CN102227445A - 结合丙型肝炎病毒的包膜蛋白2的抗体以及利用所述抗体鉴定丙型肝炎病毒的基因型的方法 - Google Patents
结合丙型肝炎病毒的包膜蛋白2的抗体以及利用所述抗体鉴定丙型肝炎病毒的基因型的方法 Download PDFInfo
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Abstract
本发明提供了特异性结合基因型2a的HCV的包膜蛋白2、但是不与基因型1a的HCV的包膜蛋白2免疫反应的抗体。
Description
技术领域
本发明涉及结合丙型肝炎病毒的包膜蛋白2的抗体,以及利用所述抗体鉴定丙型肝炎病毒的基因型的方法。
背景技术
丙型肝炎病毒(其在下文中也可以称为“HCV”)是非甲型和非乙型肝炎的主要病因病毒,其主要通过输血和性接触来感染(Choo et al., Science, Vol. 244:359-362, 1989)。估计在日本有2,000,000或更多的HCV携带者,包括没有显示肝炎症状的那些(病毒携带者),以及在世界上有170,000,000或更多的HCV携带者。HCV携带者数量不断提高的主要原因是,由于HCV感染的肝炎慢性化率高达70%到80%的事实,以及除了干扰素之外没有有效的抗病毒剂的事实。
半数或更多的慢性丙型肝炎患者所展现的病理学状况几乎必然将每况愈下,并且已知会发展成肝硬化或肝癌。因此,可以说丙型肝炎是具有不良预后的严重的传染性疾病。因此,涉及丙型肝炎的治疗和HCV的检测的研究是医学上重要的,并且新的疗法和治疗药物的开发是期望的。
HCV是单链的(+)RNA病毒,其基因组长度大约9.6 kb,其中基因组编码前体蛋白质,前体蛋白质通过宿主衍生的信号肽酶或HCV衍生的蛋白酶的翻译后切割转变成10种病毒蛋白质(即,Core、E1、E2、p7、NS2、NS3、NS4A、NS4B、NS5A和NS5B蛋白)。HCV根据基因组的核苷酸序列的系统发生分析被分类为10种或更多种基因型(例如,1a、1b、2a、2b、3a和3b)(Choo et al., Science, 1989, Vol. 244, p. 359-362;Simmonds et al., Hepatology, 1994, Vol. 10, p. 1321-1324;Okamoto et al., J. Gen. Virol., 1992, Vol. 73, p. 73-679;以及Mori et al., Biochem. Biophys. Res. Commun., 1992, Vol. 183, p. 334-342)。
近来,变为已知的是,干扰素的效果取决于HCV基因型而显著不同。已经显示的是,干扰素的抗病毒作用对基因型1a或1b的HCV难以发挥(Fried et al., N. Engl. J. Med., 2002, Vol. 347, p. 975-982以及Lusida et al., J. Clin. Microbiol., 2001, Vol. 39, p. 3858-3864)。
此外,变为已知的是,干扰素的抗病毒作用对干扰素具有相对好的效果的基因型2a的HCV和基因型2b的HCV不同地发挥,。已经提出的是,相比基因型2b的HCV,干扰素对基因型2a的HCV更显著地发挥了它们的抗病毒作用(Murakami et al., Hepatology, 1999, Vol. 30, p. 1045-1053)。
HCV抗体测试作为HCV诊断方法是已知的,通过所述测试,利用C100-3抗原检测血清中的抗HCV抗体,因为识别作为HCV的非结构区的NS4区域(C100-3抗原)的抗HCV抗体在丙型肝炎患者的血清中以70%-80%的比率存在(Choo et al., Science, 1989, Vol. 244, p. 359-362)。并且,作为这种方法的变种,已经开发了利用C100-3抗原、核心抗原和来自NS3区域的抗原的组合改善了检测灵敏度的第二代抗体分析系统,以及除了上述抗原之外还含有来自NS5区域的抗原的第三代抗体分析系统。已经使用了利用这些分析系统的HCV抗体测试(Aucella et al., Blood Purif., 2000, Vol. 18, p. 110-114)。
并且,除了前述的HCV抗体测试之外,HCV核心抗原测试(Fabrizi et al., J. Clin. Microbiol., 2005, Vol. 43, p. 414-420)被用于血清中HCV核心蛋白数量的直接测量,以及核酸扩增测试(NAT)被用于通过PCR方法确认HCV基因组的存在或缺乏(Velati et al., Euro Serveill., 2005, Vol. 10, p. 12-14)。
然而,HCV抗体测试是有问题的,因为当受试者在过去经历了HCV感染时,受试者将不可避免地成为丙型肝炎测试阳性,即使在完全痊愈之后。HCV抗体测试也是有问题的,因为血液中的抗HCV抗体仅在感染后1到3个月时被检出。如果测试在这一时间之前进行,不能检出HCV,并且受试者将是丙型肝炎测试阴性的。
并且,HCV核心抗原测试需要通过利用SDS破坏包膜进行处理来使得核心蛋白释放,因为核心蛋白(目标分子)存在于HCV颗粒之内。取决于SDS的处理时间,核心蛋白质可能变性,或可能释放抑制抗原抗体反应的物质,因而影响检测灵敏度。
此外,即使当受试者在HCV抗体测试和HCV核心抗原测试中是HCV测试阳性时,当前没有可能鉴定HCV基因型。为了进行干扰素治疗,必需进行进一步的测试,例如,核酸扩增测试以鉴定HCV基因型。这是因为干扰素的抗病毒作用取决于HCV基因型而显著地不同。特别是对HCV基因型1a和HCV基因型1b,不能产生有效的抗病毒作用,并且患者反而遭受干扰素的副作用。
同时,相对于测试样品的不充分的保存质量和稳定性,核酸扩增测试是有问题的,因为该测试使用受试者的血清RNA作为目标分子。核酸扩增测试也呈现了各种问题,并且对于RT-PCR方法的使用预防措施是必需的。例如,PCR可能在作为目标分子的RNA转录成DNA之后进行,引起由于RNA降解或逆转录酶的灭活和/或抑制的假阴性结果,或由于反应系统的交叉污染的假阳性结果。因此,核酸扩增测试被认为就准确性而言次于使用蛋白质作为目标分子的HCV抗体测试或HCV核心抗原测试。
发明内容
本发明解决的问题
本发明的目的是提供结合HCV表面的包膜、并且可以用于鉴定基因型1a的HCV、基因型1b的HCV和基因型2a的HCV的抗体,和提供利用这样的抗体鉴定HCV基因型的方法。
解决问题的手段
本发明人进行了集中的研究来实现以上目标。他们获得了产生单克隆抗体的杂交瘤,所述单克隆抗体以HCV基因型2a的包膜蛋白2作为抗原,从这些杂交瘤中获得了仅特异性结合HCV基因型2a的包膜蛋白2的抗体、仅结合HCV基因型2a的包膜蛋白2和HCV基因型1b的包膜蛋白2的抗体,以及结合HCV基因型2a的包膜蛋白2、HCV基因型1b的包膜蛋白2和HCV基因型1a的包膜蛋白2的抗体,因而他们完成了本发明。
特别地,本发明提供了特异性结合基因型2a的HCV的包膜蛋白2、但是不与基因型1a的HCV的包膜蛋白2免疫反应的抗体。
以上抗体优选地是将序列表中SEQ ID NO:1中所示氨基酸序列识别为表位的抗体。这样的抗体的实例是由具有临时登记号FERM ABP-11181的杂交瘤细胞系产生的抗体。
并且,优选地,上述抗体特异性地结合基因型2a的HCV的包膜蛋白2,但是不与基因型1a的HCV的包膜蛋白2以及基因型1b的HCV的包膜蛋白2免疫反应。
以上抗体更优选地是将序列表中SEQ ID NO:2或3中所示氨基酸序列识别为表位的抗体。这样的抗体的实例是由具有临时登记号FERM ABP-11180或FERM ABP-11179的杂交瘤细胞系产生的抗体。
此外,上述抗体优选地是特异性结合J6CF株的包膜蛋白2、但是不与JFH1株的包膜蛋白2免疫反应的抗体。这样的抗体的实例包括将序列表中SEQ ID NO:4所示氨基酸序列识别为表位的抗体,特别是由具有临时登记号FERM ABP-11183的杂交瘤细胞系产生的抗体。
并且,本发明提供了鉴定HCV基因型的方法,其中:如果病毒结合由具有临时登记号FERM ABP-11181的杂交瘤细胞系产生的抗体,但是不结合由具有临时登记号FERM ABP-11180和FERM ABP-11179的杂交瘤细胞系产生的任一抗体,所述HCV的基因型被确定为是基因型1b;如果病毒结合由具有临时登记号FERM ABP-11181的杂交瘤细胞系产生的抗体,并且结合由具有登记号FERM ABP-11180和FERM ABP-11179的杂交瘤细胞系产生的抗体,所述HCV的基因型被确定为是基因型2a;以及如果病毒结合由具有临时登记号FERM ABP-11182的杂交瘤细胞系产生的抗体,但是不结合由具有临时登记号FERM ABP-11181、FERM ABP-11180和FERM ABP-11179的杂交瘤细胞系产生的任一种抗体,所述HCV的基因型被确定为是基因型1a。
本说明书包含日本专利申请号2008-254338的说明书和/或附图的内容,本申请要求了它的优先权。
发明效果
根据本发明,HCV基因型1a、HCV基因型1b和HCV基因型2a的简单和非常精确的鉴定变为可能,并可以有效地选择干扰素治疗合适的丙型肝炎患者。特别地,对于预计没有来自干扰素治疗的治疗效果的、感染基因型1a或1b的HCV的丙型肝炎患者,可以减轻不良反应,并且可以提供选择新的治疗方法的机会。
附图说明
附图1是显示HCV前体蛋白质的示意图。黑色方框表示跨膜区域。
附图2是显示3×FLAG蛋白和抗原E2蛋白的融合蛋白的示意图。
附图3是显示抗原E2蛋白和人免疫球蛋白Fc结构域的融合蛋白的示意图。
附图4显示了在纯化3×FLAGJ6E2dTM蛋白质的步骤中获得的每个级分的SDS-PAGE结果。显示了3×FLAG-J6E2dTM在COS1细胞中的表达和纯化。3×FLAGJ6E2dTM蛋白质在洗脱级分中检出。附图4中的电泳照片的泳道分别表示以下:1,分子量标志物;2,培养物上清液;3,抗FLAG抗体柱孔隙级分;4,抗FLAG抗体柱洗脱级分1;5,抗FLAG抗体柱洗脱级分2;6,抗FLAG抗体柱洗脱级分3;7,抗FLAG抗体柱洗脱级分4;和8,分子量标志物。
附图5显示了J6E2-Fc、JFH1E2-Fc、THE2-Fc、Con1E2-Fc、J1E2-Fc和H77E2-Fc蛋白的SDS-PAGE结果。每种类型的E2 Fc蛋白在还原条件下为约97 kDa。显示了每种HCV株衍生的抗原E2蛋白质与人免疫球蛋白Fc结构域的纯化的融合蛋白。附图5中的电泳照片的泳道分别表示以下:1,分子量标志物;2,J6E2-Fc;3,JFH1E2-Fc;4,THE2-Fc;5,Con1E2-Fc;6,J1E2-Fc;7,H77E2-Fc;和8,分子量标志物。
附图6显示了每种单克隆抗体的各种HCV基因型/株的E2蛋白质的结合性质和抗体亚型。抗体与抗原E2蛋白质的结合强度表示为-到+++(-, OD450 nm < 0.1;+, 0.1 ≤ OD450 nm < 0.25;++, 0.25≤ OD450 nm < 0.4;+++, 0.4≤ OD450 nm)。附图6表明:8D10-3是结合基因型1a的HCV、基因型1b的HCV和基因型2a的HCV的抗原E2蛋白质的抗体;1G2-32和2F2-7是结合基因型2a的HCV的抗原E2蛋白的抗体;4E8-8是结合基因型1b的HCV和基因型2a的HCV的抗原E2蛋白的抗体;M1E12-1是结合JFH1株的抗原E2蛋白的单克隆抗体;以及9A5-4是结合JFH1株和H77株的抗原E2蛋白的单克隆抗体。
附图7显示了 8D10-3单克隆抗体(附图7A)、1G2-32单克隆抗体(附图7B)、4E8-8单克隆抗体(附图7C)、2F2-7 单克隆抗体(附图7D)和M1E12-1单克隆抗体(附图7E)与具有衍生自HCV J6CF株的抗原E2蛋白的氨基酸序列的肽的结合强度。
附图8显示了检测来自各种HCV基因型/HCV株的抗原E2蛋白的灵敏性,如通过利用1G2-32和8D10-3单克隆抗体的夹心ELISA测定的。在附图8中,黑色圆圈表示J6E2-Fc、白色圆圈表示JFH1E2-Fc、黑色正方形表示THE2-Fc、白色正方形表示Con1E2-Fc、黑色菱形表示J1E2-Fc、以及白色菱形表示H77E2-Fc。
