CN104271748B - 表达异源肿瘤相关抗原的腺病毒 - Google Patents
表达异源肿瘤相关抗原的腺病毒 Download PDFInfo
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Abstract
本发明涉及用于癌症治疗的腺病毒,其包含一个或更多个编码肿瘤抗原的异源核酸序列,由此所述腺病毒在其表面上表达所述肿瘤抗原。
Description
相关申请的交叉引用
本申请要求于2012年2月2日提交的美国临时专利申请No.61/594,005的权益,其全部内容通过引用并入本文。
序列表、表格和计算机程序列表的说明
序列表以名为SEQ.tx(4KB,2013年2月1日)的文件附于本申请中,并且通过引用并入本文。
背景
1.技术领域
本发明一般性地涉及肿瘤学和癌症治疗的领域。更特别地,其涉及免疫原性腺病毒。
II.相关技术描述
癌症仍然是全世界人类发病率和死亡率的主要原因之一。虽然已经利用手术、化学疗法和放射来治愈(cure)癌症取得了一些成功,但是仍需要新的策略。在肿瘤细胞中比在正常细胞中复制得更好的病毒已显示出其作为溶瘤剂(oncolytic agent)的前景。已经很好地确立了使用腺病毒进行基因转移和肿瘤溶解的可行性(Kirn,1999;Bischoff等,1996;Wildner等,1999a;Wildner等,1999b;(Sterman等;Hum.Gene Ther.9:1083-1092(1998))。
仍然需要另外的抗癌疗法。
发明内容
有复制能力的腺病毒(replication competent adenovirus)可通过至少四种机制实现抗癌治疗。第一,腺病毒可启动并完成裂解性感染,从而使细胞裂解(溶瘤作用)。第二,腺病毒可表达自杀基因,例如胸苷激酶(HSVtk)基因或胞嘧啶脱氨酶-胸苷激酶融合蛋白(Rogulski等,Clin.Cancer Res.3:2081-2088(1997)),其将增加溶瘤活性。第三,可将施用腺病毒与化学疗法(包括任意药物治疗)或者放射组合以增强各药剂的溶瘤活性(Nielsen等,Cancer Gene Ther.4:835-846(1997))。最后,病毒可以起免疫刺激剂或者表达免疫刺激性分子之载体的作用,导致刺激针对肿瘤抗原的特定免疫效应细胞。使用溶瘤作用和免疫刺激的组合策略是特别吸引人的,因为其可通过“疫苗效应”提供长期的持久应答。因此,在本发明之前,本领域仍然需要具有对表达或展示肿瘤相关抗原之肿瘤细胞改善选择性的复制选择性腺病毒。
本发明涉及这样的腺病毒组合物,其具有整合到腺病毒外壳蛋白中的癌抗原、由腺病毒表达的癌抗原或者与腺病毒一起递送的癌抗原。在某些方面中,经修饰的外壳蛋白将包含经修饰的纤维蛋白(fiber protein)、六邻体蛋白或pIX蛋白。经抗原修饰的腺病毒将从第一复制周期起呈递癌抗原,从而使肿瘤环境中的癌抗原水平升高。肿瘤环境中抗原水平的升高将刺激针对癌抗原以及针对裂解的肿瘤细胞的免疫应答。在某些方面中,刺激免疫应答与肿瘤细胞的裂解组合,提供了增加肿瘤消退可能性之增强的抗肿瘤免疫。
嵌合腺病毒外壳蛋白可包含约3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29至约30个异源氨基酸,所述异源氨基酸插入或代替外壳蛋白氨基酸序列,或者替代地与腺病毒外壳蛋白的C-末端融合。所述腺病毒外壳蛋白可以是纤维蛋白、五邻体基底蛋白、六邻体或pIX蛋白。抗原可插入六邻体高变区1(人5型腺病毒氨基酸139-167)、纤维蛋白HI环(人5型腺病毒纤维蛋白(fiber)HI环氨基酸537-549)中,和/或与蛋白IX(人5型腺病毒蛋白IX氨基酸140)缀合或融合。在某些方面中,所述异源氨基酸通过约3个氨基酸至约30个氨基酸(包括其之间的所有值和范围)的间隔序列与嵌合腺病毒外壳蛋白连接。
因此,实施方案包括具有多种肿瘤相关抗原(tumor associated antigen,TAA)的腺病毒,所述肿瘤相关抗原与有复制能力的溶瘤腺病毒偶联或与其一起施用。在某些方面中,抗原与腺病毒外壳蛋白作为融合蛋白呈递。在另一些方面中,抗原与腺病毒的外壳共价地或非共价地结合。共价结合的抗原可通过化学接头与腺病毒外壳化学连接。非共价结合的抗原可通过抗原或连接至抗原的结合部分与腺病毒外壳蛋白或连接至外壳蛋白的结合部分之间的亲合力与外壳结合。在另一些方面中,可将腺病毒与多种和腺病毒组合物共施用的抗原配制在一起。
某些实施方案涉及治疗癌症的方法,其包括向肿瘤施用有复制能力的腺病毒和一种或更多种肿瘤相关抗原。在某些方面中,有复制能力的腺病毒是Δ-24腺病毒。在另一些方面中,Δ-24腺病毒的外壳蛋白与一种或更多种肿瘤相关抗原偶联。在某些方面中,肿瘤相关抗原作为融合蛋白或蛋白嵌合体呈递在腺病毒表面上。本文使用的“嵌合体”或“嵌合”是指具有多个组分的单个转录单元,但通常也不一定来自不同的蛋白质。本文使用的“嵌合”用来指编码腺病毒蛋白的编码序列,所述腺病毒蛋白已被基因工程改造成产生包含具有包含肿瘤相关抗原之异源区段的腺病毒外壳蛋白的所有或一部分的蛋白质。在另一个方面中,抗原与腺病毒的外壳经由化学接头共价连接。在又一些方面中,将抗原与有复制能力的腺病毒配制并且与病毒共施用。在另一些方面中,可在用腺病毒处理之前或之后施用抗原。在某些方面中,抗原与免疫刺激剂或增强剂一起施用。
在某些实施方案中,提供了在其表面上表达多种肿瘤抗原的腺病毒。在某些方面中,在腺病毒的表面上表达2、3、4或5种抗原,例如,通过将编码各抗原的核酸插入编码腺病毒表面蛋白的单独基因中来实现。肿瘤抗原可作为衣壳或纤维蛋白的一部分表达,或者作为与自噬相关蛋白(例如LC3)连接的外源蛋白产生,以增加外源蛋白在腺病毒感染和复制期间的呈递。靶向多种抗原将有助于产生持久且有效的免疫应答。
肿瘤相关抗原(TAA)包括但不限于α-甲胎蛋白(AFP),黑素瘤相关抗原-MAGE-1、MAGE-2、MAGE-3,癌胚抗原(CEA)(IIGYVIGTQQATPGPAYSGREII,SEQ ID NO:1),酪氨酸酶(Tyr),中期因子(minkin,MK),BAGE,CASP-8,β-联蛋白,CA-125,CDK-1,ESO-1,gp75,gp100,MART-1,黏蛋白(MUC-1),MUM-1,p53,PAP,PSA,PSMA,ras,trp-1,HER-2,TRP-2,IL13Rα,AIM-3或NY-ESO1。在某些方面中,TAA是C9orf112、SART1、BRAP、RTN4、GLEA2、TNKS2、KIAA0376、ING4、HSPH1、C13orf24、RBPSUH、C6orf153、NKTR、NSEP1、U2AF1L、CYNL2、TPR、SOX2或GOLGA。腺病毒可表达全长肿瘤相关抗原或其免疫原性肽。
