CN110325202A - 乙型肝炎病毒pre-S蛋白的病毒样颗粒 - Google Patents
乙型肝炎病毒pre-S蛋白的病毒样颗粒 Download PDFInfo
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Abstract
如本文公开的,在传染性乙型肝炎病毒(HBV)颗粒上的preS抗原可以提供促进体液应答和细胞应答的B细胞表位和T细胞表位,并且通过克服对仅S抗原的疫苗的无应答性增强血清保护率。因此,公开了使用preS抗原以开发用于治疗或预防乙型肝炎感染的疫苗和免疫治疗的组合物和方法,特别是,公开了在其表面上包含preS抗原的病毒样颗粒(VLP)。这些VLP可以单独使用或与包含乙型肝炎表面抗原(HBsAg)的疫苗组合使用,以对受试者接种HBV的疫苗以及以活化用于过继性T细胞治疗(adoptive T cell therapy)的T细胞以根除HBV感染的肝细胞。
Description
相关申请的交叉引用
本申请要求于2016年10月31日提交的美国临时申请第62/414,899号的权益,该申请通过引用以其整体特此并入本文。
背景
尽管在抗病毒治疗中取得了巨大进展,乙型肝炎病毒(HBV)感染仍然是重大的全球公共健康问题。全世界约有20亿人已经在其一生期间被感染,并且超过3.5亿是该病毒的慢性携带者(Liaw YF等人Lancet 2009 373:582-592)。HBV感染可以引起急性和慢性肝炎,其引起肝硬化(LC)和肝细胞癌(HCC)(Chu CM.J Gastroenterol Hepatol 2000 15 Suppl:E25-30)。目前市面上的保护大多数人免于HBV感染的HBV疫苗仅包含S抗原。然而,几乎5%-10%的人用可用的疫苗接种了,却不能建立充足的抗体应答以提供保护(Kubba AK等人Commun Dis Public Health 2003 6:106-112)。
概述
如本文公开的,HBV preS蛋白或其抗原片段可以提供促进体液应答和细胞应答的B细胞表位和T细胞表位,并且通过克服对仅S抗原的疫苗的无应答性增强血清保护率。因此,公开了使用preS抗原以开发用于治疗或预防乙型肝炎感染的疫苗和免疫治疗的组合物和方法。
在一些实施方案中,preS抗原被掺入到病毒样颗粒(VLP)中,该病毒样颗粒(VLP)可以用作例如疫苗,或用来活化用于过继性细胞转移的T细胞。在这些实施方案中,preS抗原可以被掺入到融合蛋白中,该融合蛋白将掺入到VLP中。例如,公开了包含融合在病毒包膜蛋白的跨膜结构域和任选的细胞质尾的N端处的乙型肝炎preS抗原。包含适合形成VLP的跨膜结构域的病毒包膜蛋白包括一种I型跨膜蛋白,流感病毒血凝素(HA)蛋白。乙型肝炎preS抗原也可以与其他I型跨膜糖蛋白融合,所述其他I型跨膜糖蛋白诸如来自沙粒病毒、布尼亚病毒、冠状病毒、线状病毒、副黏病毒、逆转录病毒、披膜病毒和其他病毒的糖蛋白(Liu J等人VIROLOGICA SINICA 2016 31(4):279-287)。
在一些实施方案中,融合蛋白还在N端包含信号肽。作为实例,信号肽可以是来自HA的信号肽。信号肽也可以来源于其他I型跨膜糖蛋白,所述其他I型跨膜糖蛋白诸如来自沙粒病毒、布尼亚病毒、冠状病毒、线状病毒、副黏病毒、逆转录病毒、披膜病毒和其他病毒的糖蛋白(Liu J等人VIROLOGICA SINICA 2016 31(4):279-287)。
融合蛋白可以通过使其与病毒基质蛋白诸如流感病毒基质蛋白1(M1)共表达被形成到VLP中。融合蛋白也可以通过使其与其他病毒蛋白共表达被形成到VLP中,所述其他病毒蛋白包括基质蛋白、核衣壳蛋白和来自沙粒病毒、布尼亚病毒、冠状病毒、线状病毒、副粘病毒、逆转录病毒、披膜病毒和其他病毒的其他蛋白(Liu J等人VIROLOGICA SINICA 201631(4):279-287)。因此,还公开了包含所公开的融合蛋白和流感病毒M1蛋白的VLP。例如,这些VLP可以通过以下产生:以瞬时或稳定表达将表达载体引入到哺乳动物细胞(例如中国仓鼠卵巢(CHO)、人类细胞系293和Vero细胞(猴细胞))中、或者用一种或更多种表达M1蛋白和所公开的融合蛋白的重组杆状病毒共感染昆虫细胞、在适当的条件下培养细胞。当在构建融合蛋白和共表达中使用其他病毒蛋白时,VLP也可以通过相同的方法产生。VLP然后可以从细胞培养物上清液中被纯化。
还公开了疫苗,所述疫苗包含在药学上可接受的赋形剂中的有效量的所公开的VLP。在一些情况中,疫苗还包含佐剂。例如,佐剂可以选自由以下组成的组:AS04(铝盐(alum)加上单磷酰基脂质A)、细菌细胞壁组分、MF59(基于矿物油的佐剂)和以膜锚定的形式被掺入VLP的分子佐剂。
还公开了包含编码所公开的融合蛋白的核酸序列的分离的多核苷酸,所述分离的多核苷酸可以根据氨基酸密码子构建。在一些实施方案中,编码融合蛋白的核酸序列可操作地连接至表达控制序列。因此,还公开了包含所公开的核酸序列的表达载体。本文还公开了包含所公开的载体的细胞。例如,细胞可以是细菌、昆虫细胞、哺乳动物细胞或酵母细胞。
还公开了对受试者接种乙型肝炎的疫苗的方法,该方法包括通过鼻内、肌肉内、皮下、透皮或舌下施用向有相应需要的受试者施用本文公开的疫苗。该方法还可以涉及向受试者施用包含乙型肝炎表面抗原(HBsAg)的疫苗。
还公开了用于活化用于过继性细胞转移(ACT)的CD8+T细胞的方法,该方法包括将CD8+T细胞和树突状细胞与本文公开的VLP共培养。
在以下的附图和描述中阐述了本发明的一种或更多种实施方案的细节。从该描述和附图中以及从权利要求书中,本发明的其他特征、目标和优点将是明显的。
附图说明
图1A至1D显示出preS VLP的构建和表达。图1A是用于产生preS VLP的pCAGGS-preS-HA和pCAGGS-M1、和用于表达preS抗原的pET28b-preS的示意图。图1B显示出用于测量preS-HA和M1的转录的qPCR分析的结果。图1C和1D是表达preS-HA的细胞的免疫荧光图像。293T细胞用模拟物对照、pCAGGS-M1、pCAGGS-preS-HA或两种质粒转染。染色前,细胞用Triton X-100透化(图1D)或不用Triton X-100透化(图1C)。细胞核用DAPI染色,并且preS抗原用抗preS血清染色,用Alexa488-缀合的山羊抗兔二级抗体检测。
图2A至2E显示出preS VLP的表征。图2A显示出在质粒转染的细胞的裂解物和相关的上清液中preS-HA的蛋白印迹分析。图2B显示了来自样品的SDS-PAGE分析,所述样品来自蔗糖梯度离心的级分(fraction)。主要蛋白组分是在40%蔗糖级分中。图2C显示出用抗preS血清的蛋白印迹分析。泳道1针对在大肠杆菌(E.coli)中表达的重组preS蛋白。泳道2和3显示出preS-HA抗原在来自蔗糖梯度离心的级分中的存在。图2D是显示出preS病毒样颗粒(preS VLP)的电子显微照片。放大倍数,11,000×。图2E,在来自40%蔗糖级分的样品中的M1和preS-HA的LC-MS/MS鉴定。
图3A至3D显示出,与重组preS接种相比,preS VLP引发更优的HBV特异性体液免疫应答。图3A至3C显示出通过ELISA确定的血清抗preS滴度。平板用5μg/mL重组preS包被。免疫条件标记在图编码旁。在所有测定中,血清被稀释了100倍。图3D显示出HepG2/hNTCP细胞中的HBV感染性被小鼠抗preS VLP血清或乙型肝炎免疫球蛋白(HBIG)(0.144mg/mL)中和。小鼠抗preS VLP血清被稀释了10倍。感染后一周的HBeAg值使用ELISA试剂盒测量。数据以平均值±SEM表示。
图4A至4E显示出preS VLP诱导了比重组preS接种更强的T细胞应答。Balb/c小鼠用preS VLP(n=6)、重组preS蛋白(n=6)或PBS(n=6)肌肉内免疫。免疫后30天,分离脾细胞,并且通过流式细胞术(图4A-4D)或ELISPOT测定(图4E)分析CD8(图4A、4C)、CD4(图4B、4D)和IFN-γ(图4C、4D)表达。
图5A至5F显示出用preS VLP接种提供了针对流体动力学HBV攻击的保护。Balb/c小鼠用preS VLP(n=6)、重组preS蛋白(n=6)或PBS(n=6)肌肉内免疫。在第70天,HBV复制通过经由尾静脉流体动力学注射pT-HBV1.3质粒(10μg/小鼠)诱导。图5A显示出通过qPCR测量的肝相关的HBV RNA拷贝。图5B显示出肝组织的免疫组织化学分析。放大倍数,100×。图5C至5E显示出在攻击后第0天、第2天、第4天和第7天通过ELISA完成的HBsAg(图5C)、HBeAg(图5D)和抗preS抗体滴度(图5E)的血清分析。图5F显示出用Hitachi 7600自动生物化学分析仪确定的血清丙氨酸氨基转移酶(ALT)活性。所有值展示为来自每一组的平均值,并且误差线指示±SEM。
图6A至6F显示出preS VLP介导的保护与T细胞回忆应答(recall response)相关。Balb/c小鼠用preS VLP(n=6)、重组preS蛋白(n=6)或PBS(n=6)肌肉内免疫。在第70天,HBV复制通过流体动力学注射pT-HBV1.3质粒(10μg)诱导。攻击后7天,分离脾细胞(图6A-6E)和肝内淋巴细胞(图6F)和通过流式细胞术(图6A-6D)或ELISPOT测定(图6E-6F)分析CD8、CD4和IFN-γ表达。
图7A至7J显示出在HBV转基因小鼠中用preS VLP免疫诱导了稳健的抗preS抗体和T细胞应答。HBV转基因小鼠用preS VLP(n=6)或PBS(n=6)肌肉内免疫。图7A是preS VLP作为疫苗治疗HBV转基因小鼠的时间表。图7B至7D显示出通过ELISA确定的血清抗preS滴度。平板用1μg/mL纯化的重组preS包被。免疫条件被标记在图颜色编码旁。在所有测定中,血清被稀释了100倍。将CD8+T细胞(图7E)或CD4+T细胞(图7F)门控,并且产生IFN-γ的细胞展示为来自每一组的百分比平均值。图7G显示出通过ELISPOT测定的第70天被分离的脾细胞中的IFN-γ表达。ELISPOT实验在在每种条件的一式三份的孔中进行。图7H显示出来自每一组的ELISPOT的代表性图像。所有值展示为来自每一组的平均值,并且误差线指示±SEM。图7I显示出使用Hitachi 7600自动生物化学分析仪测量的血清丙氨酸氨基转移酶(ALT)活性。图7J显示出来自用苏木精和曙红染色的每一组的肝组织切片。放大倍数,100×。
详细描述
定义
必须注意,如本文和在所附的权利要求中使用的,单数形式“一(a)”、“一(an)”和“该(the)”包括复数指代物,除非上下文另有清楚的指示。因此,例如,提到的“一种肽(apeptide)”包括多于一种的这类肽,提到的“该肽(the peptide)”是提到的一种或更多种肽和本领域普通技术人员已知的其等同物,等等。
在本说明书中和跟随的权利要求书中,将提到许多术语,其应被定义为具有以下含义:
“任选的”或“任选地”意指后续地描述的事件或情形可以发生或可以不发生,并且意指该描述包括其中该事件或情形发生的情况和其中该事件或情形不发生的情况。例如,措辞“任选地信号肽”意指,信号肽可以被包括或可以不被包括。
术语“通用甲型流感疫苗”是指能够提供针对甲型流感的至少两种(包括三种、四种、五种或更多种)亚型的交叉保护的疫苗。
术语“个体”、“宿主”、“受试者”和“患者”可互换地使用,是指是施用、治疗或接种的目标的任何个体。受试者可以是脊椎动物,例如,哺乳动物。因此,受试者可以是人类或兽医学的病患。
术语“药学上可接受的”是指在合理的医学判断范围内,适于接触人类和动物的组织使用而没有过度毒性、刺激、过敏反应或其他问题或并发症、与合理的益处/风险比相称的那些化合物、材料、组合物和/或剂型。
术语“载体”意指这样的化合物、组合物、物质或结构,其当与化合物或组合物组合时,有助于或促进该化合物或组合物的制备、储存、施用、递送、有效性、选择性或该化合物或组合物的对于其预期用途或目的的任何其他特征。例如,载体可以被选择以最小化活性成分的任何降解和以最小化在受试者中的任何不良副作用。
术语“肽”、“蛋白质”和“多肽”可互换地使用,是指包含两个或更多个氨基酸的天然或合成分子,所述两个或更多个氨基酸通过一个氨基酸的羧基基团连接至另一个氨基酸的α氨基基团。
术语“蛋白质结构域”是指显示出结构完整性的蛋白质的一个部分、蛋白质的更多个部分或整个蛋白质;这可以基于蛋白质的一个部分、蛋白质的更多个部分或整个蛋白质的氨基酸组成来确定。
术语“核酸”是指天然或合成的分子,所述天然或合成的分子包含单个核苷酸或两个或更多个核苷酸,所述核苷酸通过在一个核苷酸的3’位置的磷酸基团连接至另一个核苷酸的5’末端。核酸不受长度限制,并且因此核酸可以包括脱氧核糖核酸(DNA)或核糖核酸(RNA)。
术语“变体”是指具有保守氨基酸取代、非保守氨基酸取代(即简并变体)的氨基酸序列,或者具有对述及序列60%、65%、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%或99%序列同一性的肽。
术语“序列同一性百分比(%)”或“同源性”被定义为在比对序列和引入缺口(如果为了实现最大序列同一性百分比是必要的话)后,在候选序列中与在参考核酸序列中的核苷酸或氨基酸相同的核苷酸或氨基酸的百分比。出于确定序列同一性百分比的目的的比对可以以在本领域的技术内的多种方式实现,例如,使用公众可用的计算机软件诸如BLAST、BLAST-2、ALIGN、ALIGN-2或Megalign(DNASTAR)软件。用于测量比对的适当的参数(包括在被比较的序列的全长上实现最大比对所需要的任何算法)可以通过已知方法确定。对于本文的目的,给定核苷酸或氨基酸序列C对、与、或针对给定核酸序列D的%序列同一性(其可以可选地被描述成给定序列C具有或包含对、与、或针对给定序列D的某一%序列同一性)计算如下:
