CN111918660A - 重组病毒疫苗 - Google Patents
重组病毒疫苗 Download PDFInfo
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- CN111918660A CN111918660A CN201980020826.5A CN201980020826A CN111918660A CN 111918660 A CN111918660 A CN 111918660A CN 201980020826 A CN201980020826 A CN 201980020826A CN 111918660 A CN111918660 A CN 111918660A
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Abstract
提供了疫苗,其包含重组病毒和药学上可接受的赋形剂,所述重组病毒表达免疫调节蛋白和与所述重组病毒无关的靶抗原。
Description
相关申请的交叉引用
本专利申请根据35U.S.C.§119(e)要求2018年1月24日提交的美国临时专利申请第62/621,468号的权益,该申请出于所有目的通过引用以其整体并入本文。
发明领域
本发明总体上涉及疫苗,更具体地涉及重组病毒载体,其表达免疫调节蛋白和与所述重组病毒载体无关的靶抗原。
序列表、表格或计算机程序的引用
序列表的正式拷贝作为ASCII格式的文本文件经由EFS-Web与说明书同时提交,文件名称为“VIRO408_ST25.txt”,创建日期为2019年1月22日,并且大小为22.2KB。经由EFS-Web提交的序列表是说明书的一部分,并且通过引用以其整体并入本文。
背景
疫苗或疫苗接种,即施用抗原以刺激对病原体的免疫应答,已经有数百年了。天花(被认为在大约公元前10,000年出现)是许多古代社会的瘟疫。历经几个世纪,人们已经知道天花的幸存者对该疾病具有免疫力,并且号召天花的幸存者照料那些患有该疾病的人。一种成功的用于预防最终发展为天花的方式是“疫苗接种”或“天花接种”,其包括用刺血针或锋利的器械从感染的个体采集样品,以及刺穿未感染对象的皮肤。这样的治疗有助于受试者对随后的感染产生保护性免疫。Edward Jenner博士是1796年发表这样的治疗的第一人,他现在被誉为是天花疫苗的发现者。
从那时起,疫苗得到了迅速发展,其中疫苗被用于许多常见疾病,包括例如水痘(Chickenpox/Varicella)、白喉、流感(流行性感冒)、甲型肝炎和乙型肝炎、流感嗜血杆菌(Hib)、麻疹、流行性腮腺炎、脊髓灰质炎、肺炎球菌、轮状病毒、风疹、破伤风和百日咳(Whooping Cough/Pertussis)。除了通过感染原(infectious agent)预防疾病以外,还开发了用于其它非感染性疾病如癌症的疫苗。特别地,在后一方面,关于预防癌症和治疗癌症之间的界限已经变得模糊,其中可以利用机体的免疫系统来帮助治疗疾病(而不仅仅是预防疾病)。
本发明克服了目前商业疫苗的缺点,并且还提供了另外的出乎意料的益处。
在背景部分中讨论的所有主题不一定是现有技术,并且不应仅仅由于其在背景部分中的讨论而被认为是现有技术。沿着这些思路,除非明确地陈述为现有技术,否则在背景部分中讨论的或与这种主题相关的现有技术中的问题的任何认识均不应被视为现有技术。相反,在背景部分中对任何主题的讨论都应被视为发明人解决特定问题的方法的一部分,这本身也是具有创造性的。
概述
简而言之,本发明提供了包含重组病毒的病毒载体,所述重组病毒表达免疫调节蛋白和与所述重组病毒无关的靶抗原。有利地,在某些实施方案中,病毒载体还可以表达天然病毒分子,其可以起保护性抗原或佐剂的作用以增强宿主的先天免疫系统并诱导针对靶抗原的强健的适应性应答。这样的重组病毒可以用于预防(例如作为疫苗)或治疗由病原体引起的疾病。
在本发明的一个方面,靶抗原来自病原体,如细菌、寄生虫(例如疟疾)或病毒。然而,病原体也可以包括细胞,如癌细胞(或那些细胞上的抗原,如肿瘤抗原)。在本发明的各种实施方案中,靶抗原可以在重组病毒载体的表面上表达,和/或由重组病毒载体分泌。
在本发明的另一方面,重组病毒载体来源于病毒,如腺病毒、单纯疱疹病毒(HSV)、流感病毒、弹状病毒(例如水疱性口炎病毒(VSV))和痘病毒,如牛痘病毒。在本发明的优选实施方案中,如果病原体是病毒,则重组病毒载体可以来源于不同于病原体的病毒。在本发明的各种实施方案中,重组病毒可以是有复制能力的、复制缺陷的、溶瘤的和/或非溶瘤的。
在本发明的其它方面,重组病毒载体表达免疫调节蛋白,如细胞因子、趋化因子、共刺激分子和/或这些中的任何一种或多种的活性片段。
在本发明的其它方面,提供了包含上述重组病毒载体之一的疫苗,以及用于治疗和/或预防由病原体引起的疾病的方法,所述方法包括施用如本文所述的重组病毒载体的步骤。
已经提供本简要概述来以简化的形式介绍某些概念,这些概念将在以下的详述中进一步详细地描述。除非另有明确说明,否则本简要概述不旨在确定所要求保护的主题的关键或必要特征,也不旨在限制所要求保护的主题的范围。
在以下的描述中阐述了一个或多个实施方案的细节。结合一个示例性实施方案示出或描述的特征可以与其它实施方案的特征组合。因此,可以组合本文所述的各种实施方案中的任一个以提供其它实施方案。如果必要的话,可以修改实施方案的方面,以采用如本文所确定的各种专利、申请和出版物的概念来提供另外的实施方案。根据说明书、附图和权利要求书,其它特征、目的和优点将是显而易见的。
附图简述
图1是重组病毒疫苗的一个实施方案的图解说明。
图2是保护性抗原的代表性列表。
发明详述
通过参考本发明的优选实施方案的以下详细描述和本文包括的实施例,可以更容易地理解本发明。