另一些肿瘤相关抗原包括但不限于,已鉴定在脑癌(例如神经胶质瘤)患者中出现的肿瘤相关抗原,其代表性实例包括:AIM2(在黑素瘤2中不存在)、BMI1(BMI1多梳环指致癌基因)、COX-2(环加氧酶-2)、TRP-1(酪氨酸相关蛋白2)、TRP-2(酪氨酸相关蛋白2)、GP100(糖蛋白100)、EGFRvIII(表皮生长因子受体变体III)、EZH2(zeste增强子同源物2(enhancer of zeste homolog 2))、LICAM(人L1细胞粘附分子)、Livin、Livinβ、MRP-3(多药抗性蛋白3)、巢蛋白、OLIG2(少突胶质细胞转录因子)、SOX2(SRY-相关HMG-框2)、ART1(T细胞所识别的抗原1)、ART4(T细胞所识别的抗原4)、SART1(T细胞所识别的鳞状细胞癌抗原1)、SART2、SART3、B-细胞周期蛋白、b-联蛋白、Gli1(神经胶质瘤相关致癌基因同源物1)、Cav-1(窖蛋白-1)、组织蛋白酶B、CD74(分化簇74)、E-钙黏着蛋白(上皮钙依赖性粘附)、EphA2/Eck(EPH受体A2/上皮激酶)、Fra-1/Fosl 1(fos相关抗原1)、GAGE-1(G抗原1)、神经节苷脂/GD2、GnT-V、β1,6-N(乙酰葡萄糖胺基转移酶-V)、Her2/neu(人表皮生长因子受体2)、Ki67(抗体Ki67的核增殖相关抗原)、Ku70/80(人Ku异二聚体蛋白亚基)、IL-13Ra2(白细胞介素-13受体亚基α-2)、MAGE-A(黑色素瘤相关抗原1)、MAGE-A3(黑素瘤相关抗原3)、NY-ESO-1(纽约食管鳞状细胞癌1)、MART-1(T细胞所识别的黑色素瘤抗原)、PROX1(prospero同源异型框蛋白1)、PSCA(前列腺干细胞抗原)、SOX10(SRY相关的HMG-框10)、SOX11、存活蛋白、UPAR(尿激酶型纤溶酶原激活物受体)以及WT-1(Wilms肿瘤蛋白1)。腺病毒可表达全长肿瘤相关抗原或其免疫原性肽。
在某些方面中,腺病毒可由整合到腺病毒基因组中的异源核酸表达肿瘤相关抗原。所述异源核酸可受腺病毒或异源启动子的控制。构建体的“异源”区是在较大核酸分子内核酸的可鉴定区段,在自然情况下并未发现其与所述较大分子有关。
表皮生长因子受体(EGFR)是由c-erb B原癌基因编码的170kDa糖蛋白(Ullrich等,Nature 309:418-425(1984))。该致癌基因在多种癌症中被激活,并且在约40%的恶性神经胶质瘤中扩增。在人类癌症中通常发现有EGF受体突变体(称为III型突变体或EGFRvIII),但是其在任何正常组织中都不表达,所述EGF受体突变体包含胞外域中产生新接点的267个氨基酸框内缺失。由EGFRvIII中的缺失产生的新的接点是免疫原性的。美国专利No.6,455,498描述了EGFRvIII的序列,其内容通过引入并入本文。免疫原性EGFRvIII包括美国专利申请公开No.2009/0155282(其内容通过引入并入本文)中所述的那些,特别是段落[0362]和表4.1-4.3中的那些。
在一个优选实施方案中,提供了包含含有免疫原性EGFRvIII表位之表面蛋白的腺病毒。在一个方面中,将编码全长EGFRvIII或其免疫原性肽的核酸插入编码腺病毒表面蛋白的基因中(例如,可通过PCR诱变来修饰天然基因以包含表位),由此使所述腺病毒表达包含EGFRvIII表位的嵌合表面蛋白。因此,本发明提供了具有包含编码EGFRvIII或其免疫原性肽之(异源)核酸的基因组的重组腺病毒及其在治疗癌症中的用途。在一个方面中,将EGFRvIII或其免疫原性肽插入编码纤维蛋白的基因中,优选H1环中。已经证明腺病毒的这个区域可用于抗原表达(Krause A.等,J.Virol.,80:5523-30(2006))。可将编码EGFRvIII或其免疫原性肽的核酸插入编码任意腺病毒的一种或更多种表面蛋白的基因中。在一个方面中,腺病毒是Δ-24。本文所用术语“免疫原性EGFRvIII肽”意指适当长度的肽,例如至少10或12个氨基酸以及达15、20、25或30个氨基酸或更多,其跨越(span)对应EGFRvIII蛋白(优选人EGFRvIII)的突变剪接接点。在一个优选实施方案中,插入腺病毒表面蛋白中的核酸编码8至20个氨基酸的肽,所述肽由序列EKKGNYVV(SEQ ID NO:2)组成,基本由其组成或者包含其。例如,所述肽可具有选自以下的序列:LEEKKGNY(SEQ IIDNO:3)、LEEKKGNYVVT(SEQ ID NO:4)、LEEKKGNYVVTDH(SEQ ID NO:5)或LEEKKGNYVVTDHC(SEQ ID NO:6)。在一个特别优选的实施方案中,EGFRvIII免疫原性肽是LEEKKGNYVVT(SEQ ID NO:4)并且被插入编码纤维蛋白的基因中,优选H1环中。在另一些实施方案中,将编码整个EGFRvIII胞外域的核酸插入编码腺病毒表面蛋白的基因中。
在另一些优选实施方案中,本发明提供了具有包含编码MAEG或其免疫原性肽之(异源)核酸的基因组的重组腺病毒及其在治疗癌症中的用途。优选地,将编码MAGE或其免疫原性肽的核酸插入编码表面蛋白的基因中,由此腺病毒表达包含MAGE或其免疫原性肽的嵌合表面蛋白。在一个方面中,将编码MAGE或其免疫原性肽的核酸插入腺病毒之缺失的E3区中。可将编码MAGE或其免疫原性肽的核酸插入编码任意腺病毒的一种或更多种表面蛋白的基因中。在一个方面中,腺病毒是Δ-24。在另一些方面中,癌症是原发性或转移性脑肿瘤。
在另一些优选实施方案中,本发明提供了具有包含编码NY-ESO-1(GenBankU87459.1)或其免疫原性肽(例如,SLLMWITQCFLPVF(SEQ ID NO:7))之(异源)核酸的基因组的重组腺病毒及其在治疗癌症中的用途。优选地,将编码NY-ESO-1或其免疫原性肽的核酸插入编码表面蛋白的基因中,由此腺病毒表达包含NY-ESO-1或其免疫原性肽的嵌合表面蛋白。在一个方面中,将编码NY-ESO-1或其免疫原性肽的核酸插入编码腺病毒六邻体之基因的高变区5中。已经显示腺病毒的这个区域可用于抗原表达(Crawford-Miksza和Schnurr,J.Virol.,70:1836-44(1996))。可将编码NY-ESO-1或其免疫原性肽的核酸插入编码任意腺病毒的一种或更多种表面蛋白的基因中。在一个方面中,腺病毒是Δ-24。在另一些方面中,癌症是原发性或转移性脑肿瘤。
在一个特别优选的实施方案中,本发明提供了重组腺病毒及其在治疗癌症中的用途,所述重组腺病毒具有包含以下的基因组:(a)插入编码腺病毒纤维蛋白H1环之基因中的编码免疫原性EGFRvIII肽(例如,LEEKKGNYVVT)的核酸,(b)插入腺病毒之缺失E3区中的编码MAGE或其免疫原性肽的核酸,以及(c)插入编码腺病毒六邻体蛋白之基因的高变区5中的编码NY-ESO-1或其免疫原性肽的核酸。在一个方面中,腺病毒是Δ-24。在另一些方面中,癌症是原发性或转移性脑肿瘤。
应该“框内”完成将编码肿瘤抗原的核酸插入到腺病毒基因中,使得病毒在其表面上表达肿瘤抗原。
某些方面并不需要完全切除肿瘤,这是以其他途径招募患者(recruitment ofpatient)的限制因素。此外,当前方法和组合物的某些方面具有在免疫系统中产生记忆的潜力以及预防肿瘤复发或减小其概率。
术语“有复制能力的腺病毒载体”是指在特定细胞或组织中病毒复制所需的任何基因功能没有缺陷的任何腺病毒载体。所述载体必须能够复制并且被包装,但其可仅在特定细胞或组织中有条件地复制。
术语“治疗益处”或“治疗”是指促进或增强对象在其病症的医药治疗方面的健康的任何事情,其包括初癌(pre-cancer)、癌症和过度增殖性疾病的治疗。其非穷举性实例的列表包括:使对象生命延长任意时段,降低或延迟疾病的肿瘤发展,减少过度增殖,降低肿瘤生长,延迟转移,降低癌细胞或肿瘤细胞增殖速率,以及减少可归因于对象病症的对象的疼痛。
