基因疗法联合使用获得组合的病毒溶瘤/化疗效果，或它可与yCD/5-FC和HSV-1Ad5-TKSR39/GCV自杀基因疗法以及放射疗法联合使用(称为三模型疗法)获得组合的病毒溶瘤/化疗/射线敏感效果。在人的癌症治疗中，三模型疗法可与其它常规癌症疗法如外科手术，化学疗法，激素疗法和免疫疗法组合。
为进一步开发这种基于基因治疗的方法作为癌症疗法，开发了一种新型的第二代腺病毒(Ad5-yCD/mutTKSR39rep-ADP)，该腺病毒相对于原型Ad5-CD/Tkrep病毒具有至少两种重要改进。Ad5-yCD/mutTKSR39rep-ADP含有一种改进的yCD/mutTKSR39融合基因，该基因的产物可更有效地将5-FC和GCV前体药物转化成它们的活性化疗药剂。此外，Ad5-yCD/mutTKSR39rep-ADP表达Ad5ADP蛋白，该蛋白明显地提高了具有复制能力的腺病毒的溶瘤活性。相对于原型Ad5-CDITKrep病毒，Ad5-yCD/mutTKSR39rep-ADP已被证实在临床前癌症模型中有更高的病毒溶瘤和化学疗法的活性。
通过病毒感染导入本发明的核苷酸，提供了超过其它所列方法的多种优势。由于病毒感染的特性可获得更高的效率。而且，病毒高度特异化，并且一般感染特定的细胞类型并在特定的细胞类型中增殖。因而，在体内或组织中培养或细胞混合培养时，病毒的天然特异性可使载体靶向特定的细胞类型。还可根据特定受体或配体改进病毒载体以通过受体介导改变靶特异性。
还可在载体上添加附加特征以确保它的安全性和/或增强它的治疗效果，这类特征包括但不限于，例如，可用于负选择被重组病毒感染的细胞的标记。这种负选择标记的一个实例是上述的TK基因，该基因赋予对抗生素9-(1，3-二羟-2-丙氧甲基)鸟嘌呤的敏感性。因此负选择是一种控制感染的手段，因为可通过添加抗生素诱导其自杀。这种保护确保了如果例如发生了改变病毒载体或重组序列的突变，也不会发生细胞转化。
在一些实施方式中还包括限制特定细胞类型表达的特征。这类特征包括，例如，对所需要的细胞类型特异的启动子和调控元件。
此外，重组病毒载体可用于本发明核苷酸的体内表达，因为它们提供了如横向感染和靶向特异性的优势。横向感染是例如逆转录病毒的生命周期中所固有的，它是通过单个被感染细胞产生许多子代病毒颗粒，该病毒颗粒出芽逸出并感染邻近细胞。结果造成大面积迅速地被感染，而其中的大部分开始都不是被原始病毒颗粒所感染的。这与感染因子仅通过子体后代传播的竖向型感染相反。还可产生不能横向传播的病毒载体。这种特性对于期望将特定基因仅导入局部的一些靶细胞中是有用的。
如上所述，病毒是非常特异的感染因子，在很多情况下已进化为可瓦解宿主的防御机制。通常地，病毒感染特定的细胞类型并在这类细胞中增殖。病毒载体的靶向特异性利用了它的天然特异性以特异地靶向预定细胞类型，从而将重组基因导入被感染的细胞。本发明方法中所用的载体取决于所需的待靶向的细胞类型，本发明方法中所用的载体是本领域技术人员所公知的。例如，在治疗乳腺癌时采用对这类上皮细胞特异的载体。同样地，在治疗造血系统的疾病或病状时，采用对血细胞及它们的前体特异的病毒载体，优选对特定类型的造血细胞特异的病毒载体。
可通过多种方式给予重组载体。例如，所述方法可利用病毒载体的靶向特异性从而不需要在病变位点局部给药。但是，局部给药可提供更快速更有效的治疗。还可通过例如静脉或皮下注射受试者进行给药。注射之后，病毒载体将一直循环到以适当的感染靶特异性识别宿主细胞。
可替换的给药方式可以是通过直接局部接种到疾病或病状的位点，或接种到给上述部位供应营养的血管系统中。局部给药是有利的，因为不存在稀释效应，因此只需要更小剂量就可实现在大多数靶细胞中的表达。此外，局部接种可减轻其它给药形式所要求的靶向必要条件，因为可以采用感染被接种区域的所有细胞的载体。若需要仅在被接种区域的特定亚型的细胞中表达，则可采用对所需亚型的细胞特异的启动子和调控元件以实现该目标。这种非靶向载体可以是例如病毒载体、病毒基因组、质粒和噬菌粒等。还可采用转染载体如脂质体将上述的非病毒载体导入被接种区域的受体细胞中。这种转染载体是本领域技术人员公知的。
可按照良好的医疗操作，并考虑患者个体的临床症状，给药的位点和方法，给药时间安排，患者年龄，性别，体重和执业医生公知的其它因素来给予本发明化合物并确定其剂量。因而通过本领域公知的这些考虑因素来确定为了达到本发明治疗目的的药物“有效量”。该剂量必须能有效实现改善，所述改善包括但不限于改善存活率或更快速的恢复，或改善或消除症状和通过本领域技术人员以适当措施所选择的其它指标。