术语“病毒”通常是指一类特征在于其小尺寸(从历史上看,它们是“可过滤的”)和简单组织(通常由DNA或RNA组成并被蛋白外壳或膜性包膜包围)的感染原。适于构建本文所述的重组病毒载体的病毒的代表性实例包括但不限于腺病毒、柯萨奇病毒、H-1细小病毒、单纯疱疹病毒(HSV)、流感病毒、麻疹病毒、粘液瘤病毒、新城疫病毒、细小病毒小核糖核酸病毒、呼肠孤病毒、弹状病毒(例如水疱性口炎病毒(VSV))、副粘病毒如新城疫病毒、小核糖核酸病毒如脊髓灰质炎病毒或塞内卡谷病毒(Seneca valley virus)、痘病毒如牛痘病毒(例如Copenhagen、Indiana Western Reserve和Wyeth毒株)、呼肠孤病毒或逆转录病毒如鼠白血病病毒。其它代表性实例描述于:US 8,147,822和9,045,729(弹状病毒/VSV);US 9,272,008(麻疹病毒);美国专利号7,223,593、7,537,924、7,063,835、7,063,851、7,118,755、8,216,564、8,277,818和8,680,068(疱疹病毒载体);以及US 8,980,246(牛痘病毒),其全部通过引用以其整体并入。
术语“免疫调节蛋白”是指能够改变或调节对象免疫系统的蛋白。免疫调节蛋白可以来源于天然存在的蛋白,如细胞因子、趋化因子和/或共刺激分子(例如,重组产生自编码完整分子或其活性片段的序列)。
免疫调节蛋白的代表性实例包括:a)细胞因子(或其活性片段),如IL-1、IL-2、IL-4、IL-5、IL-6、IL-10、IL-12、IL-15、IL-18、GM-CSF和干扰素γ;b)趋化因子(或其活性片段),如IL-8、SDF-1α、MCP1、MCP2、MCP3和MCP4或MCP5、RANTES、MIP-5、MIP-3、嗜酸性粒细胞趋化因子(eotaxin)、MIP-1α、MIP-1β、CMDC、TARC、LARC或SLC;和/或c)共刺激分子(或其活性片段),如CD80、CD86、ICAM-1、LFA-3、C3d、CD40-L或Flt3L。在本发明的各种实施方案中,免疫调节蛋白可以是可分泌的或连接到重组病毒载体的表面(例如,通过病毒表面蛋白)。
在各种实施方案中,免疫调节蛋白是免疫检查点调节剂(例如,免疫细胞刺激受体的激动剂,如BAFFR、BCMA、CD27、CD28、CD40、CD122、CD137、CD226、CRTAM、GITR、HVEM、ICOS、DR3、LTBR、TACI和/或OX40的激动剂,或者免疫细胞的抑制信号的拮抗剂,如A2AR、BTLA、B7-H3、B7-H4、CTLA4、GAL9、IDO、KIR、LAG3、PD-1、TDO、TIGIT、TIM3和/或VISTA的拮抗剂(参见,例如,“Immune Checkpoint Inhibitors in Cancer”2019Elsevier Inc.,ISBN-13:978-0323549486,将其通过引用以其整体并入)。
术语“靶抗原”是指来自病原体的抗原,其负责对象的疾病状态(或疾病状态的起始)。如上所述,常见的病原体包括细菌、病毒或寄生虫,但也可以包括对象的疾病状态(例如癌症)。可以选择靶抗原的病原体的代表性实例包括:a)来自诸如芽孢杆菌属、巴尔通氏体属、博德特氏菌属(Bordatella)、疏螺旋体属、布鲁氏菌属、弯曲杆菌属、衣原体属和嗜衣原体属(Chlamydophlia)、梭菌属、棒杆菌属、肠球菌属、埃希氏菌属、弗朗西斯氏菌属、嗜血杆菌属、螺杆菌属、军团菌属、钩端螺旋体属、李斯特菌属、分枝杆菌属、支原体属、奈瑟氏菌属、假单胞菌属、立克次氏体属、沙门氏菌属、链球菌属、密螺旋体属、脲原体属、弧菌属和耶尔森氏菌属的细菌;b)来自诸如腺病毒科、沙粒病毒科、布尼亚病毒科、杯状病毒科(Calciviridae)、冠状病毒科、丝状病毒科、黄病毒科、嗜肝病毒科(Hepadnaviridae)、肝炎病毒科(Hepeviridae)、疱疹病毒科、正粘病毒科、副粘病毒科、细小病毒科、乳头瘤病毒科(Papillomaviridae)、小核糖核酸病毒科(Picornoviridae)、多瘤病毒科(Polyomaviridae)、痘病毒科、呼肠孤病毒科、逆转录病毒科、弹状病毒科和披膜病毒科的病毒;和c)寄生虫,包括例如原生动物,如阿米巴、篮氏贾第鞭毛虫(Giardia lamblia)、利什曼原虫(Leshmania spp.)、疟原虫(Plasmodium spp.)、弓形虫(Toxoplasma gondii)、阴道毛滴虫(Trichomonas vaginalis)和锥虫(Trypanosoma spp.)。
本文使用的“肿瘤抗原(tumor antigen)”或“肿瘤抗原(tumor antigens)”是指在肿瘤细胞表面上由MHC I类或II类分子呈递的抗原。仅在肿瘤细胞上发现的抗原被称为“肿瘤特异性抗原”或“TSA”,而肿瘤细胞和正常细胞都呈递的抗原被称为“肿瘤相关抗原”或“TAA”。肿瘤抗原的代表性实例包括但不限于AIM-2、AIM-3、ART1、ART4、BAGE、β1,6-N、β-连环蛋白、β-细胞周期蛋白、BMI1、BRAF、BRAP、C13orf24、C6orfl53、C9orfl12、CA-125、CABYR、CASP-8、组织蛋白酶B、Cav-1、CD74、CDK-1、CEAmidkin、COX-2、CRISP3、CSAG2、CTAG2、CYNL2、DHFR、E-钙粘蛋白、EGFRvIII、EphA2/Eck、ESO-1、EZH2、Fra-1/Fosl 1、FTHL17、GAGE1、神经节苷脂/GD2、GLEA2、Glil、GnT-V、GOLGA、gp75、gplOO、HER-2、HSPH1、IL13Rα、IL13Rα2、ING4、Ki67、KIAA0376、Ku70/80、LDHC、LICAM、Livin、MAGE-A1、MAGE-2、MAGE-A3、MAGE-B6、MAPPK1、MART-1、MICA、MRP-3、MUC-1、MUM-1、巢蛋白、NKTR、NLRP4、NSEP1、NY-ES-01、OLIG2、p53、PAP、PBK、PRAME、PROX1、PSA、PSCA、PSMA、ras、RBPSUH、RTN4、SART1、SART2、SART3、SOX10、SOX11、SOX2、SPANXA1、SSX2、SSX4、SSX5、生存素、TNKS2、TPR、TRP-1、TRP-2、TSGA10、TSSK6、TULP2、酪氨酸酶、U2AF1L、UPAR、WT-1、XAGE2和ZNF165。
