CN101072792B - 设计用于在哺乳动物中进行抗肿瘤或抗病毒治疗的试剂盒 - Google Patents
设计用于在哺乳动物中进行抗肿瘤或抗病毒治疗的试剂盒 Download PDFInfo
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Abstract
本发明涉及一种包含编码通透酶的核酸序列和含有一个核碱基部分的药物或其前体的试剂盒。本发明还涉及包含含有编码通透酶的基因和包含自杀基因的核酸序列的药物前体的试剂盒。本发明还涉及包含编码通透酶的基因和自杀基因的载体。
Description
本发明涉及一种包含编码通透酶的核酸序列和含有一个核碱基(nucleobase)部分的药物或其前体的试剂盒。本发明还涉及一种包含药物前体的试剂盒,所述药物前体包含一个核碱基部分、包含编码通透酶的基因的核酸序列和包含自杀基因的核酸序列。本发明还涉及包含编码通透酶的基因和自杀基因的载体。本发明在进行增生性或感染性疾病的基因治疗处理方面尤其有用。
包含一个核碱基部分的药物是用于癌症或者病毒感染的治疗的最广泛使用的药物。其中,核苷类似物(例如阿糖胞苷、吉西他滨、氟达拉滨、克拉屈滨、曲沙他滨和克罗拉滨(clofarabine))目前被用于癌症化学疗法中。核苷类似物是阻碍核酸合成的抗代谢物。这些制剂通常是S阶段特异性的,并可以通过被掺入和改变DNA和RNA大分子本身,和/或通过抑制参与核酸合成的各种酶,和/或通过修饰生理性核苷的代谢发挥细胞毒性活性。
核苷类似物也属于被证明能有效地抗病毒感染的第一批化合物。例如,被批准的第一批四种抗HIV药物:AZT、ddI、ddC和D4T都是核苷类似物。这全部四种药物及其它核苷类似物被认为在HIV抑制上具有相似的机制,其中核苷被逐渐磷酸化为5′-三磷酸酯,然后在逆转录酶(RT)反应中用作链终止剂。
核碱基类似物也被用于癌症的治疗。例如氟尿嘧啶(5-FU)是一种氟化嘧啶,其在细胞内代谢为其活性形式氟脱氧尿苷单磷酸酯(FdUMP)。该活性形式通过抑制胸苷的正常产生从而抑制DNA的合成。氟尿嘧啶通过静脉给药治疗结肠癌、直肠癌、乳腺癌、胃癌和胰腺癌。氟尿嘧啶也可以乳剂和溶液的形式用于一些皮肤癌和生殖器疣的局部治疗。
基因治疗的发展为包含一个核碱基部分的药物的应用创造了新的可能。被称作“自杀基因治疗”的这一基因治疗的特定领域利用了其表达产物能将非活性物质(前体药物)转变为细胞毒性物质,从而引起细胞死亡的基因。
编码1型单纯疱疹病毒胸苷激酶(HSV-1TK)的基因构成了自杀基因的原型(Caruso et al.,1993,Proc.Natl.Acad.Sci.USA 90,7024-7028;Culver et al.,1992,Science 256,1550-1552;Ram et al.,1997,Nat.Med.3,1354-1361)。虽然TK多肽本身没有毒性,但其催化核苷类似物例如无环鸟苷或更昔洛韦(GCV)的转化。经修饰的核苷被掺入处于延伸过程的DNA链中,从而抑制细胞分裂。目前有大量可利用的自杀基因/前体药物组合。其中特别可提及的是:大肠杆菌(E.Coli)嘌呤核苷磷酸化酶和6-甲基嘌呤脱氧核糖核苷(Sorscher et al.,1994,Gene Therapy 1,223-238)、大肠杆菌鸟嘌呤磷酸核糖转移酶和6-硫代黄嘌呤(Mzoz and Moolten,1993,Human Gene Therapy 4,589-595)和胞嘧啶脱氨酶(CDase)和5-氟胞嘧啶(5FC)。
在人体中,将包含一个核碱基部分的药物转运通过细胞膜是被动的或是通过专门的膜转运蛋白进行的。例如,大多数核苷类似物是亲水性分子,并且其转运通过细胞膜是通过膜转运蛋白调节的。在哺乳动物细胞中,存在两个主要的核苷转运蛋白基因家族:平衡型核苷转运蛋白(ENT)和富集型核苷转运蛋白(CNT)。ENT是易化载体蛋白,CNT是Na(+)-依赖型次级主动转运蛋白(Kong et al.,2004,Curr Drug Metab,5:63-84)。核苷转运蛋白与对抗癌核苷类似物的抗性有关。药物转运蛋白中的单核苷酸多态性(SNP)可能是造成个体间对核苷类似物发生不同反应的原因(Damaraju et al.,Oncogene.2003,22:7524-36)。所以,需要一种可以克服核苷转运蛋白的低表达或不表达的新的治疗策略。此外,还需要提高包含一个核碱基部分的药物的胞内浓度,因其胞内浓度与疗效相关。
本发明的一个目的在于改善包含一个核碱基部分的药物进入细胞(例如肿瘤细胞或病毒感染的细胞)的胞内浓度。该目的通过用包含编码通透酶的基因的核酸序列转染靶细胞实现。
本发明的目的还在于通过联合使用包含编码通透酶的基因的核酸序列和包含自杀基因的核酸序列来改善自杀基因治疗的效果。这一特定的应用改善了前体药物(即包含一个核碱基部分的药物前体)的胞内浓度,该前体药物可被自杀基因编码的蛋白所转化。这一应用也可通过增强药物从自杀基因转染的细胞转移至表达通透酶的细胞而提高旁观者效应(bystander effect)。
就这方面而言,本发明也允许使用较小量的药物或前体药物,并减少由这种治疗所引起导致的副作用。
为了这个目的,本发明提供了包含如下组分的试剂盒:
-包含一个核碱基部分的药物或其前体,和
-包含编码通透酶基因的核酸序列。
根据另一个实施方式,本发明也提供了包含如下组分的试剂盒:
-包含一个核碱基部分的药物前体,和
-包含编码通透酶基因的核酸序列,和
-包含自杀基因的核酸序列。
在一个优选的实施方式中,本发明的试剂盒将被用于治疗脊椎动物尤其是人中的癌症和/或病毒性疾病。
如本申请中所用,包含一个核碱基部分的药物是在其结构中仅包含一个核碱基部分的分子。根据本发明的一个优选实施方式,包含一个核碱基部分的药物能够杀死细胞,更优选能够杀死肿瘤细胞。根据另一个优选实施方式,包含一个核碱基部分的药物能够减少或防止病毒在细胞中的复制。
根据本发明,核碱基部分选自腺嘌呤、胸腺嘧啶、鸟嘌呤、尿嘧啶、胞嘧啶及其类似物。
根据本发明的一个优选实施方式,包含一个核碱基部分的药物选自包含如下组分的组:
-核苷类似物,例如阿糖胞苷、吉西他滨、卡培他滨、氟达拉滨、克拉屈滨、曲沙他滨、克罗屈滨、叠氮胸苷(AZT)、2’,3’-双脱氧肌苷(ddI)、扎西他滨(ddC)、司他伏定(d4T)、脱氧氟亚甲基胞苷(FMdC)和拉米夫定、氟尿苷(FUdR),和
-嘧啶类似物,例如5-氟尿嘧啶(5-FU),和
-嘌呤类似物,例如硫鸟嘌呤、巯嘌呤、无环鸟苷、伐昔洛韦(valacyclovir)、泛昔洛韦(famcyclovir)、更昔洛韦。
如本申请中所用,包含一个核碱基部分的药物前体指能够通过一或多个酶促反应被转化为包含一个核碱基部分的药物的分子。