在本发明的实施方式中，本发明的化合物可通过多种方式给药。应该注意的是，本发明的化合物可作为化合物给药，并可单独或作为活性成分与药学可接受的载体，稀释剂，佐剂和媒介物组合给药。该化合物可经口服，皮下或肠胃外包括静脉内给药，动脉内给药，肌肉内给药，腹膜内给药，和鼻腔给药以及鞘内和灌注技术。也可采用化合物的埋植。受治患者是恒温动物尤其是包括人在内的哺乳动物。药学可接受的载体，稀释剂，佐剂和媒介物以及埋植载体通常是指不与本发明活性成分反应的、惰性的、无毒固体或液体填充剂，稀释剂或包封材料。
应该注意的是，治疗人的疗程一般长于本文中例举的小鼠或其它实验动物的疗程，其治疗时间的长度与疾病发展的程度和药物效力成比例。剂量可以是在几天的单剂量或多剂量。通常治疗时间的长度与疾病发展的程度和药物效力及受治患者的物种成比例。
以肠胃外的方式给予本发明化合物时，通常将本发明化合物制成单位剂量的可注射剂型(溶液剂，悬浮液剂，乳液剂)。适宜于注射的药物制剂包括灭菌水溶液或分散体和用于重制无菌注射液或分散体的灭菌粉末。载体可以是溶剂或分散介质，例如水、乙醇、多元醇(例如甘油、丙二醇、液态聚乙烯醇等)、它们的适当混合物、和植物油。
可通过例如采用包衣如卵磷脂，在分散体中维持所需颗粒大小和采用表面活性剂来保持适当的流动性。还可采用非水媒介物如棉籽油、芝麻油、橄榄油、大豆油、玉米油、葵花油，或花生油和酯如肉豆蔻酸异丙酯作为化合物组合物的溶剂体系。此外，还可添加提高组合物的稳定性、无菌性和等渗性的各种添加剂，包括抗微生物在内的防腐剂、抗氧化剂、螯合剂和缓冲液。通过各种抗细菌剂和抗真菌剂来确保抑制微生物的作用，例如对羟基甲苯酸酯、氯代丁醇、苯酚和山梨酸等。在许多情况下，还需要等渗剂，例如糖和氯化钠等。可通过使用延迟吸收剂实现可注射药物制剂的延长吸收，如单硬脂酸铝和明胶。根据本发明，所用的任何媒介物、稀释剂或添加剂必需与所述化合物相容。
可通过在所需量的适宜溶剂中将本发明操作中所采用的化合物与其它各种所需成分合并来制备无菌的可注射溶液。
本发明的药物制剂可通过含任何相容载体如各种媒介物、佐剂、添加剂和稀释剂的可注射制剂给予患者；或本发明中所用化合物可通过缓释的皮下埋植或靶向递送系统以肠胃外的形式给予患者，所述靶向递送系统如单克隆抗体、载体递送、离子渗透、聚合物基质、脂质体和微球体。许多其它的这类埋植、递送系统和模式都是本领域技术人员公知的。
在一个实施方式中，本发明化合物开始可通过静脉注射给药使血液中所述化合物的浓度到达适宜水平。然后通过口服剂型来维持患者体内的所述化合物的水平，但是可根据患者症状和以上说明采用其它给药形式。给药量随受治患者变化而变化。
定义
除非上下文特别说明或暗示，下列术语和短语的含义如下所述：
本文所用的术语“基因治疗”是指将感兴趣的遗传物质(如：DNA或RNA)转入宿主以治疗或预防遗传性或获得性疾病或症状表型。感兴趣的遗传物质编码一种产物(如蛋白质、多肽、肽，功能RNA和反义分子(antisense))，该产物是体内所需的。例如，感兴趣的遗传物质可编码一种具有治疗价值的激素、受体、酶、多肽或肽。感兴趣的遗传物质还可编码自杀基因。通常可参考教科书《基因疗法》(gene therapy)(Advances in Pharmacology 40，Academic Press，1997)。
术语“体内基因治疗”是指将待转移的遗传物质原位导入到受体生物的受体器官的靶细胞中。治疗之后，基因改变的靶细胞原位表达转染的遗传物质。若宿主基因有缺陷，这种治疗还包括原位修复基因。
术语“基因表达载体”是指任何能够将异源核苷酸递送/转移至宿主细胞内的载体。表达载体可包括控制靶向的元件，核苷酸以细胞选择的方式表达和转录是本领域公知的。应该注意的是基因的5′UTR和/或3′UTR可能被表达载体的5′UTR和/或3′UTR所取代。因此，如果需要，本文所用的表达载体可以不含有待转移的实际的基因的5’非翻译区(5′UTR)和/或3′UTR而仅含有特定的氨基酸编码区。表达载体可包括控制异源物质转录的启动子，以及可以是能进行选择性转录的组成型或诱导型启动子。可选择性地包括为了获得必要转录水平可能需要的增强子。增强子通常是任意的非翻译的DNA序列，该序列与编码序列(顺式)一起连续作用以改变由启动子所控制的基本转录水平。表达载体还可包括一个选择性基因。
实施例
1、Ad5-yCD/mutTKSR39rep-ADP腺病毒的说明