在本发明的某些实施方案中,CEACAM6、CEACAM5、NY-ESO-1和EpCAM被用作肿瘤靶向的表面标志物。简而言之,CEACAM6和CEACAM5(癌胚抗原相关细胞粘附分子)是起细胞间粘附分子作用的细胞表面糖蛋白。EpCAM(上皮细胞粘附分子)是介导同型细胞-细胞粘附的跨膜糖蛋白。EpCAM在大多数上皮来源的新生物中高度表达,并且已经被用作多种癌的诊断和预后标志物。EpCAM通过促进细胞增殖和转移以及通过转录上调癌基因c-myc和细胞周期蛋白A/E在癌形成中发挥作用。NY-ESO-1(纽约食道鳞状细胞癌1)是众所周知的在许多癌症类型中再表达的睾丸癌抗原。
术语“保护性抗原”是指病毒抗原,其由宿主的获得性免疫系统特异性靶向,并且当被引入宿主体内时,能够刺激针对某些病原体或其他疾病的病因的抗体和/或细胞介导的免疫的产生。保护性抗原的代表性实例包括但不限于在Yang等人,Nucleic AcidsResearch,2011;39(suppl_1):D1073-D1078中公开的那些,将其通过引用以其整体并入本文。在一个实施方案中,保护性抗原的代表性列表示于图2中。
本文使用的“治疗(treat)”或“治疗(treating)”或“治疗(treatment)”意指获得有益或期望结果(包括临床结果)的方法。有益的或期望的临床结果可以包括但不限于减轻或改善一种或多种症状或病况、减少疾病程度、稳定(即不恶化)疾病状态、预防疾病传播、延缓或减缓疾病进展、改善或缓和疾病状态、减少疾病复发以及缓解(无论是部分或全部),无论是可检测的或不可检测的。术语“治疗(treating)”和“治疗(treatment)”也可以意指与未接受治疗的预期存活相比延长存活。
术语“癌症”是指由对象中的细胞的不受控制或异常生长引起的疾病状态。癌症的代表性形式包括癌、白血病、淋巴瘤、骨髓瘤和肉瘤。其它实例包括但不限于胆管癌,脑癌(例如胶质母细胞瘤),乳腺癌,宫颈癌,结肠直肠癌,CNS癌症(例如听神经瘤、星形细胞瘤、颅咽管瘤(craniopharyogioma)、室管膜瘤、胶质母细胞瘤、成血管细胞瘤、成神经管细胞瘤、menangioma、成神经细胞瘤、少突神经胶质瘤、松果体瘤和视网膜母细胞瘤),子宫内膜衬癌,造血细胞癌(例如白血病和淋巴瘤),肾癌,喉癌,肺癌,肝癌,口腔癌,卵巢癌,胰腺癌,前列腺癌,皮肤癌(例如黑色素瘤和鳞状细胞癌)和甲状腺癌。癌症可以包括实体瘤(例如,肉瘤,如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤和成骨肉瘤),弥漫性肿瘤(例如,白血病)或这些肿瘤的一些组合(例如,具有实体瘤和播散性或弥漫性癌细胞的转移性癌症)。癌症也可以耐受常规治疗(例如常规化疗和/或放射治疗)。
为了进一步理解本文提供的本发明的各个方面,以下提供下述部分:A.重组病毒载体;B.靶抗原和免疫调节蛋白;C.治疗组合物/疫苗;以及D.施用。
A.重组病毒载体
如上所述,本发明提供了包含重组病毒的病毒载体,所述重组病毒表达免疫调节蛋白和与重组病毒无关的靶抗原。适于构建本文所述的重组病毒载体的病毒的代表性实例包括但不限于腺病毒、柯萨奇病毒、H-1细小病毒、单纯疱疹病毒(HSV)、流感病毒、麻疹病毒、粘液瘤病毒、新城疫病毒、细小病毒小核糖核酸病毒、呼肠孤病毒、弹状病毒(例如水疱性口炎病毒(VSV))、副粘病毒如新城疫病毒、小核糖核酸病毒如脊髓灰质炎病毒或塞内卡谷病毒、痘病毒如牛痘病毒(例如Copenhagen、Indiana Western Reserve和Wyeth毒株)、呼肠孤病毒或逆转录病毒如鼠白血病病毒。
在本发明的优选实施方案中,重组病毒载体来源于单纯疱疹病毒。简而言之,单纯疱疹病毒(HSV)1和2是感染人的疱疹病毒科的成员。HSV基因组含有两个独特的区域,其被指定为独特的长(UL)区域和独特的短(US)区域。这些区域中的每一个侧接有一对反向末端重复序列。有约75个已知的开放阅读框。已经对病毒基因组进行了工程化以开发用于例如癌症治疗的病毒。可以通过HSV ICP34.5(也称为γ34.5)基因的突变赋予HSV的肿瘤选择性复制。HSV含有两个拷贝的ICP34.5。已知灭活ICP34.5基因的一个或两个拷贝的突变体缺乏神经毒性,即是无毒性的/非神经毒性的并且是溶瘤的。