术语“神经胶质瘤”是指源于脑部或脊髓之神经胶质的肿瘤。神经胶质瘤来源于神经胶质细胞类型,例如星形胶质细胞和少突胶质细胞,因而神经胶质瘤包括星形细胞瘤和少突胶质细胞瘤,以及退行性神经胶质瘤、成胶质细胞瘤和室管膜瘤。星形细胞瘤和室管膜瘤可发生在儿童和成人二者之脑和脊髓的所有区域中。少突胶质细胞瘤通常发生在成人的大脑半球中。神经胶质瘤在儿科中占脑肿瘤的75%并且在成人中占脑肿瘤的45%。其他脑肿瘤为脑膜瘤、室管膜瘤、松果体区肿瘤、脉络丛肿瘤、神经上皮肿瘤、胚胎性肿瘤、外周成神经细胞肿瘤、颅神经肿瘤、造血系统肿瘤、生殖细胞肿瘤和星状区肿瘤(tumors of thestellar region)。
贯穿本申请,讨论了本发明的另一些实施方案。关于本发明的一个方面讨论的任何实施方案也适用于本发明的其他方面,并且反之亦然。本文所述的每个实施方案应理解为可应用于本发明所有方面的本发明实施方案。预期对于本发明的任意方法或组合物都可实施本文所讨论的任意实施方案,并且反之亦然。此外,本发明的组合物和试剂盒可用于实现本发明的方法。
在权利要求和/或说明书中,当没有数词限定的词与术语“包含”结合使用时,可意指“一”,但其也与“一或更多”、“至少一”和“一或多于一”的意思一致。
贯穿本申请,术语“约”用来表示一个值包括用来测定所述值的装置或方法之误差的标准差。
虽然本公开内容支持指仅为替代方案以及“和/或”的定义,但是权利要求中使用术语“或”用来意指“和/或”,除非明确表明其仅仅是指替代方案或者替代方案是互斥的。
本说明书和权利要求书中使用的词语“包含(comprising)”(以及“包含”的任意形式,例如“包含(comprise)”和“包含(comprises)”),“具有(having)”(以及“具有”的任意形式,例如“具有(have)”和“具有(has)”),“包括(including)”(以及“包括”的任意形式,例如“包括(includes)”和“包括(include)”)或“含有(containing)”(以及“含有”任意形式,例如“含有(contains)”和“含有(contain)”)是包括性的或开放式的,并且不排除额外的未列举的要素或方法步骤。
从以下的详细描述中,本发明的其他目的、特征和优点将变得明显。然而,应理解虽然指出了本发明的一些具体实施方案,但是详细描述和具体实施例仅以说明的方式给出,因为从该详细描述,对于本领域技术人员而言,本发明的精神和范围内的各种变化和修改将变得明显。
附图说明
图1.腺病毒的结构允许对其基因组的几个区域进行修饰以插入将作为抗原呈递的表位或插入全长cDNA以表达蛋白质。左上图描绘了插入三种单独表面蛋白(分别为纤维蛋白的H1环、六邻体的高变区5和缺失的E3区)中的具有包含编码三种单独肿瘤抗原(免疫原性EGFRvIII肽、免疫原性NY-ESO-1肽和全长MAGE蛋白)之核酸的基因组的腺病毒(Δ-24-疫苗)。这些抗原将在重组腺病毒的表面上表达,而没有溶瘤效力的任何减小并且病毒蛋白的表达之间没有干扰。当施用于癌症患者时,所述腺病毒将诱导肿瘤坏死。这些抗原在炎性肿瘤微环境中的表达应募集巨噬细胞和其他抗原呈递细胞以触发“重定向的(re-directed)”抗肿瘤免疫应答。
图2.表达免疫原性肿瘤抗原之新的腺病毒的构建。图A:已经将免疫原性EGFRvIII肽(LEEKKGNYVVT)克隆到Δ-24-疫苗纤维蛋白的HI环中。图B:已经描述了用来在HI环中克隆所述肽的技术策略(Suzuki等,Clin.Cancer Res.7:120-6(2001))。使用PCR诱变对包含纤维蛋白基因的质粒进行修饰以包含(即插入)肽,然后使其与包含含有Δ-24突变的腺病毒序列之剩余部分的质粒在细菌中进行同源重组。然后使用293细胞扩增最终产物。
图3.免疫原性EGFRvlll肽的表达。图A说明了Western印迹,其证明EGFRvIII表位在经修饰的Δ-24腺病毒表面上表达。使根据图2构建的表达含有EGFRvIII表位(D24-EGFRvIII)之纤维蛋白的Δ-24腺病毒进行细胞裂解、蛋白质提取和Western印迹分析。使用针对腺病毒纤维蛋白或EGFRvIII肽的抗体确定了EGFRvIII抗原的高表达。使用肌动蛋白作为负载对照。图B说明了使用针对病毒(Hexon)的抗体、针对EGFRvIII肽(EGFRvIII)的抗体以及4′,6-二脒基-2-苯基吲哚(DAPI)对被D24-EGFRvIII感染之癌细胞进行的免疫荧光分析。所述图像说明了被D24-EGFRvIII感染的细胞表达EGFRvIII肽。DNA染色(DAPI)证实了只有被感染的细胞表达EGFRvIII肽。腺病毒衣壳在细胞核中进行装配。
图4.EGFRvIII表位在D24-EGFRvIII感染的细胞表面上呈递的评估。用指定的腺病毒以50pfu/细胞的m.o.i.感染HeLa细胞。48小时后用小鼠单克隆抗EGFRvIIII抗体L8A4对所述细胞进行染色。用流式细胞术评估表面上具有EGFRvIII表位之细胞的百分比。使用D24(不表达EGFRvIII表位的Δ-24腺病毒)作为病毒感染的对照。使用小鼠IgG作为抗体的阴性对照。
图5.Δ-24-RGD诱导抗肿瘤免疫应答。将GL261细胞颅内植入C57BL/6小鼠中。在第7天和第9天将Δ-24-RGD注射入肿瘤中。在最后一次病毒注射后7天,分离小鼠脾细胞并将其与GL261细胞共培养。通过ELISA测量由淋巴细胞分泌的IFN-γ。
图6.Δ-24-RGD处理导致CD8+和CD4+T细胞募集到肿瘤部位内。将GL261细胞颅内植入C57BL/6小鼠中。在第7天和第10天将Δ-24-RGD注射入肿瘤中。在最后一次病毒注射后7天,将淋巴细胞从脑中分离并且通过流式细胞术进行表征。
发明详述
本发明的方法和组合物包括腺病毒疫苗的构建和确认,所述腺病毒疫苗引发针对肿瘤相关抗原的免疫应答以增强抗肿瘤治疗。
I.腺病毒疫苗
腺病毒(Ad)是感染人的大(~36kb)DNA病毒,但其表现出宽的宿主范围。生理上,腺病毒是包含双链线性DNA基因组的二十面体病毒。人腺病毒存在大约50种血清型,其基于分子、免疫学和功能标准被分为六个家族。到成年时,实际上每个人都已经感染较常见的腺病毒血清型,主要效应为感冒样症状。
宿主细胞的腺病毒感染导致腺病毒DNA保持游离,这降低了与整合载体相关的潜在基因毒性。此外,腺病毒是结构稳定的,并且在大量扩增后没有检测到基因组重排。腺病毒可感染几乎大部分的上皮细胞,不论其细胞周期阶段。迄今为止,腺病毒感染似乎仅与轻微疾病(例如人急性呼吸疾病)有关。
57种人腺病毒血清型(HAdV-1至57)中任何的成员可与根据本发明的一种或更多种肿瘤相关抗原肽合并、偶合或一起施用。人Ad5在遗传和生物化学上进行了很好地表征(GenBank M73260;AC_000008)。因此,在一个优选实施方案中,腺病毒是有复制能力的Ad5血清型或包含Ad5组分的杂合血清型。腺病毒可为野生型毒株或可对其进行基因修饰以增强肿瘤选择性,例如通过削弱病毒在正常休眠细胞内复制的能力而不影响病毒在肿瘤细胞中复制的能力。本发明所涵盖的腺病毒的非限制性实例包括Δ-24、Δ-24-RGD、ICOVIR-5、ICOVIR-7、ONYX-015、ColoAd1、H101和AD5/3-D24-GMCSF。Onyx-015是病毒血清型Ad2和Ad5的杂合体,其在E1B-55K和E3B区中有缺失,以增强癌症选择性。H101是Onyx-015的一种修饰形式。ICOVIR-5和ICOVIR-7包含E1A的Rb结合位点缺失并且E1A启动子被替换为E2F启动子。ColoAd1是嵌合Add11p/Ad3血清型。AD5/3-D24-GMCSF(CGTG-102)是编码GM-CSF的经血清型5/3衣壳修饰的腺病毒(Ad5衣壳蛋白结节(knob)被替换为血清型3的结节结构域)。