在以下参考文献部分列表中公开了Ad5-yCD/mutTKSR39rep-ADP腺病毒、yCD/mutTKSR39融合基因和ADP基因(SEQ ID NOs.1-5)的完整和部分DNA和翻译的蛋白质序列。将从这类序列的角度介绍以下实施例。
实施例中的Ad5-yCD/mutTKSR39rep-ADP病毒(序列NO：1)是具有复制能力的5型腺病毒(对于本领域技术人员而言，该病毒的序列是公知的且易于获得的)，该病毒的序列包括在E1区的改进yCD/mutTKSR39融合基因和在E3区的Ad5ADP基因。图1提供了Ad5-yCD/mutTKSR39rep-ADP的示意图(在图1中，“CMV”＝人类巨细胞病毒启动子；“SV40”＝猴病毒40多腺苷序列；和“mu”＝图谱单位。)如图1所示，CMV-yCD/mutTKSR39-SV40表达盒位于E1区，取代了缺失的55kDa E1B基因。CMV-ADP-SV40表达盒位于E3区，取代了缺失的E3基因。
Ad5-yCD/mutTKSR39rep-ADP在55kDa E1B基因中缺失了1255个碱基对(bp)(碱基2271-3524)(参见SEQ ID NO：2)。通过本领域技术人员公知的方法，两个翻译提前终止密码子(premature translation stop codon)被构建到55kDa E1B基因中，产生截短的、无功能的并具有78个氨基酸的E1B蛋白。Ad5-yCD/mutTKSR39rep-ADP表达野生型Ad5E1A和19kDa E1B蛋白。插入yCD/mutTKSR39融合基因(SEQ ID NO：4)以取代缺失的55kDa E1B基因。yCD/mutTKSR39融合基因的表达是由人类巨细胞病毒(CMV)启动子启动的，并利用了猴病毒40(SV40)多腺苷酸化元件。yCD/mutTKSR39融合基因编码一个59kDa yCD/mutTKSR39融合蛋白，该蛋白可以酶的方式将5-氟胞嘧啶(5-FC)转化成氟尿嘧啶(5-FU)并可将9-(1，3-二羟-2-丙氧甲基)鸟嘌呤(GCV)及其衍生物转化成它们相应的单磷酸盐(如GCV-MP)。5-FU和GCV-MP的下游代谢产物是有效的DNA复制的抑制因子并可使正在分裂的细胞死亡。这些下游代谢产物还是有效的辐射敏化剂，可显著地增强放射疗法的治疗效果(参考文献1-14)。表达yCD/mutTKSR39融合蛋白的细胞以及通过观者效应的邻近细胞被yCD/5-FC和HSV-1 TKSR39/GCV自杀基因疗法杀死，并对离子辐射的杀伤效应敏感。
Ad5-yCD/mutTKSR39rep-ADP还含有缺失了2.68kb(碱基28，133-30，181)的E3区，E3区影响抑制宿主免疫反应但不是病毒复制所必需的基因(参见SEQ ID NO：3)。Ad5-yCD/mutTKSR39rep-ADP含有Ad5ADP表达盒，该表达盒取代了天然的Ad5E3基因。ADP基因(SEQ ID NO：5)的表达是由人类巨细胞病毒(CMV)启动子启动的并利用了猴病毒40(SV40)多腺苷酸化元件。产生了一个真正的111.6kDa Ad5ADP蛋白，该蛋白可显著增强具有复制能力的腺病毒的溶瘤活性。Ad5-yCD/mutTKSR39rep-ADP缺乏所有其它已知的Ad5E3基因(gp19，10.4kDa，14.5kDa和14.7kDa基因)。
2、Ad5-yCD/mutTKSR39rep-ADP腺病毒的构建
用于构建Ad5-yCD/mutTKSR39rep-ADP的含有腺病毒序列的质粒从Microbix(多伦多，加拿大)获得。为了构建pCMV-yCD/mutTKSR39表达质粒(左端载体)，通过链式聚合酶反应(PCR)以线性化的pET23d：HSVTKSR39为模板扩增突变型的SR39 HSV-1 TK基因(参考文献16)。以下引物对用于产生mutTKSR39PCR产物。
5′-GATCGGATCCCTCGAGATC2CTAGCATGGCTTCGTACCCCGGC-3′(SEQ ID NO：8)
5′-GATCGAATTCTTCCGTGTTTCAGTTAGCCTC-3′(SEQ ID NO：9)
将得到的1128碱基对(bp)片段用BamHI(GGATCC)+EcoRI(GAATTC)消化，在已去除原型CD/HSV-1 TK融合基因的pCA14-CDglyTK-E1aE1b(参考文献10)的BamHI+EcoRI位点间克隆，产生pCA14-CMV-mutTKSR39-E1aE1b。通过PCR以线性化pBAD-ByCD为模板扩增酵母胞嘧啶脱氨酶基因(yCD)基因(参考文献17)。以下引物对用于产生yCD的PCR产物。