合适的HSV可以来源于HSV-1或HSV-2,包括任何实验室毒株或临床分离物。在一些实施方案中,HSV可以是或可以来源于实验室毒株HSV-1毒株17、HSV-1毒株F、HSV-1毒株KOS、HSV-1毒株McKrae或HSV-2毒株HG52中的一种。在其它实施方案中,它可以是或来源于非实验室毒株JS-1。其它合适的HSV-1病毒包括HrrR3(Goldstein和Weller,J.Virol.62,196-205,1988);G2O7(Mineta等人,Nature Medicine.1(9):938-943,1995;Kooby等人,TheFASEB Journal,13(11):1325-1334,1999);G47Delta(Todo等人,Proceedings of theNational Academy of Sciences.2001;98(11):6396-6401);HSV 1716(Mace等人,Head&Neck,2008;30(8):1045-1051;Harrow等人,Gene Therapy.2004;11(22):1648-1658);HF10(Nakao等人,Cancer Gene Therapy.2011;18(3):167-175);NV1020(Fong等人,MolecularTherapy,2009;17(2):389-394);T-VEC(Andtbacka等人,Journal of Clinical Oncology,2015:33(25):2780-8);J100(Gaston等人,PloS one,2013;8(11):e81768);M002(Parker等人,Proceedings of the National Academy of Sciences,2000;97(5):2208-2213);NV1042(Passer等人,Cancer Gene Therapy.2013;20(1):17-24);G2O7-IL2(Carew等人,Molecular Therapy,2001;4(3):250-256);rQNestin34.5(Kambara等人,CancerResearch,2005;65(7):2832-2839);G47Δ-mIL-18(Fukuhara等人,Cancer Research,2005;65(23):10663-10668);以及公开于标题为“在癌细胞中具有增强的复制的HSV载体(HSV Vectors with Enhanced Replication in Cancer Cells)”的PCT申请PCT/US2017/030308和标题为“使用Stat1/3抑制剂和溶瘤疱疹病毒的组合物和方法(Compositions andMethods of Using Stat1/3Inhibitors with Oncolytic Herpes Virus)”的PCT/US2017/018539中的那些载体,所有以上文献通过引用以其整体并入。
HSV载体可以具有至少一个γ34.5基因的修饰、突变或缺失。在一些实施方案中,两个基因都被缺失、突变或修饰。在其它实施方案中,一个被缺失,而另一个被突变或修饰。可以缺失天然γ34.5基因任一个。在一个实施方案中,缺失包含γ34.5基因和ICP4基因的末端重复。突变(如核苷酸改变、插入和缺失)可以用于使基因不可表达或使产物失活。γ34.5基因可以在其3'UTR中用miRNA靶序列修饰。靶序列结合miRNA,该miRNA在肿瘤细胞中以低于其正常对应物中的水平表达。在一些实施方案中,修饰的或突变的γ34.5基因在体外构建并插入HSV载体作为病毒基因的替换物。当修饰的或突变的γ34.5基因仅是一个γ34.5基因的替换物时,缺失另一个γ34.5。γ34.5基因可以包含另外的变化,如具有外源启动子。在进一步的实施方案中,可以例如经由添加外源性5'UTR,如大鼠FGF-25'UTR翻译调节γ34.5基因。这种5'UTR形成二级发夹结构,其可以在存在足够的真核起始因子(eIF)4E/eIF4F复合物的情况下解旋,导致mRNA的翻译起始。已知eIF4E蛋白(eIF4F复合物的一部分)在多种癌症类型中过表达。在本发明的其它实施方案中,可以在不修饰γ34.5基因的情况下通过使用首先阻止病毒进入神经元的突变,例如通过缺失糖蛋白K的氨基酸31-68来阻止神经毒性。
HSV可以具有另外的突变,所述突变可以包括失效突变(disabling mutation)(例如,缺失、取代、插入),其可以影响病毒的毒力或其复制能力。例如,可以在ICP6、ICPO、ICP4、ICP27、ICP47、ICP 24、ICP56中的任何一个或多个中进行突变。优选地,这些基因之一的突变(适当的时候任选地在基因的两个拷贝中在)导致HSV不能(或能力降低)表达相应的功能多肽。在一些实施方案中,病毒基因的启动子可以被在靶细胞中具有选择性活性,或者在递送诱导物时可诱导的,或者在细胞事件或特定环境中可诱导的启动子取代。在特定的实施方案中,肿瘤特异性启动子驱动HSV复制所必需的病毒基因的表达。在某些实施方案中,ICP4或ICP27或两者的表达由外源启动子,例如肿瘤特异性启动子控制。示例性的肿瘤特异性启动子包括CEA、CXCR4、TERT、生存素或端粒酶;其它合适的肿瘤特异性启动子可以对单一肿瘤类型具有特异性,并且是本领域已知的。可以存在其它元件。在一些情况下,诸如NF-kB/OCT4/SOX2增强子的增强子存在于例如ICP4或ICP27或两者的调节区中。5'UTR也可以是外源的,如来自生长因子基因如FGF的5'UTR。
HSV也可以具有原本非HSV的基因和核苷酸序列。例如,编码上述靶抗原之一、免疫调节蛋白、前药的序列、编码细胞因子或其它免疫刺激因子的序列、肿瘤特异性启动子、诱导型启动子、增强子、与宿主细胞同源的序列等可以在HSV基因组中。示例性序列编码IL12、IL15、OX40L、PD-L1阻断剂或PD-1阻断剂。对于编码产物的序列,它们与启动子序列和表达所必需或期望的其它调节序列(例如,增强子、聚腺苷酸化信号序列)可操作地连接。
可以修饰病毒基因的调节区以包含影响表达的应答元件。示例性应答元件包括NF-κB、Oct-3/4-SOX2的应答元件、增强子、沉默子、cAMP应答元件、CAAT增强子结合序列和绝缘子。也可以包括其它应答元件。可以用不同的启动子替换病毒启动子。启动子的选择将取决于许多因素,如所提议的HSV载体的使用、患者的治疗、疾病状态或状况以及应用诱导物(对于诱导型启动子)的容易性。对于癌症的治疗,通常当启动子被替换时,将用细胞特异性或组织特异性或肿瘤特异性启动子替换。肿瘤特异性、细胞特异性和组织特异性启动子是本领域已知的。也可以修饰其它基因元件。例如,可以用外源UTR替换病毒基因的5'UTR。