在一个特别优选的实施方案中,腺病毒是Δ-24或Δ-24-RGD。美国专利申请公开No.20030138405和No.20060147420中对Δ-24进行了描述,其各自通过引用并入本文。Δ-24腺病毒来源于5型腺病毒(Ad-5)并且在E1A基因的CR2部分内包含24个碱基对缺失,其包含负责结合对应于所编码E1A蛋白中氨基酸120至127的Rb蛋白(核苷酸923-946)的区域(Fueyo J等,Oncogene,19:2-12(2000))。Δ-24-RGD还包含RGD-4C序列(其与αvβ3和αvβ5整联蛋白强结合)插入纤维结节蛋白的H1环中(Pasqualini R.等,NatBiotechnol,15:542-546(1997))。E1A缺失使病毒对癌症细胞的选择性增加;RGD-4C序列使在神经胶质瘤中病毒的感染性增加。
在细胞培养物系统和恶性神经胶质瘤异种移植物模型中已显示出Δ-24的显著抗肿瘤作用。Δ-24-RGD在1期临床试验中已显示出出乎意料的抗肿瘤作用并且目前是另一些临床试验的对象。本发明的一些方面涉及增强该抗肿瘤功效。
腺病毒的感染周期以2个步骤发生:早期阶段,其在腺病毒基因组复制开始之前并且其允许产生调节蛋白以及参与病毒DNA复制和转录的蛋白质;以及后期阶段,其导致结构蛋白的合成。早期基因分布在分散于腺病毒基因组中的4个区域中,称为E1至E4(E表示“早期”)。早期区域包含至少六个转录单元,其各自具有其自身的启动子。早期基因的表达是自身调节的,一些基因在另一些基因之前表达。三个区域E1、E2和E4对病毒的复制是必要的。因此,如果腺病毒对于这些功能之一而言是缺陷的,则必须反式补给该蛋白质,否则病毒就不能复制。
E1早期区域位于腺病毒基因组的5′末端,并且包含2个病毒转录单元E1A和E1B。这个区域编码在病毒周期中非常早参与的蛋白质并且对腺病毒的几乎所有其他基因的表达都是必要的。特别地,E1A转录单元编码反式激活其他病毒基因之转录的蛋白质,诱导来自E1B、E2A、E2B、E3、E4区域和晚期基因的启动子转录。通常,整合外源序列以代替E3区域的所有或部分。
腺病毒经由细胞表面受体进入许可的宿主细胞,然后使其内在化。与复制周期第一步所需的某些病毒蛋白质相关的病毒RNA进入受感染细胞的细胞核中,在这里开始转录。腺病毒DNA的复制在受感染细胞的细胞核中发生而不需要细胞复制。装配新的病毒颗粒或病毒体,之后使其从受感染细胞中释放,并且可感染其他允许的细胞。
本发明的一些方面包括开发、生产和评价包含一种或更多种肿瘤相关抗原(TAA)的疫苗。腺病毒载体体系不仅提供了可行的递送载剂,而且还可引发抗肿瘤免疫应答。腺病毒可用于多种治疗应用(包括抗癌症免疫治疗和心血管血管再生成)中的基因转移被广泛接受。
腺病毒是具有吸引力的递送系统。本发明的实施方案可利用平均产率为1×1016个病毒颗粒/批的悬浮细胞方法。该方法可不含或基本不含蛋白质、血清和动物来源的成分,使得其适于预防性和治疗性疫苗产品二者的宽范围。
多个因素有助于溶瘤腺病毒用于脑肿瘤治疗。第一,神经胶质瘤通常是局部化的,因此有效的局部方法应足以治愈该疾病。第二,神经胶质瘤具有多个表达不同遗传异常的细胞群体。因此,可限制对单一基因向癌细胞转移敏感的肿瘤谱。第三,有复制能力的腺病毒可感染并破坏在G0期停滞的癌细胞。因为神经胶质瘤总是包含非周期性细胞,所以这个性质是重要的。最后,p16-Rb途径在大多数神经胶质瘤中是异常的,因而使得Δ-24策略适于这些肿瘤中的大多数。虽然视网膜母细胞肿瘤阻抑基因功能的丧失与多种类型肿瘤的原因有关,但是并不受限于治疗神经胶质瘤。
如果使腺病毒突变使得其不能复制或者有条件地复制(在某些条件下有复制能力),则病毒复制可能需要辅助细胞。需要时,辅助细胞系可来源于人细胞,例如人胚胎肾细胞、肌肉细胞、造血细胞或者其他人胚胎间充质细胞或上皮细胞。或者,辅助细胞可来源于许可人腺病毒的其他哺乳动物物种的细胞。这样的细胞包括例如Vero细胞或者其他猴胚胎间充质细胞或上皮细胞。在某些方面中,辅助细胞系是293。在本技术领域中可发现培养宿主和辅助细胞的多种方法,例如Racher等,1995。
在某些方面中,腺病毒通常在具有突变Rb途径的细胞中是有复制能力的。在转染之后,将腺病毒噬菌斑从琼脂糖覆盖的细胞中分离并且使病毒颗粒扩增以进行分析。对于详细方案,技术人员参考Graham和Prevac,1991。
用于产生腺病毒载体的替代技术包括利用细菌人工染色体(BAC)系统(利用包含互补腺病毒序列的两个质粒在recA+细菌菌株中进行体内细菌重组),以及酵母人工染色体(YAC)系统(PCT公开95/27071和96/33280,其通过引用并入本文)。
腺病毒易于生长和操纵并且在体外和体内表现出宽的宿主范围。该组病毒可以以高效价获得(例如,大于109个噬菌斑形成单位(pfu)/ml),并且其是高感染的。腺病毒的生命周期不需要整合到宿主细胞基因组中。
可对本文描述的溶瘤腺病毒进行修饰以改进溶瘤腺病毒治疗癌症的能力。Jiang等(Curr Gene Ther.2009Oct 9(5):422-427)已经描述了对溶瘤腺病毒进行的这样的修饰,还参见美国专利申请No.20060147420,其各自通过引用并入本文。
多种肿瘤类型上柯萨奇病毒和腺病毒受体(CAR)的不存在或低水平存在可限制溶瘤性腺病毒的功效。可将多种肽基序添加至纤维蛋白结节,例如RGD基序(RGD序列模拟细胞表面整联蛋白的正常配体)、Tat基序、聚赖氨酸基序、NGR基序、CTT基序、CNGRL基序、CPRECES基序或strept-标签基序(Rouslahti和Rajotte,2000)。可将基序插入腺病毒纤维蛋白的HI环中。修饰衣壳允许不依赖于CAR的靶细胞感染。这允许更高复制、更有效感染以及肿瘤细胞裂解的增加(Suzuki等,2001,通过引用并入本文)。也可添加结合特定人神经胶质瘤受体(例如EGFR或uPR)的肽序列。仅存在于或优选存在于癌细胞表面上的特定受体可用作腺病毒结合和感染的靶标,例如EGFRvIII。
II.表达盒
在本发明的某些实施方案中,本文所述的方法涉及编码TAA的核酸序列,其中所述核酸包含在“表达盒”中。术语“表达盒”意指包括包含编码基因产物(例如,抗原决定簇)之核酸的任意类型的遗传构建体,其中所述核酸编码序列的部分或全部能够进行转录。
启动子和增强子-为了使表达盒实现转录物的表达,核酸编码基因将受启动子的转录控制。“启动子”是控制序列,其是核酸序列中控制转录起始和速率的区域。短语“有效地定位”、“有效地连接”、“受……控制”以及“受……转录控制”意指启动子对于核酸序列处在正确功能位置和/或方向中,以控制该序列的转录起始和/或表达。启动子可与“增强子”结合使用或者也可不与其结合使用,所述增强子是指参与核酸序列转录激活的顺式作用调节序列。