附图9显示了利用单克隆抗体8D10-3通过蛋白质印迹方法检测的,各种基因型/株的HCVE2蛋白质的有无。
具体实施方式
在下文中说明实施本发明的优选的实施方式。
本发明的抗体的特征在于特异性结合基因型2a的HCV(在下文中称为HCV2a)的包膜蛋白2(在下文中称为E2蛋白),但不与基因型1a的HCV(在下文中称为HCV1a)的E2蛋白免疫反应。在优选的实施方式中,这样的抗体不与HCV1a的 E2蛋白和基因型1b的HCV(在下文中称为HCV1b)的 E2蛋白两者免疫反应。
上述抗体可以这样制备:用抗原蛋白或所述抗原蛋白的部分肽做为抗原免疫动物,所述抗原蛋白由没有HCV的E2蛋白的跨膜区域(也称为跨膜结构域)的区域组成,制备产生针对所述E2蛋白的单克隆抗体的杂交瘤,然后筛选产生特异性结合HCV2a的E2蛋白、但不与HCV1a的E2蛋白免疫反应、并且进一步优选不与HCV1a的E2蛋白和HCV1b的E2蛋白两者免疫反应的抗体的杂交瘤。
在此,“E2蛋白”是通过用由宿主细胞衍生的信号肽酶和HCV自身编码的2种蛋白酶切割HCV前体蛋白产生的功能性病毒蛋白质。这使用HCV2a的J6CF株作为例子来解释,当位于前体蛋白的N-末端的甲硫氨酸被确定为是第1个氨基酸时,E2蛋白是从前体蛋白的氨基酸位置384到750的367个氨基酸残基的蛋白质。E2蛋白中从氨基酸位置722到750的区域是跨膜结构域(Cocquerel et al., J. Virol., 2000, Vol. 74, p. 3623-3633)。附图1是显示HCV前体蛋白质的示意图。
在下文中,将按顺序描述获得上述抗体的技术。
1)作为抗原的E2蛋白衍生的蛋白或肽的选择
作为为了获得上述抗体而免疫动物的抗原,可以使用由没有HCV2a E2蛋白的跨膜区域的区域组成的蛋白质(在下文中称为抗原E2蛋白)、或所述蛋白质的部分肽(抗原E2肽)。抗原E2肽必须由与2a以外基因型的HCV的E2蛋白具有低同源性的区域组成。
作为抗原E2蛋白,可以选择包含HCV2a的前体蛋白(例如,SEQ ID NO:5)的氨基酸384到720的蛋白质。优选地,选择包含前体蛋白的氨基酸位置530到562的氨基酸序列的蛋白质,并且更优选地,选择包含选自以下的一个或更多个氨基酸序列的蛋白质:包含前体蛋白的氨基酸465到484的氨基酸序列;包含前体蛋白的氨基酸559到584的氨基酸序列;以及包含前体蛋白的氨基酸683到719的氨基酸序列。
并且,作为抗原E2肽,可以选择包含HCV2a的前体蛋白(例如,SEQ ID NO:5)的氨基酸530到562(更优选地,氨基酸531到549,进一步优选地,氨基酸531到540)并具有10到19个氨基酸的肽长度(更优选地,10个氨基酸)的肽。更优选地,选择包含前体蛋白的氨基酸465到484(更优选地,氨基酸465到477,进一步优选地,氨基酸468到477)并具有10到13个氨基酸(更优选地,10个氨基酸)的肽长度的肽;包含前体蛋白的氨基酸559到584(更优选地,氨基酸564到576,进一步优选地,位置567到576的氨基酸残基)并具有10到13个氨基酸(更优选地,10个氨基酸)的肽长度的肽;或包含前体蛋白的氨基酸683到719(优选地,氨基酸704到719,更优选地,氨基酸709到719)并具有10到19个氨基酸(更优选地,10个氨基酸)的肽长度的肽。
此外,HCV2a基因组的核苷酸序列已经在许多病毒株(Yanagi et al., Virology, 1999, Vol. 262, p. 250-263)中显示,并可以从GenBank获得。例如,HCV2a的JFH1株的基因组的核苷酸序列在GenBank中以登记号AB047639公开,J6CF株的基因组的核苷酸序列在GenBank中以登记号AF177036公开。
2)抗原E2肽的制备
以上选择的抗原E2肽可以根据HCV2a的前体蛋白的氨基酸序列信息直接地化学合成。例如,可以用于动物免疫的这样的抗原可以通过使用肽合成仪容易地大量制备。
3)抗原E2蛋白的制备
通过根据关于编码所述HCV2a的前体蛋白的区域的核苷酸序列信息合成编码抗原E2蛋白的DNA片段,然后在 细胞中使来自这样获得的DNA片段的抗原E2蛋白翻译,可以大量地制备上述选择的抗原E2蛋白,作为可以用于动物免疫的抗原。具体如下描述。
通过构建其中插入了编码抗原E2蛋白的DNA片段的表达载体,然后转导到哺乳动物细胞、昆虫细胞、酵母菌、大肠杆菌(Escherichia coli)等等中,可以在各细胞中产生抗原E2蛋白。优选地,所述蛋白通过哺乳动物细胞的分泌性表达来生产。在这种情况下,编码抗原E2肽的DNA片段按阅读框连接到信号肽序列的下游使得密码子的框架匹配,将终止密码子添加到3'末端,然后产物可以插入到表达载体中。
用于抗原E2蛋白的分泌表达的哺乳动物细胞的实例包括,COS-1、COS-7、Vero、CV-1、CHO、dhfr基因缺陷的CHO、仓鼠细胞BHK、大鼠GH3、大鼠嗜铬细胞瘤PC12、小鼠L细胞、小鼠C127细胞、小鼠骨髓瘤细胞SP2/0、NSO和NS-1、小鼠淋巴瘤细胞EL4、小鼠成纤维细胞NIH3T3和10T1/2、小鼠成肌细胞C2C12、小鼠基质细胞PA6、ST2、OP9和Tst-4、人类成巨核细胞CMK、人类T细胞Jurkat、人类肾脏上皮细胞293、人类肝癌细胞Huh7、HepG2和IMY-N9、人类骨肉瘤细胞MG-63、人类FL细胞、白色脂肪细胞、卵细胞和ES细胞。
编码蛋白质的DNA在启动子的控制下插入,然后用于在细胞中抗原E2蛋白的重组表达。可以用于在哺乳动物细胞中抗原E2蛋白的重组表达的这样的启动子的实例包括SRα启动子、SV40启动子、LTR启动子、CMV启动子、肌动蛋白启动子、EF-1α(延伸因子-1α)启动子、遍在蛋白启动子和PGK(磷酸甘油酸激酶)启动子。
用于哺乳动物细胞中抗原E2蛋白的分泌表达的表达载体的实例包括pSecTag/FRT/V5-His(Invitrogen Corporation)、p3×FLAG-CMV-9(Sigma)、p3×FLAG-CMV13(Sigma)、pFUSE-Fc2(InvivoGen)和pTriEx-7(Novagen)。掺入到表达载体的信号肽序列优选地是前胰蛋白酶原的信号肽。具有前胰蛋白酶原的信号肽序列的载体的实例包括p3×FLAG-CMV-9(Sigma)和p3×FLAG-CMV-13(Sigma)。此外,由于含有信号肽的蛋白质在哺乳动物细胞中表达时信号肽被除去,这种信号肽对抗原E2蛋白的使用不构成问题。
在抗原E2蛋白在哺乳动物细胞中分泌表达时,目标抗原E2蛋白作为与标记蛋白质(例如,Tag)的融合蛋白表达,然后利用针对或特异性结合所述标记蛋白质的抗体或分子可检测和纯化所述抗原E2蛋白。标记蛋白质的实例包括FLAG肽、3×FLAG肽、HA肽、3×HA肽、myc肽、6xHis肽、GST多肽、MBP多肽、PDZ结构域多肽、碱性磷酸酶、免疫球蛋白Fc结构域和抗生物素蛋白。作为用于制备抗原E2蛋白的标记蛋白质,FLAG肽、HA肽和免疫球蛋白Fc结构域是适合的,免疫球蛋白Fc结构域是更适合的。
附图2是显示了抗原E2蛋白与3×FLAG蛋白的融合蛋白的示意图。附图3是显示了抗原E2蛋白与免疫球蛋白Fc结构域的融合蛋白的示意图。
作为这样的免疫球蛋白Fc结构域,可以使用人类衍生的、猴衍生的、小鼠衍生的、大鼠衍生的、兔衍生的、仓鼠衍生的、或鸡衍生的免疫球蛋白Fc结构域,人类衍生的免疫球蛋白Fc结构域是优选的。此外,免疫球蛋白Fc结构域的免疫球蛋白重链的种类可以是IgM、IgG1、IgG2、IgG3或IgG4。
人免疫球蛋白的氨基酸序列是由Edelman等(Proc. Natl. Acad. Sci. U.S.A., 1969, Vol. 63, p. 78-85)报道的。并且,人免疫球蛋白重链的cDNA的核苷酸序列信息可以从GenBank获得(例如,重链:登记号BX640627)。根据获得的核苷酸序列设计PCR引物,然后利用人类脾脏细胞的cDNA文库或人类基因组DNA作为模板进行PCR,从而可以克隆免疫球蛋白Fc结构域的cDNA。
HCV E2蛋白可以直接在它们之间的连接位点处连接到免疫球蛋白Fc结构域,或通过插入其中的接头肽来连接。接头肽的实例包括Ser-Gly、Asp-Pro、Asp-Pro-Glu、Gly-Asp-Pro-Glu、Gly-Gly-Gly-Ser和(Gly-Gly-Gly-Ser)×3。
此外,例如,抗原E2蛋白由昆虫细胞分泌表达时,昆虫细胞如Sf21、Sf9和High FiveTM利用多角体蛋白(多角体)启动子、p10启动子等等表达载体来转导。然后,可以表达抗原E2蛋白或抗原E2蛋白与标记蛋白质的融合蛋白。
另外,在抗原E2蛋白由酵母菌分泌表达时,例如,酿酒酵母(Saccharomyces cerevisiae)、粟酒裂殖酵母(Schizosaccharomyces pombe)或巴斯德毕赤氏酵母(Pichia pastoris)用表达载体转导,所述表达载体利用gal1启动子、gal10启动子、热激蛋白启动子、MFα1启动子、PHO5启动子、PGK启动子、GAP启动子、ADH启动子、AOX1启动子等等,然后可以表达抗原E2蛋白或抗原E2蛋白与标记蛋白质的融合蛋白。
当抗原E2蛋白通过大肠杆菌分泌表达时,例如,大肠杆菌菌株如XL1-Blue菌株、BL-21菌株、JM107菌株、TB1菌株、JM109菌株、C600菌株或HB101菌株用表达载体转化,所述表达载体利用trp启动子、lac启动子、PL启动子、T7启动子、tac启动子等等,然后可以表达抗原E2蛋白或抗原E2蛋白与标记蛋白质的融合蛋白。
用表达载体转导以引起哺乳动物细胞和昆虫细胞的抗原E2蛋白分泌性表达的方法的实例包括脂转染方法、磷酸钙方法、电穿孔方法、DEAE-葡聚糖方法和显微注射方法。更具体地,转导可以根据 Molecular Cloning 3rd. Ed. 16. 1-16. 62(Cold Spring Harbor Laboratory, New York, 2001)中描述的方法来进行。
将表达载体导入大肠杆菌的方法没有特别的限制,只要它是用于将DNA导入大肠杆菌的方法。这样的方法的实例包括利用钙离子的方法(Cohen et al., Proc. Natl. Acad. Sci., U.S.A., 1972, Vol. 69, p. 2110-2114)和电穿孔方法。
将表达载体导入酵母菌的方法没有特别的限制,只要它是用于将DNA导入酵母菌的方法。这样的方法的实例包括电穿孔方法(Becker et al., Methods. Enzymol., 1990, Vol. 194, p. 182-187)、原生质球方法((Hinnen et al., Proc. Natl. Acad. Sci., U.S.A., 1978, Vol. 75, p. 1929-1933)和醋酸锂方法(Itoh et al., J. Bacteriol., 1983, Vol. 153, p. 163-168)。
转导的细胞可以通过本身已知的方法来培养。用于培养哺乳动物细胞的培养基,例如,使用含有约5%-20%胎牛血清(FBS)的MEM培养基、DMEM培养基、RPMI 1640培养基、199培养基(Proceeding of the Society for the Biological Medicine, 1950, Vol. 73, p. 1)等等。pH值优选是约6到8。作为无血清培养基,可以使用CD-CHO、293 SFM-II和Hybridoma-SFM(所有这些都由Invitrogen Corporation生产),可以根据需要向其中添加血清或补充物。细胞可以在30℃到40℃培养15小时到60小时,优选地根据需要进行通气或搅动。
在细胞培养完成之后,通过离心等等从培养溶液除去细胞,然后可以从这样获得的培养上清液纯化抗原E2蛋白或抗原E2蛋白与标记蛋白质的融合蛋白。抗原E2蛋白或抗原E2蛋白与标记蛋白质的融合蛋白可以根据本领域的技术人员已知的蛋白质分离和纯化技术来纯化。例如,蛋白质可以通过硫酸铵沉淀、凝胶层析、离子交换层析、亲和层析等等的任一的组合来分离和纯化。