HSV载体的代表性实例描述于PCT/2017/018539、PCT/US2017/030308、PCT/US2017/044993、PCT/US2018/061687、USSN15/374893和USSN 15/588616中,其全部通过引用以其整体并入。
B.靶抗原和免疫调节蛋白
如上所述,本发明提供了表达期望的靶抗原和免疫调节蛋白(两者均在上文进行了详细讨论)的重组病毒载体。在本发明的各种实施方案中,靶抗原和/或免疫调节蛋白可以从重组病毒载体分泌,和/或在病毒表面上表达(例如,通过与病毒表面蛋白融合)。
例如,在本发明的一个实施方案中,产生在包膜蛋白的胞外域中具有缺失的HSV重组病毒载体(例如,通过同源重组技术容易地产生gC、gD或gG。具体地,使用在克隆到细菌人工染色体(BAC)中的HSV-1基因组上实施的λRed介导的重组工程系统进行病毒诱变。利用这种方法,可以将期望的靶抗原或免疫调节蛋白连接到截短的gC、gD或gG上以在病毒载体的表面上表达。
在本发明的其它实施方案中,还可以通过将靶抗原和/或免疫调节蛋白插入病毒包膜蛋白的胞外域而没有病毒包膜蛋白的任何截短来产生HSV重组病毒载体。
用于插入靶抗原和/或免疫调节蛋白的代表性病毒载体和位点也描述于2017年4月29日提交的PCT申请号PCT/US2017/030308中,将其在此通过引用以其整体并入。
C.治疗组合物/疫苗
如上所述,本发明提供了包含本文所述的重组病毒载体之一以及药学上可接受的赋形剂的疫苗。短语“药学上可接受的载体”意在涵盖不干扰病毒的生物活性的效力并且对其所施用的对象无毒的任何载体、稀释剂或赋形剂(一般参见Remington:The Science andPractice of Pharmacy,Lippincott Williams&Wilkins;21st ed.(May 1,2005and inThe United States PharmacopE1A:The National Formulary(USP 40–NF 35andSupplements)。
在本文所述的疫苗的情况下,合适的药物载体的非限制性实例包括磷酸盐缓冲盐水溶液、水、乳剂(如油/水乳剂)、各种类型的润湿剂、无菌溶液等。另外的药学上可接受的载体包括凝胶、可生物吸附的基质材料、含有病毒的植入元件或者任何其它合适的媒介物、递送或分配装置或材料。这样的载体可以通过常规方法配制并且可以以有效剂量施用于对象。另外的药学上可接受的赋形剂包括但不限于水、盐水、聚乙二醇、透明质酸和乙醇。药学上可接受的盐也可以包括在其中,例如无机酸盐(如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐等)和有机酸的盐(如乙酸盐、丙酸盐、丙二酸盐、苯甲酸盐等)。可以用于将HSV递送至靶癌细胞的这种药学上可接受的(药物级)载体、稀释剂和赋形剂将优选地不在接受组合物的个体(对象)中诱导免疫应答(并且将优选地在没有过度毒性的情况下施用)。
本文提供的组合物可以以各种浓度提供。例如,可以提供范围为约106至约109pfu/ml的重组病毒剂量。在进一步的实施方案中,剂量的范围可以为约106至约108pfu/ml,在每2-3周的治疗中,向具有大病变(例如,>5cm)的患者中注射入多达4ml以及向具有小病变(例如,<0.5cm)的患者中注射入较小的量(例如,至多0.1ml)。
在本发明的某些实施方案中,可以使用比标准更低的剂量。因此,在某些实施方案中,可以向患者施用小于约106pfu/ml(每2-3周将多达4ml注射入到患者中)。
组合物可以在有利于稳定储存寿命的温度下储存,并且所述温度包括室温(约20℃)、4℃、-20℃、-80℃和在液氮中。因为旨在体内使用的组合物通常不含防腐剂,所以储存通常在较冷的温度下进行。组合物可以干燥(例如冻干)或以液体形式储存。
D.施用
除了本文所述的组合物以外,如上所述,本发明提供了针对病原体接种对象的方法,其包括向对象施用有效量的本文所述的一种重组病毒载体的步骤。
术语“有效剂量”和“有效量”是指足以防止对象感染有毒病原体(例如,如本文所述的被细菌、病毒或寄生虫感染)的重组病毒载体的量。在其它实施方案中,术语“有效剂量”和“有效量”是指足以实现靶向癌症的治疗的重组病毒载体的量,例如有效降低靶向肿瘤大小或负荷或者以其它方式阻碍靶向肿瘤细胞生长速率的量。
更具体地,这样的术语是指在必要的剂量和治疗周期有效地获得期望结果的病毒的量。例如,在治疗癌症的背景下,本文所述的组合物的有效量是诱导缓解、减轻肿瘤负荷和/或防止肿瘤扩散或癌症生长的量。
有效量可以根据诸如对象的疾病状态、年龄、性别和体重以及药物制剂、施用途径等因素而变化,但仍可由本领域技术人员常规确定。
本文使用的术语“治疗(treat)”或“治疗(treating)”或“治疗(treatment)”意指获得有益或期望结果(包括临床结果)的方法。有益的或期望的临床结果可以包括但不限于减轻或改善一种或多种症状或病况、减轻疾病程度、稳定(即不恶化)疾病状态、预防疾病传播、延缓或减缓疾病进展、改善或缓和疾病状态、减少疾病复发以及缓解(无论是部分或全部),无论是可检测的或不可检测的。术语“治疗(treating)”和“治疗(treatment)”也可以意指与未接受治疗的预期存活相比延长的存活。
在本发明的优选实施方案中,根据疫苗的类型通过多种途径(例如肌内、皮下或透皮)施用疫苗。
病毒的最佳或适当的剂量方案在本领域的技术范围内由主治医师基于患者数据、患者观察和各种临床因素(包括例如对象的尺寸、体表面积、年龄、性别和所施用的具体病毒、施用的时间和途径、所治疗的癌症类型、患者的总体健康状况以及患者经受的其它药物治疗)容易地确定。