5′-GATCCTCGAGCCACCATGGTGACAGGGGGAATG-3′(SEQ ID NO：10)
5′-GATCGCTAGCACCTCCCCCACCGCCTCtCCCTCCACCCTCACCAATATCTTC-3′(SEQ ID NO：11)
将得到的526bp片段用XhoI(CTCGAG)+NheI(GCTAGC)消化，并在pCA14-CMV-mutTKSR39-E1aE1b的XhoI+NheI位点之间克隆，产生pCA14-CMV-yCD/mutTKSR39-E1aE1b。
为制备pBHG10-Paclmod-CMV-ADP(右端载体)，通过PCR扩增ADP基因，并将该基因在pBHG10-PacImod的PacI和SwaI位点之间克隆。pBHG10-PacImod是pBHG10(Microbix；Toronto，Canada)的衍生物，并在E3区含有PacI和SwaI位点以方便定向克隆。
pBHG10是一种质粒，该质粒包括不含E1区的188-1，339碱基和E3区的28，133-30，818碱基的整个5型腺病毒基因组。以野生型Ad5DNA为模板，产生含ADP基因的333bp的PCR产物。以下引物对用于产生ADP PCR产物。
5′-GATCGGATCCCCTGCTCCAGAGATGACCGGC-3’(SEQ ID NO：12)
5′-GATCAAGCTTGGAATCATGTCTCAMAATC-3′(SEQ ID NO：13)
将得到的333bp的片段PCR产物用BamHI(GGATCC)+HindIII(AAGCTT)消化，并克隆到用BamHI-HindIII消化的pCA14(Microbix；Toronto，Canada)中产生pCA14-ADP。通过PCR利用以下引物对产生完整的CMV-ADP-SV40polyA表达盒。
5′-GATCATTTAAATAATTCCCTGGCATTATGCCCAGTA-3′(SEQ ID NO：14)
5′-GATCTTAATTAATCGATGCTAGACGATCCAGACATG-3′(SEQ IDNO：15)
在引物5′端的CMV启动子的上游引入了SwaI限制性酶切位点(ATTTAAAT)，并且在引物3′端的SV40 poly A区的下游引入了PacI限制性酶切位点(TTAATTAA)。用SwaI和PacI消化PCR产物，并克隆到产生pBGH10-PacImod-CMV-ADP的经SwaI-PacI消化的pBGH10-PacImod。
为制备Ad5-yCD/mutTKSR39rep-ADP病毒，将pCA14-CMV-yCD/mutTKSR39-E1aE1b(10μg)通过PvuI消化而线性化，并将获得的产物与经ClaI线性化的pBHG10-PacImod-CMV-ADP(30μg)通过CaPO4-DNA沉淀法一起共转染至HEK 293细胞(Microbix)中。在7-14天后获得分离的噬斑，并在HEK 293细胞中第二次纯化噬斑。将来自于两次纯化噬斑的病毒用于感染HEK 293细胞以产生病毒粗悬浮物，然后经CsCl梯度纯化腺病毒。
3、含有ADP基因的Ad5-yCD/mutTKSR39rep-ADP在体外的优势
以5×104细胞/孔的浓度将人类DU145前列腺癌细胞种到24孔板中，用梯度浓度的Ad5-CD/TKrep(第1行)和Ad5-yCD/mutTKSR39rep-ADP病毒(第2行)进行感染。5天后，固定细胞并以结晶紫染色。结果(如图2所示，“Vp”＝病毒颗粒)清楚地表明了含有Ad5 ADP基因并表达ADP蛋白的具有复制能力的腺病毒(即Ad5-yCD/mutTKSR39rep-ADP)具有比缺乏ADP的腺病毒明显更高的溶瘤活性。换言之，Ad5 ADP基因的存在明显增强了具有复制能力的腺病毒的溶瘤活性。这些结果表明了含有ADP基因的Ad5-yCD/mutTKSR39rep-ADP在体外的优势。
4、含有yCD/mutTKSR39基因的Ad5-yCD/mutTKSR39rep-ADP在体外的优势
A、CD试验