根据本发明的一个优选实施方式,包含一个核碱基部分的药物前体选自包含如下组分的组:叠氮胸苷(AZT)、更昔洛韦(GCV)、5-氟胞嘧啶(5-FC)、5-氟尿嘧啶(5-FU)、6-甲基嘌呤脱氧核糖核苷、更昔洛韦反油酸酯、喷昔洛韦、无环鸟苷、伐昔洛韦、(E)-5-(2-溴乙烯基)-2′-脱氧尿苷、齐多夫定、2′-Exo-methanocarbathymidine。
如本申请中所用,通透酶指参与将包含一个核碱基部分的药物或其前体转移通过细胞膜的跨膜蛋白。
根据本发明的通透酶特别地指嘌呤通透酶、胞嘧啶通透酶和核苷转运蛋白。
根据本发明的一个优选实施方式,通透酶是酿酒酵母(S.Cerevisiae)的嘌呤或胞嘧啶通透酶。酿酒酵母的核碱基转运蛋白由嘌呤-胞嘧啶通透酶(被称为“FCY2”)和尿嘧啶通透酶(被称为“FUR4”)组成。根据本发明的一个更优选的实施方式,所述通透酶具有选自SEQ ID NO:1和SEQ ID NO:2的氨基酸序列。
嘌呤-胞嘧啶通透酶(FCY2)介导质子以及腺嘌呤、鸟嘌呤、次黄嘌呤和胞嘧啶同向转运通过酵母质膜(Grenson 1969,Jund and Lacroute 1970,Polak and Grenson 1973,Chevallier et al.,1975,Hopkins et al.1988)。FCY2蛋白也介导5-氟胞嘧啶(一种胞嘧啶类似物)的转运(Grenson 1969,Jund and Lacroute 1970)。FCY2基因编码一种533个氨基酸的蛋白质(58kDa),其最初被预测具有10-12个跨膜结构域(Weber et al.1990),目前证实了9个(Ferreira et al.1999)。FCY2对嘌呤核碱基和胞嘧啶显示出相似的亲合力(Brethes et al.1992)。尿嘧啶进入酿酒酵母由尿嘧啶通透酶FUR4介导(Jund and Lacroute 1970,Jund et al.1977)。FUR4是一种尿嘧啶-质子同向转运蛋白(Hopkins et al.1988),其被预测为是一种633个氨基酸的蛋白质(71.7kDa),具有10个跨膜结构域和长胞质亲水性N末端及C末端尾部(Jund et al.1988,Garnier et al.1996)。FUR4蛋白还可以介导5-氟尿嘧啶(一种尿嘧啶类似物)的转运(Jund and Lacroute 1970)。
就这一方面,根据一个优选实施方式,所述通透酶选自FCY2、Fur4及其类似物。特别地,FCY2和Fur4的氨基酸序列可在swissprot数据库中获得(登录号分别为:P17064和P05316)。Fur4和FCY2的类似物指具有与母本蛋白(parent protein)的氨基酸序列的相同性至少大于70%,优选大于80%,更优选大于90%,最优选大于95%的氨基酸序列,并保留将包含一个核碱基部分的药物转运通过细胞膜的能力的多肽。
根据另一个优选实施方式,所述通透酶选自hENT1、hENT2、hCNT1、hCNT2和hCNT3及其类似物。这些通透酶的氨基酸序列对于本领域技术人员来说是可以获得的,特别是可在swissprot数据库中获得。这些多肽的类似物指具有与母本多肽的氨基酸序列的相同性至少大于70%,优选大于80%,更优选大于90%,最优选大于95%的氨基酸序列,并保留将包含一个核碱基部分的药物转运通过细胞膜的能力的多肽。
本领域技术人员能够选择与包含一个核碱基部分的药物或该药物前体相关的通透酶。例如,FCY2和Fur4优选与5-FC有关。
自杀基因指编码能够将包含一个核碱基部分的药物前体转化为包含一个核碱基部分的药物的基因。
自杀基因包含但不限于编码具有胞嘧啶脱氨酶活性、胸苷激酶活性、尿嘧啶磷酸核糖基转移酶活性、嘌呤核苷磷酸化酶活性和/或胸苷酸激酶活性的蛋白质的基因。
优选地,包含在本发明的试剂盒中的自杀基因编码能够转化包含在相同的试剂盒中的包含一个核碱基部分的药物前体的蛋白质。自杀基因和相应的包含一个核碱基部分的药物前体的例子如下表中所示:
自杀基因 | 包含一个核碱基部分的药物前体 |
胸苷激酶 | 更昔洛韦;更昔洛韦反油酸酯;喷昔洛韦;无环鸟苷;伐昔洛韦;(E)-5-(2-溴乙烯基)-2′-脱氧尿苷;齐多夫定;2′-Exo-methanocarbathymidine |
胞嘧啶脱氨酶 | 5-氟胞嘧啶 |
嘌呤核苷磷酸化酶 | 6-甲基嘌呤脱氧核糖核苷;氟达拉滨 |
尿嘧啶磷酸核糖基转移酶 | 5-氟胞嘧啶;5-氟尿嘧啶 |
胸苷酸激酶 | 叠氮胸苷 |
根据本发明的一个优选实施方式,本发明的自杀基因编码至少具有CDase活性的蛋白质。CDase参与嘧啶代谢途径,其通过水解脱氨作用将外源胞嘧啶转化为尿嘧啶。尽管已经在原核生物和低等真核生物中证实了CDase活性(Jund and Lacroute,1970,J.Bacterid.102,607-615;Beck etal.,1972,J.Bacteriol.110,219-228;De Haan et al.,1972,Antonie vanLeeuwenhoek 38,257-263;Hoeprich et al.,1974,J.Inf.Dis.130,112-118;Esders and Lynn,1985,J.Biol.Chem.260,3915-3922),但在哺乳动物中不存在CDase活性(Koechlin et al.,1966,Biochem Pharmacol.15,435-446;Polak et al.,1976,Chemotherapy 22,137-153)。酿酒酵母FCY1和大肠杆菌codA基因(分别编码这两种生物的CDase)是已知的,且它们的序列已被公开(EP 402108;Erbs et al.,1997,Curr Genet.31,1-6;WO93/01281)。
CDase也使胞嘧啶类似物,即5-氟胞嘧啶(5-FC)脱去氨基,从而形成5-氟尿嘧啶(5-FU),当其被转化为5-氟-尿苷酸(5-FUMP)时是一种具有很高的细胞毒性的化合物。缺乏CDase活性的细胞(或因为突变使编码该酶的基因失活或因为天然缺乏该酶),例如如哺乳动物细胞,对5-FC具有抗性(Jund and Lacroute,1970,J.Bacteriol,102,607-615;Kilstrup et al.,1989,J.Bacteriol.1989 171,2124-2127)。相反,其中转移进了编码Cdase活性的序列的哺乳动物细胞变得对5-FC敏感(Huber et al.,1993,Cancer Res.53,4619-4626;Mullen et al.,1992,Proc.Natl.Acad.Sci.USA 89,33-37;WO 93/01281)。此外,邻近的未转化细胞也变得对5-FC敏感(Huber et al.,1994,Proc.Natl.Acad.Sci.USA 91,8302-8306)。这一现象,称为旁观者效应,是由于表达CDase活性的细胞分泌5-FU,然后通过直接扩散通过质膜使邻近的细胞中毒。5-FU的这一被动扩散特性与tk/GCV参比系统相比较表现出了优点,在该参比系统中旁观者效应要求与表达tk的细胞相接触(Mesnil et al.,1996,Proc.Natl.Acad.Sci.USA 93,1831-1835)。因此,可以容易地了解CDase所提供的在基因治疗,特别是抗癌基因治疗范围内的所有优点。