以下是本公开内容的另外的示例性实施方案:
1)重组病毒载体,其包含重组病毒,所述重组病毒表达免疫调节蛋白和与所述重组病毒无关的靶抗原。如本文所用,应理解,如果靶抗原来源于与重组病毒不同的物种,则靶抗原与重组病毒是“无关的”。在某些实施方案中,靶抗原来自细菌。在相关的实施方案中,靶抗原是保护性抗原,其代表性实例示于图2中。在其它实施方案中,保护性抗原来源于图2中示出的有机体之一。本文所述的靶抗原可以包括完整的蛋白序列或其片段(例如,图2中示出的抗原的免疫活性片段)。
2)根据实施方案1所述的病毒载体,其中所述病毒选自腺病毒、牛痘病毒和疱疹病毒。
3)根据实施方案1或2所述的病毒载体,其中所述病毒是具有复制能力的病毒。在相关的实施方案中,病毒可以是减毒的(例如通过UV),或者被有条件地调节(例如,它主要在肿瘤组织中复制,而不在正常组织中复制)。
4)根据实施方案1或2所述的病毒载体,其中所述病毒是复制缺陷的病毒。
5)根据实施方案1至4中任一项所述的病毒载体,其中所述靶抗原在所述病毒的表面上表达。在本发明的其它实施方案中,靶抗原可以从病毒载体分泌。
6)根据实施方案5所述的病毒载体,其中所述靶抗原与病毒糖蛋白融合。在其它实施方案中,免疫调节蛋白与病毒糖蛋白融合。在本发明的其它实施方案中,靶抗原(例如,图2中示出的抗原或来自图2中示出的有机体的抗原)可以与包膜糖蛋白融合或以其它方式与包膜糖蛋白组合(参见,例如,PCT/US2018/061687,将其通过引用以其整体并入)。
7)根据实施方案6所述的病毒载体,其中所述重组病毒是疱疹病毒,并且所述病毒糖蛋白是选自gB、gC、gD、gE、gG、gI、gJ、gK、gM、gN、UL20、UL24、UL43、UL45、UL56和US9的包膜蛋白。
8)根据实施方案1至7中任一项所述的病毒载体,其中所述靶抗原是来自与所述重组病毒载体的亲本病毒无关的病毒的抗原。如本文所用,“无关”病毒是与重组病毒载体不同物种的病毒。在其它实施方案中,“无关”病毒可以来自重组病毒载体不同的界、亚界、门、亚门、纲、亚纲、目、亚目、科、亚科、属或亚属。
9)根据实施方案1至7中任一项所述的病毒载体,其中所述靶抗原来自细菌或寄生虫。
10)根据实施方案1至7中任一项所述的病毒载体,其中所述靶抗原是肿瘤抗原。
11)根据实施方案1至7中任一项所述的病毒载体,其中所述重组病毒载体表达多种靶抗原。在本发明的某些实施方案中,靶抗原可以来源于有机体的不同变体或毒株(例如,来自不同的流感毒株)。
12)根据实施方案1至11中任一项所述的病毒载体,其中所述免疫调节蛋白是细胞因子、趋化因子、共刺激分子或这些中任一种的活性片段。免疫调节蛋白的代表性实例包括IL-12、IL-15、IL-15Rα。其它代表性实例包括免疫检查点调节剂,其示例性实例包括检查点调节剂(例如,针对PD-1、PD-L1、VISTA、TIM3、TIGIT的肽或抗体)、TNF-α、TLR激动剂、TGF-b拮抗剂和OX40配体。
13)根据实施方案11所述的病毒载体,其中所述免疫调节蛋白是从所述病毒载体分泌的。
14)疫苗,其包含实施方案1至13中任一项所述的病毒载体以及药学上可接受的赋形剂。
15)针对病原体为对象接种疫苗的方法,其包括施用有效量的实施方案14所述的疫苗的步骤,所述疫苗表达来自所述病原体的靶抗原。
本文引用或提及的所有专利、出版物、科学文章、网站和其它文献和材料指示了本发明所属领域的技术人员的技术水平,并且每个这样的引用文献和材料在此通过引用并入,其程度如同其单独地通过引用以其整体并入或者在本文以其整体示出。申请人保留将来自任何这样的专利、出版物、科学文章、网站、电子可获得的信息和其它参考材料或文献的任何和所有材料和信息以物理方式并入本说明书的权利。
本专利的书面描述部分包括所有权利要求。此外,所有权利要求(包括所有原始权利要求以及来自任何和所有优先权文件的所有权利要求)在此通过引用以其整体并入说明书的书面描述部分中,并且申请人保留将任何和所有这样的权利要求以物理方式并入本申请的书面描述或任何其它部分中的权利。因此,例如,在任何情况下,该专利都不能被解释为关于主张该权利要求的精确措辞未示于该专利的书面描述部分中而声称未提供权利要求的书面描述。
将根据法律解释权利要求。然而,尽管声称或感知到容易或难于解释任何权利要求或其部分,但在任何情况下,在对导致本专利的一个或多个申请进行审查期间,对权利要求或其任何部分的任何调整或修改都不能被解释为对不形成现有技术的一部分的任何及其所有等同物丧失任何权利。
本说明书中公开的所有特征可以以任何组合方式组合。因此,除非另有明确说明,否则所公开的每个特征仅是等同或类似特征的一般系列的示例。
应理解,虽然已经结合本发明的详述描述了本发明,但上述描述旨在说明而不是限制由所附权利要求书的范围限定的本发明的范围。因此,从上文将理解,虽然为了说明的目的在本文中已经描述了本发明的具体非限制性实施方案,但可以在不脱离本发明的精神和范围的情况下进行各种修改。其它方面、优点和修改在所附权利要求的范围内,并且除了所附权利要求之外,本发明不受限制。
本文所述的具体方法和组合物代表了优选的非限制性实施方案,是示例性的,并且不旨在限制本发明的范围。其它目的、方面和实施方案在本领域技术人员考虑本说明书时将会被想到,并且被涵盖在由权利要求的范围限定的本发明的精神内。对于本领域技术人员将显而易见的是,在不脱离本发明的范围和精神的情况下,可以对本文公开的发明进行各种取代和修改。本文中示例性描述的发明可以在不存在任何一个或多个要素、或者一个或多个限制的情况下合适地实施,所述要素或限制在本文中没有具体公开为是必要的。因此,例如,在本文的每个实例中,在本发明的非限制性实施方案或实例中,术语“包含(comprising)”、“包括(including)”“含有(containing)”等应被广泛地理解而不受限制。本文示例性描述的方法和过程可以以不同的步骤顺序来实施,并且它们不必限于在本文中或权利要求中指出的步骤顺序。