LNCaP C4-2细胞被模拟感染(第1和5行)，或用感染复数(MOI)值为10的Ad5-CD/Tkrep(第2和6行)，Ad5-yCD/mutTKSR39rep-ADP(第3和7行)，Ad5-yCD/mutTKSR39rep-hNIS(第4和8行)进行感染。72小时后，以[14C]-胞嘧啶(第1-4行)和[3H]-5-FC(第4-8行)为底物检测细胞的CD活性。结果如图3A所示[(胞嘧啶(靠下的左箭头)、尿嘧啶(靠上的左箭头)、5-FC(靠上的右箭头)和5-FU(靠下的右箭头)]。如图3A所示，与表达包含在原型Ad5-CD/Tkrep病毒中的CD/HSV-1TK融合基因的病毒相比，表达改进yCD/mutTKSR39rep基因的重组腺病毒(如Ad5-yCD/mutTKSR39rep-ADP)表现出比更强的将5-FC转化成5-FU的能力，但不能将胞嘧啶转化成尿嘧啶。
B、细胞病理效应试验
将细胞(106细胞，在60mm培养皿)模拟感染或用MOI值为3的Ad5-CD/Tkrep或Ad5-yCD/mutTKSR39rep-ADP进行感染。第二天，将细胞重新种植到(24孔板)含多种浓度(μg/ml)的5-FC(第3-7和15-19孔，从左到右，从上到下)或GCV(第8-12和20-24孔，从左到右，从上到下)的培养液中。9天后用结晶紫染色细胞。结果(如图3B所示)证明：当与5-FC前体药物治疗组合使用时，与表达包含在原型Ad5-CD/Tkrep病毒中的CD/HSV-1TK融合基因的病毒相比，表达改进的yCD/mutTKrep基因的重组腺病毒(如Ad5-yCD/mutTKSR39rep-ADP)导致更多的细胞死亡。图3A和3B的结果一起显示了包含在Ad5-yCD/mutTKSR39rep-ADP中的yCD/mutTKSR39基因在体外的优势。
该实施例的结果还证明了yCD/5-FC和HSV-1 TKSR39/GCV自杀基因疗法可用于增强Ad5-yCD/mutTKSR39rep-ADP病毒本身的治疗效果。Ad5-yCD/mutTKSR39rep-ADP含有一种新型的yCD/mutTKSR39融合基因，该基因的产物与由原型Ad5-CD/Tkrep病毒产生的CD/HSV-1TK融合蛋白相比具有改进的催化活性。表达改进yCD/mutTKSR39融和蛋白的重组腺病毒表现出比表达原型CD/HSV-1TK融合蛋白的病毒更强的将5-FC转化成5-FU的能力，将GCV转化成GCV-MP的能力也可能增强。因而，可独立和联合使用yCD/5-FC和HSV-1TKSR39/GCV自杀基因疗法以增强Ad5-yCD/mutTKSR39rep-ADP病毒的肿瘤破坏效果。
5、含有ADP基因的Ad5-yCD/mutTKSR39rep-ADP在体内的优势
在第0、2和4天将1010vp的Ad5-CD/Tkrep或Ad5-CD/TKrep-ADP注射入肌肉内(腿)的C33A肿瘤(150-200mm3)(图4中的箭头)。在第5-11天给予5-FC(500毫克/千克/天)和GCV(30毫克/千克/天)(图4中的阴影条)。每隔一天监测肿瘤体积。预定终点是500mm3。存活定义为动物在第90天没有肿瘤(治愈)或肿瘤＜500mm3。结果(如图4和下表1所示)显示了在体内对肿瘤细胞的更强破坏，从而证明了含有ADP基因的Ad5-yCD/mutTKSR39rep-ADP的优势。换言之，Ad5ADP基因的存在明显增强了具有复制能力的腺病毒在体内或体外的溶瘤活性。
a半数存活时间按天数算。
bAd5-CD/TKrep-ADP对Ad5-CD/TKrep
cAd5-CD/TKrep-ADP+5-FC+GCV对Ad5-CD/TKrep+5-FC+GCV
6、Ad5-yCD/mutTKSR39rep-ADP在小鼠模型体内的效力
在第0天将约109vp的Ad5-yCD/mutTKSR39rep-ADP注射入患有前列腺内LNCaP C4-2肿瘤(大小为约25-50mm3)的雄性重症联合免疫缺陷(SCID)小鼠(图5中的箭头)。在第3-9天给予5-FC(500毫克/千克/天)和GCV(30毫克/千克/天)(图5中的阴影条)。每周测定血清中的前列腺特异性抗原(PSA)。预定终点是PSA＝500ng/ml。结果(如图5和下表2所示)显示了在小鼠模型中利用本发明的Ad5-yCD/mutTKSR39rep-ADP提高了半数存活时间和/或肿瘤治愈率。
aAd5-yCD/mutTKSR39rep-ADP对PBS；
bAd5-yCD/mutTKSR39rep-ADP+5-FC+GCV对PBS。
7.利用yCD/5-FC和HSV-1TKSR39/GCV使人类癌细胞对辐射敏感