100乘以分数W/Z,
其中W是在序列比对程序对C和D的比对中,C和D通过该程序被评分成相同匹配的核苷酸或氨基酸的数目,并且其中Z是D中的核苷酸或氨基酸的总数目。将理解的是,在序列C的长度不等于序列D的长度的情况,C对D的%序列同一性将不等于D对C的%序列同一性。
“融合蛋白”是指通过在一个多肽的氨基端和另一个多肽的羧基端之间形成的肽键将两个或更多个多肽连接而形成的多肽。融合蛋白可以通过组分多肽的化学偶联形成,或者它可以从编码单个连续融合蛋白的核酸序列被表达成单个多肽。单链融合蛋白是具有单个连续多肽主链的融合蛋白。融合蛋白可以使用分子生物学中的常规技术制备,所述常规技术如下:将符合读框的两个基因连接成单个核酸,并然后在产生融合蛋白的条件下在适当的宿主细胞中表达该核酸。
如本文使用的,“间隔子(spacer)”是指连接融合蛋白的蛋白的肽。通常地,间隔子除连接蛋白或保持它们之间的某最小距离或其他空间关系外不具有特殊的生物学活性。然而,间隔子的组分氨基酸可以被选择以影响分子的一些性质,诸如分子的折叠、净电荷或疏水性。
乙型肝炎preS构建体
本文公开了融合蛋白,该融合蛋白包含与病毒包膜蛋白的膜锚定结构域,诸如跨膜结构域和任选的细胞质结构域融合的乙型肝炎preS表位,用于在产生病毒样颗粒中使用。
例如,乙型肝炎preS表位序列可以来源于人类。在一些实施方案中,乙型肝炎preS抗原具有氨基酸序列 或其具有对SEQ ID NO:1的至少约70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98%、99%或100%序列同一性(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个保守氨基酸取代)的保守变体。
来自其他基因型或亚型的乙型肝炎病毒preS抗原也可以用于通过相同的方法产生VLP。
在一些实施方案中,流感病毒M1蛋白具有氨基酸序列 或其具有对SEQ ID NO:3的至少约70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98%、99%或100%序列同一性(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个保守氨基酸取代)的保守变体。
来自血凝素的跨膜-细胞质结构域可以具有氨基酸序列KLESVGVHQILAIYSTVASSLVLLVSLGAI SFWMCSNGSL QCRICI(SEQ ID NO:15),或其具有对SEQ ID NO:15的至少70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98%、99%或100%序列同一性的保守变体。
融合蛋白还可以在N端包含信号肽以促进分泌。例如,融合蛋白可以包含血凝素(HA)信号肽。来自血凝素的信号肽可以具有氨基酸序列MEAKLFVLFC AFTALKA(SEQ ID NO:16),或其具有对SEQ ID NO:16的至少70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98%、99%或100%的序列同一性的保守变体。其他信号肽是已知的,并且包括在下表1中列出的那些。
因此,在一些实施方案中,所公开的融合蛋白具有氨基酸序列
或其具有对SEQ ID NO:2的至少约70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98%、99%或100%序列同一性(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个保守氨基酸取代)的保守变体。
还公开了包含编码所公开的融合蛋白的核酸序列的多核苷酸。例如,核酸序列可以可操作地连接至表达控制序列。因此,还公开了用于产生所公开的融合蛋白的表达载体以及包含这些多核苷酸和载体以便复制该多核苷酸和载体或以产生所公开的融合蛋白和/或VLP的细胞。因此,所公开的细胞也可以包含编码所公开的融合蛋白的核酸序列,包括包含编码所公开的融合蛋白的核酸序列的载体。
还公开了包含编码流感病毒M1蛋白的核酸序列的多核苷酸。例如,核酸序列可以可操作地连接至表达控制序列。因此,还公开了用于产生所公开的融合蛋白的表达载体以及包含这些多核苷酸和载体以便复制该多核苷酸和载体或以产生所公开的融合蛋白和/或VLP的细胞。因此,所公开的细胞也可以包含编码M1蛋白的核酸序列,包括包含编码M1蛋白的核酸序列的载体。
还公开了双重载体,所述双重载体包含编码所公开的融合蛋白的第一核酸序列和编码M1蛋白的第二核酸序列。细胞可以是原核细胞或真核细胞。例如,细胞可以是细菌、昆虫细胞、酵母细胞或哺乳动物细胞。细胞可以是人类细胞。基于被用于产生VLP的细胞的选择,合适的载体可以常规地选择。例如,当使用昆虫细胞时,合适的载体包括杆状病毒。在哺乳动物细胞的情况中,可使用用于蛋白质表达的质粒。
融合蛋白,也被称为嵌合蛋白,是通过将初始地编码单独蛋白质的两个或更多个的基因连接而创建的蛋白质。该融合基因的翻译产生具有来源于每种初始蛋白质的功能性质的单个多肽。重组融合蛋白可以通过重组DNA技术被人为地创建,用于在生物学研究或治疗中使用。
许多蛋白质功能结构域是模块化的,这个事实使得融合蛋白的官能性成为可能。换言之,多肽的对应于给定结构域诸如酪氨酸激酶结构域的线性部分可以从蛋白质的其余部分移除,而不破坏其固有的酶促能力。因此,本文所公开的任何功能结构域可以用于设计融合蛋白。
重组融合蛋白是通过融合基因的遗传工程化而创建的蛋白质。这通常地涉及从编码第一蛋白质的cDNA序列去除终止密码子,然后通过连接或重叠延伸PCR符合读框地附接第二蛋白质的cDNA序列。然后,该DNA序列将被细胞表达成单个蛋白质。蛋白质可以被工程化以包含两种初始蛋白质的全部序列,或者仅包含任一种的一部分。
如果两个实体是蛋白质,通常还添加接头(或“间隔子”)肽,这使蛋白质独立地折叠和如预期地表现变得更可能。特别地,在其中接头促进蛋白质纯化的情况中,在蛋白质或肽融合物中的接头有时被工程化成具有使两种单独蛋白质的释放实现的用于蛋白酶或化学药剂(chemical agent)的切割位点。
病毒样颗粒(VLP)
所公开的构建体可以在颗粒的表面上表达,以模拟在乙型肝炎病毒粒子上的preS的天然构象。例如,所公开的融合蛋白可以通过在融合蛋白中包含膜锚定结构域,诸如病毒包膜蛋白的跨膜结构域和任选的细胞质结构域而被掺入到病毒样颗粒(VLP)中。
非复制的VLP在结构和形态学方面类似于感染性病毒颗粒,并且包含免疫学上相关的病毒结构蛋白质。VLP已经从无包膜的病毒和有包膜的病毒二者产生。VLP的包膜来源于宿主细胞,类似于如有包膜的病毒(诸如甲型流感病毒)从其宿主细胞获得其脂质包膜的方式。因此,在有包膜的病毒表面上的膜锚定蛋白,如果其以膜锚定形式被表达,将以天然样构象被表达。
流感VLP包括脂质双层和宿主细胞膜蛋白(Song,J.M.等人J Proteome Res201110:3450-3459)。例如,包含野生型M2蛋白的流感VLP已经被描述(Song,J.M.等人ProcNatl Acad Sci U S A 2011 108:757-761;Song,J.M.等人PLoS One 20116:e14538)。包膜的VLP可以包括作为颗粒形成核心的流感基质1(M1)蛋白。例如,这些VLP通过以下产生:用共表达M1蛋白和所公开的融合蛋白的一种或更多种重组杆状病毒共感染昆虫细胞,在生理学条件下培养昆虫细胞,和从昆虫细胞培养物上清液纯化VLP。
疫苗组合物
公开了包含一种或更多种以上描述的融合蛋白的疫苗组合物。尽管不是必需的,疫苗组合物任选地包含一种或更多种免疫刺激剂。免疫刺激剂主要地是指增强或加强对外源抗原的免疫应答(抗体或细胞介导的)的任何物质。一种优选的类型的免疫刺激剂是佐剂。
许多佐剂包含被设计以保护抗原免受快速分解代谢的物质,诸如氢氧化铝或矿物油,和免疫应答的刺激剂,诸如脂质A、百日咳杆菌(Bordetellapertussis)或结核分枝杆菌(Mycobacterium tuberculosis)来源的蛋白质。佐剂可以是可代谢的油和乳化剂的亚微细粒水包油乳液。例如,佐剂可以包括MF59TM,MF59TM是角鲨烯、聚氧乙烯脱水山梨醇单油酸酯(TweenTM 80)和脱水山梨醇三油酸酯的亚微细粒水包油乳液。佐剂也可以是TLR4激动剂MPL(3-O-去酰基-4’-单磷酰基脂质A)和铝盐的组合,例如AS04(GlaxoSmithKline,Philadelphia,Pa.)。
某些佐剂是商购可得的如,例如,弗氏不完全佐剂和完全佐剂(DifcoLaboratories,Detroit,Mich.);默克佐剂65(Merck and Company,Rahway,N.J.);AS01、AS02、AS03和AS04(GlaxoSmithKline,Philadelphia,Pa.);铝盐诸如氢氧化铝凝胶(铝盐(alum))或磷酸铝;钙盐、铁盐或锌盐;酰化酪氨酸的不溶性悬浮液;酰化糖;阳离子或阴离子来源的多糖;聚磷腈(polyphosphazenes);生物可降解微球;单磷酰基脂质A和quil A。细胞因子,诸如GM-CSF、白细胞介素-2、白细胞介素-7、白细胞介素-12和其他类似生长因子,也可以用作佐剂。
佐剂组合物可以是诱导抗炎性免疫应答(抗体或细胞介导的)的组合物。因此,高水平的抗炎性细胞因子(抗炎性细胞因子可以包括,但不限于,白细胞介素4(IL-4)、白细胞介素5(IL-5)、白细胞介素10(IL-10)和转化生长因子β(TGFβ)。任选地,抗炎性应答将被CD4+T辅助细胞介导。细菌鞭毛蛋白已经显示出具有佐剂活性(McSorley等人,J.Immunol.169:3914-19,2002)。还公开了编码可以在佐剂组合物中被使用的鞭毛蛋白蛋白质的多肽序列。
任选地,佐剂增加脂多糖(LPS)的反应性。说明性佐剂包括但不限于,单磷酰基脂质A(MPL)、氨基烷基氨基葡糖苷4-磷酸酯(AGP),包括但不限于RC-512、RC-522、RC-527、RC-529、RC-544和RC-560(Corixa,Hamilton,Mont.)。
此外,佐剂组合物可以是诱导主要是Th1型的免疫应答的佐剂组合物。高水平的Th1型细胞因子(例如IFN-γ、TNFα、IL-2和IL-12)倾向于偏好诱导细胞介导的对施用的抗原的免疫应答。相反,高水平的Th2型细胞因子(例如,IL-4、IL-5、IL-6和IL-10)倾向于偏好诱导体液免疫应答。在施加如本文提供的疫苗后,受试者将支持包括Th1型和Th2型应答的免疫应答。任选地,Th1型细胞因子的水平将比Th2型细胞因子的水平增加至更大的程度。这些细胞因子的水平可以容易地使用标准测定评估。用于引发主要是Th1型应答的某些佐剂包括,例如,单磷酰基脂质A(优选地3-去氧酰化单磷酰基脂质A)连同铝盐佐剂的组合,是从Corixa Corporation(Seattle,Wash.)可得的。包含CpG的寡核苷酸(其中CpG二核苷酸未被甲基化)也诱导主要是Th1应答。另一种佐剂包含皂苷,诸如QuilA,或其衍生物,包括QS21和QS7(Aquila Biopharmaceuticals Inc.,Framingham,Mass.);七叶皂苷;洋地黄皂苷;或满天星(Gypsophila)或昆诺藜(Chenopodium quinoa)皂苷。
用于在所公开的疫苗组合物中使用的其他的说明性佐剂包括Montamide ISA 720(Seppic,France)、SAF(Chiron,Calif.,United States)、ISCOMS(CSL)、MF-59(Chiron)、SBAS系列的佐剂(例如,SBAS-2或SBAS-4,从GlaxoSmithKline,Philadelphia,Pa.可得)、Detox(EnhanzynTM)(Corixa,Hamilton,Mont.)、RC-529(Corixa,Hamilton,Mont.)和其他氨基烷基氨基葡糖苷4-磷酸酯(AGP)。
在一些实施方案中,佐剂以膜锚定形式被掺入到VLP中。例如,GM-CSF或包含膜锚定的细菌鞭毛蛋白蛋白质可以被掺入到所公开的VLP中。
药物组合物
所公开的疫苗可以与药学上可接受的载体组合被治疗上使用。“药学上可接受的”意指不是生物学上或其他方面不期望的材料,即该材料可以向受试者施用,而不引起任何不期望的生物学作用或以有害的方式与包含它的药物组合物的任何其他组分相互作用。如本领域普通技术人员将熟知的,载体将被天然地选择以最小化活性成分的任何降解和以最小化在受试者中的任何不良副作用。
材料可以呈溶液、悬浮液(例如,被掺入到微颗粒、脂质体或细胞中)。合适的载体及其制剂在Remington:The Science and Practice of Pharmacy(第22版)Loyd V.Allen,Jr.等人编著,Pharmaceutical Press,2012中描述。通常地,适当的量的药学上可接受的盐在制剂中被使用以使制剂等渗。药学上可接受的载体的实例包括,但不限于盐水、林格氏溶液(Ringer’s solution)和右旋糖溶液。溶液的pH优选地是从约5至约8,且更优选地是从约7至约7.5。其他的载体包括持续释放制剂,诸如包含抗体的固体疏水聚合物的半可渗透性基质,该基质呈成型制品,例如,薄膜、脂质体或微粒的形式。对本领域普通技术人员将明显的是,取决于,例如,施用的途径和被施用的组合物的浓度,某些载体可以是更优选的。
对本领域普通技术人员,药物载体是已知的。最通常地,这些将是用于向人类施用疫苗的标准载体,包括溶液诸如无菌水、盐水和在生理学pH的缓冲溶液。除疫苗外,药物组合物可以包含载体、增稠剂、稀释剂、缓冲液、防腐剂、表面活性剂等。药物组合物还可以包含一种或更多种活性成分,诸如抗微生物剂、抗炎性剂、麻醉剂等。