就这一方面,根据本发明的一个更优选的实施方式,编码具有CDase活性的蛋白质的基因是FCY1或CodA或其类似物。这些基因的类似物指具有与母本基因(parent gene)的核酸序列的相同性至少大于70%,优选大于80%,更优选大于90%,最优选大于95%的核酸序列的基因。专利申请FR2004/001657公开了编码具有增强的CDase活性的蛋白质的基因。该多肽通过氨基酸序列的添加衍生自天然CDase。根据本发明的另一个优选实施方式,具有CDase活性的蛋白质是FR2004/001657中公开的多肽,更优选该多肽为FR2004/001657中的SEQ ID NO:1所示的序列。
在原核生物和低等真核生物中,尿嘧啶在尿嘧啶磷酸核糖基转移酶(UPRTase)的作用下被转化成UMP。该酶将5-FU转化为5-FUMP。根据另一个优选实施方式,根据本发明的自杀基因编码具有UPRTase活性的蛋白质。
本发明所述的UPRTase可以是任何来源的,尤其是原核生物、真菌或酵母来源的。举例证来说,编码来自大肠杆菌(Anderson et al.,1992,Eur.J.Biochem 204,51-56)、乳酸乳球菌(Lactococcus lactis)(Martinussen andHammer,1994,J.Bacteriol.176,6457-6463)、牛分枝杆菌(Mycobacteriumbovis)(Kim et al.,1997,Biochem Mol.Biol,Int 41,1117-1124)和枯草芽孢杆菌(Bacillus subtilis)(Martinussen et al.,1995,J.Bacteriol.177,271-274)的UPRTase的核酸序列可用于本发明。然而,最特别优选使用酵母UPRTase;特别是由酿酒酵母FUR1基因编码的UPRTase,该基因的序列在Kern et al(1990,Gene 88,149-157)中被公开,该文献通过引用并入本申请。例如,所述基因的序列以及相应的UPRTase的序列可从文献中以及专业数据库(SWISSPROT、EMBL、Genbank、Medline等)中找到。
此外,申请PCT/FR99/00904描述了一种在编码区的5′端缺失105个核苷酸的FUR1基因,其能够合成在N末端位置缺失35个最初的残基并在天然蛋白质的第36位以甲硫氨酸开始的UPRTase。突变基因的表达产物,命名为FUR1Δ105,能够与酿酒酵母的fur1突变株互补。此外,截短的突变株与天然酶相比呈现出更高的UPRTase活性。因此,根据一个特别优选的实施方式,根据本发明的由自杀基因编码的多肽是天然UPRTase的缺失突变体。缺失优选位于天然UPRTase的N末端区域。其可以是完全缺失(影响所述N末端区域的所有残基)或部分缺失(影响一级结构中的一或多个连续或不连续的残基)。通常,多肽由各自代表该分子大约三分之一的N末端部分、中间部分和C末端部分组成。例如,因为酿酒酵母的UPRTase具有251个氨基酸,其N末端部分由最初的83个残基组成,其以位于天然形式的第一位的所谓的起始子甲硫氨酸开始。至于大肠杆菌的UPRTase,其N末端部分覆盖了第1至69位。
优选的具有UPRTase活性的蛋白质包含基本上如PCT/FR99/00904的SEQ ID NO:1所示的氨基酸序列,其从第1位的Met残基开始,以第216位的Val残基结束。术语“基本上”指与PCT/FR99/00904的所述序列SEQ ID NO:1的相同性程度大于70%,优选大于80%,更优选大于90%,最优选大于95%。更优选地,其包含PCT/FR99/00904的SEQ IDNO:1所示的氨基酸序列。如上所述,其可以包含额外的突变。可特别提及的是,第2位(天然UPRTase的第37位)的丝氨酸残基被丙氨酸残基取代。
根据另一个优选实施方式,本发明的自杀基因编码具有至少一种Cdase和一种UPRTase活性的蛋白质。专利申请WO96/16183和PCT/FR99/00904描述了编码具有两个结构域的酶的融合蛋白的应用,所述结构域具有CDase和UPRTase活性,并证明由表达质粒携带的杂种基因codA::upp或FCY1::FUR1或FCY1::FUR1Δ105的转移提高了被转染的B16细胞对5-FC的敏感性。将这两个申请中所描述的蛋白质和核苷酸序列并入本申请的说明书中。
尽管融合可以发生在第一种多肽的任何位点,但是优选N-末端或C-末端,特别是N-末端。优选地,同相(in phase)融合使用具有胞嘧啶脱氨酶(CDase)活性并衍生自天然胞嘧啶脱氨酶的第二种多肽,以使根据本发明的融合多肽呈现CDase和UPRTase活性。优选FCY1::FUR1融合。这样的双功能多肽使得可以提高靶细胞对于5-FC和5-FU的敏感性。
使用原核或低等真核生物来源的CDase。更优选地,其为酵母CDase,特别是由酿酒酵母FCY1基因编码的CDase。在文献和专业数据库中提供了编码各种来源的CDase的基因的克隆和测序。需要提到的是FCY1基因的序列在Erbs et al(1997,Curr.Genet.31,1-6)中被公开。当然可使用具有相当于或高于天然酶的转化能力的CDase的突变体。
本领域技术人员能够根据公开的资料克隆CDase或UPRTase序列、实施可能的突变、根据现有技术或基于申请PCT/FR99/00904所述的方案检测非细胞系统或细胞系统中的突变形式的酶活性、以及融合(特别是同相融合)具有CDase和UPRTase活性的多肽,从而融合相应基因的全部或部分。
根据本发明的一个更优选的实施方式,自杀基因编码包含基本上如PCT/FR99/00904的SEQ ID NO:2所示的氨基酸序列的多肽,其从第1位的Met残基开始,并以第373位的Val残基结束。术语“基本上”具有以上给出的定义。包含如PCT/FR99/00904的SEQ ID NO:2所示的氨基酸序列的多肽尤其适于实施本发明。