如发明人之前的实验所示(参见参考文献1-14)，yCD/5-FC和HSV-1TKSR39/GCV自杀基因可用于使人类癌细胞对辐射敏感。Ad5-yCD/mutTKSR39rep-ADP含有一个新型的yCD/mutTKSR39融合基因，该基因的产物的催化活性与由原型Ad5-CD/Tkrep病毒产生的CD/HSV-1TK融合蛋白相比有所改进。之前的研究证明了CD/5-FC和HSV-1TKSR39/GCV自杀基因可使人类癌细胞对离子辐射敏感。因而，由于Ad5-yCD/mutTKSR39rep-ADP表达的是改进的yCD/mutTKSR39融合蛋白，它在体内可导致更强的癌细胞辐射敏化作用。
在整个本申请中，不同参考文献标注以不同的文献标号。下文提供了带有完整引用出处的参考文献列表。这些参考文献的全文被引入本申请作为参考以更充分地描述本发明所属领域的现状。
尽管通过前述的优选和可选择的实施方式和实施例详细展示和描述本发明时，本领域技术人员可以理解的是本文所描述的发明的实施方式的各种替换形式也可被用于实施本发明，且不偏离下列权利要求所定义的本发明的实质和范围。这就意味着由下列权利要求限定本发明的范围，并且所述权利要求书范围内的方法和组合物，以及与它们等同的方法和组合物都在权利要求书的保护范围之内。本发明的说明书应理解为包括本文所述的所有新颖的和非显而易见的元素的组合，该申请或后续申请的权利要求包括这类元素任何新颖和非显而易见的组合。前述的实施方式是例证性的，并且没有单个特征或元素对于本申请或后续申请所要求的所有可能的组合是必不可少的。对于使用了“一种”或“第一”其等效形式的权利要求，应理解为这些权利要求包括了一种或多种这类元素的组合，既不必需也不排除两种或多种这类元素。
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SEQ ID NO：6
Met Gly Thr Gly Gly Met Ala Ser Lys Trp Asp Gln Lys Gly Met Asp
1 5 10 15
Ile Ala Tyr Glu Glu Ala Ala Leu Gly Tyr Lys Glu Gly Gly Val Pro
20 25 30
Ile Gly Gly Cys Leu Ile Asn Asn Lys Asp Gly Ser Val Leu Gly Arg
35 40 45
Gly His Asn Met Arg Phe Gln Lys Gly Ser Ala Thr Leu His Gly Glu
50 55 60
Ile Ser Thr Leu Glu Asn Cys Gly Arg Leu Glu Gly Lys Val Tyr Lys
65 70 75 80
Asp Thr Thr Leu Tyr Thr Thr Leu Ser Pro Cys Asp Met Cys Thr Gly
85 90 95
Ala Ile Ile Met Tyr Gly Ile Pro Arg Cys Val Val Gly Glu Asn Val
100 105 110
Asn Phe Lys Ser Lys Gly Glu Lys Tyr Leu Gln Thr Arg Gly His Glu
115 120 125
Val Val Val Val Asp Asp Glu Arg Cys Lys Lys Ile Met Lys Gln Phe
130 135 140
Ile Asp Glu Arg Pro Gln Asp Trp Phe Glu Asp Ile Gly Glu Gly Gly
145 150 155 160
Gly Gly Gly Gly Gly Gly Gly Ala Ser Met Ala Ser Tyr Pro Cys His
165 170 175
Gln His Ala Ser Ala Phe Asp Gln Ala Ala Arg Ser Arg Gly His Ser
180 185 190
Asn Arg Arg Thr Ala Leu Arg Pro Arg Arg Gln Gln Glu Ala Thr Glu
195 200 205
Val Arg Leu Glu Gln Lys Met Pro Thr Leu Leu Arg Val Tyr Ile Asp
210 215 220
Gly Pro His Gly Met Gly Lys Thr Thr Thr Thr Gln Leu Leu Val Ala
225 230 235 240
Leu Gly Ser Arg Asp Asp Ile Val Tyr Val Pro Glu Pro Met Thr Tyr
245 250 255