本领域普通技术人员已知的在对象细胞中具有活性的任意启动子都可被考虑为可应用于本发明方法和组合物的启动子。本领域普通技术人员熟悉可以应用于本发明方法和组合物的多种类型的启动子。在某些实施方案中,例如,启动子是组成型启动子、诱导型启动子或阻抑型启动子。启动子还可以是组织选择性启动子。本文定义的组织选择性启动子是指与其他组织类型相比,在某些组织类型中具有相对更多活性的任意启动子。启动子的实例包括CMV启动子。
启动子在细胞中具有活性,并且来自所述启动子的表达导致抗原决定簇向对象的免疫系统呈递。例如,当细胞是上皮细胞时,用于本实施方案的启动子将在该特殊细胞类型中具有活性的启动子。
启动子可以是与基因或序列天然缔合的,因为其可通过分离位于编码区段和/或外显子上游的5′非编码序列获得。这样的启动子可称为“内源性”的。类似地,增强子可以是与核酸序列天然缔合的,位于该序列的下游或上游。或者,通过定位编码核酸区段在重组或异源启动子控制下将得到某些优势,所述启动子指在其自然环境中通常不与核酸序列缔合的启动子。重组或异源增强子也指在其自然环境中通常不与核酸序列缔合的增强子。这样的启动子或增强子可包括其他基因的启动子或增强子,从任意其他原核、病毒或真核细胞中分离的启动子或增强子以及非“天然存在”的启动子或增强子(即包含不同转录调节区的不同元件和/或改变表达的突变)。除了合成地产生启动子和增强子的核酸序列之外,还可使用重组克隆技术和/或核酸扩增技术(包括PCRTM)产生序列(参见美国专利No.4,683,202和No.5,928,906,其各自通过引用并入本文)。
自然地,利用启动子和/或增强子是非常重要的,其有效引导DNA区段在选择用于表达的细胞类型、细胞器和生物体中的表达。分子生物学领域技术人员一般理解使用启动子、增强子以及细胞类型组合来进行蛋白质表达,例如,参见Sambrook等(2001),其通过引用并入本文。启动子可以是异源的或内源的。
采用的控制目的核酸表达的特殊启动子并不被认为是关键的,只要其能够在靶细胞中以足够的水平表达多核苷酸。因此,当靶向人细胞时,优选地使多核苷酸编码区定位于邻近能够在人细胞中表达的启动子并且受所述启动子控制。一般而言,这样的启动子可包括人启动子或病毒启动子。
在多个实施方案中,可使用人巨细胞病毒(CMV)即刻早期基因启动子、SV40早期启动子和劳斯肉瘤病毒长末端重复。只要表达水平足以产生免疫应答,还考虑使用本领域公知的其他病毒或哺乳动物细胞或细菌噬菌体启动子来实现多核苷酸的表达。
本发明的上下文中可采用之启动子/元件的另一些实例包括以下,其并不旨在穷举所有可能的启动子和增强子元件,而仅是其示例性的。
免疫球蛋白重链(Banerji等,1983;Gilies等,1983;Grosschedl等,1985;Atchinson等,1986,1987;Imler等,1987;Weinberger等,1984;Kiledjian等,1988;Porton等;1990)、免疫球蛋白轻链(Queen等,1983;Picard等,1984)、T细胞受体(Luria等,1987;Winoto等,1989;Redondo等;1990)、HLA DQ a和/或DQβ(Sullivan等,1987)、β干扰素(Goodbourn等,1986;Fuiita等,1987;Goodbourn等,1988)、白细胞介素-2(Greene等,1989)、白细胞介素-2受体(Greene等,1989;Lin等,1990)、II类MHC(Koch等,1989)、II类MHCHLA-DRa(Sherman等,1989)、β-肌动蛋白(Kawamoto等,1988;Ng等;1989)、肌肉肌酸激酶(MCK)(Jaynes等,1988;Horlick等,1989;Johnson等,1989);前白蛋白(运甲状腺素蛋白)(Costa等,1988)、弹性蛋白酶I(Omitz等,l 987)、金属硫蛋白(MTlI)(Karin等,1987;Culotta等,1989)、胶原酶(Pinkert等,1987;Angel等,1987)、白蛋白(Pinkert等,1987;Tronche等,1989,1990)、α-甲胎蛋白(Godbout等,1988;Campere等,1989)、t-珠蛋白(Bodine等,1987;Perez-Stable等,1990)、β-珠蛋白(Trudel等,1987)、c-fos(Cohen等,1987);c-HA-ras(Triesman,1986;Deschamps等,1985)、胰岛素(Edlund等,1985)、神经细胞粘附分子(NCAM)(Hirsh等,1990)、α1-抗胰蛋白酶(Latimer等,1990)、H2B(TH2B)组蛋白(Hwang等,1990)、小鼠和/或I型胶原(Ripe等,1989)、葡萄糖调节蛋白(GRP94和GRP78)(Chang等,1989)、大鼠生长激素(Larsen等,1986)、人血清淀粉状蛋白A(SAA)(Edbrooke等,1989)、肌钙蛋白I(TN I)(Yutzey等,1989)、血小板衍生生长因子(PDGF)(Pech等,1989)、杜兴肌营养不良(Klamut等,1990)、SV40(Banerji等,1981;Moreau等,1981;Sleigh等,1985;Firak等,1986;Herr等,1986;Imbra等,1986;Kadesch等,1986;Wang等,1986;Ondek等,1987;Kuhl等,1987;Schaffner等,1988)、多瘤(Swartzendruber等,1975;Vasseur等,1980;Katinka等,1980,1981;Tyndell等,1981;Dandolo等,1983;de Villiers等,1984;Hen等,1986;Satake等,1988;Campbell和/或Villarreal,1988)、逆转录病毒(Kriegler等,1982,1983;Levinson等,1982;Kriegler等,1983,1984a,b,1988;Bosze等,1986;Miksicek等,1986;Celander等,1987;Thiesen等,1988;Celander等,1988;Choi等,1988;Reisman等,1989)、乳头瘤病毒(Campo等,1983;Lusky等,1983;Wilkie,1983;Spalholz等,1985;Lusky等,1986;Cripe等,1987;Gloss等,1987;Hirochika等,1987;Stephens等,1987)、乙型肝炎病毒(Bulla等,1986;Jameel等,1986;Shaul等,1987;Spandau等,1988;Vannice等,1988)、人免疫缺陷病毒(Muesing等,1987;Hauber等,1988;Jakobovits等,1988;Feng等,1988;Takebe等,1988;Rosen等,1988;Berkhout等,1989;Laspia等,1989;Sharp等,1989;Braddock等,1989)、巨细胞病毒(CMV)(Weber等,1984;Boshart等,1985;Foecking等,1986)、长臂猿白血病病毒(Holbrook等,1987;Quinn等,1989)。