例如,培养溶液中的抗原E2蛋白可以利用肝素柱或凝集素柱容易地纯化。在与3×FLAG肽的融合蛋白的情况下,抗原E2蛋白可以利用抗FLAG抗体柱来有效地纯化,在与6xHis肽的融合蛋白的情况下,抗原E2蛋白可以利用镍柱、锌柱或钴柱来有效地纯化,在与免疫球蛋白Fc结构域的融合蛋白的情况下,抗原E2蛋白可以利用蛋白A柱、或蛋白G柱来有效地纯化,在含有HA肽的嵌合蛋白质的情况下,抗原E2蛋白可以利用抗HA抗体柱来有效地纯化。
这样纯化的抗原E2蛋白或抗原E2蛋白与标记蛋白质的融合蛋白可以在通过SDS-PAGE分级之后通过考马斯亮蓝染色或银染色来检测。在融合蛋白的情况下,融合蛋白可以利用针对融合的标记蛋白质的抗体通过蛋白质印迹方法来检测。
4)利用抗原E2肽或抗原E2蛋白的免疫
为了获得特异性结合HCV2a的E2蛋白、但是不与HCV1a的E2蛋白免疫反应、更优选地不与HCV1a的E2蛋白和HCV1b的E2蛋白两者免疫反应的抗体,应当进行利用上述抗原E2肽或抗原E2蛋白的动物免疫,获得多克隆抗体或筛选生产目标单克隆抗体的杂交瘤。
免疫的动物可以是具有能够用于产生杂交瘤细胞的脾细胞的非人动物。这样的动物的实例包括小鼠、大鼠、仓鼠、兔和鸡。可以更优选地使用小鼠。
免疫方法的实例包括,与佐剂一起向4到10周龄的小鼠皮下地或腹膜内施用上述抗原E2肽或抗原E2蛋白几次,确认血液抗体滴度的提高,通过单独的抗原E2肽或抗原E2蛋白的静脉内或腹膜内的施用进行强化,然后在第3到10天(优选地在第4天)采集血液或脾细胞。测量从采集的血液获得的血清的抗体滴度。在这种情况下,如果它特异性识别目标抗原,它可以用作多克隆抗体。
佐剂的实例包括弗氏完全佐剂、弗氏不完全佐剂、氢氧化铝凝胶与百日咳疫苗的混合物、Titer Max Gold(Vaxel)和GERBU佐剂(GERBU Biotechnik)。
通过经由眼底静脉丛或尾静脉从免疫的动物采集血液,然后通过酶免疫分析(EIA)检查获得的血液中与抗原E2肽或抗原E2蛋白反应的抗体的存在或缺乏,来测量血液中的抗体滴度。
5)杂交瘤细胞的制备
在强化后3-10天从已经确认了血液中提高的抗体滴度的、免疫的动物采集的脾脏细胞被融合到骨髓瘤细胞,从而可制备具有自主复制性的杂交瘤细胞。通过筛选产生具有目标特异性的抗体的杂交瘤细胞可以大量地制备单克隆抗体。
用于细胞融合的骨髓瘤细胞,可以使用,例如,小鼠衍生的建立的细胞系P3-X63Ag8-U1(P3-U1)、SP2/0-Ag14(SP2/0)、P3-X63-Ag8653(653)、P3-X63-Ag8(X63)、P3/NS1/1-Ag4-1(NS1)等等。这些细胞系可以从RIKEN BioResource Center, ATCC(美国典型培养物保藏中心)或ECACC(欧洲细胞培养物保藏中心)获得。
脾脏细胞和骨髓瘤细胞的细胞融合通过洗涤两种细胞、以1:1-10的比例混合骨髓瘤细胞和脾脏细胞、然后添加平均分子量1000-6000的聚乙二醇或聚乙烯醇作为融合促进剂,或利用商业的细胞融合装置使用电刺激(例如,电穿孔)来进行。
在完成细胞融合的处理之后,融合的细胞悬浮于培养基中并用培养基洗涤,然后通过有限稀释或集落形成方法在甲基纤维素培养基中克隆。有限稀释的实例是以下方法,该方法包括稀释到103到107个细胞/mL,将细胞以102到106个细胞/孔播种到96孔细胞培养微板中,然后培养细胞。
当进行杂交瘤细胞的克隆时,优选地向培养基添加HAT补充物,以能够选择性地获得单独的目标融合细胞。更具体地,根据Antibodies:A Laboratory Manual(Cold Spring Harbor Laboratory, 1988)或Selected Methods in Cellular Immunology(W. H. Freeman and Company, 1980)中描述的方法,获得和克隆目标杂交瘤细胞。
6)杂交瘤细胞的筛选
例如,通过如下所述的EIA方法筛选目标杂交瘤细胞。
具体地,首先,将抗原E2肽或抗原E2蛋白固定在载体上,添加每个克隆的杂交瘤细胞产生的抗体,在4℃到37℃的条件下反应足以形成抗体-抗原复合物的时间。
接下来,用酶、染料、放射性同位素等等标记的,能够特异性结合由此形成的抗体-抗原复合物的抗体部分的二级抗体与形成的抗体-抗原复合物接触,在4℃-37℃的条件下反应足以形成抗体-抗原-二级抗体复合物的时间。
最后,由此形成的抗体-抗原-二级抗体复合物的有无利用来自用于标记二级抗体的酶、染料或放射性同位素的信号作为指标来检测,从而确定是否为具有目标特征的抗体。
7)单克隆抗体的制备
使通过上述方法选择的杂交瘤细胞适应于无血清培养基,例如,Hybridoma-SFM(Invitrogen Corporation),然后可以从无血清培养基中培养物的上清液制备单克隆抗体。对于培养细胞,可以使用烧瓶、陪氏培养皿、旋转培养瓶、滚瓶或高密度培养烧瓶CELLine(Becton, Dickinson and Company)。
另外,为了大量制备单克隆抗体,例如,6到8周龄裸鼠或SCID小鼠可以腹膜内施用0.5 mL异十八烷(2,6,10,14-四甲基十五烷),饲养2周,然后腹膜内施用5×106到2×107个细胞/小鼠的杂交瘤细胞,饲养10到21天,从而可以从产生的腹腔积液制备单克隆抗体。
通过离心从这样采集的腹腔积液中除去细胞和细胞碎屑。纯化方法,例如,利用40%-50%饱和硫酸铵的盐析、辛酸沉淀法、DEAE-琼脂糖柱、蛋白A柱、蛋白质G柱、HiTrap IgM纯化HP-柱(GE Healthcare)、甘露聚糖结合蛋白柱(Pierce)和凝胶过滤柱单独地或组合地使用,从而采集IgG或IgM级分,然后可以用作纯化的单克隆抗体。
8)单克隆抗体的表位的分析
通过合成具有8到12个连续氨基酸的氨基酸序列的肽,所述连续氨基酸被设计以在抗原E2蛋白中移位一个到几个氨基酸,用该肽作为抗原时检查单克隆抗体对所述肽的结合,然后确定抗体的表位,可以分析单克隆抗体的线性表位。
具体地,将这样合成的肽固定在平板上,并与纯化的抗体反应。添加标记的二级抗体,然后让平板静置。通过酶免疫分析(ELISA)或放射免疫分析(RIA)来测量结合能力。
在某些情况下可能无法通过这种方法测定表位。在这种情况下,单克隆抗体的表位可能是构象表位,因而抗体可识别抗原的构象。
特异性结合HCV2a的E2蛋白、但是不与HCV1a的E2蛋白免疫反应的抗体的实例是将序列表中SEQ ID NO:1所示氨基酸序列识别为表位的抗体。这样的抗体的具体实例是从具有临时登记号FERM ABP-11181的杂交瘤细胞系产生的抗体。
另外,特异性结合HCV2a的E2蛋白、但是不与HCV1a的E2蛋白和HCV1b的E2蛋白两者免疫反应的抗体的实例是将序列表中SEQ ID NO:2或3所示氨基酸序列识别为表位的抗体。这样的抗体的具体实例是由具有临时登记号FERM ABP-11180或FERM ABP-11179的杂交瘤细胞系产生的抗体。
此外,特异性结合HCV2a的J6CF株的包膜蛋白2、但是不与JFH1株的包膜蛋白2免疫反应的抗体的实例是将序列表中SEQ ID NO:4所示氨基酸序列识别为表位的抗体。这样的抗体的具体实例是由具有临时登记号FERM ABP-11183的杂交瘤细胞系产生的抗体。这种抗体可以从HCV基因型2a中辨别J6CF株,因此它可以用于鉴定J6CF株。
此外,上述具有临时登记号FERM ABP-11181、FERM ABP-11180、FERM ABP-11179、FERM ABP-11183和FERM ABP-11182的杂交瘤细胞系已经保藏在国际保藏机构,国家先进工业科学和技术学会国际专利生物保藏所(邮政编码:305-8566 Central 6,1-1-1 Higashi,Tsukuba,Ibaraki,日本)(保藏日期:2008年9月19日),因而它们是可获得的。这些细胞系原本各自被国内保藏(原始保藏日期:2008年9月19日)在同一保藏机构,登记号FERM P-21677(临时登记号FERM AP-21677)、FERM P-21676(临时登记号FERM AP-21676)、FERM P-21675(临时登记号FERM AP-21675)、FERM P-21679(临时登记号FERM AP-21679)和FERM P-21678(临时登记号FERM AP-21678),然后根据布达佩斯条约转为国际保藏。
另外,本发明的鉴定HCV基因型的方法包括:如果HCV结合由具有临时登记号FERM ABP-11181的杂交瘤细胞系产生的抗体,但是不结合由具有临时登记号FERM ABP-11180和FERM ABP-11179的杂交瘤细胞系产生的任一抗体,确定HCV的基因型是基因型1b;如果HCV结合由具有临时登记号FERM ABP-11181的杂交瘤细胞系产生的抗体,并且结合由具有临时登记号FERM ABP-11180和FERM ABP-11179的杂交瘤细胞系产生的抗体,确定HCV的基因型是基因型2a;以及如果HCV结合由具有临时登记号FERM ABP-11182的杂交瘤细胞系产生的抗体,但是不结合由具有临时登记号FERM ABP-11181、FERM ABP-11180和FERM ABP-11179的杂交瘤细胞系产生的任一种抗体,确定HCV的基因型是基因型1a。
未知基因型的HCV是否结合具有临时登记号FERM ABP-11181、FERM ABP-11180、FERM ABP-11179或FERM ABP-11182的杂交瘤细胞系生产的抗体,可以使用没有特别限制的任何分析系统来确定,只要它能够检测抗原抗体反应的有无。这样的方法的实例是如下所述的免疫分析和蛋白质印迹方法。
(免疫分析)
首先,含有未知基因型的HCV的测试样品与载体或平板接触,在所述载体或平板上要检查有无结合的上述抗体已经作为初级抗体固定,然后在4℃-37℃下反应足以形成抗体-抗原复合物的时间。
接下来,用酶、染料、放射性同位素等等标记的,以非基因型特异性方式结合HCV的二级抗体与所述抗体-抗原复合物接触,然后在4℃-37℃的条件下反应足以形成抗体-抗原-二级抗体复合物的时间。
最后,利用来自用于标记所述二级抗体的酶、染料或放射性同位素的指示信号,检测形成的抗体-抗原-二级抗体复合物的有无,从而可以确定与上述抗体有无结合。
(蛋白质印迹方法)
首先,将含有未知基因型的HCV的测试样品点在膜,例如硝化纤维膜或PVDF膜上,然后所述测试样品中所含的蛋白质被固定。
然后,将膜浸入5%脱脂乳、1% BSA溶液或商业的封闭试剂中用于封闭,用缓冲液充分洗涤,然后转移到含有用酶、染料、放射性同位素等等标记以检查有无结合的上述抗体的缓冲液中。反应在4℃-37℃下进行足以形成抗体-抗原复合物的时间。
随后,充分地洗涤膜,然后检测来自用于标记上述抗体的酶、染料或放射性同位素的信号用于检查有无结合,从而确定与上述抗体有无结合。
在此引用的所有出版物、专利和专利申请通过以它们的整体引用而合并在此。
实施例
将参考以下实施例更具体地说明本发明。然而,这些实施例仅仅是说明性的,本发明的范围不受这些实施例的限制。
(实施例1)用于表达HCV株的抗原E2蛋白与标记蛋白质的融合蛋白的载体的制备。
(1)用于表达来自HCV2a的J6CF株的抗原E2蛋白与3×FLAG标签的融合蛋白的载体的构建
来自HCV2a的J6CF株的抗原E2蛋白,即,由没有HCV2a的J6CF株的E2蛋白的跨膜区域的区域组成的蛋白质,如下所述地制备。
首先,利用HCV2a的J6CF株的基因组RNA的cDNA(GenBank Accession No. AF177036)作为模板,Advantage GC2 PCR试剂盒(Takara Bio Inc .),和J6E2dTM-s(SEQ ID NO :6 :CACAAGCTTCGCACCCATACTGTTGGGG)与J6E2dTM-as(SEQ ID NO :7 :GCTCTAGATTACCATCGGACGATGTATTTTGT)作为引物,通过PCR方法来扩增编码由相应于J6CF株的前体蛋白(SEQ ID NO:5)的氨基酸位置384到720的区域组成的蛋白质的基因,此时N-末端的起始甲硫氨酸被确定为是第一个氨基酸。
然后,将这样扩增的DNA片段克隆到pCR-TOPO(Invitrogen Corporation)中,然后对3个克隆进行序列分析。编码抗原E2蛋白的基因片段用Hind III和BamH I消化,从具有正确的核苷酸序列插入物的克隆上切下。基因片段按阅读框插入到p3×FLAG-CMV-9(Sigma)的Hind III和BamH I位点之间,使得阅读框匹配。结果,获得了表达抗原E2蛋白的CMV-3XFLAGJ6E2dTM载体,所述抗原E2蛋白上连接了3×FLAG-tag(在下文中称为3×FLAG-J6E2dTM蛋白)。