所公开的疫苗优选地被配制成用于通过鼻内、肌肉内、皮下、透皮或舌下施用递送。
用于肠胃外施用的制剂包括无菌水性溶液或非水性溶液、悬浮液和乳液。非水性溶剂的实例是丙二醇、聚乙二醇、植物油诸如橄榄油和可注射的有机酯诸如油酸乙酯。水性载体包括水、醇/水性溶液、乳液或悬浮液,包括盐水和缓冲介质。肠胃外媒介物包括氯化钠溶液、林格氏右旋糖、右旋糖和氯化钠、乳酸林格氏液(lactated Ringer′s)或不挥发油。静脉内媒介物包括流体和营养物补充剂、电解质补充剂(诸如基于林格氏右旋糖的那些补充剂)等。防腐剂和其他添加剂也可以存在,诸如,例如,抗微生物剂、抗氧化剂、螯合剂和惰性气体等。
用于局部施用的制剂可以包括软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾、液体和粉末。常规药物载体、水性、粉末或油性基质、增稠剂等可以是必要的或期望的。
一些组合物可以潜在地作为药学上可接受的酸加成盐或碱加成盐被施用,所述药学上可接受的酸加成盐或碱加成盐通过与无机酸诸如盐酸、氢溴酸、高氯酸、硝酸、硫氰酸、硫酸和磷酸反应形成,和与有机酸诸如甲酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸和富马酸反应形成,或通过与无机碱诸如氢氧化钠、氢氧化铵、氢氧化钾反应形成,和与有机碱诸如单、二、三烷基和芳基胺类和取代的乙醇胺类反应形成。
所公开的疫苗可以用于补充现有的人类疫苗,以改善交叉保护。因此,所公开的疫苗可以还包括(或与之组合施用)完整的灭活的病毒、裂解病毒疫苗、减毒活乙型肝炎疫苗或另一种乙型肝炎病毒样颗粒(VLP)疫苗、以及DNA疫苗。例如,所公开的疫苗可以与乙型肝炎疫苗组合。
所公开的疫苗还可以包含(或与之组合施用)一个或更多个类别的抗生素、类固醇、镇痛剂、抗炎性剂、抗组胺剂或其任何组合。抗生素包括氨基糖苷类、头孢菌素类、氯霉素、克林霉素、红霉素类、氟喹诺酮类(Fluoroquinolones)、大环内酯类、Azolides、甲硝唑、青霉素类、四环素类、甲氧苄啶-磺胺甲噁唑和万古霉素。合适的类固醇包括环氧柏木烷类(andranes),诸如睾酮。麻醉性和非麻醉性镇痛剂包括吗啡、可待因、海洛因、氢吗啡酮、左啡诺、哌替啶、美沙酮、氧化酮、右丙氧芬、芬太尼、美沙酮、纳洛酮、丁丙诺啡、布托啡诺、纳布啡和喷他佐辛。抗炎性剂包括阿氯芬酸、阿氯米松二丙酸酯、阿孕奈德、α淀粉酶、安西法尔、安西非特、氨芬酸钠、盐酸氨普立糖、阿那白滞素(anakinra)、阿尼罗酸、阿尼扎芬、阿扎丙宗、巴柳氮二钠、苄达酸、苯噁洛芬、盐酸苄达明、菠萝蛋白酶类、溴哌莫、布地奈德、卡洛芬、环洛芬、辛喷他宗、克利洛芬、氯倍他索丙酸酯、氯倍他松丁酸酯、氯吡酸、氯硫卡松丙酸酯、可米松乙酸酯、可托多松癸酸酯、地夫可特、庚酸睾酮(delatestryl)、环戊丙酸睾酮(depo-testosterone)、地奈德、去羟米松、地塞米松二丙酸酯、双氯酚酸钾、双氯酚酸钠、二氟拉松二乙酸酯、二氟米酮钠、二氟尼柳、二氟泼尼酯、地弗他酮、二甲基亚砜、羟西奈德、恩甲羟松(endrisone)、恩莫单抗、依诺利康钠、依匹唑、依托度酸、依托芬那酯、联苯乙酸、非那莫、芬布芬、芬氯酸、苯克洛酸、芬度柳、苯吡帕酮(Fenpipalone)、芬替酸、夫拉扎酮、氟扎可特、氟芬那酸、氟咪唑(flumizole)、氟尼缩松乙酸酯、氟尼辛、氟尼辛甲基葡胺、氟可丁丁酯、氟米龙醋酸酯、氟喹宗、氟比洛芬、氟瑞托芬、氟替卡松丙酸酯、呋喃洛芬、呋罗布芬、哈西奈德、卤倍他索丙酸酯、卤泼尼松乙酸酯、异丁芬酸、布洛芬、布洛芬铝、布洛芬吡啶甲醇、伊洛达普、吲哚美辛、吲哚美辛钠、吲哚洛芬、吲哚克索、吲四唑、异氟泼尼松乙酸酯、伊索克酸、伊索昔康、酮洛芬、盐酸洛非咪唑、氯诺昔康(lomoxicam)、氯替泼诺依他波酸酯、甲氯芬那酸钠、甲氯芬那酸、甲氯松二丁酸酯、甲芬那酸、美沙拉明、美西拉宗、美睾酮(mesterolone)、去氢甲睾酮、美替诺龙、美替诺龙乙酸酯、磺庚甲泼尼龙、吗尼氟酯、萘丁美酮、诺龙、萘普生、萘普生钠、萘普索、尼马宗、奥柳氮钠、奥古蛋白、奥帕诺辛、氧雄龙、奥沙普秦、羟布宗、羟甲烯龙、盐酸瑞尼托林、戌聚糖聚硫酸钠、甘油保泰松钠(phenbutazonesodium glycerate)、吡非尼酮、吡罗昔康、吡罗昔康肉桂酸酯、吡罗昔康乙醇胺、吡洛芬、泼那扎特、普立非酮、普罗度酸、普罗喹宗、普罗沙唑、普罗沙唑柠檬酸酯、利美索龙、氯马扎利、柳胆来司、沙那西定(salnacedin)、双水杨酯、血根氯铵、司克拉宗、丝美辛、司坦唑醇、舒多昔康、舒林酸、舒洛芬、他美辛、他尼氟酯、他洛柳酯、特丁非隆、替尼达普、替尼达普钠、替诺昔康、替昔康、苄叉异喹酮(tesimide)、睾酮、睾酮混合物、四氢甲吲胺(tetrydamine)、硫平酸、替可的松新戊酸酯、托美丁、托美丁钠、三氯奈德、三氟米酯、齐多美辛和佐美酸钠。抗组胺剂包括乙醇胺类(例如,苯海拉明、卡比沙明)、乙二胺(例如,曲毗那敏、美吡拉敏)、烷基胺(例如,氯苯那敏、右氯苯那敏、溴苯那敏、曲普利啶)、其他抗组胺剂如阿司咪唑、氯雷他定、非索非那定(fexofenadine)、溴苯那敏、氯马斯汀、扑热息痛、伪麻黄碱、曲普利啶)。
对受试者接种的方法
公开了针对乙型肝炎对受试者接种的方法,该方法涉及向有相应需要的受试者施用所公开的疫苗。所公开的疫苗可以以许多方式施用。例如,所公开的疫苗可以被肌肉内、鼻内或通过在皮肤中的微针施用。组合物可以口服、静脉内、皮下、透皮(例如,通过微针)、腹膜内、眼内、阴道、直肠、舌下或通过吸入施用。
肠胃外施用组合物,如果被使用,通常地以注射为特征。可注射物可以以常规形式被制备,作为液体溶液或悬浮液、适合于注射前在液体中形成溶液或悬浮液的固体形式、或作为乳液。用于肠胃外施用的改进方法涉及使用缓慢释放或持续释放系统使得恒定剂量被维持。
需要的组合物的确切量因受试者而不同,取决于受试者的物种、年龄、体重和一般状况、被治疗的过敏障碍的严重性、使用的特定核酸或载体、其施用的模式等。因此,具体说明用于每种组合物的确切量是不可能的。然而,根据本文的教导,适当的量可以由本领域普通技术人员仅使用常规实验确定。例如,用于施用组合物的有效剂量和时间表可以凭经验确定,并且进行这类确定在本领域的技术中。用于施用组合物的剂量范围是足够大以产生影响症状障碍的期望作用的那些剂量范围。剂量不应该太大以引起不良副作用,诸如不期望的交叉反应、过敏反应等。通常地,剂量将随年龄、状况、性别和患者中疾病的程度、施用的途径、或其他药物是否包括在方案中而不同,并且可以由本领域普通技术人员确定。在任何禁忌症(counterindication)的事件中,剂量可以由单个医生调整。剂量可以不同,并且可以以每天一次或更多次剂量施用被施用,持续一天或几天。在文献中可以发现用于针对给定类别的药物产品的适当的剂量的指导。取决于以上提到的因素,所公开的疫苗单独被使用的通常的剂量可以范围从在每次接种约1μg/kg体重至高达100mg/kg体重或更高,诸如10μg/kg至50mg/kg,或50μg/kg至10mg/kg。
用于继承性细胞转移的T细胞扩增
还公开了用于活化和扩增用于过继性细胞转移(ACT)的CD8+T细胞的方法。该方法通常地涉及将CD8+T细胞和树突状细胞与本文所公开的VLP共培养。
ACT可以通过以下进行:(i)从哺乳动物获得自体淋巴细胞、(ii)培养自体淋巴细胞以产生扩增的淋巴细胞、和(ii)向哺乳动物施用扩增的淋巴细胞。优选地,淋巴细胞从待治疗的哺乳动物分离,即自体转移。
通过所公开的方法产生的扩增的淋巴细胞可以以动脉内或静脉内输注施用,其优选地持续约30分钟至约60分钟。施用的途径的其他实例包括腹膜内、鞘内和淋巴管内(intralymphatic)。同样地,任何合适的剂量的淋巴细胞可以被施用。在一个实施方案中,约1×1010个淋巴细胞至约15×1010个淋巴细胞被施用。
已经描述了本发明的许多实施方案。尽管如此,将理解的是,可以做出多种改变而不偏离本发明的精神和范围。因此,其他实施方案在所附权利要求的范围内。
实施例
实施例1:乙型肝炎病毒preS抗原的病毒样颗粒疫苗保护小鼠免于攻击。
在HBV病毒粒子中存在三种包膜蛋白,S、M和L。preS蛋白是L蛋白的部分、在S蛋白(基因型A)的N端处的163个氨基酸延伸物。preS还可以被分为preS1(a.a.1-108)和preS2(a.a.109-163)。在M蛋白中,除在S、M和L蛋白中共同的氨基酸外,仅preS2存在于N端(Churin Y等人Hepatobiliary Surg Nutr 2015 4:1-10)。两个熟知的功能是与preS相关的。首先,preS包含与特定宿主受体相互作用的区域(Yan H等人Elife 2012 1:e00049)。其他研究将相互作用基序定义在preS的前48个氨基酸中(Barrera A等人J Virol 2005 79:9786-9798;Glebe D等人Gastroenterology 2005 129:234-245;Gripon P等人J Virol2005 79:1613-1622)。preS的另一个重要功能是在preS区域中,存在免疫原性极大的位点作为B细胞表位和T细胞表位(Vento S等人Immunology 1987 62:593-598)。据报道,preS可以在对S抗原无应答的小鼠中诱导体液应答,指示preS代表针对新的HBV疫苗候选物的可能的抗原(Milich DR.Immunol Today 1988 9:380-386)。特别地,体液应答可以在防止HBV病毒传播至未感染的细胞中发挥主要作用。此外,通常认为适当的CD4+辅助T细胞应答是充足的体液应答的先决条件(Celis E等人J Immunol 1984 132:1511-1516)。此外,T细胞应答可有助于延长体液免疫的持久性(Bauer T等人Vaccine 2006 24:572-577;Wiegand J等人J Viral Hepat 2010 17:631-639)。然而,并不是很清楚这些preS表位如何与病毒清除关联。广泛地公认的是,CD8+T细胞应答主要地负责以引起细胞病变和不引起细胞病变两种方式清除HBV(Chisari FV等人Pathol Biol 2010 58:258-266)。更近期的研究证明,HBV特异性CD8+T细胞能够通过分泌抗病毒细胞因子诸如IFN-γ和TNF-α清除HBV感染的肝细胞(Kosinska AD等人Hepat Res Treat 2010 2010:817580)。
病毒样颗粒(VLP)在结构和形态学方面类似于真正的天然病毒,但是是非传染性的,因为它们不包含遗传物质地组装。与单独的蛋白或肽相比,VLP通过呈递更类似于天然病毒的构象表位而显著地改善体液应答。由于其高度重复的表面,VLP能够通过有效地交联在B细胞上的特异性受体而在缺乏佐剂的情况下引发稳健的B细胞应答(Roldao A等人Expert Rev Vaccines 2010 9:1149-1176)。此外,VLP也可以在免疫的动物中诱导有效的细胞毒性T淋巴细胞(CTL)应答(Liu XS等人Virology 1998 252:39-45)。
产生了这样的病毒样颗粒(preS VLP),其包含来自流感病毒的基质蛋白M1和流感病毒血凝素(HA)的跨膜结构域和细胞质尾以形成支架。HBV preS抗原通过将其与HA片段融合而被呈递在VLP的表面上。作为潜在的疫苗候选物,评估preS VLP的免疫原性。用preSVLP免疫诱导了有效的体液免疫应答和细胞免疫应答二者,并且保护了小鼠免受HBV攻击。
材料与方法
质粒和细胞
用于在大肠杆菌中表达HBV preS(adw亚型,登记号AGW20902)的载体(PE28b-preS)是先前构建的(Lian M等人Virol J 20074:93)。如先前地描述的(Lian M等人VirolJ 2007 4:93),将加His标签的preS蛋白表达和纯化。用于表达流感病毒A/sw/Spain/53207/04的M1蛋白(基质蛋白)和preS-HA(HA=血凝素)嵌合蛋白的质粒通过将编码序列插入到pCAGGS中构建。M1的第41个氨基酸被突变成Ala(pCAGGS-M1)。preS-HA具有HBVpreS的序列,跟随的是HA的aa521-566(pCAGGS-preS-HA)。将293T细胞维持在补充了10%胎牛血清(FBS)的DMEM中。
间接免疫荧光
使293T细胞在玻璃盖玻片上生长,并且用pCAGGS-M1和pCAGGS-preS-HA转染。转染后48hr,细胞用4%多聚甲醛固定。细胞被分类成两组。一组用0.2%Triton X-100透化5min,另一组不透性化。在包含5%山羊血清的PBS中封闭持续1h后,所有细胞与多克隆兔抗preS血清在4℃孵育过夜。在37℃用Alexa 488-缀合山羊抗兔二级抗体孵育1小时后,用PBS洗涤细胞。洗涤后,细胞用DAPI染色10分钟,并且然后被封片到显微镜载玻片上。共聚焦切片使用具有随机采样的Zeiss510共聚焦显微镜,用100×物镜获得。
病毒样颗粒的制备和表征
pCAGGS-M1和pCAGGS-preS-HA质粒用聚乙烯亚胺(polyethylenimine)转染到293T细胞中。转染后72hr,将培养基在4℃在6000rpm离心持续15min以去除细胞碎片,随后在4℃在22,000rpm离心持续3hr。将沉淀物重悬在PBS中在4℃过夜,并且通过在4℃在30,000rpm的Beckman SW41Ti转子中,持续3hr而进一步通过20%-60%蔗糖梯度纯化。收集40%蔗糖级分并且用PBS稀释约5倍。在4℃在22,000rpm离心3小时以去除蔗糖后,将病毒样颗粒重悬浮在PBS中在4℃过夜。将样品施加至400目碳包被的铜网格,并且用1%磷钨酸(J&KScientific)染色。在以120kV运行的Tecnai G2Spirit透射电子显微镜上观察preS VLP。