在WO 96/16183中公开了另一个优选的被编码的多肽,更优选由coda::upp或FCY1::FUR1编码的多肽。
根据正在使用的传统方法,通过克隆、PCR或化学合成可以容易地获得核酸序列。它们可以是天然基因或来源于天然基因的经一或多个核苷酸的突变、缺失、取代和/或添加的基因。此外,在本领域技术人员可以查阅的文献中广泛地记载了其序列。
本发明还涉及如上所述的试剂盒,其特征在于所述核酸序列被插入质粒或病毒来源的一或多个重组载体中;以及携带位于其在寄主细胞中表达所必需的元件的控制下的所述核苷酸序列的重组载体。
更特别地,本发明的试剂盒可以包含所述包含编码通透酶的基因的核酸序列和所述包含被插入相同的重组载体或不同的重组载体中的自杀基因的核酸序列。根据本发明的一个优选的实施方式,所述核酸序列包含在相同的重组载体中。
本发明还涉及携带至少一种根据本发明的核苷酸序列的重组载体,所述核苷酸序列位于其在宿主细胞中表达所必需的元件的控制下。更特别地,本发明涉及包含编码通透酶的核酸序列的重组载体。
所述重组载体可以是质粒或病毒来源的,并可与一或多种提高该载体的转染效率和/或稳定性的物质适当地组合在一起。这些物质广泛地记载于本领域技术人员可获得的文献中(参见,例如,Feigner et al.,1987,Proc.West.Pharmacol.Soc.32,115-121;Hodgson and Solaiman,1996,Nature Biotechnology 14,339-342;Remy et al.,1994,BioconjugateChemistry,5,647-654)。作为非限制性举例说明,所述物质可以是聚合物、脂质(特别是阳离子脂质)、脂质体、核蛋白或中性脂脂。这些物质可以单独使用或组合使用。可以预期的组合有与阳离子脂质(DOGS、DC-CHOL、精胺-胆固醇、亚精胺-胆固醇等)、溶血磷脂(例如:十六烷基磷酸胆碱)和中性脂质(DOPE)组合的重组质粒载体。
根据本发明的一个优选实施方式,可用于本发明的阳离子脂质是在EP901463B1中描述的阳离子脂质,更优选是pcTG90。
可用于本发明范围内的质粒的选择是巨大的。其可以是克隆载体和/或表达载体。一般而言,它们是本领域技术人员所已知的,同时其中大部分可商购获得,也可以利用遗传操纵的技术对它们进行构建或修饰。可提到的例子有衍生自pBR322(Gibco BRL)、pUC(Gibco BRL)、pBluescript(Stratagene)、pREP4、pCEP4(Invitrogene)或pPoly(Lathe et al.,1987,Gene 57,193-201)的质粒。优选地,用于本发明的范围的质粒含有确保复制在生产细胞和/或宿主细胞中起始的复制原点(例如,将选择ColEI起点用于欲在大肠杆菌中生产的质粒;如果希望质粒能在哺乳动物宿主细胞中自我复制,则选择oriP/EBNA1系统,Lupton and Levine,1985,Mol.Cell.Biol.5,2533-2542;Yates et al.,Nature 313,812-815)。所述质粒可以额外地包含使转染细胞被选择或被识别的选择基因(营养突变体的互补基因、编码抗生素抗性的基因等)。当然,所述质粒可包含改善其在给定细胞中的维持和/或稳定性的其它元件(促进质粒以单体形式维持的cer序列(Summers and Sherrat,1984,Cell 36,1097-1103,sequences forintegration into cell genome))。
对于病毒载体,可预期衍生自痘病毒(痘苗病毒,特别是MVA、金丝雀痘病毒等)、腺病毒、逆转录病毒、疱疹病毒、甲病毒(aiphavirus)、泡沫病毒或腺病毒相关病毒的载体。可使用可复制或复制缺陷型病毒载体。优选使用不完整的载体。在这方面,腺病毒载体和MVA尤其适于实施本发明。
根据本发明的一个优选实施方式,本发明的病毒载体衍生自修饰的痘苗病毒安卡拉株(MVA)。欧洲专利EP83286和EP206920以及Mayr etal.(1975,Infection 3,6-14)和Sutter et Moss(1992,Proc.Natl.Acad.Sci.USA 89,10847-10851)完整地描述了MVA载体和生产这种载体的方法。根据更优选的实施方式,可以将本发明的核苷酸序列插入MVA载体的缺失体I、II、III、IV、V和VI中,更优选插入缺失体III中(Meyer et al.,1991,J.Gen.Virol.72,1031-1038;Sutter et al.,1994,Vaccine 12,1032-1040)。
逆转录病毒具有感染并在大多数情况下整合到分裂细胞中的特性,这方面对于癌症尤其适用。根据本发明的重组逆转录病毒通常含有LTR序列、壳体化区域(encapsidation region)和根据本发明的核苷酸序列,该核苷酸序列位于逆转录病毒LTR或内部启动子例如以下所述的那些启动子的控制下。所述重组逆转录病毒可衍生自任何来源的逆转录病毒(鼠、灵长类、猫、人类等),特别是衍生自M0MuLV(莫洛尼鼠类白血病毒)、MVS(鼠肉瘤病毒)或弗罗德鼠逆转录病毒(Fb29)。其在壳体化细胞系(encapsidation cell line)中进行增殖,所述细胞系能够反式提供组成病毒颗粒所需的病毒多肽gag、pol和/或env。在文献中描述了这样的细胞系(PA317、Psi CRIP GP+Am-12等)。根据本发明的逆转录病毒载体可含有修饰,特别是在LTR(用真核启动子置换启动子区域)或壳体化区域(用异源壳体化区域,例如VL3O型,进行置换)(参见法国专利申请9408300和9705203)。
也优选使用缺失复制所必需的至少一个区域的全部或部分的腺病毒载体以避免所述载体在宿主生物体或环境中扩增,所述区域选自E1、E2、E4和L1-L5区。优选缺失E1区。但是,其可与(一或多种)其它的修饰/缺失相结合,特别是影响E2、E4和/或L1-L5区的全部或部分的修饰/缺失从而使有缺陷的必需功能通过互补细胞系和/或辅助病毒得以反式互补。在这方面,可以使用现有技术中的第二代载体(参见,例如,国际申请WO-A-94/28152和WO-A-97/04119)。举例来说,尤其优选E1区和E4转录单元的主要部分的缺失。为了提高克隆能力,所述腺病毒载体可额外缺失全部或部分的非必需的E3区。根据另一个替代的实施方式,可以利用保留了壳体化所必需的序列(即5′和3′ITR(末端反向重复序列)和壳体化区域的最小腺病毒载体。已知各种腺病毒载体和它们的制备方法(参见,例如,Graham and Prevect,1991,in Methods in Molecular Biology,Vol 7,p109-128;Ed:E.J.Murey,The Human Press mc)。