(2)用于来自HCV2a的J6CF株的抗原E2蛋白与添加到所述抗原E2蛋白的人类IgG Fc蛋白的融合蛋白表达的载体的构建
首先,利用HCV2a的J6CF株的cDNA的基因组RNA(GenBank Accession No. AF177036)作为模板,Advantage GC2 PCR试剂盒(Takara Bio Inc .),和J6E2Fc-s(SEQ ID NO:8:CACAAGCTTCGCACCCATACTGTTGGGG)和J6E2Fc-as(SEQ ID NO:9:ACAGGATCCCATCGGACGATGTATTTTGTG)作为引物,通过PCR方法来扩增编码由与J6CF株的前体蛋白(SEQ ID NO:5)的氨基酸位置384到720相应的区域组成的蛋白质的基因,此时N-末端的起始甲硫氨酸确定为第一个氨基酸。
然后,将这样扩增的DNA片段克隆到pCR-TOPO(Invitrogen Corporation)中,然后对3个克隆进行序列分析。编码抗原E2蛋白的基因片段用Hind III和BamH I消化,由此从具有正确的核苷酸序列插入物克隆上切下。基因片段插入到p3×FLAG-CMV-13(Sigma)的信号肽序列的下游Hind III位点和BamH I位点之间,使得阅读框(可读框)匹配,也就是说,按阅读框插入的。产生的载体被称为 CMV-13-J6E2 。
随后,CMV-13-J6E2 用Sac I和BamH I消化。编码信号肽序列和抗原E2蛋白的DNA片段各自分别通过琼脂糖凝胶电泳分离,然后利用GeneElute(Sigma)纯化。
此后,编码上述信号肽序列和抗原E2蛋白的DNA片段分别按阅读框插入(使得阅读框匹配)到CDM-mIL7R-Ig载体(Sudo et al., Proc Natl. Acad Sci U.S.A., 1993, Vol. 90, p. 9125-9129)的Sac I位点和BamH I位点之间,所述载体表达包含小鼠IL-7受体-人免疫球蛋白Fc结构域的嵌合蛋白。因而,获得表达抗原E2蛋白的CDM-J6E2Fc载体,所述抗原E2蛋白上连接了人免疫球蛋白Fc结构域(在下文中称为J6E2-Fc蛋白)。
(3)用于来自HCV2a的JFH1株的抗原E2蛋白与人类IgG Fc蛋白的融合蛋白表达的载体的构建
首先,利用HCV2a的JFH1株的基因组RNA的cDNA(GenBank Accession No. AB047639)作为模板,Advantage GC2 PCR试剂盒(Takara Bio Inc .),和JFE2Fc-s(SEQ ID NO:10:CACAAGCTTGGCACCACCACCGTTGGAG)和JFE2Fc-as(SEQ ID NO:11:ACAGGATCCTCCCATCGAACGACGTATTTTGTG)作为引物,通过PCR方法来扩增编码与JFH1株的前体蛋白的氨基酸位置384到721相应的区域组成的蛋白质的基因,此时N-末端的起始甲硫氨酸确定为第一个氨基酸。
然后,将这样扩增的DNA片段克隆到pCR-TOPO(Invitrogen Corporation)中,然后对3个克隆进行序列分析。编码抗原E2蛋白的基因片段用Hind III和BamH I消化,由此从具有正确核苷酸序列插入物的克隆上切下,然后按阅读框插入到p3×FLAG-CMV-13(Sigma)的信号肽序列下游的Hind III位点和BamH I位点之间。该载体被称为 CMV-13-JFH1E2。
随后,CMV-13-JFH1E2用Sac I和BamH I消化。编码信号肽序列和抗原E2蛋白的DNA片段各自分别通过琼脂糖凝胶电泳分离,然后利用GeneElute(Sigma)纯化。
此后,编码上述信号肽序列和抗原E2蛋白的DNA片段分别按阅读框插入到CDM-mIL7R-Ig的Sac I位点和BamH I位点之间。因而,获得表达抗原E2蛋白的CDM-JFH1E2Fc载体,所述抗原E2蛋白上连接了人免疫球蛋白Fc结构域(在下文中称为JFH1E2-Fc蛋白)。
(4)用于来自HCV1b的TH株的抗原E2蛋白与人类IgG Fc蛋白的融合蛋白表达的载体的构建
首先,利用HCV1b的TH株的基因组RNA的cDNA(国际专利公开WO2006/022422)作为模板,Advantage GC2 PCR试剂盒(Takara Bio Inc .)和THE2Fc-s(SEQ ID NO:12:CAAAGCTTGCGACCTACGTGACGGGGGGGTCG),和THE2Fc-as(SEQ ID NO:13:CCTCTAGATTATGGATCCCATTTGATTGCATAGGAGACAACCG)作为引物,通过PCR方法来扩增编码由与TH株的前体蛋白的氨基酸位置384到717相应的区域组成的蛋白质的基因,此时N-末端的起始甲硫氨酸确定为第一个氨基酸。
然后,将这样扩增的DNA片段克隆到pCR-TOPO(Invitrogen Corporation)中,然后对3个克隆进行序列分析。编码抗原E2蛋白的基因片段用Hind III和BamH I消化,这样从具有正确的核苷酸序列插入物的克隆切下。基因片段按阅读框插入到p3×FLAG-CMV-13(Sigma)的信号肽序列下游的Hind III位点和BamH I位点之间。该载体被称为 CMV-13-THE2。
随后,CMV-13-THE2用Sac I和BamH I消化。编码信号肽序列和抗原E2蛋白的DNA片段各自分别通过琼脂糖凝胶电泳分离,然后利用GeneElute(Sigma)纯化。
此后,编码信号肽序列和抗原E2蛋白的DNA片段分别按阅读框插入到CDM-mIL7R-Ig的Sac I位点和BamH I位点之间。因而,获得表达抗原E2蛋白的CDM-THE2Fc载体,所述抗原E2蛋白上连接了人免疫球蛋白Fc结构域(在下文中称为THE2-Fc蛋白)。
(5)用于来自HCV1b的Con1株的抗原E2蛋白与人类IgG Fc蛋白的融合蛋白表达的载体的构建
首先,利用HCV1b的Con1株的基因组RNA的cDNA(GenBank Accession No. AJ238799)作为模板,Advantage GC2 PCR试剂盒(Takara Bio Inc .)和Con1E2Fc-s(SEQ ID NO:14:CAAAGCTTGGAACCTATGTGACAGGGGGGACGAT),和Con1E2Fc-as(SEQ ID NO:15:CCTCTAGATTATGGATCCCATTTGATTGCAAAGGAGACAAC)作为引物,通过PCR方法来扩增编码与Con1株的前体蛋白的氨基酸位置384到716相应的区域组成的蛋白质的基因,此时N-末端的起始甲硫氨酸确定为第一个氨基酸。
然后,将这样扩增的DNA片段克隆到pCR-TOPO(Invitrogen Corporation)中,然后对3个克隆进行序列分析。编码抗原E2蛋白的基因片段用Hind III和BamH I消化,这样从具有正确的核苷酸序列插入物的克隆切下。基因片段按阅读框插入到p3×FLAG-CMV-13(Sigma)的信号肽序列下游的Hind III位点和BamH I位点之间。该载体被称为 CMV-13-Con1E2。
随后,CMV-13-Con1E2用Sac I和BamH I消化。编码信号肽序列和抗原E2蛋白的DNA片段各自分别通过琼脂糖凝胶电泳分离,然后利用GeneElute(Sigma)纯化。
此后,编码信号肽序列和抗原E2蛋白的DNA片段分别按阅读框插入到CDM-mIL7R-Ig的Sac I位点和BamH I位点之间。因而,获得表达抗原E2蛋白的CDM-Con1E2Fc载体,所述抗原E2蛋白上连接了人免疫球蛋白Fc结构域(在下文中称为Con1E2-Fc蛋白)。
(6)用于来自HCV1b的J1株的抗原E2蛋白与人类IgG Fc蛋白的融合蛋白表达的载体的构建
首先,利用衍生自HCV1b的J1株的基因组RNA的cDNA(GenBank Accession No. D89815)作为模板,Advantage GC2 PCR试剂盒(Takara Bio Inc .),和J1E2Fc-s(SEQ ID NO:16:CAAAGCTTCATACCCGCGTGACGGGGGGGGTGC),和J1E2Fc-as(SEQ ID NO:17:CCTCTAGATTATGGATCCCACTTGATGGCAATGGAGACGACC)作为引物,通过PCR方法来扩增编码由与J1株的前体蛋白的氨基酸位置384到716相应的区域组成的蛋白质的基因,此时N-末端的起始甲硫氨酸确定为第一个氨基酸。
然后,将这样扩增的DNA片段克隆到pCR-TOPO(Invitrogen Corporation)中,然后对3个克隆进行序列分析。编码抗原E2蛋白的基因片段用Hind III和BamH I消化,这样从具有正确的核苷酸序列插入物的克隆切下。基因片段按阅读框插入到p3×FLAG-CMV-13(Sigma)的信号肽序列下游的Hind III位点和BamH I位点之间。该载体被称为 CMV-13-J1E2。
随后,CMV-13-J1E2用Tth111 I消化,用T4 DNA聚合酶平端化,然后用BamH I消化。产生的编码信号肽序列和抗原E2蛋白的DNA片段各自分别通过琼脂糖凝胶电泳分离,然后利用GeneElute(Sigma)纯化。
此后,CDM-mILR7R-Ig用BamH I和Xba I消化来切下含有编码人免疫球蛋白Fc结构域的序列的DNA片段。然后将该片段插入到pcDL-SRα296(Takebe et al., Proc Natil Acad Sci. U.S.A., 1987, Vol. 84, p. 7388-7392)中启动子区域的下游来制备SRαIgG1Fc。此外,编码信号肽序列和抗原E2蛋白的DNA片段分别按阅读框插入到SRαIgG1Fc中EcoR V位点和BamH I位点之间。因而,获得了表达抗原E2蛋白的SRα-J1E2Fc载体,所述抗原E2蛋白上连接了人免疫球蛋白Fc结构域(在下文中称为J1E2-Fc蛋白)。
(7)用于来自HCV1a的H77株的抗原E2蛋白与人类IgG Fc蛋白的融合蛋白表达的载体的构建
首先,利用HCV1a的H77株的基因组RNA的cDNA(GenBank Accession No. AF011751)作为模板,Advantage GC2 PCR试剂盒(Takara Bio Inc .),和H77E2Fc-s(SEQ ID NO:18:CAAAGCTTGAAACCCACGTCACCGGGGGAAA)和H77E2Fc-as(SEQ ID NO:19:CCTCTAGATTATGGATCCCACTTAATGGCCCAGGACGCGAT)作为引物,通过PCR方法来扩增编码由与H77株的前体蛋白的氨基酸位置384到716相应的区域组成,此时N-末端的起始甲硫氨酸确定为第一个氨基酸。
然后,将这样扩增的DNA片段克隆到pCR-TOPO(Invitrogen Corporation)中,然后对3个克隆进行序列分析。编码抗原E2蛋白的基因片段用Hind III和Xba I消化,这样从具有正确的核苷酸序列插入物的克隆切下。基因片段按阅读框插入到p3×FLAG-CMV-13Xho载体的信号肽序列下游的Hind III位点和Xba I位点之间,所述载体通过在p3×FLAG-CMV-13(Sigma)中将Sac I位点转变成Xho I位点来制备。产生的载体被称为 CMV-13-XhoH77E2。
随后,CMV-13-XhoH77E2用Xho I和BamH I消化,然后编码信号肽序列和抗原E2蛋白的DNA片段各自分别通过琼脂糖凝胶电泳分离,然后使用GeneElute(Sigma)来纯化。
此后,编码信号肽序列和抗原E2蛋白的DNA片段分别按阅读框插入到上文5)中构建的SRα-IgG1Fc的Xho I位点和BamH I位点之间。获得了表达抗原E2蛋白的SRα-H77E2Fc载体,所述抗原E2蛋白上连接了人免疫球蛋白Fc结构域(在下文中称为H77E2-Fc蛋白)。
(实施例2)抗原E2蛋白和标记蛋白质的融合蛋白的表达
将实施例1中构建的CMV-3XFLAGJ6E2dTM、CDM-J6E2Fc、CDM-JFH1E2Fc、CDM-THE2Fc、CDM-Con1E2Fc、SRα-J1E2Fc和SRα-H77E2Fc导入到来自猴肾的COS1细胞中,然后每种融合蛋白如以下描述地表达。