LC-MS/MS分析
M1和preS-HA的表达通过LC-MS/MS分析。简而言之,40%蔗糖级分在12%-SDS-PAGE凝胶上经受电泳,该12%-SDS-PAGE凝胶用考马斯R250染色。切割考马斯R250染色的凝胶条带,随后用胰蛋白酶[Promega,酶∶蛋白=1∶50(wt/wt)]在37℃在25mM碳酸氢铵缓冲液中凝胶内消化持续12h。将冻干的胰蛋白酶消化的样品重新溶解在2%乙腈、0.1%甲酸中,并且上样到ChromXP C18(3μm、)nanoLC捕集柱上。在线捕集、脱盐程序用100%溶剂A(溶剂A∶水/乙腈/甲酸=98/2/0.1%;溶剂B:2/98/0.1%)在2μL/min的流速进行。然后,范围从5%-35%乙腈(0.1%甲酸)的60-min梯度洗脱在分析柱(75μm×15cm C18-3μm ChromXP Eksigent)上使用。LC-MS/MS分析用配备Nanospray III源(AB SCIEX,Concord,ON)的Triple TOF 5600系统(AB SCIEX,Concord,ON)进行。数据使用2.5kV的离子喷射电压、30 PSI的气帘气体(curtain gas)、5 PSI的喷雾气体(nebulizer gas)和150℃的接口加热器温度获得。MS用TOF-MS扫描操作。对于IDA,测量扫描(survey scan)在250ms中采集,并且如果超过150个计数/秒(计数/s)的阈值并且具有+2至+4电荷状态,则多达25次产物离子扫描(90ms)被收集。滚动碰撞能量设置被应用于用于碰撞诱导的解离的所有前体离子。对于峰宽的1/2(~12s)设置了动态排除。对于数据分析,.wiff文件用ProteinPilot 5.0处理。使用默认设置,针对包括M1和preS-HA的蛋白序列的本地数据库进行搜索。
免疫和攻击
6-8周龄的雌性Balb/c小鼠通过在后肢中注射抗原制剂来免疫。在第22天给予了加强。血液在第52天和第112天收集,并且中和抗体滴度通过ELISA确定。在第52天,脾细胞或肝内白细胞中的活化的T细胞通过ELISPOT和FACS分析。在第70天攻击免疫的小鼠。如先前地描述的(Yang PL等人Proc NatlAcad Sci U S A 2002 99:13825-13830),在流体动力学条件下注射10μg的pT-HBV1.3(包含1.3倍HBV基因组长度的质粒)以建立HBV感染。流体动力学注射病毒DNA是公认的急性乙型肝炎病毒感染的小鼠模型。血液样品在不同的时间点收集以测量HBV抗原。在第67天,将小鼠处死,并且肝组织用于测量HBV的抗原和RNA。活化的T细胞还通过FACS和ELISPOT测定分析。所有小鼠实验均遵循由北京大学的动物实验委员会(Committee for Animal Experiments at Peking University)审查和批准的实验方案、按照制度方针进行。
HBV转基因小鼠中的免疫
所有小鼠实验均遵循由北京大学的动物护理和使用制度委员会(InstitutionalAnimal Care and Use Committee of Peking University)审查和批准的实验方案、按照制度方针进行。六至八周龄雌性HBV转基因小鼠(ayw亚型)从458医院(Guangzhou,China)的传染病中心获得。HBV转基因小鼠用20μg的preS VLP在后肢肌肉内免疫,并且分别地在第22天和第43天加强。在第0天、第30天和第70天收集血液,并且通过ELISA确定抗preS抗体滴度。在第70天,脾细胞中的活化的T细胞用ELISPOT和流式细胞术分析。所有小鼠实验均遵循由北京大学的动物实验委员会审查和批准的实验方案、按照制度方针进行。
脾细胞和肝内白细胞的分离
为了分离脾细胞,轻轻地研磨脾细胞,随后通过40μm过滤器,并且用ACK裂解缓冲液处理。用PBS洗涤后,将细胞重悬浮在补充了10%胎牛血清(FBS)和1%青霉素-链霉素-L-谷氨酰胺的DMEM中。为了分离肝内白细胞,将小鼠肝用预加热的不具有Ca2+、Mg2+的Hank’s平衡溶液灌注,随后用20mL在Hank’s平衡盐溶液中的0.025%胶原酶D灌注,并且在37℃静置10分钟。然后轻轻地研磨肝,随后通过40μm过滤器。离心后,将细胞重悬浮在DMEM中的40%(vol/vol)Percoll中,并且在PBS中70%Percoll(vol/vol)上分层。在2000rpm离心该梯度20分钟后,收集处在间期的细胞。然后将细胞用ACK裂解缓冲液处理,用PBS洗涤,并且重悬在补充了10%胎牛血清(FBS)和1%青霉素-链霉素-L-谷氨酰胺的DMEM中,用于进一步分析。
酶联免疫斑点测定
遵循制造商的方案,T细胞应答使用IFN-γ ELISPOT集(BD Biosciences)确定。简而言之,将96孔板在4℃用纯化的抗小鼠IFN-γ抗体(1∶200)包被过夜,并且然后使用补充了10%胎牛血清(FBS)和1%青霉素-链霉素-L-谷氨酰胺的DMEM封闭2h。脾细胞或肝内白细胞以2×105/孔接种。代表先前描述的存在于preS(表1)或纯化的preS蛋白中的表位的肽用于在5%CO2和加湿的培养箱中在37℃刺激细胞36h,培养基和佛波醇肉豆蔻酸乙酸酯(PMA)/离子霉素处理的细胞分别用作阴性对照和阳性对照。洗涤后,将细胞与生物素化的抗小鼠IFN-γ抗体(1∶250)在室温孵育持续2h,并且然后与链霉亲和素-辣根过氧化物酶(HRP)(1∶1000)孵育1h。最后洗涤后,将3-氨基-9-乙基咔唑(AEC)底物(Alfa Aesar)添加至孔,并且允许在室温显色40min。反应用蒸馏水停止,并且允许板风干,然后形成斑点的细胞通过使用ELISPOT读板机计数。
流式细胞术
将脾细胞或肝内白细胞重悬浮在补充了10%胎牛血清和1%青霉素-链霉素-L-谷氨酰胺的DMEM中,并且然后以2×106/孔接种。然后将细胞用在补充了2μg/ml布雷菲德菌素A(BD Biosciences)的DMEM中被稀释至10μg/ml的最终浓度的preS特异性肽或纯化的重组preS刺激6h。然后在染色缓冲液(包含2%胎牛血清的PBS)中洗涤细胞,并且对于CD8和CD4表面表达,使用异硫氰酸荧光素(FITC)缀合的抗小鼠CD8抗体(BD Biosciences)和多甲藻素叶绿素蛋白(PerCP)缀合的抗小鼠CD4抗体(BD Biosciences)在4℃染色持续30分钟。然后将细胞使用商购可得的Cytofix/Cytoperm试剂盒(BD Biosciences)洗涤、固定和透化。然后对于细胞内细胞因子表达,将细胞使用藻红蛋白(PE)缀合的抗小鼠IFN-γ抗体(BDBiosciences)在4℃染色40min。洗涤后,将细胞重悬在染色缓冲液中,并使用BD FACSCantoTM II流式细胞仪(BD Biosciences)和FACSDiva 6.1.3版分析。结果从从200,000个细胞收集的数据产生。
ELISA
将纯化的preS抗原(5μg/m1)或preS VLP(1μg/ml)吸附至96孔板,用10%BSA封闭,并且然后将50μl的1∶100稀释的血清在37℃孵育持续30min,随后与添加的HRP缀合的抗小鼠IgG、IgG1或IgG2a(Santa Cruz Biotechnology)在37℃孵育30分钟,并且然后与TMB底物孵育10分钟,然后用2M H2SO4终止,用于测量在450nm的光密度。此外,将血清样品1∶5稀释用于HBsAg和HBeAg检测。
中和
对于感染实验,将5×105个HepG2/hNTCP细胞/孔在24孔板中培养,并且与单独的病毒接种物(500的M.O.I.)或连同不同稀释的小鼠抗preS VLP血清或1000倍稀释的乙型肝炎免疫球蛋白(HBIG)(来自Chengdu Rongsheng Bioproduct Company,具有144mg/ml的蛋白质浓度)的病毒接种物(500的M.O.I.)孵育过夜,在病毒感染期间存在4%PEG。培养基每2天或3天更换,并且HBeAg在感染后1周使用用于乙型肝炎e抗原的诊断ELISA试剂盒(KehuaBio-engineering)测量。
qPCR分析
为了检测在用表达载体转染的293T细胞中的mRNA,转染后48hr,来自293T细胞的总RNA使用QIAGEN RNeasy Mini试剂盒遵循制造商的说明提取。将总RNA存储在-20℃直到使用。任何可能的污染性DNA用DNA酶I(Takara)清除。总RNA使用NanoDrop 2000分光光度计(Thermo Scientific)定量。如先前地描述的(Zheng W等人Cell Chem Biol 201623:1002-1013),在20μL的反应中,将1μg总RNA使用带有gDNA Eraser(Takara)的PrimeScript RTReagent试剂盒逆转录成cDNA。来源于5ng总RNA的cDNA用作用于实时PCR扩增的模板。引物(preS-HA-FW:5’-CCACCAATCGGCAGTC-3’(SEQ ID NO:4))和(preS-HA-RV:5’-GCCACCAGCAGGAAGAT-3’(SEQ ID NO:5))用于preS-HA转录物;(M1-FW:5’-TGACAACAACCAACCCACT-3’(SEQ ID NO:6))和(M1-RV:5’-CTGCTGCTTGCTCACTCG-3’(SEQ IDNO:7))用于M1转录物;(β-肌动蛋白-FW:5’-TCATGAAGTGTGACGTGGACATC-3’(SEQ ID NO:8))和(β-肌动蛋白-RV:5’-CAGGAGGAGCAATGATCTTGATCT-3’(SEQ ID NO:9))用于β-肌动蛋白转录物。遵循用于20μL的总反应体积的制造商的方案,qRT-PCR用GoTaq qPCR Master Mix(Promega)在CFX96实时PCR检测系统(Bio-Rad)中进行。对反应产物进行琼脂糖凝胶电泳。
对于攻击研究,来自HBV攻击的小鼠的肝的总RNA用Trizol试剂(Invitrogen)分离。然后添加氯仿和混合。离心后,小心地收集水性层并且与异丙醇混合,并且静置10min。离心后,抽吸上清液,并且沉淀物用70%乙醇洗涤,随后用无核酸酶的水溶解。任何可能的污染性DNA用DNA酶I(Takara)清除。总RNA使用NanoDrop 2000分光光度计(ThermoScientific)定量。如先前地描述的(Zheng W等人Cell Chem Biol 2016 23:1002-1013),在20μL的反应中,将1μg总RNA使用带有gDNA Eraser(Takara)的PrimeScript RT Reagent试剂盒逆转录成cDNA。来源于2ng总RNA的cDNA用作用于实时PCR扩增的模板。引物(HBV2270FW:5’-GAGTGTGGATTCGCACTCC-3’(SEQ ID NO:10))和(HBV2392RV:5’-GAGGCGAGGGAGTTCTTCT-3’(SEQ ID NO:11))用于HBV RNA转录物(Yan H等人.Elife 20121:e00049)。,qRT-PCR用GoTaq qPCR Master Mix(Promega)遵循制造商对于20μL的总反应体积的说明在CFX96实时PCR检测系统(Bio-Rad)中进行。
免疫组织化学
收集肝组织并且在10%中性福尔马林中固定。石蜡包埋后,肝切片用于通过使用多克隆兔抗HBcAg抗体(Dako)的免疫组织化学染色检测HBV核心抗原。
结果
preS VLP的构建和制备
流感病毒M1和HA的共表达释放出用HA抗原修饰的病毒样颗粒(Galarza JM等人Viral Immunol 2005 18:244-251)。为了产生用HBV preS抗原修饰的病毒样颗粒,构建嵌合蛋白,该嵌合蛋白具有融合在HA片段的N端的preS序列,HA片段包括其跨膜结构域和细胞质尾(图1A)。来自HA的信号肽也被添加在preS序列之前,来自HA的信号肽可以在表达嵌合蛋白后去除。M1的第41个氨基酸被突变成Ala,以增强病毒样颗粒的释放(Campbell PJ等人J Virol 2014 88:7569-7577)。分别地用pCAGGS-M1、pCAGGS-preS-HA或两种质粒转染293T细胞后,总RNA通过QIAGEN Rneasy Mini试剂盒提取并分析M1和preS-HA的转录水平。qPCR结果表明,转染后48hr,M1基因和preS-HA基因二者都已在293T细胞中被充分地转录(图1B)。将分别表达M1和preS-HA的pCAGGS载体共转染到293T细胞中后,preS抗原的表达容易地通过免疫荧光显微术在细胞膜上检测到(图1C和1D)。这与preS-HA嵌合蛋白的构建是一致的,因为HA的跨膜区将嵌合蛋白保留在细胞膜中。如果M1蛋白没有被共表达,preS-HA嵌合蛋白表现得不能使preS抗原暴露在细胞膜的外部,因为preS抗原仅在细胞膜用TritonX-100透化后才是能够检测的。蛋白印迹分析也证实了preS-HA在293T细胞中的表达(图2)。有趣地,仅当M1蛋白被共表达时,在上清液中检测到preS-HA的存在,表明从细胞分泌preS-HA需要M1(图2A)。
preS VLP的纯化与表征
在转染后72hr,培养基从用pCAGGS-M1和pCAGGS-preS-HA共转染的细胞收集。将培养基放置在蔗糖梯度上并且进行超速离心。从40%蔗糖级分收集样品。通过SDS-PAGE和蛋白印迹分析,鉴定对应于preS-HA抗原的蛋白(图2B和2C)。负染电子显微照片显示出该样品包含病毒样颗粒(图2D)。该样品进一步通过LC-MS/MS表征(图2E)。通过MS分析鉴定的M1序列覆盖了全长M1序列的90%以上。然而,在preS-HA中仅两种肽以高置信度(≥95%)被鉴定出,这可能是由于preS的糖基化导致的(Lambert C等人Virol J 2007 4:45)。这些数据显示出,包括M1蛋白和preS-HA蛋白的VLP被成功地纯化。