Trp Gln Val Leu Gly Ala Ser Glu Thr Ile Ala Asn Ile Tyr Thr Thr
260 265 270
Gln His Arg Leu Asp Gln Gly Glu Ile Ser Ala Gly Asp Ala Ala Val
275 280 285
Val Met Thr Ser Ala Gln Ile Thr Met Gly Met Pro Tyr Ala Val Thr
290 295 300
Asp Ala Val Leu Ala Pro His Val Gly Gly Glu Ala Gly Ser Ser His
305 310 315 320
Ala Pro Pro Pro Ala Leu Thr Ile Phe Leu Asp Arg His Pro Ile Ala
325 330 335
Phe Met Leu Cys Tyr Pro Ala Ala Arg Tyr Leu Met Gly Ser Met Thr
340 345 350
Pro Gln Ala Val Leu Ala Phe Val Ala Leu Ile Pro Pro Thr Leu Pro
355 360 365
Gly Thr Asn Ile Val Leu Gly Ala Leu Pro Glu Asp Arg His Ile Asp
370 375 380
Arg Leu Ala Lys Arg Gln Arg Pro Gly Glu Arg Leu Asp Leu Ala Met
385 390 395 400
Leu Ala Ala Ile Arg Arg Val Tyr Gly Leu Leu Ala Asn Thr Val Arg
405 410 415
Tyr Leu Gln Gly Gly Gly Ser Trp Trp Glu Asp Trp Gly Gln Leu Ser
420 425 430
Gly Thr Ala Val Pro Pro Gln Gly Ala Glu Pro Gln Ser Asn Ala Gly
435 440 445
Pro Arg Pro His Ile Gly Asp Thr Leu Phe Thr Leu Phe Arg Ala Pro
450 455 460
Glu Leu Leu Ala Pro Asn Gly Asp Leu Tyr Asn Val Phe Ala Trp Ala
465 470 475 480
Leu Asp Val Leu Ala Lys Arg Leu Arg Pro Met His Val Phe Ile Leu
485 490 495
Asp Tyr Asp Gln Ser Pro Ala Gly Cys Arg Asp Ala Leu Leu Gln Leu
500 505 510
Thr Ser Gly Met Val Gln Thr His Val Thr Thr Pro Gly Ser Ile Pro
515 520 525
Thr Ile Cys Asp Leu Ala Arg Thr Phe Ala Arg Glu Met Gly Glu Ala
530 535 540
Asn
545
SEQ ID NO：7
Met Thr Gly Ser Thr Ile Ala Pro Thr Thr Asp Tyr Arg Asn Thr Thr
1 5 10 15
Ala Thr Gly Leu Thr Ser Ala Leu Asn Leu Pro Gln Val His Ala Phe
20 25 30
Val Asn Asp Trp Ala Ser Leu Asp Met Trp Trp Phe Ser Ile Ala Leu
35 40 45
Met Phe Val Cys Leu Ile Ile Met Trp Leu Ile Cys Cys Leu Lys Arg
50 55 60
Arg Arg Ala Arg Pro Pro Ile Tyr Arg Pro Ile Ile Val Leu Asn Pro
65 70 75 80
His Asn Glu Lys Ile His Arg Leu Asp Gly Leu Lys Pro Cys Ser Leu
85 90 95
Leu Leu Gln Tyr Asp
100
Claims (4)