此外,根据本发明的腺病毒载体的来源可根据物种和血清型改变。所述载体可衍生自人类或动物(犬、禽、牛、鼠、羊、猪、猿等)来源的腺病毒的基因组,或衍生自包含至少两种不同来源的腺病毒基因组片段的杂种。更特别提到的可以是由犬类来源的CAV-1或CAV-2腺病毒、禽类来源的DAV腺病毒或来源于牛的Bad 3型腺病毒构成的腺病毒载体(Zakharchuk et al.,Arch.Virol.,1993,128:171-176;Spibey and Cavanagh,J.Gen.Virol.1989,70:165-172;Jouvenne et al.,Gene,1987,60:21-28;Mittalet al.,J.Gen.Virol.,1995,76:93-102)。但是,优选人类来源的腺病毒载体,其优选衍生自血清型C腺病毒,特别是2型或5型的血清型C腺病毒。
本申请中所用术语“可复制的”指在没有任何反式互补的情况下能在宿主细胞中复制的病毒载体。在本发明中,该术语还包括选择复制型或条件复制型腺病毒载体,其被加工以在癌症或过度增殖的宿主细胞中更好地或选择性地进行复制。
根据本发明的一个优选的实施方式,所述可复制的载体是可复制的腺病毒载体。这些可复制的腺病毒载体是本领域技术人员所熟知的。其中,特别优选在编码55kD P53抑制剂的E1b区有缺失的腺病毒载体,如在ONYX-015病毒中缺失E1b区(Bischoff et al.,1996;Heise et al.,2000;WO 94/18992)。因此,该病毒可用于选择性地感染和杀死p53缺陷型新生细胞。本领域普通技术人员还可以根据已建立的技术对腺病毒5或其它病毒中的p53抑制基因进行突变和破坏。在E1A Rb结合区有缺失的腺病毒载体也可以用于本发明,例如,在E1A区具有24个碱基对缺失的突变腺病毒Δ24病毒(Fueyo et al.,2000)。Δ24在Rb结合区具有缺失,且不与Rb结合。因此,在正常细胞中突变病毒的复制被Rb抑制。然而,如果Rb被失活且细胞发生肿瘤性转化,则Δ24不再被抑制。相反,突变病毒高效地进行复制,并裂解Rb缺陷型细胞。
根据本发明的腺病毒载体可以在体外在大肠杆菌(E.coli)中通过连接或同源重组产生(参见,例如,国际申请WO-A-96/17070),或在互补细胞系中通过重组产生。
表达所需的元件由使核苷酸序列转录成RNA以及使mRNA被翻译成多肽的全部元件组成。特别地,这些元件包括调控型或组成型启动子。当然,该启动子要适于所选择的载体和宿主细胞。可提及的实例有PGK(磷酸甘油酸激酶)、MT(金属硫蛋白;Mclvor et al.,1987,Mol.Cell Biol.7,838-848)、α-1抗胰蛋白酶、CFTR、表面活性剂、免疫球蛋白、β-肌动蛋白(Tabin et al.,1982,Mol.Cell Biol.2,426-436)和Sra(Takebe et al.,1988,Mol.Cell Biol.8,466-472)等基因的真核启动子,SV40病毒(猿病毒)早期启动子,RSV(劳斯肉瘤病毒)的LTR,HSV-I TK启动子,CMV病毒(巨细胞病毒)早期启动子,痘苗病毒的p7.5K pH5R、pK1L、p28和p11启动子,以及E1A和MLP腺病毒启动子。该启动子还可以是在肿瘤或癌细胞中刺激表达的启动子。所述启动子还可以是刺激肿瘤或癌细胞中的表达的启动子。可特别提到以下基因的启动子:MUC-I基因,其在乳腺癌和前列腺癌中过表达(Chen et al.,1995,J.Clin.Invest.96,2775-2782);CEA(代表癌胚抗原)基因,其在结肠癌中过表达(Schrewe et al.,1990,Mol.Cell.Biol.10,2738-2748);酪氨酸酶基因,其在黑素瘤中过表达(Vileet al.,1993,Cancer Res.53,3860-3864);ERBB-2基因,其在乳腺癌和胰腺癌中过表达(Harris et al.,1994,Gene Therapy 1,170-175)和α-胎蛋白基因,其在肝癌中过表达(Kanai et al.,1997,Cancer Res.57,461-465)。尤其优选巨细胞病毒(CMV)早期启动子。
但是,当使用衍生自痘苗病毒的载体(例如MVA载体)时,尤其优选胸苷激酶7.5K基因的启动子。
必需的元件还可包括增加根据本发明的核苷酸序列在宿主细胞中的表达或维持的额外元件。可特别提及的有内含子序列、分泌信号序列、核定位序列、IRES型翻译再起始的内部位点、转录终止polyA序列、三联前导序列和复制起点。这些元件是本领域技术人员已知的。
根据本发明的重组载体还可以包含一或多个感兴趣的额外基因,这些基因可处于相同调控元件(多顺反子盒)或独立元件的控制下。可特别提及的基因有编码白细胞介素IL-2、IL-4、IL-7、IL-10和IL-12,干扰素,肿瘤坏死因子(TNF),集落刺激因子(CSF)、特别是GM-CSF,以及影响血管发生的因子(例如PAI-1,代表纤溶酶原激活物抑制剂)。在一个特定的实施方式中,根据本发明的重组载体包含编码IL-2或编码干扰素γ(INFγ)的感兴趣的基因。也可以预期将根据本发明的核苷酸序列与其它自杀基因例如HSV-1TK基因、蓖麻毒蛋白基因、霍乱毒素基因等结合起来。
本发明还涉及包含根据本发明的重组载体的病毒颗粒。可以利用本领域中的任何常规技术从病毒载体产生这样的病毒颗粒。将病毒颗粒在互补细胞中增殖,所述互补细胞与载体的缺陷相适应。对于腺病毒载体,将使用例如由293细胞系,其使用人胚肾细胞建立并有效地互补E1功能(Graham et al.,1977,J.Gen.Virol.36,59-72);A549-E1细胞系(Imler et al.,1996,Gene Therapy 3,75-84)或允许双重互补的细胞系(Yeh et al.,1996,J.Virol.70,559-565;Krougliak and Graham,1995,Human Gene Therapy 6,1575-1586;Wang et al.,1995 Gene Therapy 2,775-783;国际申请WO97/04119)组成的互补细胞。也可使用辅助病毒以至少部分互补有缺陷的功能。互补细胞被认为是能够反式提供早期和/或晚期因子的细胞,所述因子是使病毒基因组在病毒壳体中壳体化以产生含有所述重组载体的病毒颗粒所必需的。所述细胞自身不能互补载体全部有缺陷的功能,在这种情况下可用提供额外功能的载体/辅助病毒对其进行转染/转导。
本发明还涉及制备病毒颗粒的方法,其中:
(i)将根据本发明的重组载体导入互补细胞,所述互补细胞能够反式互补所述载体,以获得转染的互补细胞,
(ii)将所述转染的互补细胞在适于产生所述病毒颗粒的条件下进行培养,以及
(iii)从细胞培养物回收所述病毒颗粒。
病毒颗粒当然可从培养物上清液回收,其还可以从细胞回收。一种通常使用的方法是通过连续的冻/融循环裂解细胞以便在裂解上清液中收集病毒体。然后可以对病毒体进行扩增和利用现有技术(层析法、超速离心法(特别是通过氯化铯梯度超速离心)等)进行纯化。
本发明还涉及包含根据本发明的试剂盒、重组载体或病毒颗粒以及药学上可接受的赋形剂的组合物。
更具体地,根据本发明的试剂盒是针对通过基因治疗预防性地或治疗性地治疗疾病,更特别地是针对增殖性疾病(癌症、肿瘤、再狭窄等);以及感染性疾病,特别是病毒性疾病(由乙型肝炎病毒或丙型肝炎病毒、HIV、疱疹、逆转录病毒等引起的疾病)。
可以局部、肠胃外或通过消化道施用为目的常规制备根据本发明的试剂盒。特别地,将治疗有效量的治疗性或预防性制剂与药学上可接受的赋形剂相组合。可预期大量的施用途径。可提及的实例有胃内、皮下、心内、肌内、静脉内、腹膜内、肿瘤内、鼻内、肺内和气管内施用的途径。在后面的三个实施方式中,优选通过气雾剂或通过滴注进行施用。可以以单剂量或特定时间间隔之后的一或多次重复的剂量的形式进行施用。施用的适当途径和剂量根据多种参数(例如个体、待治疗的疾病或待转移的感兴趣的基因)而不同。基于本发明的病毒颗粒的制剂可以配制成介于104到1014pfu(空斑形成单位)之间的剂量形式,优选105到1013pfu,优选106到1012pfu,当使用腺病毒颗粒时更优选109到1010pfu,当使用MVA颗粒时更优选106到107pfu。就本发明的重组载体而言,可预期的剂量包含从0.01到100mg的DNA,优选从0.05到10mg,尤其优选从0.5到5mg。
该配制品还可以包括药学上可接受的稀释剂、辅剂或赋形剂,以及增溶剂、稳定剂和保存剂。对于注射施用的情况,优选用水性、非水性或等渗溶液形式的配制品。其可以以单剂量或多剂量、液体形式或可在使用时利用适当的稀释剂重建的固体(粉末、冻干物等)形式存在。所述配制品还可以包含适当量的前体药物。
本发明还涉及根据本发明的试剂盒、重组载体或病毒颗粒在制备用于通过基因治疗治疗人体或动物体的药物中的治疗性或预防性应用。根据第一个可能性,该药物可直接进行体内施用(例如通过静脉注射进入的易接近的肿瘤内、通过气雾剂进入肺、利用适当的导管进入血管系统等)。也可采用离体方法,包括将细胞从患者体内移出(骨髓干细胞、外周血淋巴细胞、肌细胞等),根据现有技术在体外对其进行转染或感染,然后将其重新施用给所述患者。优选的应用是治疗或预防癌症、肿瘤和由不需要的细胞增殖所引起的疾病。可提及的可预期的应用是治疗或预防乳腺癌、子宫癌(特别是由乳头瘤病毒诱导的子宫癌)、前列腺癌、肺癌、膀胱癌、肝癌、结肠癌、胰腺癌、胃癌、食管癌、喉癌、中枢神经系统癌(例如成胶质细胞瘤)和血癌(淋巴瘤、白血病等)。它还可以用于心血管疾病范围,例如为了抑制或延缓血管壁的平滑肌细胞的增殖(再狭窄)。最后,就感染性疾病而言,可预期到用于AIDS的药物。
本发明还提供了通过基因治疗用于治疗疾病的方法,其特征在于:将根据本发明的试剂盒、重组载体、病毒颗粒或宿主细胞施用给需要此类治疗的宿主生物体或细胞。
包含一个核碱基部分的药物或其前体可根据常规方法(例如经口,全身性)施用。举例来说,对于5-FU,可使用从50到500mg/kg/天的剂量,优选使用200mg/kg/天的剂量。在本发明的范围内,在施用根据本发明的核酸序列之前、同时或之后,根据常规方法(例如经口,全身性)施用所述前体药物。优选口服途径。可以施用单剂量的前体药物,或者在一段足够长以能够在宿主生物体或细胞内产生毒性代谢物的时间内进行重复施用的剂量。
此外,根据本发明的试剂盒或方法可与一或多种加强包含一个核碱基部分的药物的细胞毒性效应的物质联合使用。可特别提及的是抑制嘧啶从头生物合成途径中的酶的药物(例如在以下所提及的那些),例如甲酰四氢叶酸(Waxman et al.,1982,Eur.J.Cancer Clin.Oncol.18,685-692),其在存在5-FU的代谢产物(5-FdUMP)的情况下增强对胸苷酸合酶的抑制,导致复制所需的dTMP池和最终药物例如氨甲喋呤的下降(Cadmanet al.,1979,Science 250,1135-1137),所述氨甲喋呤通过抑制二氢叶酸还原酶和增加PRPP(磷酸核糖焦磷酸)的集中增加5-FU掺入细胞RNA。
根据本发明的试剂盒或方法可与一或多种在抗癌治疗中有效的物质联合使用。根据本发明的试剂盒或方法还可以与放射治疗联合使用。
图1:腺病毒与125和50mg/kg/天的5-FC的组合对Swiss裸小鼠中LoVo结肠癌异种移植物的生长的抗癌活性。通过将5x106个细胞皮下植入到裸小鼠体内建立肿瘤。当肿瘤可触知时,用空腺病毒(A)、Ad-FCU1(B)和Ad-FCY2FCU1(C)对动物进行瘤内接种3次,并经口施用5-FC处理3周。使用空腺病毒(A)时,存在或不存在5-FC之间的生长曲线无差异(P>0.05)。使用Ad-FCU1(B)时,仅在存在或不存在125mg/kg/天的5-FC的生长曲线之间存在显著差异(P<0.05)。使用Ad-FCY2FCU1(C)时,在不存在5-FC与存在全身施用125和50mg/kg/天的5-FC的生长曲线之间存在显著差异(P<0.05)。
实施例:
表达来自E1区的FCY2的腺病毒的构建:
利用聚合酶链反应(PCR),自作为模板的质粒pAJ14(Bloch et al.1992)扩增完整的酵母嘌呤-胞嘧啶通透酶基因(FCY2,1599bp)。将寡核苷酸SEQ ID NO.3:5′-TAACGATCTCGAGCCATGGTGGAAGAGGGAAATAATGTTTACG-3′(OTG14626,对应于FCY2编码序列的5′末端,但插入了在第2位由Val取代Leu的Kozak共有序列,并在起始密码子的上游插入一个XhoI限制性位点)和SEQ ID NO.4:5′-CCCTAATCACGCGTTCCTAACGACCGAAGTATTTTAAT-3′(OTG14627,对应于3′末端,并在终止密码子的下游插入一个MluI限制性位点)用作引物。将PCR产物通过XhoI和MluI进行消化,并亚克隆到形成质粒pTG15829的哺乳动物表达载体pCIneo(Promega)的相应位点中。来自pTG15829的序列揭示在FCY2基因的开放读框中的核苷酸+1272的一个沉默突变(G到A)。将来自质粒pTG15829的含有FCY2基因的XhoI-MluI片段插入由相同的酶切割的转移载体pTG13387中,产生转移载体pTG15857。通过BJ5183大肠杆菌菌株中pTG15857的片段PacI-BstEII与由ClaI线性化的载体pTG6624之间的同源重组产生腺病毒载体Ad-FCY2(pTG15895)。最终构建的Ad-FCY2(pTG15895)含有E3(核苷酸第28592到30470位)的缺失,而E1区(核苷酸第459到3510位)被表达盒所取代,所述表达盒从5′到3′含有CMV即刻早期增强子/启动子、嵌合人β-球蛋白/IgG内含子、FCY2基因和bGH多腺苷酸化信号。在互补E1功能的细胞系(例如PERC6细胞系)中通过转染产生表达FCY2的腺病毒颗粒(AdTG15895)。