用preS VLP免疫
每只Balb/c小鼠分别地用10μg的作为VLP的preS抗原,或从大肠杆菌表达纯化的重组preS(Lian M等人Virol J 2007 4:93)与铝盐佐剂免疫。PBS还用作空白对照。在第22天给予了加强。血液样品在第52天和第112天从每只小鼠收集,并且从这些样品制备血清。如在图3中显示出的,所有血清样品被稀释100倍,并且血清抗体滴度通过ELISA确定。数据揭示了,在产生抗preS中和抗体方面,即使不使用任何佐剂,VLP仍是比重组preS蛋白更有效的preS抗原。特别是,preS VLP引发高水平的总IgG,包括抗preS IgG1(Th2同种型)和IgG2a(Th1同种型)二者。
为了进一步测试抗preS VLP血清是否可以阻断HBV感染人类肝细胞,进行体外感染实验。使用乙型肝炎免疫球蛋白(HBIG)作为阳性对照,抗preS VLP血清明显地防止HBV感染HepG2/hNTCP细胞,如通过HBeAg在细胞培养物的上清液中的减少的水平证明的(图3E)。共同地,这些结果指示preS VLP可以在小鼠中刺激抗preS中和抗体。
T细胞应答在诱导体液免疫中发挥作用,并且是对治疗性HBV疫苗的有效性至关重要的(Celis E,等人J Immunol 1984 132:1511-1516;Chisari FV等人Pathol Biol 201058:258-266)。为了评价preS特异性T细胞应答是否产生,从脾分离T淋巴细胞并且在培养板中培养。用preS特异性T细胞肽表位(表2)刺激持续6hr后,通过FACS分析T细胞的CD4、CD8和INF-γ。活化的T细胞的结果显示在图4中。在用preS VLP免疫的小鼠中,CD4+和CD8+T细胞比对照或用重组preS免疫的那些小鼠高得多。CD8+T细胞或CD4+T细胞的数目与产生胞内IFN-γ的CD8+T细胞或CD4+T细胞的数目一致。被认为是在控制和清除HBV复制中的关键的INF-γ的分泌通过ELISPOT分析。结果显示出,当小鼠用preS VLP免疫时,preS特异性IFN-γ产生是更丰富的(图4E)。这表明preS VLP可以引发能够清除HBV的有效的preS特异性CD8+T细胞。
用preS VLP接种提供了抗攻击保护
在第70天攻击免疫的小鼠。HBV复制通过流体动力学注射包含1.3倍HBV基因组的超长的pT-HBV1.3质粒(10μg)诱导。在第77天收集肝组织用于HBV RNA检测、免疫组织化学和T细胞应答分析。HBV RNA拷贝通过qPCR测量(图5A)。preS VLP免疫的动物中的HBV RNA水平明显地低于用重组preS免疫的动物中的HBV RNA水平。针对HBV核心抗原染色的肝切片指示,HBcAg阳性肝细胞在preS VLP免疫的动物中几乎被完全消除,而在preS免疫的动物中保持高水平(图5B)。在第70天、第72天、第74天和第77天从每只小鼠收集血液样品,并且从这些样品制备血清。preS VLP免疫的动物中的HBsAg水平贯穿至少7天保持几乎检测不到,而在用重组preS免疫的动物中在攻击后第4天上升至高水平(图5C)。在preS VLP免疫的动物中,血清HBeAg的水平在跨7天的过程中也保持几乎检测不到。在另一方面,在preS免疫的动物中的HBeAg水平在攻击后第4天升高,然后在攻击后第7天下降至几乎检测不到的水平(图5D)。这个清除HBsAg和HBeAg的阶段与抗preS中和抗体的发展一致(图5E)。因此,在通过流体动力学注射超长的1.3倍HBV基因组的HBV攻击后7天内,用preS VLP免疫控制并且清除HBV复制。
保护作用与记忆T细胞应答相关
由于CD8T细胞应答将可能在HBV清除中发挥重要作用,在脾中的T细胞回忆应答通过FACS分析(图6A-D)。在用preS VLP免疫的小鼠中,CD8+和CD4+T细胞的数目明显地高于对照和用重组preS免疫的那些小鼠,并且产生胞内INF-γ的CD8+T细胞或CD4+T细胞的数目也较高,但没有那么多。值得注意地,当小鼠用preS VLP免疫时,CD8+T细胞的数目显著地更高,指示出preS VLP诱导在HBV攻击时可以被回忆的记忆T细胞,并且该T细胞负责清除HBV。此外,在对脾细胞(图6E)和肝内白细胞(图6F)二者攻击后7天,还通过IFN-γ ELISPOT测定来测量T细胞回忆应答。有趣地,在preS VLP免疫的小鼠的肝和脾中存在的preS特异性T细胞应答比在重组preS免疫的小鼠中的那些应答更有效,表明preS特异性T细胞介导HBV从转染的肝细胞中的清除。综上所述,preS VLP引发稳健的抗preS中和抗体和preS特异性T细胞应答,并且能够保护小鼠免于HBV攻击,代表了对于人类中的HBV感染的新的预防性或可能是治疗性的疫苗候选物。
HBV转基因小鼠中的免疫应答
preS VLP免疫的治疗性潜力通过使用HBV转基因小鼠作为慢性感染的模型来研究。HBV转基因小鼠首先用preS VLP或PBS初免,并且然后分别地在第22天和第43天加强。尽管HBV转基因小鼠已经变得对HBV耐受(Allweiss L,Dandri M.J Hepatol 2016;64:S17-31),preS VLP仍然可以诱导高水平的抗preS总IgG,包括抗preS IgG1(Th2同种型)和IgG2a(Th1同种型)二者(图7B-D),表明抗preS VLP的平衡的Th1/Th2应答。此外,preS VLP免疫也可以刺激比对照或重组preS免疫更高百分比的preS特异性CD4+和CD8+T细胞(图7E和7F)。此外,产生preS特异性IFN-γ的T细胞在用preS VLP免疫的小鼠中比对照或用重组preS蛋白免疫的那些小鼠更丰富(图7G和7H),暗示了preS VLP的治疗性潜力。综上所述,preS VLP疫苗可以在HBV转基因小鼠中诱导preS特异性CD8+和CD4+T细胞应答。
讨论
尽管目前可得的基于HBV S抗原的疫苗的成功,但仍然存在5%-10%的人无法充足地应答以提供针对暴露于HBV的保护(Kubba AK等人Commun Dis Public Health 20036:106-112)。由于在HBV preS区域中的另外的B细胞表位和T细胞表位,preS代表用于HBV疫苗候选物的有吸引力的抗原,能够克服对基于S抗原的疫苗的无响应性(Grgacic EV等人Methods 2006 40:60-65)。当与基于S抗原的疫苗组合时,preS抗原可以以协同方式增强整体保护。
基于VLP的疫苗因缺乏遗传物质而有高安全性。此外,由于呈递更类似于天然病毒的高度重复表位(Roldao A等人Expert Rev Vaccines 2010 9:1149-1176),VLP通常表现出高免疫原性。此外,流感基质蛋白M1和血凝素(HA)的共表达可以自组装成病毒样颗粒(Galarza JM等人Viral Immunol 2005 18:244-251)。该流感VLP支架可以被开发成非基于卵的、细胞培养物来源的疫苗平台,以呈递外来抗原,诸如HBV preS抗原(Lee DH等人ClinExp Vaccine Res 2014 3:133-139)。
独特的系统已经被成功地设计以通过共表达来自流感病毒的M1蛋白和preS-HA嵌合蛋白产生preS病毒样颗粒。培养基中的preS VLP可以通过在蔗糖梯度中超速离心来纯化。即使没有任何佐剂,preS VLP能够引发比重组preS高得多的抗体滴度。这可能是由于HBVpreS VLP的形成,因为这允许被抗原呈递细胞的内吞。此外,preS VLP引发高抗体滴度的潜力最可能被呈递到VLP的表面上的高度重复preS抗原促进。
抗preS抗体先前地被发现在中和HBV方面是引人注目地有效的(Neurath AR等人Vaccine 1989 7:234-236)。在preS1区域内的保护表位的鉴定揭示了,preS1特异性抗体通过阻断宿主NTCP受体的结合而中和病毒(Yan H等人Elife 2012 1:e00049;Sankhyan A等人Sci Rep 2016 6:21240)。这些观察结果支持这一观念,有效的基于preS的疫苗可以扩大受保护个体的群体。所公开的结果证明,preS VLP可能是有效的preS疫苗候选物。同时,因为preS抗原被携带在VLP的表面上,在宿主细胞内的I类抗原呈递途径可以被利用,引起有效的T细胞应答,其还可以在引发高B细胞应答中发挥作用。此外,preS VLP能够保护小鼠免受HBV攻击,其可能是由于有效的诱导B细胞应答和产生能够控制感染的记忆CD8+T细胞导致的。
preS抗原已经先前地被用作预防性或治疗性疫苗的候选物(Shouval D等人MedMicrobiol Immunol 2015 204:57-68)。当重组preS蛋白被用于免疫时,抗体滴度不是非常高(Sylvan SP等人Vaccine 2009 28:446-451)。这些抗体中和HBV的能力是有限的。更至关重要地,没有展示抗HBV的T细胞应答(Raz R等人Vaccine 1996 14:207-211;Shapira MY等人J Hepatol 2001 34:123-127)。这与分离的蛋白质通常地不诱导T细胞应答是一致的,因为它们通常不被抗原呈递细胞内化(Pennock ND等人Trends in immunology 2016 37:170-180)。为了克服该障碍,病毒或酵母载体用于表达HBV抗原(Sallberg M等人Humangene therapy 1998 9:1719-1729;Martin P等人Gut 2015 64:1961-1971;Reynolds TD等人Journal of virology 2015 89:10407-10415;King TH等人PloS one 2014 9:e101904)。然而,尽管复制性载体诱导强T细胞应答的能力,当它们被使用时存在安全性忧虑。此外,这些载体仅可以被给予一次,因为宿主将建立针对该载体的免疫。所公开的preSVLP的设计具有模拟病毒颗粒的抗原表面和能够进入抗原呈递细胞以引发强的T细胞应答的优点,并且在同时,它允许多种剂量并且不复制任何外来微生物。
总之,该preS VLP可以用作针对人类中的乙型肝炎病毒感染的预防性和治疗性疫苗。
除非另外定义,否则本文使用的所有技术术语和科学术语具有如本公开发明所属领域的普通技术人员通常地理解的相同的含义。本文引用的出版物及针对它们引用的材料通过引用具体地并入本文。
本领域技术人员将认识到,或能够使用不超过常规的实验确定,本文描述的本发明的具体实施方案的许多等同方式。此类等同方式意图被跟随的权利要求书涵盖。
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<110> 佐治亚州立大学研究基金会公司
<120> 乙型肝炎病毒pre-S蛋白的病毒样颗粒
<130> 220707-2030
<150> US 62/414,899
<151> 2016-10-31
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Asn Arg Met Val Leu Ala Ser Thr Thr Ala Lys Ala Met Glu Gln Met
180 185 190
Ala Gly Ser Ser Glu Gln Ala Ala Glu Ala Met Glu Val Ala Ser Gln
195 200 205
Thr Arg Gln Met Val His Ala Met Arg Thr Ile Gly Thr His Pro Ser
210 215 220
Ser Ser Ala Gly Leu Lys Asp Asp Leu Leu Glu Asn Leu Gln Ala Tyr
225 230 235 240
Gln Lys Arg Met Gly Val Gln Ile Gln Arg Phe Lys
245 250
<210> 4
<211> 16
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 4
ccaccaatcg gcagtc 16
<210> 5
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 5
gccaccagca ggaagat 17
<210> 6
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 6
tgacaacaac caacccact 19
<210> 7
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 7
ctgctgcttg ctcactcg 18
<210> 8
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 8
tcatgaagtg tgacgtggac atc 23
<210> 9
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 9
caggaggagc aatgatcttg atct 24
<210> 10
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 10
gagtgtggat tcgcactcc 19
<210> 11
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 11