已经使用的术语和表述被用作描述性的术语而非限制性的,并且在使用这样的术语和表述时没有意图排除示出和描述的特征或其部分的任何等同物,但是应认识到,在所要求保护的本发明的范围内,各种修改是可能的。因此,应理解,虽然通过各种非限制性实施方案和/或优选的非限制性实施方案和任选的特征具体公开了本发明,但本领域技术人员可以采用的本文公开的概念的任何和所有修改和变型都被认为在由所附权利要求限定的本发明的范围内。
本文中已经广泛地和一般地描述了本发明。落入一般性公开内容内的较窄种类和亚属组群中的每一个也形成了本发明的一部分。这包括本发明的一般描述,其附带条件或负面限制是从属中去除任何主题,而不管切离的材料是否在本文中具体叙述。还应理解,如本文和所附权利要求中所用,单数形式“一个/一种(a)”、“一个/一种(an)”和“所述”包括复数指代物,除非上下文另外明确规定;术语“X和/或Y”意指“X”或“Y”或“X和Y”两者,以及名词后的字母“s”指定该名词的复数和单数形式。另外,其中本发明的特征或方面按照马库什组(Markush group)描述,意图是并且本领域技术人员将认识到本发明包含并且也按照马库什组中的任何单个成员和成员的任何亚组来描述,并且申请人保留修改本申请或权利要求的权利以具体地指代马库什组的任何单个成员或成员的任何亚组。
其它非限制性实施方案在所附权利要求范围内。该专利不能被解释为限于本文具体和/或明确公开的具体实例或非限制性实施方案或方法。在任何情况下,该专利都不能被解释受到由专利商标局的任何审查员或任何其它官员或雇员作出的任何声明的限制,除非这样的声明是申请人在答复性书面文件中特别且无限制或保留地明确采用的。
实施例
使用本领域技术人员熟悉的标准分子克隆和重组技术产生所有构建体。
实施例1
具有表面结合的肿瘤抗原的重组病毒疫苗的设计
可以工程化重组病毒疫苗,其中CEACAM5和/或MUC1蛋白或其片段与HSV-1病毒颗粒的表面融合,如图1中的简化形式所示。在一个实施方案中,缺乏信号肽以及跨膜和细胞质结构域的CEACAM5和/或MUC1片段与HSV-1表面糖蛋白融合。例如,包含胞外结构域的CEACAM5蛋白(SEQ ID NO:1)的氨基酸36-681与信号肽下游位置处的糖蛋白C(gC)或糖蛋白D(gD)的胞外结构域框内融合。在另一个实施方案中,包含胞外结构域的MUC1蛋白(SEQ IDNO:2)的氨基酸33-387与信号肽下游位置处的gC或gD的胞外结构域框内融合。
实施例2
诱导肿瘤抗原分泌的重组病毒疫苗的设计
在重组病毒疫苗的另一个实施方案中,将编码CEACAM5和/或MUC1的转基因克隆到HSV-1基因组中,使得重组蛋白产物由感染的细胞表达和分泌。将编码CEACAM5和/或MUC1(包括信号肽)的胞外结构域的表达盒在以下一个位置插入HSV-1基因组:UL3和UL4之间、UL50和UL51之间、US1和US2之间、UL7和UL8之间、UL10和UL11之间、UL15和UL18之间、UL21和UL22之间、UL26和UL27之间、UL35和UL36之间、UL40和UL41之间、UL45和UL46之间、UL55和UL56之间或Us9和US10之间。
对于CEACAM5抗原,使用编码包含CEACAM5的胞外结构域(包括信号肽)的氨基酸1-681(SEQ ID NO:3)的核酸,而对于MUC1抗原,使用编码包含MUC1的胞外结构域(包括信号肽)的氨基酸1-287(SEQ ID NO:4)的核酸。构建不表达任何转基因的另外的重组病毒,以用作阴性对照。
实施例3
具有表面结合的细菌抗原的重组病毒疫苗的设计
在针对感染性疾病的重组病毒疫苗的一个实施方案中,来自伯氏疏螺旋体(Borrelia burgdorferi)(莱姆病的病原体)的OspA脂蛋白在HSV-1病毒颗粒的表面上表达。在该实施方案中,缺乏信号肽(SEQ ID NO:5)的全长OspA蛋白与HSV-1表面糖蛋白,如糖蛋白C(gC)或糖蛋白D(gD)在信号肽下游的位置处框内融合。
实施例4
诱导细菌抗原分泌的重组病毒疫苗的设计
在针对感染性疾病的重组病毒疫苗的另一个实施方案中,将编码来自伯氏疏螺旋体(莱姆病的病原体)的OspA脂蛋白的核酸克隆到HSV-1基因组中,使得蛋白产物由感染的细胞表达和分泌。将编码包含氨基酸1-273(SEQ ID NO:6)的完整OspA蛋白的表达盒在以下一个位置插入HSV-1基因组:UL3和UL4之间、UL50和UL51之间、US1和US2之间、UL7和UL8之间、UL10和UL11之间、UL15和UL18之间、UL21和UL22之间、UL26和UL27之间、UL35和UL36之间、UL40和UL41之间、UL45和UL46之间、UL55和UL56之间或Us9和US10之间。
实施例5
重组病毒疫苗的分析
使用凝胶过滤、离心、切向流过滤或其它方法的组合来纯化所有重组病毒。利用动物模型测试每一种疫苗候选物。使用范围为107-109pfu/小鼠的病毒剂量经由皮下、肌内、腹膜内和/或皮内注射免疫BALB/c和C57B/6小鼠。测试1-3个剂量的范围,剂量之间间隔1周。在不同的时间点(免疫前、免疫后5天、免疫后7天、免疫后14天、免疫后21天和免疫后28天)从免疫的小鼠收集血清。ELISA用于测量对免疫抗原的体液免疫应答。基于ELISA结果和检测到的血清抗体滴度,收集脾细胞以使用IFN-γ和IL-2ELISPOT测定来测试细胞免疫应答。用感染原(在来源于病原体的抗原的情况下)或用表达肿瘤相关抗原的肿瘤细胞系(在基于TAA的疫苗的情况下)攻击免疫的小鼠。
序列表
<110> 复诺健生物科技加拿大有限公司(Virogin Biotech Canada Ltd.)