增强子最初被检测为增加从位于DNA相同分子远处位置上之启动子转录的遗传元件。增强子与启动子之间的基本区别是操作上的。增强子区作为整体在一定距离下必须能够刺激转录;这对于启动子区或其组成元件并不需要如此。在另一方面,启动子必须具有一个或更多个在特殊位点并且以特殊方向引导RNA合成起始的元件,而增强子缺乏这些特征。启动子和增强子经常是重叠并且相邻的,经常看起来具有非常类似的模块组织。此外,任意启动子/增强子组合(根据真核生物启动子数据库(Eukaryotic Promoter Data Base)EPDB)也可用来驱动基因表达。对响应于特定生理信号而调节之启动子的进一步选择可允许构建体的诱导型表达。例如,受人PAI-1启动子控制的多核苷酸,通过肿瘤坏死因子诱导表达。可响应于特定刺激而激活的核酸序列之区域的诱导型元件的实例包括(元件/诱导物):MT II/佛波醇酯(TFA)或重金属(Palmiter等,1982;Haslinger等,1985;Searle等,1985;Stuart等,1985;Imagawa等,1987,Karin等,1987;Angel等,1987b;McNeall等,1989);MMTV(小鼠乳腺肿瘤病毒)/糖皮质激素(Huang等,1981;Lee等,1981;Majors等,1983;Chandler等,1983;Ponta等,1985;Sakai等,1988);β-干扰素/聚(rI)x或聚(rc)(Tavernier等,1983);腺病毒5E2/E1A(Imperiale等,1984);胶原酶/佛波醇酯(TPA)(Angel等,1987a);溶基质蛋白酶/佛波醇酯(TPA)(Angel等,1987b);SV40/佛波醇酯(TPA)(Angel等,1987b);鼠科MX基因/干扰素,新城疫病毒(Hug等,1988);GRP78基因/A23187(Resendez等,1988);α-2-巨球蛋白/IL-6(Kunz等,1989);波形蛋白/血清(Rittling等,1989);I类MHC基因H-2κb/干扰素(Blanar等,1989);HSP70/E1A、SV40大T抗原(Taylor等,1989,1990a,1990b);增殖蛋白/佛波醇酯-TPA(Mordacq等,1989);肿瘤坏死因子/PMA(Hensel等,1989);以及促甲状腺激素a基因/甲状腺激素(Chatterjee等,1989)。
起始信号-编码序列的有效翻译还可能需要的特定起始信号。这些信号包括ATG起始密码子或相邻序列。可能需要提供外源的翻译控制信号,包括ATG起始密码子。本领域普通技术人员能够很容易地确定其并提供必需的信号。
IRES-在本发明的某些实施方案中,使用内部核糖体进入位点(IRES)元件用来产生多基因或多顺反子信息(message)。IRES元件能够避免5′甲基化帽依赖性翻译的核糖体扫描模型,并且在内部位点开始翻译(Pelletier和Sonenberg,1988)。已经描述了来自微小核糖核酸病毒家族之两个成员(脊髓灰质炎和脑心肌炎)的IRES元件(Pelletier和Sonenberg,1988),还描述了来自哺乳动物信息的IRES(Macejak和Sarnow,1991)。IRES元件可与异源开放阅读框连接。多个开放阅读框可一起转录(各自由IRES隔开),产生多顺反子信息(参见美国专利No.5,925,565和5,935,819)。
多克隆位点-表达盒可包含多克隆位点(MCS),其是包含多个限制酶位点的核酸区域,其中的任何都可与标准重组技术结合使用以消化载体。
聚腺苷酸化信号-在表达中,通常包括聚腺苷酸化信号来实现转录物适当的聚腺苷酸化。聚腺苷酸化信号的性质并不被认为是本发明成功实践的关键,和/或可采用任意这样的序列。优选的实施方案包括SV40聚腺苷酸化信号和/或牛生长激素聚腺苷酸化信号,其在多种靶细胞中是方便的和/或已知是功能良好的。还预期表达盒的一个元件是转录终止位点。这些元件可用来增强信息水平和/或使从该盒到其他序列的整个阅读最小化。
其他表达盒组件-在本发明的某些实施方案中,可通过在表达载体中包含报道基因来在体外鉴定被腺病毒载体感染的细胞。一般地,可选择的报道基因是赋予允许进行选择之性质的基因。阳性可选择报道基因是其中报道基因的存在允许其选择的基因,而阴性可选择报道基因是其中报道基因的存在阻止其选择的基因。阳性可选择标记物的一个实例是药物抗性标记物(赋予新霉素、嘌呤霉素、潮霉素、DHFR、GPT、博莱霉素(zeocin)和组氨醇抗性的基因)。报道基因的其他类型包括可筛选的报道基因,例如GFP。
本发明的实施方案可使用目前的腺病毒平台技术,所述技术被设计成通过制备包含编码肿瘤相关抗原之异源核酸区段的腺病毒核酸来产生疫苗。腺病毒疫苗构建的方面包括将遗传物质插入腺病毒载体中并且通过核酸、病毒和病毒产物的表征和测序来确定构建体。然后使腺病毒疫苗通过设计来评估可扩展性(scalability)的一系列可行性研究。
III.癌抗原
本发明可用于开发基因抗癌免疫法和肿瘤溶解。通过肿瘤相关抗原(TAA)的最新鉴定已经使抗癌症疫苗接种策略的开发合理化,所述肿瘤相关的抗原可被免疫系统识别为癌症细胞的特定标记物,从而鉴定作为靶标的这些细胞。这些肿瘤相关抗原包括由具有对肿瘤细胞独特的突变或重排的基因编码的蛋白质、再激活的胚胎基因、组织特异性分化抗原以及多种其他自身蛋白。然而,尽管鉴定了这些靶标,但是缺少用于针对这些弱的自衍生之抗原成功疫苗接种的手段,在很大程度上限制了有效抗癌疫苗接种策略的发展。因此,产生有力的抗肿瘤相关抗原免疫应答被认为是在开发有效的抗癌免疫策略中的一个关键问题。
本发明的方法在治疗或预防疾病中是有效的。许多疾病具有与疾病状态相关的特定抗原。将这样的抗原或这些抗原的免疫显性表位用于免疫识别并最终消除或控制患者的疾病。这样的抗原在本领域中被称为保护性抗原。
本发明的方法可用来治疗癌症。癌症类型的具体实例包括但不限于神经胶质瘤、黑素瘤、转移瘤(metastases)、腺癌、胸腺瘤(thyoma)、淋巴瘤、肉瘤、肺癌、肝癌、结肠癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、白血病、子宫癌、乳腺癌、前列腺癌、卵巢癌、宫颈癌、膀胱癌、肾癌、胰腺癌等。
术语黑素瘤包括但不限于,黑素瘤、转移性黑素瘤、来源于黑素细胞或黑素细胞相关痣细胞的黑素瘤、黑素癌、黑素上皮癌、黑素肉瘤、原位黑素瘤、表浅蔓延型黑素瘤(superficial spreading melanoma)、结节型黑色素瘤、恶性着色斑型黑素瘤、肢端色斑样黑素瘤、侵袭性黑素瘤或家族性非典型痣和黑素瘤(FAM-M)综合征。哺乳动物中这样的黑素瘤可由染色体异常、退行性生长和发育紊乱、促有丝分裂剂、紫外辐射(UV)、病毒感染、基因的不适当组织表达、基因表达改变、和细胞上的呈递或致癌剂引起。可通过本发明的方法对上述癌症进行评估或治疗。在癌症的情况下,将编码癌症相关抗原的基因与编码一个或更多个免疫刺激分子的基因一起整合到重组病毒基因组或其部分中。可使癌症相关抗原在癌细胞的表面上表达,其可以是分泌型或者可以是内部抗原。在一个实施方案中,癌症相关抗原是肿瘤相关抗原(TAA)或其部分。可用于本发明之TAA的实例包括但不限于黑素瘤TAA,其包括但不限于MART-1(Kawakami等.J.Exp.Med.180:347-352,1994)、MAGE-1、MAGE-3、GP-100、(Kawakami等.Proc.Nat′l.Acad.Sci.U.S.A.91:6458-6462,1994)、CEA、TRP-1、TRP-2、P-15和络氨酸酶(Brichard等.J.Exp.Med.178:489,1993)等。