首先,COS1细胞在含有10%胎牛血清(Invitrogen Corporation)、100 U/ml青霉素和100 μg/ml链霉素的RPMI1640培养基(Invitrogen Corporation)中传代培养。基因转导前一天,COS1细胞以1:2的分离比播种到150 cm2培养烧瓶(Corning Coaster Corporation)中,然后在5% CO2培养箱中在37℃培养过夜。
随后,将DEAE葡聚糖(GE Healthcare)和氯喹(Sigma)分别以400 μg/ml和100 μM的终浓度添加到RPMI1640培养基中。50 μg的上述表达载体(CMV-3×FLAGJ6E2dTM、CDM-J6E2Fc、CDM-JFH1E2Fc、CDM-THE2Fc、CDM-Con1E2Fc、SRα-J1E2Fc或 SRα-H77E2Fc)以每13 mL 0.1μg/μl的浓度添加,然后培养细胞3到4天。
此后,吸出培养的COS1细胞的上清液。添加10ml的PBS(-)(Nissui Pharmaceutical Co., Ltd),再一次地,吸出PBS(-)以洗涤细胞。随后,以13 ml/150 cm2烧瓶添加DEAE葡聚糖-DNA混合物,然后产物在存在5% CO2的情况下在37℃保持静止。
四小时后,吸出DEAE dextran-DNA混合物,每个烧瓶用10 ml PBS洗涤一次,以50 ml/烧瓶添加Hybridoma-SFM培养基(Invitrogen Corporation),然后细胞在存在5% CO2的条件下在37℃培养4天。此后,将培养物上清液采集在50 ml离心管(Corning Coaster Corporation)中,然后在2500 rpm在4℃离心30分钟。上清液通过0.2 μm滤过器(Whatman)过滤。
(实施例3)抗原E2蛋白和标记蛋白的融合蛋白的纯化
已经导入了CMV-3×FLAG-J6E2dTM的细胞的培养上清液如下所述利用抗-FLAG M2琼脂糖(Sigma)进行纯化。
首先,将1 ml抗-FLAG M2琼脂糖添加到500 ml培养物上清液中,然后在4℃反应2小时,其间在旋转瓶子中搅动。在2小时后,将上清液和抗-FLAG M2琼脂糖的混合物转移到Econocolumn(Bio-Rad Laboratories Inc.),除去孔隙级分,然后采集抗-FLAG M2琼脂糖。
然后,抗-FLAG M2琼脂糖用10 ml TBS(50 mm Tris-HCl,150 mM NaCl,pH 7.4)洗涤两次。六个级分(抗-FLAG抗体柱洗脱级分1-6)用0.1 M甘氨酸-HCl(pH 3.5)洗脱到1 ml/级分。在洗脱之后立即添加1M Tris-HCl(pH 9.5)使pH值回到中性。20 μl的每个级分在还原条件下通过SDS-聚丙烯酰胺凝胶电泳分级,然后用考马斯亮蓝染色。结果,确认的是,纯化了J6CF菌株衍生的抗原E2蛋白与3×FLAG标签的融合蛋白(3×FLAG-J6E2dTM蛋白)(附图4)。
导入了CDM-J6E2Fc、CDM-JFH1E2Fc、CDM-THE2Fc、CDM-Con1E2Fc、SRα-J1E2Fc或SRα-H77E2Fc的细胞的培养物上清液利用结合了蛋白-A的载体Prosep-A(Millipore)如下所述进行纯化。
首先,用1 mL的Prosep-A填充Econocolumn,使500 ml的培养物上清液以1-1.5 mL/分钟的流速通过,然后用20 mL的PBS(-)洗涤。
然后,5个级分用0.1 M甘氨酸-HCl(pH 3.0)洗脱到1 ml/级分。在洗脱之后立即添加1M Tris-HCl(pH 9.5)使pH值回到中性。20 μl的每个级分在还原条件下通过SDS-聚丙烯酰胺凝胶电泳分级,然后用考马斯亮蓝染色。结果,纯化了来自每种HCV株的抗原E2蛋白与人免疫球蛋白Fc结构域的融合蛋白,在还原条件下分子量显示为约97 kDa(附图5)。
(实施例4)用HCV2a的J6CF株的抗原E2蛋白免疫小鼠
混合含有10 μg 3×FLAG-J6E2dTM蛋白的0.3 ml的PBS溶液和0.3 ml弗氏完全佐剂来制备乳剂。用一半数量的乳剂皮下接种7周龄Balb/c 小鼠(雌性)。
2周后,混合含有10 μg 3×FLAG-J6E2dTM蛋白的0.3 ml PBS溶液和0.3 ml弗氏不完全佐剂来制备乳剂,将一半数量的乳剂皮下地施用给小鼠。再2周后,将含有10 μg 3×FLAG-J6E2dTM蛋白的0.15 ml PBS溶液向小鼠腹膜内施用。3天后,从小鼠制备脾脏细胞。
在另一个实验中,混合含有20 μg J6E2-Fc蛋白的0.3 ml PBS溶液和0.3 mL Alum(Pierce)来制备施用的溶液。用全部数量的乳剂腹膜内接种7周龄Balb/c小鼠(雌性)。
在2、4和6周之后,类似地,混合含有20 μg J6E2-Fc蛋白的0.3 ml PBS溶液和0.3 ml Alum来制备要施用的溶液,将全部数量的乳剂向小鼠腹膜内施用。再2个月后,将含有20 μg J6E2-Fc蛋白的0.3 ml PBS溶液向小鼠腹膜内施用。3天后,从小鼠制备脾脏细胞。
(实施例5)杂交瘤细胞的制备
首先,将小鼠骨髓瘤细胞系SP2/0(获自ECACC)在含有55μM的2-巯基乙醇、100 U/ml青霉素、100μg/ml链霉素和10%胎牛血清(FCS;Invitrogen Corporation)的Dulbecco’s修饰的Eagle’s培养基(DMEM;Invitrogen Corporation)中培养,获得处在对数生长期的SP2/0细胞。用无血清DMEM洗涤细胞3次。
然后,从已经施用了3×FLAG-J6E2dTM蛋白或J6E2-Fc蛋白的小鼠制备脾脏细胞,然后用无血清DMEM洗涤3次。将SP2/0细胞和小鼠脾脏细胞以1:5的比例添加到50 ml离心试管中,然后在1,000rpm进行离心10分钟。通过抽吸完全地除去上清液。随后,轻敲离心管来疏松沉淀。添加在37℃预热的1 ml 50%聚乙二醇-1500溶液(Roche)1分钟,并在37℃反应1分钟。
随后,向上述离心管中用1分钟添加1 ml无血清DMEM ,再次用1分钟添加无血清DMEM 1 ml ,然后用3分钟添加最后的7 ml无血清DMEM ,从而稀释乙二醇溶液。此后,将上述离心管在1,000 rpm离心10分钟来采集细胞。使细胞以1×106个细胞/ml悬浮在含有55μM的2-巯基乙醇、100 U/ml青霉素、100μg/ml链霉素、15% FCS和10%杂交瘤克隆因子(BioVeris)的DMEM中。
将这样获得的细胞悬浮液以100 μl/孔播种在96孔平板的每个孔中,然后在5% CO2培养箱中在37℃培养。在第二天,向每个孔添加含有2×HAT(Invitrogen Corporation)、15% FCS和10%杂交瘤克隆因子的 DMEM 100 μl,然后将细胞在5% CO2培养箱中在37℃连续培养。
在培养10到14天后,采集每个反应孔中的培养物上清液,如实施例6中描述地筛选培养物上清液中含有的识别抗原E2蛋白的抗体。
(实施例6)筛选产生结合抗原E2蛋白的抗体的杂交瘤细胞
通过将抗原E2蛋白固定在平板上,然后通过EIA评估杂交瘤细胞的培养物上清液中的抗体是否与固定在平板上的抗原E2蛋白结合,来筛选杂交瘤细胞。
(1)抗原E2蛋白固定的平板的制备
将3×FLAG-J6E2dTM蛋白或J6E2-Fc蛋白用PBS稀释到1 μg/ml,然后将50 μl的每种产物添加到免疫平板(Nunc)的每个孔中。免疫平板在4℃静置过夜,使得蛋白质固定在平板上。从每个孔除去蛋白溶液,将200 μl每份的根据所包含的手册制备的Blocking One溶液(NACALAI TESQUE, INC .)添加到每个孔,然后在室温下进行封闭2小时。
(2)杂交瘤细胞的筛选
上述进行了封闭的蛋白质固定的平板用于筛选杂交瘤细胞的培养物上清液中含有的抗E2蛋白抗体。固定了J6E2-Fc蛋白的平板用于筛选从施用3×flag-J6E2dTM蛋白的小鼠制备的杂交瘤细胞产生的单克隆抗体。固定了3×FLAG-J6E2dTM蛋白的平板用于筛选从施用J6E2-Fc蛋白的小鼠制备的杂交瘤细胞产生的单克隆抗体。
具体地,上述蛋白质固定的平板用含有 0.1% Tween20(Sigma)的PBS洗涤4次。以50 μl/孔添加实施例5中获得的每个杂交瘤细胞的上清液样品,然后在室温下反应1小时。在反应完成后,用含有0.1% Tween20 的PBS洗涤孔4次。随后,以50 μl/孔添加用含有0.1% Tween20的PBS稀释5,000倍的HRP-标记的抗小鼠IgG抗体(GE Healthcare)在室温下反应1小时。在反应完成后,用含有0.1% Tween20的PBS洗涤孔4次,使用过氧化物酶显色试剂盒(Sumitomo Bakelite Co., Ltd.)显色,然后测量450 nm处的吸光度,选择阳性克隆。
结果,对于从施用3×FLAG-J6E2dTM蛋白的小鼠制备的杂交瘤细胞,可从进行筛选的980个孔中确定地选出11个克隆。这些克隆通过有限稀释来进行克隆,从而获得具有良好增殖性和抗体生产性的杂交瘤细胞系1G2-32、2F2-7、2F3-7、4E8-8、5D4-6、9G3-2、9A5-4、9C4-2、8D10-3和10G4-1。
同时,对于从施用了J6E2-Fc蛋白的小鼠制备的杂交瘤细胞,从筛选的2064个孔中可以确定地选择10个克隆。这些克隆的克隆通过有限稀释来进行,从而获得具有良好的增殖性和抗体生产性的M1E12-1杂交瘤细胞系。
(3)同种型和亚型分析
利用ImmunoPure单克隆抗体同种型试剂盒(Pierce)根据所包含的手册来分析由此获得的杂交瘤细胞产生的单克隆抗体的同种型和亚型。结果,每个克隆的抗体亚型如附图6所示。它们都被发现具有κ-免疫球蛋白轻链。
(4)IgG抗体的纯化
将获得的杂交瘤细胞通过逐步降低培养基中的FCS浓度使其最终适应于无血清培养。
杂交瘤细胞各自在无血清培养基Hybridoma SFM(Invitrogen Corporation)中培养到汇合。将培养溶液采集到离心管中,然后在1500 rpm离心5分钟。将培养物上清液添加到Prosep-G(Millipore)中,然后用30倍床体积(bed volumn)的PBS洗涤。随后,用1倍床体积的0.1 M甘氨酸-HCl(pH 3.0)洗脱了6个级分。在洗脱之后立即地,添加1M Tris-HCl(pH 9.5)使pH值回到中性。20 μl的每种级分在还原条件和非还原条件下进行SDS-聚丙烯酰胺凝胶电泳用于分级。通过用考马斯亮蓝染色来确认蛋白质的有无。集中IgG级分,然后用PBS进行透析,或通过凝胶过滤来脱矿质,从而制备抗体样品。
(实施例7)针对抗原E2蛋白的单克隆抗体的HCV基因型特异性
检查通过用HCV2a的J6CF株的抗原E2蛋白免疫制备的每种杂交瘤细胞产生的单克隆抗体是否结合衍生自基因型2a的J6CF株以及基因型2a的JFH1株的E2蛋白,衍生自基因型1b的TH株、基因型1b的J1株和基因型1b的Conl株的E2蛋白,以及衍生自基因型1a的H77株的E2蛋白。
作为抗原,使用实施例1-3制备的J6E2-Fc蛋白、JFH1E2-Fc蛋白、THE2-Fc蛋白、J1E2-Fc蛋白、Con1E2-Fc蛋白和H77E2-Fc蛋白,它们是抗原E2蛋白与人免疫球蛋白Fc结构域的融合蛋白。将这些蛋白固定在平板上,然后如实施例6中描述地用于评估。
具体地,将每种上述融合蛋白用PBS稀释到1 μg/ml,将稀释溶液以50 μl/孔添加到免疫平板,然后使免疫平板在4℃保持静置过夜,使得每种融合蛋白固定在平板上。除去蛋白溶液,然后以200 μl/孔添加根据包含的手册制备的Blocking One溶液(NACALAI TESQUE, INC.),随后在室温下封闭2小时。
接下来,将每种杂交瘤细胞产生的单克隆抗体用PBS稀释到1 μg/ml,以50 μl/孔添加到上述蛋白固定的平板中,然后在室温下反应1小时。在反应完成之后,用含有 0.05% Tween20的PBS洗涤孔4次,以50 μl/孔添加用含0.05% Tween20的PBS稀释5,000倍的HRP标记的抗小鼠IgG抗体,然后在室温下反应1小时。在反应完成后,用含有0.05% Tween20的PBS洗涤孔4次,使用过氧化物酶显色试剂盒显色,然后测量450 nm处的吸光度。