gaggcgaggg agttcttct 19
<210> 12
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 12
Pro Leu Gly Phe Phe Pro Asp His Gln Leu
1 5 10
<210> 13
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 13
Trp Pro Ala Ala Asn Gln Val Gly Val Gly Ala Phe Gly Pro Gly Leu
1 5 10 15
<210> 14
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 14
Met Gln Trp Asn Ser Thr Ala Phe His Gln Ala Leu Gln Asp Pro Arg
1 5 10 15
Val Arg Gly Leu Tyr Leu Pro Ala Gly Gly
20 25
<210> 15
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 15
Lys Leu Glu Ser Val Gly Val His Gln Ile Leu Ala Ile Tyr Ser Thr
1 5 10 15
Val Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
20 25 30
Trp Met Cys Ser Asn Gly Ser Leu Gln Cys Arg Ile Cys Ile
35 40 45
<210> 16
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 16
Met Glu Ala Lys Leu Phe Val Leu Phe Cys Ala Phe Thr Ala Leu Lys
1 5 10 15
Ala
<210> 17
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 17
Val Leu Leu Leu Ala Ile Val Ser Leu Val Lys Ser
1 5 10
<210> 18
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 18
Met Glu Arg Ile Val Ile Ala Leu Ala Ile Ile Ser Val Val Lys Gly
1 5 10 15
<210> 19
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 19
Met Glu Lys Phe Ile Ile Leu Ser Thr Val Leu Ala Ala Ser Phe Ala
1 5 10 15
Tyr
<210> 20
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 20
Met Asn Thr Gln Ile Leu Val Phe Ile Ala Cys Val Leu Ile Glu Ala
1 5 10 15
Lys Gly
<210> 21
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 21
Met Asn Thr Gln Ile Leu Ile Leu Thr Leu Val Ala Ala Ile His Thr
1 5 10 15
Asn Ala
<210> 22
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 22
Met Ala Arg Leu Pro Ile Leu Leu Leu Leu Ile Ser Leu Val Tyr Ser
1 5 10 15
<210> 23
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 23
Met Asn Thr Gln Ile Leu Val Phe Ala Leu Val Ala Val Ile Pro Thr
1 5 10 15
Asn Ala
<210> 24
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 24
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Phe Cys Leu Ala Leu Gly
1 5 10 15
<210> 25
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 25
Met Lys Lys Val Leu Leu Phe Ala Ala Ile Ile Ile Cys Ile Arg Ala
1 5 10 15
<210> 26
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 26
Met Lys Thr Thr Ile Ile Leu Ile Leu Leu Thr His Trp Val Tyr Ser
1 5 10 15
<210> 27
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 27
Met Lys Thr Thr Ile Val Leu Ile Leu Leu Thr His Trp Val Tyr Ser
1 5 10 15
<210> 28
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 28
Met Lys Ala Ile Ile Val Leu Leu Met Val Val Thr Ser Asn Ala
1 5 10 15
<210> 29
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 29
Ser Leu Val Lys Ser
1 5
<210> 30
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 30
Met Glu Lys Thr Leu Leu Phe Ala Ala Ile Phe Leu Cys Val Lys Ala
1 5 10 15
<210> 31
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 31
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Phe Cys Leu Val Leu Gly
1 5 10 15
<210> 32
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 32
Met Lys Thr Ile Ile Val Leu Ser Cys Phe Phe Cys Leu Ala Phe Ser
1 5 10 15
<210> 33
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 33
Met Asp Ile Arg Pro Ile Ile Ile Ser Leu Leu Ile Ser Thr Cys Val
1 5 10 15
Gln Ala
<210> 34
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 34
Leu Met Val Val Thr Ser Asn Ala
1 5
<210> 35
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 35
Ile Val Leu Leu Met Val Val Thr Ser Asn Ala
1 5 10
<210> 36
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 36
Ala Ile Val Ser Leu Val Lys Ser
1 5
<210> 37
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 37
Met Asn Thr Gln Ile Leu Ile Leu Ala Thr Ser Ala Phe Leu Cys Val
1 5 10 15
Arg Ala
<210> 38
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 38
Met Leu Ser Ile Thr Ile Leu Phe Leu Leu Ile Ala Glu Gly Ser Ser
1 5 10 15
<210> 39
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 39
Met Glu Ala Lys Leu Leu Val Leu Phe Cys Thr Phe Ala Ala Leu Lys
1 5 10 15
Ala
<210> 40
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 40
Met Thr Arg Leu Pro Ile Leu Leu Leu Leu Ile Ser Leu Val Tyr Ala
1 5 10 15
<210> 41
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 41
Met Leu Ser Ile Val Ile Leu Phe Leu Leu Ile Ala Glu Asn Ser Ser
1 5 10 15
<210> 42
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 42
Met Lys Thr Thr Ile Ile Leu Ile Leu Leu Ile His Trp Val His Ser
1 5 10 15
<210> 43
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 43
Met Leu Ser Leu Ile Met Arg Thr Val Ile Ala Leu Ser Tyr Ile Phe
1 5 10 15
Cys Leu Ala Phe Gly
20
<210> 44
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 44
Met Glu Lys Ile Val Leu Leu Leu Ala Ile Val Ser Leu Val Lys Ser
1 5 10 15
<210> 45
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 45
Met Lys Thr Thr Thr Ile Leu Ile Leu Leu Thr His Trp Val His Ser
1 5 10 15
<210> 46
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 46
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Leu Ser Ala Thr Asp
1 5 10 15
Ala
<210> 47
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 47
Met Ala Ile Ile Tyr Leu Ile Leu Leu Phe Thr Ala Val Arg Gly
1 5 10 15
<210> 48
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 48
Met Asn Thr Gln Ile Leu Ile Leu Ala Ile Ser Ala Phe Leu Cys Val
1 5 10 15
Arg Ala
<210> 49
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 49
Met Glu Glu Ile Val Leu Leu Phe Ala Ile Val Ser Leu Ala Arg Ser
1 5 10 15
<210> 50
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 50
Met Glu Lys Ile Val Leu Leu Leu Ala Thr Val Ser Leu Val Lys Ser
1 5 10 15
<210> 51
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 51
Met Lys Ala Lys Leu Leu Val Leu Leu Tyr Ala Phe Val Ala Thr Asp
1 5 10 15
Ala
<210> 52
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 52
Met Asp Ile Arg Ala Ile Val Ile Ser Leu Leu Ile Ser Thr Cys Val
1 5 10 15
Gln Ala
<210> 53