在某些实施方案中,腺病毒将在其表面上表达多种抗原。在某些方面,可在所述表面上表达2、3、4或5种抗原。所述抗原可作为衣壳或纤维蛋白的一部分表达,或者可作为与自噬相关的蛋白(例如LC3)相连接的外源蛋白产生,以增加外源蛋白在腺病毒感染和复制期间的呈递。靶向多种抗原将帮助产生持久且有效的免疫应答。肿瘤相关抗原(TAA)包括但不限于以下蛋白的肽:EGFRvIII,α甲胎蛋白(AFP),黑素瘤相关抗原-MAGE-1、MAGE-2、MAGE-3,癌胚抗原(CEA)(IIGYVIGTQQATPGPAYSGREII,SEQ ID NO:1),络氨酸酶(Tyr),中期因子(MK),BAGE,CASP-8,β-联蛋白,CA-125,CDK-1,ESO-1,gp75,gp100,MART-1,黏蛋白(MUC-1),MUM-1,p53,PAP,PSA,PSMA,ras,trp-1,HER-2,TRP-2,IL13Rα,AIM-3,NY-ESO1,C9orf112,SART1,BRAP,RTN4,GLEA2,TNKS2,KIAA0376,ING4,HSPH1,C13orf24,RBPSUH,C6orf153,NKTR,NSEP1,U2AF1L,CYNL2,TPR,SOX2或GOLGA。本发明决不限于编码上面列出之TAA的基因。对技术人员而言其他TAA是已知的并且可容易地通过已知方法制备,例如美国专利No.4,514,506中公开的那些。
IV.药物组合物
本发明还提供了包含本发明之任意组合物以及可药用载体的药物组合物。本发明还提供了包含本发明之任意组合物的疫苗组合物。所述疫苗组合物还可包含至少一种佐剂。
本发明还提供了在对象中刺激抗肿瘤免疫应答的方法,其包括将本发明的组合物施用于对象。
根据本发明,将腺病毒与抗原决定簇组合施用于对象以诱导用于治疗或预防目的的免疫应答。因此,在某些实施方案中,将表达构建体配制到适合于此目的的组合物中。短语“药物”或“可药用”是指当施用于动物或人时不产生不利反应、过敏反应或其他不良反应的组合物。本文使用的“可药用载体”包括任意以及所有的溶剂、载体、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。将这样的介质和试剂用于药物活性物质在本领域中是公知的。除了任何常规介质或试剂与本发明的表达构建体是不相容的之外,将其用于治疗组合物是可预期的。还可将补充活性成分合并到组合物中。例如,补充活性成分可以是另外的免疫原性剂。
适于可注射使用的药物形式包括无菌水溶液或分散体以及用于无菌可注射的溶液或分散体之临时制备的无菌粉末。在所有的情况下,形式都必须是无菌的并且必须是在某种程度上以易注射性的流体存在。其在制造和存储的条件下必须是稳定的并且必须保护其免受微生物(例如细菌和真菌)的污染。载体可以是溶剂或分散介质,包括例如水、乙醇、多元醇(如甘油、丙二醇和液体聚乙二醇等)、其合适的混合物以及植物油。如果需要,可使用多种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等。在许多情况下,其将优选地包含等渗剂,例如糖类或氯化钠。可通过将延迟吸收试剂(例如单硬脂酸铝和明胶)用于组合物实现可注射组合物的延长吸收。
通过在适当溶剂中将所需量的化合物与多种以上列举的其他成分(如果需要的话)整合在一起,然后进行过滤除菌来制备无菌可注射溶液。一般地,通过将多种无菌活性成分整合到包含基础分散介质和来自以上列举的那些所需的其他成分的无菌载体中来制备分散体。在用于制备无菌可注射溶液之无菌粉末的情况下,制备的优选方法是真空干燥和冷冻干燥技术,这从其先前经无菌过滤的溶液产生活性成分加上任意额外期望之成分的粉末。
在配制后,溶液将以与剂型相容的方式并且以治疗或预防有效的量施用。对于以水溶液的肠胃外施用而言,应对溶液进行适当缓冲(如果必要的话),并且首先用足够的盐水或葡萄糖使液体稀释液变成等渗的。这些特殊的水溶液特别适合于血管内和瘤内施用。就此而言,根据本公开内容,可采用的无菌水介质对于本领域技术人员是已知的。
根据被治疗对象的病症,必定会发生剂量上的一些变化。在任何情况下,负责施用的人将决定个体对象的适当剂量。此外,对于人施用,制剂应满足FDA所要求的无菌性、热原性、一般安全性和纯度标准。
剂量-基于预期目的来确定治疗剂或预防剂的有效量,例如刺激针对肿瘤的免疫应答。本领域技术人员清楚地知道如何在体内和体外情况下应用基因递送。对病毒载体而言,通常制备病毒载体原液。根据病毒种类和可达到的效价,向对象递送至少约、至多约、或约1×104、1×105、1×106、1×107、1×108、1×109、1×1010、1×1011或1×1012个感染性颗粒,或者其之间的任意值或范围。在另一些方面中,根据本发明的腺病毒可以以单次施用或多次施用来施用。病毒可以以1×105个噬菌斑形成单位(PFU)、5×105PFU、至少1×106PFU、5×106或约5×106PFU、1×107、至少1×107PFU、1×108或约1×108PFU、至少1×108PFU、约或至少5×108PFU、1×109或至少1×109PFU、5×109或至少5×109PFU、1×1010PFU或至少1×1010PFU、5×1010或至少5×1010PFU、1×1011或至少1×1011、1×1012或至少1×1012、1×1013或至少1×1013的剂量施用。例如,病毒可以以约107至1013、约108至1013、约109至1012或约108至1012的剂量施用。
根据本发明的腺病毒可局部或全身施用。例如,非限制的,根据本发明的溶瘤病毒可通过以下途径施用:血管内(动脉内或静脉内)、瘤内、肌内、皮内、腹膜内、皮下、经口、肠胃外、鼻内、气管内、经皮、脊髓内、经眼或颅内。
根据本发明的腺病毒还可以以细胞载体施用。在此方面中,神经元干细胞(neuronal stem cell)和间充质干细胞具有高迁移潜力,但是仍只限于肿瘤组织。已经显示出成人间充质细胞(源于骨髓的肿瘤浸润细胞或BM-TIC)亚群在注射到神经胶质瘤中之后,浸润整个肿瘤。因此,根据本发明的溶瘤病毒可以以产生病毒的神经元或间充质干细胞(例如BM-TIC)载体施用(例如通过将载体细胞注射入肿瘤中)。
根据治疗次数和剂量两者,待施用的量取决于待治疗对象、对象的状态和期望的保护。治疗性组合物的精确量还取决于从业者的判断并且对每一个体是独特的。
还可将编码一种或更多种共刺激/辅助分子的基因和/或编码细胞因子的基因整合到腺病毒基因组中或将其与腺病毒一起配制,用于本发明的方法。共刺激分子的实例包括但不限于B7-1、B7-2、ICAM1、ICAM-2、LFA-1、LFA-3、CD72等。本发明所涵盖的细胞因子的实例包括但不限于受激活调节的正常T细胞表达的IL-2、IL-1、IL-3至IL-9、IL-11、IL-13到IL-15、G-CSF、M-CSF、GM-CSF、TNFα、IFNα、IFNγ、IL-10、IL-12和假定分泌细胞因子(RANTES)等。本发明所涵盖的趋化因子的实例包括但不限于CTAP III、ENA-78、GRO、I-309、PF-4、IP-10、LD-78、MBSA、MIP-1α、MIP1B等。
Claims (23)