1.一种含有酵母胞嘧啶脱氨酶/突变的SR39I型单纯疱疹病毒胸腺嘧啶核苷激酶融合基因的核苷酸序列的分离的多核苷酸，该分离的多核苷酸的核苷酸序列如SEQ ID NO：4所示。
2.一种重组腺病毒，该重组腺病毒包括分离的多核苷酸，该分离的多核苷酸由酵母胞嘧啶脱氨酶/突变的SR39I型单纯疱疹病毒胸腺嘧啶核苷激酶融合基因的核苷酸序列和5型腺病毒的腺病毒死亡蛋白基因组成，其中，所述5型腺病毒的腺病毒死亡蛋白基因的核苷酸序列如SEQ ID NO：5所示。
3.一种含有由分离的多核苷酸编码的氨基酸序列的分离的多肽，所述分离的多核苷酸含有酵母胞嘧啶脱氨酶/突变的SR39I型单纯疱疹病毒胸腺嘧啶核苷激酶融合基因的核苷酸序列，该分离的多肽能够将前体药物5氟胞嘧啶和9-(1，3-二羟-2-丙氧甲基)鸟嘌呤转化成活性化疗药剂，该分离的多肽的氨基酸序列如SEQ ID NO：6所示。
4.一种包括分离的多核苷酸的重组腺病毒，所述分离的多核苷酸含有酵母胞嘧啶脱氨酶/突变的SR 39I型单纯疱疹病毒胸腺嘧啶核苷激酶融合基因的核苷酸序列和5型腺病毒的腺病毒死亡蛋白基因，所述重组腺病毒的核苷酸序列如SEQ ID NO：1所示。
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| US11/342,719 US7815902B2 (en) | 2003-07-09 | 2006-01-30 | Methods and compositions for cancer therapy using a novel adenovirus |
| PCT/US2007/002682 WO2007087462A2 (en) | 2006-01-30 | 2007-01-30 | Methods and compositions for cancer therapy using a novel adenovirus |
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| US10130667B1 (en) * | 2013-01-28 | 2018-11-20 | Microvax, Llc | TAA/ecdCD40L oncolytic virus |
| JP2016519570A (ja) | 2013-03-14 | 2016-07-07 | エペイウス バイオテクノロジーズ コーポレイション | 改善されたチミジンキナーゼ遺伝子 |
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| US7589069B1 (en) | 1999-07-12 | 2009-09-15 | Saint Louis University | Replication-competent anti-cancer vectors |
| WO2005007109A2 (en) | 2003-07-09 | 2005-01-27 | Henry Ford Health System | Methods and compositions for cancer therapy using a novel adenovirus |
| US7815902B2 (en) * | 2003-07-09 | 2010-10-19 | Henry Ford Health System | Methods and compositions for cancer therapy using a novel adenovirus |
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| JP2009524435A (ja) | 2009-07-02 |
| CN101374853A (zh) | 2009-02-25 |
| WO2007087462A3 (en) | 2007-12-27 |
| WO2007087462A2 (en) | 2007-08-02 |
| US7815902B2 (en) | 2010-10-19 |
| KR20080090486A (ko) | 2008-10-08 |
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| US20110178282A1 (en) | 2011-07-21 |
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