附图6显示了每种单克隆抗体与各种HCV基因型或株的抗原E2蛋白的结合。对于吸光度值,小于0.1的值用“-”表示,0.1或更高并且小于0.25的值用“+”表示,0.25或更高并且小于0.4的值用“++”表示,0.4或更高的值用“+++”表示。这些值表示与抗原E2蛋白结合的强度。如附图6中所示,8D10-3是结合HCV基因型1a、1b和2a的抗原E2蛋白的抗体,1G2-32和2F2-7是结合基因型2a的抗原E2蛋白的抗体,4E8-8是结合基因型1b和2a的抗原E2蛋白的抗体。此外,如附图6中所示,M1E12-1是结合J6CF株的抗原E2蛋白的单克隆抗体。
这些结果表明,可以使用上述单克隆抗体组用于鉴定HCV基因型或HCV株。
另外,于2008年9月19日,产生单克隆抗体8D10-3的杂交瘤细胞(8D10-3)以临时登记号FERM ABP-11182保藏,产生单克隆抗体1G2-32的杂交瘤细胞(1G2-32)以临时登记号FERM ABP-11179保藏,产生单克隆抗体2F2-7的杂交瘤细胞(2F2-7)以临时登记号FERM ABP-11180保藏,产生单克隆抗体 4E8-8 的杂交瘤细胞(4E8-8)以临时登记号NO. FERM ABP-11181保藏,以及产生单克隆抗体 M1E12-1 的杂交瘤细胞(M1E12-1)以临时登记号FERM ABP-11183保藏在日本国家先进工业科学和技术学会,国际专利生物保藏所(central 6, 1-1, Higashi 1, Tsukuba, Ibaraki, Japan)。
(实施例8)单克隆抗体的表位的分析
合成了一组肽(肽编号1-110),每种肽具有10个连续氨基酸的氨基酸序列,其被设计以在相应于氨基酸位置384到720的抗原E2蛋白氨基酸序列中从N-末端移位三个氨基酸,此时在J6CF株的前体蛋白(SEQ ID NO:5)的N-末端的起始甲硫氨酸被确定为第一个氨基酸。每种肽的N-末端被生物素化,甘氨酰胺位于肽的C-末端(由委托的JPT来合成)。
由此合成的肽各自溶于DMSO中,然后在PBS中以0.01 nmol/μl溶解。肽溶液以50 μl/孔添加到链霉抗生物素蛋白包被的平板(Nunc),然后在室温下反应2小时。弃去肽溶液,以200 μl/孔添加根据所包含的手册制备的Blocking One溶液(NACALAI TESQUE, INC .),然后孔在4℃保持静置过夜,从而进行封闭。
随后,丢弃封闭溶液,孔用含有0.05% Tween20的PBS洗涤4次,然后以50 μl/孔添加用含有0.05% Tween20的PBS稀释到1 μg/ml的每种单克隆抗体,随后在室温下反应1.5小时。在反应完成后,弃去抗体溶液,孔用含有0.05% Tween20的PBS洗涤4次,以50 μl/孔添加用含有0.05% Tween20的PBS稀释5000倍的HRP标记的抗小鼠IgG山羊抗体(GE Healthcare),然后在室温下反应1小时。在反应之后,弃去抗体溶液,然后用含有0.05% Tween20的PBS洗涤孔5次。在洗涤之后,利用过氧化物酶显色试剂盒显色,然后在450 nm测量吸光度,从而可以检测结合肽的抗体。
附图7A-E显示了每种单克隆抗体与衍生自J6CF株衍生的抗原E2蛋白的肽的结合强度。0D 450 nm的高测量值(在附图7A-E的纵轴上显示)表明单克隆抗体与相关的肽的结合强度是强的,抗体特异性地识别所述肽。每种单克隆抗体识别来自J6CF株的抗原E2蛋白的某些肽。
单克隆抗体8D10-3的特别强的表位是DRCGAPTYTW(SEQ ID NO:20;肽编号47),以及与该表位肽重叠的GAPTYTWGEN(SEQ ID NO:21;肽编号48)(附图7A)。根据该结果,认为表位可能包含氨基酸序列DRLGAPTYTWGEN(SEQ ID NO:22)中的至少10个连续氨基酸的氨基酸序列。YPYRLWHYPC(SEQ ID NO:23;肽编号78)是弱表位(附图7A)。
单克隆抗体4E8-8的特别强的表位是 WGENETDVFL(SEQ ID NO:1;肽编号50)。与肽编号50重叠的NETDVFLLNS(SEQ ID NO :24;肽编号51)、DVFLLNSTRP(SEQ ID NO :25;肽编号52)和LLNSTRPPLG(SEQ ID NO :26;肽编号53)是弱表位(附图7C)。根据该结果,认为每种表位具有WGENETDVFLLNSTRPPLG(SEQ ID NO:27)中的至少10个连续氨基酸的氨基酸序列。
单克隆抗体2F2-7的特别强的表位是GWGALQYEDN(SEQ ID NO:2;肽编号29)(附图7D)。与肽编号29重叠的 FRVGWGALQY(SEQ ID NO:28;肽编号28)是弱表位(附图7D)。根据该结果,认为的是每种表位具有氨基酸序列FRVGWGALQYEDN(SEQ ID NO:29)中的至少10个连续氨基酸的氨基酸序列。
单克隆抗体1G2-32的特别强的表位是KTCGAPPCRT(SEQ ID NO:3;肽编号61)和GAPPCRTRAD(SEQ ID NO:30;肽编号62)(附图7B)。根据该结果,认为每种表位具有氨基酸序列KTCGAPPCRTRAD(SEQ ID NO:31)中的至少10个连续氨基酸的氨基酸序列。
单克隆抗体M1E12-1的特别强的表位是NYTIFKIRMY(SEQ ID NO:4;肽编号82)和IFKIRMYVGG(SEQ ID NO:32;肽编号83)(附图7E)。根据该结果,认为每种表位具有氨基酸序列NYTIFKIRMYVGG(SEQ ID NO:33)中的至少10个连续氨基酸的氨基酸序列。
(实施例9)利用单克隆抗体的HCV包膜蛋白的检测
通过夹心ELISA方法和蛋白质印迹方法检查利用从上述制备的杂交瘤细胞制备的单克隆抗体是否检测到衍生自基因型1a的H77株的抗原E2蛋白,衍生自基因型2a的J6CF株和基因型2a的JFH1株的抗原E2蛋白,以及衍生自基因型1b的TH株、基因型1b的J1株、基因型1b的Con1株的抗原E2蛋白。
(1)夹心ELISA
单克隆抗体1G2-32用PBS稀释到1 μg/ml。抗体溶液以50 μl/孔添加到免疫平板(Nunc),然后孔在室温保持静止2小时,使得抗体固定在平板上。除去抗体溶液,以200 μl/孔添加根据包含的手册制备的Blocking One溶液(NACALAI TESQUE, INC .),然后孔在室温保持静止2小时用于封闭。
接下来,抗原E2蛋白与添加在其上的人免疫球蛋白Fc结构域的融合蛋白的每一种(即,JFH1E2-Fc蛋白、J6E2-Fc蛋白、THE2-Fc蛋白、Con1E2-Fc蛋白、J1E2-Fc蛋白或H77E2-Fc蛋白)用PBS稀释,然后以50 μl/孔添加到上述固定了蛋白的平板上,随后在室温下反应1.5小时。在反应完成后,用含有0.05% Tween20的PBS洗涤孔3次。以50 μl/孔添加用含有0.05% Tween20的PBS稀释到1 μg/ml的生物素化的8D10-3单克隆抗体,然后在室温下反应2小时。在反应之后,孔用含有0.05% Tween20的PBS洗涤3次。添加用含有0.05% Tween20的PBS稀释5,000倍的HRP-标记的抗链霉抗生物素蛋白(GE Healthcare)50 μl,然后在室温下反应1.5小时。
在反应完成后,孔用含有0.05% Tween20的PBS洗涤4次,使用过氧化物酶显色试剂盒(Sumitomo Bakelite Co. , Ltd .)显色,然后测量490 nm处的吸光度。结果在附图8中示出。
附图8显示了利用单克隆抗体1G2-32和8D10-3通过夹心ELISA测定的各种基因型/株的抗原E2蛋白的检测灵敏度。水平轴表明抗原E2蛋白的数量,纵轴表明490 nm处的吸光度;也就是,抗原E2蛋白的检测的数量。利用单克隆抗体1G2-32和8D10-3的夹心ELISA显示了仅可以检测HCV基因型2a的抗原E2蛋白,不能检测基因型1a和基因型1b的抗原E2蛋白。这些结果表明,HCV基因型或株可以利用根据本发明获得的抗体的组来鉴定。
(2)蛋白质印迹方法
将五分之一体积的5×样品缓冲液(0.3125 M Tris-HCl、pH 6.8,5% SDS 50% 甘油,0.05% BPB 5% 2-ME)添加到0.1μg到0.3μg的抗原E2蛋白与添加在其上的Fc结构域的融合蛋白的每一种中(JFH1E2-Fc蛋白、J6E2-Fc蛋白、THE2-Fc蛋白、Con1E2-Fc蛋白、J1E2-Fc蛋白或H77E2-Fc蛋白),随后在100℃处理5分钟。产物用作样品。每种样品施加到4%-20%梯度凝胶(TEFCO)上,使用40 mA的恒定电流进行电泳,然后利用半干型印迹装置以120 mA的恒定电流印迹到PVDF膜上。
在印迹之后,PVDF膜在室温下浸入Block Ace(Snow Brand Milk Products Co. , Ltd .)中1小时用于封闭,用含有0.1% Tween20的TBS洗涤,浸入到用Can Get Signal(Toyobo Co. , Ltd .)稀释到1 μg/ml的8D10-3单克隆抗体中,然后在室温下反应1小时。在反应之后,膜用含有0.1% Tween20的TBS洗涤,随后浸入用Can Get Signal稀释5,000倍的HRP标记的抗小鼠IgG抗体中,然后在室温下反应1小时。膜用含有0.1% Tween20的TBS洗涤,然后利用ECL试剂盒(GE Healthcare)检测条带。
附图9显示了利用8D10-3单克隆抗体通过蛋白质印迹方法,各种基因型/株的抗原E2蛋白的检出或未检出。所有六种株类型的抗原E2蛋白可以用8D10-3单克隆抗体检出。
工业实用性
本发明的抗体使得以高精度简单地鉴定HCV基因型1a、1b和2a成为可能。因而,对干扰素疗法的治疗效果不可以预先预期的感染基因型1a或1b的HCV的丙型肝炎患者,可以减轻副作用并可以提供选择新的治疗方法的机会。
序列表
<110> 东丽株式会社
日本国立感染症研究所
<120> 结合丙型肝炎病毒的包膜蛋白2的抗体以及利用所述抗体鉴定丙型肝炎病毒的基因型的方法
<130> PH-4140-PCT
<140> PCT/JP2009/067051
<141> 2009-09-30
<150> JP 2008-254338
<151> 2008-09-30
<160> 33
<170> PatentIn version 3.1
<210> 1
<211> 10
<212> PRT
<213> 丙型肝炎病毒
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Pro Glu Asp Met Arg Pro Tyr Cys Trp His Tyr Pro Pro Arg Gln Cys
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Gly Val Val Ser Ala Lys Thr Val Cys Gly Pro Val Tyr Cys Phe Thr
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Pro Ser Pro Val Val Val Gly Thr Thr Asp Arg Leu Gly Ala Pro Thr
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Arg Pro Pro Leu Gly Ser Trp Phe Gly Cys Thr Trp Met Asn Ser Ser
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Gly Tyr Thr Lys Thr Cys Gly Ala Pro Pro Cys Arg Thr Arg Ala Asp
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Phe Asn Ala Ser Thr Asp Leu Leu Cys Pro Thr Asp Cys Phe Arg Lys