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 53
Met Glu Arg Ile Val Ile Ala Leu Ala Ile Ile Asn Ile Val Lys Gly
1 5 10 15
<210> 54
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 54
Met Glu Ala Lys Leu Phe Val Leu Phe Cys Thr Phe Thr Val Leu Lys
1 5 10 15
Ala
<210> 55
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 55
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Phe Cys Leu Ala Phe Ser
1 5 10 15
<210> 56
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 56
Met Lys Ala Lys Leu Leu Val Leu Leu Cys Ala Phe Thr Ala Thr Asp
1 5 10 15
Ala
<210> 57
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 57
Met Thr Arg Leu Ser Ile Leu Leu Leu Leu Ile Ser Leu Val Tyr Ser
1 5 10 15
<210> 58
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 58
Met Glu Ala Arg Leu Leu Val Leu Leu Cys Ala Phe Ala Ala Thr Asn
1 5 10 15
Ala
<210> 59
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 59
Met Glu Lys Phe Ile Ala Ile Ala Thr Leu Ala Ser Thr Asn Ala Tyr
1 5 10 15
<210> 60
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 60
Met Lys Ala Ile Leu Leu Val Leu Leu Cys Ala Phe Ala Ala Thr Asn
1 5 10 15
Ala
<210> 61
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 61
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Phe Cys Leu Ala Phe Ala
1 5 10 15
<210> 62
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 62
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Phe Cys Gln Val Phe Ala
1 5 10 15
<210> 63
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 63
Met Asp Ile Gln Ala Val Ala Leu Leu Ile Leu Thr Ser Thr Cys Val
1 5 10 15
Gln Ala
<210> 64
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 64
Met Lys Gln Leu Ser Ile Val Ile Leu Leu Leu Ser Ile Val Tyr Thr
1 5 10 15
<210> 65
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 65
Met Thr Ile Thr Phe Leu Ile Leu Leu Phe Thr Val Val Lys Gly
1 5 10 15
<210> 66
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 66
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Phe Cys Leu Val Phe Ala
1 5 10 15
<210> 67
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 67
Met Ala Leu Asn Val Ile Ala Thr Leu Thr Leu Ile Ser Val Cys Val
1 5 10 15
His Ala
<210> 68
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 68
Met Glu Arg Thr Val Ile Ala Leu Ala Ile Ile Ser Val Val Lys Gly
1 5 10 15
<210> 69
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 69
Met Val Val Thr Ser Asn Ala
1 5
<210> 70
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 70
Met Lys Lys Ile Val Leu Leu Leu Ala Ile Val Ser Leu Val Lys Ser
1 5 10 15
<210> 71
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 71
Met Lys Thr Val Ile Ala Leu Ser Tyr Ile Leu Cys Leu Thr Phe Gly
1 5 10 15
<210> 72
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 72
Met Glu Arg Ile Val Leu Phe Leu Ala Ile Val Ser Leu Val Lys Ser
1 5 10 15
<210> 73
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 73
Met Lys Thr Ile Ile Val Leu Ser Tyr Phe Phe Cys Leu Ala Leu Ser
1 5 10 15
<210> 74
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 74
Met Tyr Lys Val Val Val Ile Ile Ala Leu Leu Gly Ala Val Lys Gly
1 5 10 15
Leu
<210> 75
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 75
Lys Ile Val Leu Leu Leu Ala Ile Val Ser Leu Val Lys Ser
1 5 10
<210> 76
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 76
Met Asn Thr Gln Ile Leu Ile Leu Ala Thr Ser Ala Phe Phe Tyr Val
1 5 10 15
Arg Ala
<210> 77
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 77
Met Glu Arg Val Val Leu Leu Leu Ala Met Ile Ser Leu Val Lys Ser
1 5 10 15
<210> 78
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 78
Met Lys Thr Leu Ile Ala Leu Ser Tyr Ile Phe Cys Leu Val Leu Gly
1 5 10 15
<210> 79
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 79
Met Asn Thr Gln Ile Leu Val Phe Ala Leu Val Ala Val Ile His Thr
1 5 10 15
Asn Ala
<210> 80
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 80
Met Ile Ala Ile Ile Val Val Ala Ile Leu Ala Thr Ala Gly Arg Ser
1 5 10 15
<210> 81
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 81
Met Glu Lys Ile Val Leu Leu Phe Ala Ile Val Ser Leu Val Arg Ser
1 5 10 15
<210> 82
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 82
Met Glu Lys Thr Val Leu Leu Leu Ala Thr Val Ser Leu Val Lys Ser
1 5 10 15
<210> 83
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 83
Met Glu Arg Ile Val Leu Leu Leu Ala Ile Val Ser Leu Val Lys Ser
1 5 10 15
<210> 84
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 84
Met Leu Ser Val Val Ile Leu Phe Leu Leu Val Ala Glu Asn Ser Ser
1 5 10 15
<210> 85
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 85
Met Lys Lys Ile Leu Leu Phe Thr Val Ile Phe Leu Tyr Ala Lys Ala
1 5 10 15
<210> 86
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 86
Met Glu Lys Leu Leu Leu Phe Ala Thr Ile Ile Leu Cys Val Lys Ala
1 5 10 15
<210> 87
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 87
Met Leu Ser Ile Val Val Leu Leu Leu Leu Ile Ala Glu Ser Ser Ser
1 5 10 15
<210> 88
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 88
Met Glu Ala Lys Leu Phe Val Leu Phe Cys Ala Phe Thr Thr Leu Glu
1 5 10 15
Ala
<210> 89
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 89
Met Lys Thr Ile Ile Ala Leu Ser His Ile Phe Cys Leu Val Leu Gly
1 5 10 15
<210> 90
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 90
Met Leu Ser Ile Val Val Leu Leu Leu Leu Met Ala Glu Gly Ser Ser
1 5 10 15
<210> 91
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 91
Met Ile Ala Leu Ile Leu Val Ala Leu Ala Leu Ser His Thr Ala Tyr
1 5 10 15
Ser
<210> 92
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 92
Met Lys Ala Ile Leu Leu Val Leu Leu Tyr Thr Phe Thr Ala Ala Asn
1 5 10 15
Ala
<210> 93
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 93
Met Lys Ala Asn Leu Leu Val Leu Leu Cys Ala Leu Ala Ala Ala Asp
1 5 10 15
Ala
<210> 94
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 94
Met Lys Ala Ile Leu Leu Val Leu Leu Cys Thr Phe Ala Ala Thr Asn