1.重组溶瘤腺病毒,其具有包含一个或更多个编码肿瘤抗原之异源核酸序列的基因组,由此所述腺病毒在其表面上表达所述肿瘤抗原以刺激免疫应答,其中所述腺病毒是Δ-24并且其中所述异源核酸插入所述腺病毒六邻体高变区1中、六邻体基因的高变区5中、纤维蛋白基因的H1环区中和/域与蛋白IX缀合。
2.权利要求1所述的重组溶瘤腺病毒,其中所述腺病毒是A-24-RGD。
3.权利要求1所述的重组溶瘤腺病毒,其包含1至5个异源核酸序列,所述异源核酸序列各自编码选自以下的肿瘤抗原或其免疫原性肽:MAGE-1、MAGE-2、MAGE-3、CEA、酪氨酸酶、中期因子、BAGE、CASP-8、β-联蛋白、CA-125、CDK-1、ESO-1、gp75、gp100、MART-1、MUC-1、MUM-1、p53、PAP、PSA、PSMA、ras、trp-1、HER-2、TRP-1、TRP-2、IL13Rα、IL13Rα2、AIM-2、AIM-3、NY-ESO-1、C9orf112、SART1、SART2、SART3、BRAP、RTN4、GLEA2、TNKS2、KIAA0376、ING4、HSPH1、C13orf24、RBPSUH、C6orf153、NKTR、NSEP1、U2AF1L、CYNL2、TPR、SOX2、GOLGA、BMI1、COX-2、EGFRvIII、EZH2、LICAM、Livin、Livinβ、MRP-3、巢蛋白、OLIG2、ART1、ART4、B-细胞周期蛋白、Gli1、Cav-1、组织蛋白酶B、CD74、E-钙黏着蛋白、EphA2/Eck、Fra-1/Fosl 1、GAGE-1、神经节苷脂/GD2、GnT-V、β1,6-N、Ki67、Ku70/80、PROX1、PSCA、SOX10、SOX11、存活蛋白、UPAR和WT-1,由此所述腺病毒在其表面上表达1至5种肿瘤抗原。
4.权利要求1所述的重组溶瘤腺病毒,其包含编码CEA或其免疫原性肽的异源核酸,由此所述腺病毒表达包含CEA或其免疫原性肽的嵌合表面蛋白。
5.权利要求4所述的重组溶瘤腺病毒,其中所述CEA的免疫原性肽是SEQ ID NO:1。
6.权利要求4所述的重组溶瘤腺病毒,其中所述异源核酸序列插入所述腺病毒六邻体基因的高变区5中。
7.权利要求1所述的重组溶瘤腺病毒,其包含编码EGFRvIII或其免疫原性肽的异源核酸序列,由此所述腺病毒表达包含EGFRvIII或其免疫原性肽的嵌合表面蛋白。
8.权利要求7所述的重组溶瘤腺病毒,其中所述EGFRvIII的免疫原性肽选自SEQ IDNO:2至6。
9.权利要求7所述的重组溶瘤腺病毒,其中所述异源核酸序列插入所述腺病毒纤维蛋白基因的H1环区中。
10.权利要求1所述的重组溶瘤腺病毒,其具有包含2至5个各自编码肿瘤抗原之异源核酸序列的基因组,由此所述腺病毒在其表面上表达所述肿瘤抗原。
11.权利要求1所述的重组溶瘤腺病毒,其包含编码MAGE或其免疫原性肽的异源核酸序列。
12.权利要求1所述的重组溶瘤腺病毒,其中所述腺病毒包含E3基因区的部分或全部缺失。
13.权利要求12所述的重组溶瘤腺病毒,其中所述异源核酸序列插入所述腺病毒的E3缺失基因区中,由此所述腺病毒表达MAGE或其免疫原性肽。
14.权利要求1所述的重组溶瘤腺病毒,其包含编码NY-ESO-I或其免疫原性肽的异源核酸序列,由此所述腺病毒表达包含NY-ESO-1或其免疫原性肽的嵌合表面蛋白。
15.权利要求14所述的重组溶瘤腺病毒,其中所述NY-ESO-1的免疫原性肽是SEQ IDNO:7。
16.权利要求14所述的重组溶瘤腺病毒,其中所述异源核酸序列插入所述腺病毒六邻体基因的高变区5中。
17.权利要求1所述的重组溶瘤腺病毒,其具有E3基因区的部分或全部缺失并且具有包含以下的基因组:
a.插入所述腺病毒六邻体基因之高变区5中的编码CEA或其免疫原性肽的异源核酸序列;
b.插入所述腺病毒纤维蛋白基因之H1环区中的编码EGFRvIII或其免疫原性肽的异源核酸序列;
c.插入所述腺病毒之E3缺失基因区中的编码MAGE或其免疫原性肽的异源核酸序列;以及
d.插入所述腺病毒六邻体基因之高变区5中的编码NY-ESO-1或其免疫原性肽的异源核酸序列。
18.权利要求1所述的重组溶瘤腺病毒,其中所述腺病毒是人5型腺病毒或包含人5型腺病毒组分的杂合体。
19.权利要求1至18中任一项所述的重组溶瘤腺病毒用于制造用于在有此需要的患者中治疗癌症之药物的用途,其中所述患者任选地为人患者。
20.权利要求19所述的用途,其中所述患者患有选自以下的癌症:原发性或转移性脑癌、黑素瘤、腺癌、胸腺癌、淋巴瘤、肉瘤、肺癌、肝癌、结肠癌、非霍金奇淋巴瘤、霍金奇淋巴瘤、白血病、子宫癌、乳腺癌、前列腺癌、卵巢癌、宫颈癌、膀胱癌、肾癌和胰腺癌。
21.权利要求20所述的用途,其中所述患者患有低水平或高水平的神经胶质瘤。
22.权利要求19所述的用途,其中通过瘤内、血管内、或者在神经元干细胞或间充质干细胞载体中施用所述腺病毒。
23.权利要求19至22中任一项所述的用途,其中所述腺病毒以108至1013个噬菌斑形成单位(pfu)的剂量施用一次或多次。
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HK1205182A1 (zh) | 2015-12-11 |
BR112014019049A2 (pt) | 2017-07-04 |
AU2013214776B2 (en) | 2017-11-09 |
SG10201606356YA (en) | 2016-09-29 |
ZA201405755B (en) | 2020-05-27 |
CN110042086A (zh) | 2019-07-23 |
KR102100092B1 (ko) | 2020-04-13 |
KR20140125834A (ko) | 2014-10-29 |
CA2863523A1 (en) | 2013-08-08 |
JP2018138033A (ja) | 2018-09-06 |
JP2015506704A (ja) | 2015-03-05 |
ES2759785T3 (es) | 2020-05-12 |
NZ628213A (en) | 2016-10-28 |
SG10201913795TA (en) | 2020-03-30 |
JP6325459B2 (ja) | 2018-05-16 |
WO2013116778A2 (en) | 2013-08-08 |
WO2013116778A3 (en) | 2013-12-19 |
DK2809788T3 (da) | 2019-12-09 |
CN104271748B9 (zh) | 2019-05-24 |
EP2809788A2 (en) | 2014-12-10 |
AU2013214776A1 (en) | 2014-08-21 |
US20140377294A1 (en) | 2014-12-25 |
US11155599B2 (en) | 2021-10-26 |
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CN104271748A (zh) | 2015-01-07 |
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