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His Pro Asp Thr Thr Tyr Leu Lys Cys Gly Ser Gly Pro Trp Leu Thr
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Leu Ser Thr Gly Leu Leu His Leu His Gln Asn Ile Val Asp Val Gln
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Phe Met Tyr Gly Leu Ser Pro Ala Leu Thr Lys Tyr Ile Val Arg Trp
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Glu Lys Leu Val Ile Leu His Ala Ala Ser Ala Ala Ser Cys Asn Gly
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Phe Leu Tyr Phe Val Ile Phe Phe Val Ala Ala Trp Tyr Ile Lys Gly
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Arg Val Val Pro Leu Ala Thr Tyr Ser Leu Thr Gly Leu Trp Ser Phe
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Ser Leu Leu Leu Leu Ala Leu Pro Gln Gln Ala Tyr Ala Tyr Asp Ala
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Ser Val His Gly Gln Ile Gly Ala Ala Leu Leu Val Met Ile Thr Leu
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Phe Thr Leu Thr Pro Gly Tyr Lys Thr Leu Leu Ser Arg Phe Leu Trp
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Trp Leu Cys Tyr Leu Leu Thr Leu Gly Glu Ala Met Val Gln Glu Trp
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Ala Pro Pro Met Gln Val Arg Gly Gly Arg Asp Gly Ile Ile Trp Ala
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Val Ala Ile Phe Tyr Pro Gly Val Val Phe Asp Ile Thr Lys Trp Leu
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Leu Ala Val Leu Gly Pro Ala Tyr Leu Leu Lys Gly Ala Leu Thr Arg
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Val Pro Tyr Phe Val Arg Ala His Ala Leu Leu Arg Met Cys Thr Met
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Ala Arg His Leu Ala Gly Gly Arg Tyr Val Gln Met Ala Leu Leu Ala
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Leu Gly Arg Trp Thr Gly Thr Tyr Ile Tyr Asp His Leu Thr Pro Met
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Ser Asp Trp Ala Ala Ser Gly Leu Arg Asp Leu Ala Val Ala Val Glu
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Pro Ile Ile Phe Ser Pro Met Glu Lys Lys Val Ile Val Trp Gly Ala
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Glu Thr Ala Ala Cys Gly Asp Ile Leu His Gly Leu Pro Val Ser Ala
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Ser Lys Gly Trp Ser Leu Leu Ala Pro Ile Thr Ala Tyr Ala Gln
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Arg Asp Lys Thr Glu Gln Ala Gly Glu Ile Gln Val Leu Ser Thr
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Val Thr Gln Ser Phe Leu Gly Thr Ser Ile Ser Gly Val Leu Trp
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Thr Val Tyr His Gly Ala Gly Asn Lys Thr Leu Ala Gly Ser Arg
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Gly Pro Val Thr Gln Met Tyr Ser Ser Ala Glu Gly Asp Leu Val
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Gly Trp Pro Ser Pro Pro Gly Thr Lys Ser Leu Glu Pro Cys Thr
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Ile Pro Ala Arg Arg Arg Gly Asp Lys Arg Gly Ala Leu Leu Ser
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Pro Arg Pro Leu Ser Thr Leu Lys Gly Ser Ser Gly Gly Pro Val
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Leu Cys Pro Arg Gly His Ala Val Gly Val Phe Arg Ala Ala Val
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Cys Ser Arg Gly Val Ala Lys Ser Ile Asp Phe Ile Pro Val Glu
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Thr Leu Asp Ile Val Thr Arg Ser Pro Thr Phe Ser Asp Asn Ser
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Thr Pro Pro Ala Val Pro Gln Thr Tyr Gln Val Gly Tyr Leu His
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Ala Pro Thr Gly Ser Gly Lys Ser Thr Lys Val Pro Val Ala Tyr
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Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala
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Ala Thr Leu Gly Phe Gly Ala Tyr Leu Ser Lys Ala His Gly Ile
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Asn Pro Asn Ile Arg Thr Gly Val Arg Thr Val Thr Thr Gly Ala
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Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly
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Ala Val Asp Ser Thr Thr Ile Leu Gly Ile Gly Thr Val Leu Asp
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Gln Ala Glu Thr Ala Gly Val Arg Leu Thr Val Leu Ala Thr Ala
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Thr Pro Pro Gly Ser Val Thr Thr Pro His Pro Asn Ile Glu Glu
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Val Ala Leu Gly Gln Glu Gly Glu Ile Pro Phe Tyr Gly Arg Ala
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Ile Pro Leu Ser Tyr Ile Lys Gly Gly Arg His Leu Ile Phe Cys
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His Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Ala Leu Arg Gly
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Met Gly Leu Asn Ser Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser
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Val Ile Pro Thr Gln Gly Asp Val Val Val Val Ala Thr Asp Ala
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Leu Met Thr Gly Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys
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Asn Val Ala Val Thr Gln Val Val Asp Phe Ser Leu Asp Pro Thr