表达来自E1区的双顺反子单位FCY2 IRES FCU1的腺病毒的构建:
分离含有FCY2基因的质粒pTG15829的NheI-NotI片段,并将其导入用NheI-NotI线性化的载体pTG14347(在p53FCU1的专利中描述的质粒pTG4369p53FCU1)。如此获得的质粒pTG16055从5′到3′含有FCY2基因、ECMV(脑心肌炎病毒)的IRES(内部核糖体进入位点)序列和FCU1基因。将来自质粒pTG16055的NheI-BamHI片段插入由相同的酶切割的转移载体pTG14799(在FCU1-8专利中描述的质粒)中,产生转移载体pTG16066。通过BJ5183大肠杆菌菌株中pTG16066的片段PacI-BstEII与由ClaI线性化的载体pTG6624之间的同源重组产生腺病毒载体Ad-FCY2FCU1(pTG16079)。最终构建的Ad-FCY2FCU1(pTG16079)包含E3(核苷酸第28592到30470位)的缺失,而E1区(核苷酸第459到3510位)被表达盒所取代,所述表达盒从5′到3′含有CMV即刻早期增强子/启动子、嵌合人β-球蛋白/IgG内含子、FCY2 IRES FCU1双顺反子单位和bGH多腺苷酸化信号。在互补E1功能的细胞系(例如细胞系PERC6)中通过转染产生表达FCY2 IRES FCU1的腺病毒颗粒(AdTG16079)。
5-氟胞嘧啶摄取分析:
用Mock、空腺病毒(AdTG15149)、表达FCU1(FCU1-8专利中描述的AdTG14800)或FCY2(AdTG15895)或FCY2和FCU1(AdTG16079)的腺病毒感染人肿瘤细胞系A549(ATCC CCL-185)。以MOI 20感染细胞(5x106),并将其置于60-mm平板上。24小时之后,通过常规示踪技术测量感染细胞对5-FC的摄取。利用1分钟温育期测量5-FC(10μM、室温)最初的速率,并以0.15μCi/ml浓度的[3H]5-FC进行追踪。
简而言之,在感染之后24小时,用转运缓冲液(100mM NaCl、2mMKCl、1mM CaCl2、1mM MgCl2和10mM HEPES,pH7.5)洗涤细胞一次。摄取分析从添加2ml含有10μM5-FC(0.15μCi/ml的[3H]5-FC)的转运缓冲液开始。温育结束时,用冰冷的转运缓冲液三次快速洗涤去除胞外标记。将细胞溶解在1ml的5%SDS中用于通过液体闪烁计数对放射性进行定量。
表1:转染的A549细胞对5-FC的摄取:
利用含有10μM5-FC的转运缓冲液测量5-FC的摄取。
每一数值代表三个独立试验的平均值±SD。
载体 | 5-FC的摄取(pmol/分/5x106个细胞) |
Mock | 7.97±3.76 |
空腺病毒(AdTG15149) | 9.74±3.31 |
Ad-FCU1(AdTG14800) | 13.28±5.74 |
Ad-FCY2(AdTG15895) | 38.94±7.61 |
Ad-FCY2FCU1(AdTG16079) | 77±28.7 |
表1中所示的结果证明在被表达FCY2的腺病毒(AdFCY2和AdFCY2FCU1)感染的细胞中5-FC转运的增加。该结果表明在人细胞中表达的酵母FCY2编码功能性的5-FC转运蛋白。
对5-FC的体外细胞敏感性:
比较用不同的腺病毒感染的肿瘤细胞对5-FC的敏感性。用Mock、空腺病毒(AdTG15149)、表达FCU1(FCU1-8专利中描述的AdTG14800)或FCY2(AdTG15895)或FCY2和FCU1(AdTG16079)的腺病毒感染人肿瘤细胞系A549(ATCC CCL-185)。以MOI 1感染细胞,然后在存在不同浓度的5-FC的条件下进行培养。培养6天之后,利用台盼蓝测定细胞的成活力。列于表2中的5-FC的LD50值是四次计数的平均值。
体内试验:
本研究的目的是比较在携带有LoVo人结肠肿瘤的裸鼠中,联合经口服施用的125或50mg/kg/天的5-氟胞嘧啶(5-FC)时,重组Ad-FCU1和Ad-FCY2FCU1的抗肿瘤活性。
将LoVo细胞皮下(s.c.)注射到Swiss裸小鼠的侧腹。将悬浮于100mlPBS中的5x106个LoVo细胞植入每一动物体内。当肿瘤达到30-50mm3时,以盲法对小鼠进行随机分组,并用1x108IU剂量的指示载体处理。在肿瘤植入后第12、15和18天将载体(悬浮于100ml的10mM Tris-HCl、pH7.5,1mM MgCl2中)直接注射到肿瘤中。从第12天开始,在三周内每天两次以经口管饲法给予62.5mg/kg/天的5-FC(0.6ml 0.25%5-FC的水溶液)或25mg/kg/天的5-FC(0.6ml 0.1%5-FC的水溶液)。使用测径器以二维测量肿瘤的大小。使用公式(p6)(长度x宽度2)计算肿瘤的体积(mm3)。
使用非参数的Mann-Whitney U检验和Statistica 6.1软件(StatSoft公司)进行统计学分析。将p<0.05认为具有统计学显著性。
施用125mg/kg/天的5-FC,注射Ad-FCU1和Ad-FCY2FCU1导致对肿瘤生长在统计学上显著的抑制(图1B,C)。这一抗肿瘤效应是FCU1/5-FC特有的,因为感染不诱导FCU1活性的空腺病毒在5-FC存在的条件下没有明显缩小肿瘤大小(图1A)。在较低剂量的5-FC(50mg/kg/天)的条件下,在递送Ad-FCY2FCU1之后观察到对肿瘤生长的显著抑制,而使用Ad-FCU1则没有观察到肿瘤生长的改变。该结果表明FCY2和FCU1的组合明显比单独的FCU1更有效,表明在癌症基因治疗方法中FCY2FCU1/5-FC系统比FCU1/5-FC系统更有效。
表2:腺病毒转导的A549细胞的5-FC的LD50值
载体 | LD50(μM) |
Mock | >1000 |
空腺病毒(AdTG15149) | >1000 |
Ad-FCU1(AdTG14800) | 50 |
Ad-FCY2(AdTG15895) | >1000 |
Ad-FCY2FCU1(AdTG16079) | 20 |