<120> 重组病毒疫苗
<130> VIRO.408PC
<150> US 62/621,468
<150> 2018-01-24
<160> 6
<170> PatentIn version 3.5
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<400> 1
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Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr Arg Asn Asp Thr
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Ser Pro Leu Asn Thr Ser Tyr Arg Ser Gly Glu Asn Leu Asn Leu Ser
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Val Asn Asn Ser Gly Ser Tyr Thr Cys Gln Ala His Asn Ser Asp Thr
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Ser Ala Pro Asp Asn Lys Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala
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His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr
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Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Asn Arg Pro Ala
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Leu Gly Ser Thr Ala Pro Pro Val His Asn Val Thr Ser Ala Ser Gly
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Ser Ala Ser Gly Ser Ala Ser Thr Leu Val His Asn Gly Thr Ser Ala
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Arg Ala Thr Thr Thr Pro Ala Ser Lys Ser Thr Pro Phe Ser Ile Pro
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Ser His His Ser Asp Thr Pro Thr Thr Leu Ala Ser His Ser Thr Lys
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Thr Asp Ala Ser Ser Thr His His Ser Thr Val Pro Pro Leu Thr Ser
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Ser Asn His Ser Thr Ser Pro Gln Leu Ser Thr Gly Val Ser Phe Phe
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Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn
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Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly
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Val Pro Gly
385
<210> 5
<211> 257
<212> PRT
<213> 伯氏疏螺旋体(Borrelia burgdorferi)
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Asp Leu Pro Gly Glu Met Lys Val Leu Val Ser Lys Glu Lys Asn Lys
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Asp Gly Lys Tyr Asp Leu Ile Ala Thr Val Asp Lys Leu Glu Leu Lys
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Gly Thr Ser Asp Lys Asn Asn Gly Ser Gly Val Leu Glu Gly Val Lys
50 55 60
Ala Asp Lys Ser Lys Val Lys Leu Thr Ile Ser Asp Asp Leu Gly Gln
65 70 75 80
Thr Thr Leu Glu Val Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Lys
85 90 95
Lys Val Thr Ser Lys Asp Lys Ser Ser Thr Glu Glu Lys Phe Asn Glu
100 105 110
Lys Gly Glu Val Ser Glu Lys Ile Ile Thr Arg Ala Asp Gly Thr Arg
115 120 125
Leu Glu Tyr Thr Gly Ile Lys Ser Asp Gly Ser Gly Lys Ala Lys Glu
130 135 140
Val Leu Lys Gly Tyr Val Leu Glu Gly Thr Leu Thr Ala Glu Lys Thr
145 150 155 160
Thr Leu Val Val Lys Glu Gly Thr Val Thr Leu Ser Lys Asn Ile Ser
165 170 175
Lys Ser Gly Glu Val Ser Val Glu Leu Asn Asp Thr Asp Ser Ser Ala
180 185 190
Ala Thr Lys Lys Thr Ala Ala Trp Asn Ser Gly Thr Ser Thr Leu Thr
195 200 205
Ile Thr Val Asn Ser Lys Lys Thr Lys Asp Leu Val Phe Thr Lys Glu
210 215 220
Asn Thr Ile Thr Val Gln Gln Tyr Asp Ser Asn Gly Thr Lys Leu Glu
225 230 235 240
Gly Ser Ala Val Glu Ile Thr Lys Leu Asp Glu Ile Lys Asn Ala Leu
245 250 255
Lys
<210> 6
<211> 273
<212> PRT
<213> 伯氏疏螺旋体(Borrelia burgdorferi)
<400> 6
Met Lys Lys Tyr Leu Leu Gly Ile Gly Leu Ile Leu Ala Leu Ile Ala
1 5 10 15
Cys Lys Gln Asn Val Ser Ser Leu Asp Glu Lys Asn Ser Val Ser Val
20 25 30
Asp Leu Pro Gly Glu Met Lys Val Leu Val Ser Lys Glu Lys Asn Lys
35 40 45
Asp Gly Lys Tyr Asp Leu Ile Ala Thr Val Asp Lys Leu Glu Leu Lys
50 55 60
Gly Thr Ser Asp Lys Asn Asn Gly Ser Gly Val Leu Glu Gly Val Lys
65 70 75 80
Ala Asp Lys Ser Lys Val Lys Leu Thr Ile Ser Asp Asp Leu Gly Gln
85 90 95
Thr Thr Leu Glu Val Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Lys
100 105 110
Lys Val Thr Ser Lys Asp Lys Ser Ser Thr Glu Glu Lys Phe Asn Glu
115 120 125
Lys Gly Glu Val Ser Glu Lys Ile Ile Thr Arg Ala Asp Gly Thr Arg
130 135 140
Leu Glu Tyr Thr Gly Ile Lys Ser Asp Gly Ser Gly Lys Ala Lys Glu
145 150 155 160
Val Leu Lys Gly Tyr Val Leu Glu Gly Thr Leu Thr Ala Glu Lys Thr
165 170 175
Thr Leu Val Val Lys Glu Gly Thr Val Thr Leu Ser Lys Asn Ile Ser
180 185 190
Lys Ser Gly Glu Val Ser Val Glu Leu Asn Asp Thr Asp Ser Ser Ala
195 200 205
Ala Thr Lys Lys Thr Ala Ala Trp Asn Ser Gly Thr Ser Thr Leu Thr
210 215 220
Ile Thr Val Asn Ser Lys Lys Thr Lys Asp Leu Val Phe Thr Lys Glu
225 230 235 240
Asn Thr Ile Thr Val Gln Gln Tyr Asp Ser Asn Gly Thr Lys Leu Glu
245 250 255
Gly Ser Ala Val Glu Ile Thr Lys Leu Asp Glu Ile Lys Asn Ala Leu
260 265 270
Lys
Claims (15)
1.重组病毒载体,其包含重组病毒,所述重组病毒表达免疫调节蛋白和与所述重组病毒无关的靶抗原。
2.根据权利要求1所述的病毒载体,其中所述病毒选自腺病毒、牛痘病毒和疱疹病毒。
3.根据权利要求1或2所述的病毒载体,其中所述病毒是有复制能力的病毒。
4.根据权利要求1或2所述的病毒载体,其中所述病毒是复制缺陷型病毒。
5.根据权利要求1至4中任一项所述的病毒载体,其中所述靶抗原在所述病毒的表面上表达。
6.根据权利要求5所述的病毒载体,其中所述靶抗原与病毒糖蛋白融合。
7.根据权利要求6所述的病毒载体,其中所述重组病毒是疱疹病毒,并且所述病毒糖蛋白是选自gB、gC、gD、gE、gG、gI、gJ、gK、gM、gN、UL20、UL24、UL43、UL45、UL56和US9的包膜蛋白。
8.根据权利要求1至7中任一项所述的病毒载体,其中所述靶抗原是来自与所述重组病毒载体的亲本病毒无关的病毒的抗原。
9.根据权利要求1-7中任一项所述的病毒载体,其中所述靶抗原来自细菌或寄生虫。
10.根据权利要求1-7中任一项所述的病毒载体,其中所述靶抗原是肿瘤抗原。
11.根据权利要求1至7中任一项所述的病毒载体,其中所述重组病毒载体表达多种靶抗原。
12.根据权利要求1至11中任一项所述的病毒载体,其中所述免疫调节蛋白是细胞因子、趋化因子、共刺激分子或这些中任一种的活性片段。
13.根据权利要求11所述的病毒载体,其中所述免疫调节蛋白是从所述病毒载体分泌的。
14.疫苗,其包含权利要求1至13中任一项所述的病毒载体以及药学上可接受的赋形剂。
15.针对病原体为对象接种疫苗的方法,其包括施用有效量的权利要求15所述的疫苗的步骤,所述疫苗表达来自所述病原体的靶抗原。
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