1 5 10 15
Ala
<210> 95
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 95
Met Lys Ala Lys Leu Leu Ile Leu Phe Cys Ala Phe Thr Ala Thr Asp
1 5 10 15
Ala
<210> 96
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 96
Met Glu Lys Ile Val Leu Leu Phe Ala Ile Val Ser Leu Val Lys Ser
1 5 10 15
<210> 97
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 97
Met Glu Thr Lys Ala Ile Ile Ala Ala Leu Leu Met Val Thr Ala Ala
1 5 10 15
Asn Ala
<210> 98
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 98
Met Leu Ser Ile Thr Ile Leu Phe Leu Leu Ile Ala Glu Val Ser Ser
1 5 10 15
<210> 99
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 99
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Phe Cys Gln Val Leu Ala
1 5 10 15
<210> 100
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 100
Met Lys Ala Lys Leu Leu Val Leu Phe Cys Ala Phe Thr Ala Thr Asp
1 5 10 15
Ala
<210> 101
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 101
Val Thr Ser Asn Ala
1 5
<210> 102
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 102
Met Tyr Lys Val Val Val Ile Ile Ala Leu Leu Gly Ala Val Arg Gly
1 5 10 15
Leu
<210> 103
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 103
Leu Val Ala Leu Ala Leu Ser Gln Thr Ala Tyr Ser
1 5 10
<210> 104
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 104
Ile Ile Val Leu Leu Met Val Val Thr Ser Asn Ala
1 5 10
<210> 105
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 105
Met Tyr Lys Ile Val Leu Val Leu Thr Leu Phe Gly Ala Val Asn Gly
1 5 10 15
Leu
<210> 106
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 106
Met Asn Thr Gln Ile Leu Val Phe Ile Ala Cys Val Leu Ile Lys Ala
1 5 10 15
Lys Gly
<210> 107
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 107
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Leu Cys Leu Val Phe Ala
1 5 10 15
<210> 108
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 108
Met Phe Leu Leu Pro Arg Phe Val Leu Val Ser Cys Ile Ile Gly Ser
1 5 10 15
Leu Gly
<210> 109
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa可以是任何天然存在的氨基酸
<400> 109
Met Cys Ile Ala Met Ala Pro Arg Thr Leu Leu Leu Leu Ile Xaa Cys
1 5 10 15
Gln Leu Val Phe
20
<210> 110
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 110
Met Phe Leu Leu Leu Arg Phe Val Leu Val Ser Cys Ile Ile Gly Ser
1 5 10 15
Leu Gly
<210> 111
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 111
Met Gly Ser Met Cys Ile Ala Met Ala Pro Arg Thr Leu Leu Leu Leu
1 5 10 15
Ile Gly Cys Gln Leu Ala Leu Gly
20
<210> 112
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 112
Met Leu Ser Leu Ile Leu Phe Phe Pro Ser Phe Ala Phe Ala
1 5 10
<210> 113
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 113
Met Phe Leu Leu Pro Arg Phe Ile Leu Val Ser Cys Ile Ile Gly Ser
1 5 10 15
Leu Gly
<210> 114
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 114
Met Leu Ile Ile Phe Leu Phe Phe Asn Phe Cys Tyr Gly
1 5 10
<210> 115
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 115
Met Gly Arg Met Cys Ile Ala Met Ala Pro Arg Thr Leu Leu Leu Leu
1 5 10 15
Ile Gly Cys Gln Leu Val Phe Gly
20
<210> 116
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 116
Met Leu Arg Met Arg Val Arg Pro Pro Ser Ala Ile Pro Val Phe Leu
1 5 10 15
Ile Phe Val Leu Leu Pro Phe Val Leu Thr Ser
20 25
<210> 117
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 117
Met Leu Ile Ile Phe Leu Phe Phe Tyr Phe Cys Tyr Gly
1 5 10
<210> 118
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 118
Met Cys Ile Ala Met Ala Pro Arg Thr Leu Leu Leu Leu Ile Gly Cys
1 5 10 15
Gln Leu Val
<210> 119
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 119
Met Ala Arg Thr Asp Ala Met Ala Pro Arg Thr Leu Leu Leu Val Leu
1 5 10 15
Ser Leu Gly Tyr Ala Phe Gly
20
<210> 120
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 120
Met Phe Leu Leu Pro Arg Phe Cys Leu Val Cys Ser Ile Ile Ser Thr
1 5 10 15
Phe Gly
<210> 121
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 121
Met Gly Ser Thr Cys Ile Ala Met Ala Pro Arg Thr Leu Leu Leu Leu
1 5 10 15
Ile Gly Cys Gln Leu Val
20
<210> 122
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 122
Met Phe Leu Leu Pro Arg Phe Cys Leu Val Cys Ser Ile Ile Gly Thr
1 5 10 15
Phe Gly
<210> 123
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 123
Met Phe Phe Ser Leu Leu Leu Met Leu Gly Leu Thr Glu Ala
1 5 10
<210> 124
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 124
Met Phe Phe Ser Leu Leu Leu Val Leu Gly Leu Thr Glu Ala
1 5 10
<210> 125
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 125
Met Leu Gly Leu Thr Glu Ala
1 5
Claims (20)
1.一种融合蛋白,所述融合蛋白包含融合在病毒包膜蛋白的跨膜结构域和任选的细胞质尾的N端处的乙型肝炎preS抗原。
2.权利要求1所述的融合蛋白,其中所述preS抗原包含氨基酸序列SEQ ID NO:1,或其具有对SEQ ID NO:1的至少90%同一性的抗原变体。
3.权利要求1或2所述的融合蛋白,其中所述病毒包膜蛋白包含病毒I型跨膜糖蛋白。
4.权利要求3所述的融合蛋白,其中所述病毒包膜蛋白包含流感病毒血凝素(HA)蛋白。
5.权利要求4所述的融合蛋白,所述融合蛋白包含氨基酸序列SEQ ID NO:2。
6.权利要求1至5的任一项所述的融合蛋白,所述融合蛋白还在所述N端包含信号肽。
7.权利要求6所述的融合蛋白,其中所述信号肽包含来自HA的信号肽。
8.一种病毒样颗粒(VLP),所述病毒样颗粒(VLP)包含权利要求1至5任一项所述的融合蛋白和与I型跨膜糖蛋白相容的病毒基质蛋白。
9.权利要求8所述的VLP,其中所述基质蛋白包含流感病毒基质蛋白1(M1)。
10.权利要求8所述的VLP,所述VLP通过以下产生:用一种或更多种表达基质蛋白和权利要求1至7任一项所述的融合蛋白的重组杆状病毒共感染昆虫细胞,在生理学条件下培养所述昆虫细胞,和从昆虫细胞培养物上清液纯化所述VLP。
11.权利要求10所述的VLP,所述VLP通过以下产生:将一种或更多种表达基质蛋白和权利要求1至7任一项所述的融合蛋白的表达载体引入到哺乳动物细胞中,在适当的条件下培养所述哺乳动物细胞,和从细胞培养物上清液纯化所述VLP。
12.一种疫苗,所述疫苗包含在药学上可接受的赋形剂中的有效量的权利要求8至11任一项所述的VLP。
13.权利要求11或12所述的疫苗,所述疫苗还包含佐剂。
14.一种分离的多核苷酸,所述分离的多核苷酸包含编码权利要求警告!未发现参考文献来源至5任一项所述的融合蛋白的核酸序列。
15.权利要求14所述的分离的多核苷酸,其中所述编码融合蛋白的核酸序列可操作地连接至表达控制序列。
16.一种细胞,所述细胞包含权利要求14或15所述的分离的多核苷酸。
17.权利要求16所述的细胞,其中所述细胞是细菌、昆虫细胞、哺乳动物细胞或酵母细胞。
18.一种对受试者接种乙型肝炎的疫苗的方法,所述方法包括通过鼻内、肌肉内、皮下、透皮或舌下施用向有相应需要的受试者施用权利要求12或13所述的疫苗。
19.权利要求18所述的方法,所述方法还包括向所述受试者施用包含乙型肝炎表面抗原(HBsAg)的疫苗。
20.一种用于活化用于过继性细胞治疗(ACT)的CD8+ T细胞的方法,所述方法包括将CD8+ T细胞和树突状细胞与权利要求8至11任一项所述的VLP共培养。
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CN110325202B (zh) | 2023-10-31 |
CA3046778A1 (en) | 2018-05-03 |
US20200046824A1 (en) | 2020-02-13 |
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