这些结果证明与FCU1基因(AdTG14800)的表达相比,来自腺病毒载体(AdTG16079)的FCY2和FCU1基因的共表达使细胞对5-FC的敏感性更高。这一对5-FC的更高的敏感性是摄取由FCY2基因所编码的5-FC的结果。利用Ad-FCY2(AdTG15895)感染的细胞,没有观察到抗增殖的效果,这表明在缺乏胞嘧啶脱氨酶活性的条件下,FCY2的单独施用不足以用作有效的抗肿瘤治疗方案。
序列表
<110>特兰斯吉恩股份有限公司
<120>设计用于在哺乳动物中进行抗肿瘤或抗病毒治疗的试剂盒
<130>D 22887
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Claims (24)
1.一种用于治疗脊椎动物的癌症和/或病毒性疾病的试剂盒,其包含:
-包含一个核碱基部分的药物的前体,所述的包含一个核碱基部分的药物的前体选自包含如下组分的组:叠氮胸苷、更昔洛韦、5-氟胞嘧啶、5-氟尿嘧啶、6-甲基嘌呤脱氧核糖核苷、更昔洛韦反油酸酯、喷昔洛韦、无环鸟苷、伐昔洛韦、(E)-5-(2-溴乙烯基)-2′-脱氧尿苷、齐多夫定、2′-Exo-methanocarbathymidine,和
-编码通透酶的基因,所述通透酶参与所述前体转移通过细胞膜,和
-自杀基因,所述自杀基因编码能将所述前体转化为包含一个核碱基部分的药物的蛋白质。
2.根据权利要求1的试剂盒,其中所述包含一个核碱基部分的药物选自包含如下组分的组:阿糖胞苷、吉西他滨、卡培他滨、氟达拉滨、克拉屈滨、曲沙他滨、克罗屈滨、叠氮胸苷、2’,3’-双脱氧肌苷、扎西他滨、司他伏定、脱氧氟亚甲基胞苷、拉米夫定、氟尿苷、5-氟尿嘧啶、硫鸟嘌呤、巯嘌呤、无环鸟苷、伐昔洛韦、泛昔洛韦和更昔洛韦。
3.权利要求1的试剂盒,其中所述通透酶是酿酒酵母(S.Cerevisiae)的嘌呤或胞嘧啶通透酶。
4.权利要求3的试剂盒,其中所述通透酶选自FCY2和Fur4。
5.权利要求1的试剂盒,其中所述自杀基因选自编码具有胞嘧啶脱氨酶活性和/或尿嘧啶磷酸核糖基转移酶活性的蛋白质的基因。
6.权利要求5的试剂盒,其中所述自杀基因编码具有胞嘧啶脱氨酶活性的蛋白质。
7.权利要求5的试剂盒,其中所述自杀基因编码至少具有胞嘧啶脱氨酶活性和尿嘧啶磷酸核糖基转移酶活性的蛋白质。
8.权利要求5的试剂盒,其中所述自杀基因选自CodA、upp、FUR1、FCY1和FUR1Δ105。
9.权利要求7的试剂盒,其中所述蛋白质是一种融合蛋白,其中呈现尿嘧啶磷酸核糖基转移酶或胞嘧啶脱氨酶活性的第一种多肽至少与第二种多肽同相融合,所述第二种多肽相应地呈现胞嘧啶脱氨酶或尿嘧啶磷酸核糖基转移酶活性。
10.权利要求7的试剂盒,其中所述自杀基因包含选自upp、FUR1和FUR1Δ105的第一种核酸序列和选自CodA和FCY1的第二种核酸序列。
11.权利要求1到10中任一项的试剂盒,其中所述核酸序列被插入质粒或病毒来源的重组载体中。
12.权利要求1的试剂盒,其中所述的核酸序列被插入相同的重组载体中。
13.权利要求1的试剂盒,其中所述核酸序列被插入不同的重组载体中。
14.权利要求1的试剂盒,其中所述脊椎动物是人。
15.包含编码通透酶的基因和自杀基因的重组载体。
16.权利要求15的重组载体,其特征在于所述载体选自质粒和病毒载体,其与一或多种提高所述载体的转染效率和/或稳定性的物质适当地组合在一起。
17.权利要求16的重组载体,其中所述提高所述载体的转染效率和/或稳定性的物质选自阳离子脂质、阳离子聚合物、溶血磷脂和多肽。
18.权利要求16的重组载体,其中所述载体是衍生自痘病毒、腺病毒、逆转录病毒、疱疹病毒、甲病毒、泡沫病毒或腺病毒相关病毒的病毒载体。
19.权利要求18的重组载体,其中所述载体衍生自修饰的痘苗病毒安卡拉株。
20.权利要求19的重组载体,其中所述编码通透酶的基因和所述自杀基因被插入MVA基因组中的天然存在的缺失体的位点,所述缺失体选自缺失体I、II、III、IV、V和VI。
21.权利要求20的重组载体,其中所述基因被插入天然存在的缺失体III的位点。
22.权利要求19的重组载体,其中所述载体是额外缺失全部或部分非必需的E3区的腺病毒载体。
23.一种药物组合物,其包含权利要求1到14中任一项的试剂盒或权利要求15到22中任一项的重组载体。
24.权利要求23的药物组合物在制备用于治疗癌症、心血管疾病或AIDS的药物中的应用。
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CA2584681A1 (en) | 2006-05-11 |
JP5372374B2 (ja) | 2013-12-18 |
MX2007005474A (es) | 2007-07-10 |
CN101072792A (zh) | 2007-11-14 |
WO2006048768A8 (en) | 2007-06-14 |
DK1814907T3 (da) | 2009-05-18 |
ES2320157T3 (es) | 2009-05-19 |
JP2008519024A (ja) | 2008-06-05 |
KR101134185B1 (ko) | 2012-04-09 |
KR20070091614A (ko) | 2007-09-11 |
IL183015A (en) | 2012-02-29 |
AU2005300248A1 (en) | 2006-05-11 |
CA2584681C (en) | 2014-05-13 |
JP2013209415A (ja) | 2013-10-10 |
PT1814907E (pt) | 2009-03-27 |
WO2006048768A2 (en) | 2006-05-11 |
HK1107360A1 (en) | 2008-04-03 |
IL183015A0 (en) | 2007-09-20 |
ATE421534T1 (de) | 2009-02-15 |
CY1109850T1 (el) | 2014-09-10 |
US8470591B2 (en) | 2013-06-25 |
DE602005012535D1 (de) | 2009-03-12 |
WO2006048768A3 (en) | 2006-08-03 |
US20090170795A1 (en) | 2009-07-02 |
PL1814907T3 (pl) | 2009-07-31 |
AU2005300248B2 (en) | 2012-04-26 |
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