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Phe Thr Ile Thr Thr Gln Ile Val Pro Gln Asp Ala Val Ser Arg
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Ser Gln Arg Arg Gly Arg Thr Gly Arg Gly Arg Leu Gly Ile Tyr
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Arg Tyr Val Ser Thr Gly Glu Arg Ala Ser Gly Met Phe Asp Ser
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Val Val Leu Cys Glu Cys Tyr Asp Ala Gly Ala Ala Trp Tyr Glu
1520 1525 1530
Leu Thr Pro Ser Glu Thr Thr Val Arg Leu Arg Ala Tyr Phe Asn
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Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu
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Ala Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser
1565 1570 1575
Gln Thr Lys Gln Ser Gly Glu Asn Phe Ala Tyr Leu Thr Ala Tyr
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Gln Ala Thr Val Cys Ala Arg Ala Lys Ala Pro Pro Pro Ser Trp
1595 1600 1605
Asp Val Met Trp Lys Cys Leu Thr Arg Leu Lys Pro Thr Leu Val
1610 1615 1620
Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ser Val Thr Asn Glu
1625 1630 1635
Val Thr Leu Thr His Pro Val Thr Lys Tyr Ile Ala Thr Cys Met
1640 1645 1650
Gln Ala Asp Leu Glu Val Met Thr Ser Thr Trp Val Leu Ala Gly
1655 1660 1665
Gly Val Leu Ala Ala Val Ala Ala Tyr Cys Leu Ala Thr Gly Cys
1670 1675 1680
Val Cys Ile Ile Gly Arg Leu His Ile Asn Gln Arg Ala Val Val
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Ala Pro Asp Lys Glu Val Leu Tyr Glu Ala Phe Asp Glu Met Glu
1700 1705 1710
Glu Cys Ala Ser Arg Ala Ala Leu Ile Glu Glu Gly Gln Arg Ile
1715 1720 1725
Ala Glu Met Leu Lys Ser Lys Ile Gln Gly Leu Leu Gln Gln Ala
1730 1735 1740
Ser Lys Gln Ala Gln Asp Ile Gln Pro Thr Val Gln Ala Ser Trp
1745 1750 1755
Pro Lys Val Glu Gln Phe Trp Ala Lys His Met Trp Asn Phe Ile
1760 1765 1770
Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn
1775 1780 1785
Pro Ala Val Ala Ser Met Met Ala Phe Ser Ala Ala Leu Thr Ser
1790 1795 1800
Pro Leu Ser Thr Ser Thr Thr Ile Leu Leu Asn Ile Leu Gly Gly
1805 1810 1815
Trp Leu Ala Ser Gln Ile Ala Pro Pro Ala Gly Ala Thr Gly Phe
1820 1825 1830
Val Val Ser Gly Leu Val Gly Ala Ala Val Gly Ser Ile Gly Leu
1835 1840 1845
Gly Lys Val Leu Val Asp Ile Leu Ala Gly Tyr Gly Ala Gly Ile
1850 1855 1860
Ser Gly Ala Leu Val Ala Phe Lys Ile Met Ser Gly Glu Lys Pro
1865 1870 1875
Ser Met Glu Asp Val Val Asn Leu Leu Pro Gly Ile Leu Ser Pro
1880 1885 1890
Gly Ala Leu Val Val Gly Val Ile Cys Ala Ala Ile Leu Arg Arg
1895 1900 1905
His Val Gly Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu
1910 1915 1920
Ile Ala Phe Ala Ser Arg Gly Asn His Val Ala Pro Thr His Tyr
1925 1930 1935
Val Thr Glu Ser Asp Ala Ser Gln Arg Val Thr Gln Leu Leu Gly
1940 1945 1950
Ser Leu Thr Ile Thr Ser Leu Leu Arg Arg Leu His Asn Trp Ile
1955 1960 1965
Thr Glu Asp Cys Pro Ile Pro Cys Gly Gly Ser Trp Leu Arg Asp
1970 1975 1980
Val Trp Asp Trp Val Cys Thr Ile Leu Thr Asp Phe Lys Asn Trp
1985 1990 1995
Leu Thr Ser Lys Leu Phe Pro Lys Met Pro Gly Leu Pro Phe Val
2000 2005 2010
Ser Cys Gln Lys Gly Tyr Lys Gly Val Trp Ala Gly Thr Gly Ile
2015 2020 2025
Met Thr Thr Arg Cys Pro Cys Gly Ala Asn Ile Ser Gly Asn Val
2030 2035 2040
Arg Leu Gly Ser Met Arg Ile Thr Gly Pro Lys Thr Cys Met Asn
2045 2050 2055
Ile Trp Gln Gly Thr Phe Pro Ile Asn Cys Tyr Thr Glu Gly Gln
2060 2065 2070
Cys Val Pro Lys Pro Ala Pro Asn Phe Lys Val Ala Ile Trp Arg
2075 2080 2085
Val Ala Ala Ser Glu Tyr Ala Glu Val Thr Gln His Gly Ser Tyr
2090 2095 2100
His Tyr Ile Thr Gly Leu Thr Thr Asp Asn Leu Lys Val Pro Cys
2105 2110 2115
Gln Leu Pro Ser Pro Glu Phe Phe Ser Trp Val Asp Gly Val Gln
2120 2125 2130
Ile His Arg Phe Ala Pro Thr Pro Lys Pro Phe Phe Arg Asp Glu
2135 2140 2145
Val Ser Phe Cys Val Gly Leu Asn Ser Phe Val Val Gly Ser Gln
2150 2155 2160
Leu Pro Cys Asp Pro Glu Pro Asp Thr Asp Val Leu Met Ser Met
2165 2170 2175
Leu Thr Asp Pro Ser His Ile Thr Ala Glu Thr Ala Ala Arg Arg
2180 2185 2190
Leu Ala Arg Gly Ser Pro Pro Ser Glu Ala Ser Ser Ser Ala Ser
2195 2200 2205
Gln Leu Ser Ala Pro Ser Leu Arg Ala Thr Cys Thr Thr His Gly
2210 2215 2220
Lys Ala Tyr Asp Val Asp Met Val Asp Ala Asn Leu Phe Met Gly
2225 2230 2235
Gly Asp Val Thr Arg Ile Glu Ser Gly Ser Lys Val Val Val Leu
2240 2245 2250
Asp Ser Leu Asp Pro Met Val Glu Glu Arg Ser Asp Leu Glu Pro
2255 2260 2265
Ser Ile Pro Ser Glu Tyr Met Leu Pro Lys Lys Arg Phe Pro Pro
2270 2275 2280
Ala Leu Pro Ala Trp Ala Arg Pro Asp Tyr Asn Pro Pro Leu Val
2285 2290 2295
Glu Ser Trp Lys Arg Pro Asp Tyr Gln Pro Ala Thr Val Ala Gly
2300 2305 2310
Cys Ala Leu Pro Pro Pro Arg Lys Thr Pro Thr Pro Pro Pro Arg
2315 2320 2325
Arg Arg Arg Thr Val Gly Leu Ser Glu Asp Ser Ile Gly Asp Ala
2330 2335 2340
Leu Gln Gln Leu Ala Ile Lys Ser Phe Gly Gln Pro Pro Pro Ser
2345 2350 2355
Gly Asp Ser Gly Leu Ser Thr Gly Ala Gly Ala Ala Asp Ser Gly
2360 2365 2370
Ser Gln Thr Pro Pro Asp Glu Leu Ala Leu Ser Glu Thr Gly Ser
2375 2380 2385
Ile Ser Ser Met Pro Pro Leu Glu Gly Glu Leu Gly Asp Pro Asp
2390 2395 2400
Leu Glu Pro Glu Gln Val Glu Pro Gln Pro Pro Pro Gln Gly Gly
2405 2410 2415
Val Ala Ala Pro Gly Ser Asp Ser Gly Ser Trp Ser Thr Cys Ser
2420 2425 2430
Glu Glu Asp Asp Ser Val Val Cys Cys Ser Met Ser Tyr Ser Trp
2435 2440 2445
Thr Gly Ala Leu Ile Thr Pro Cys Ser Pro Glu Glu Glu Lys Leu
2450 2455 2460
Pro Ile Asn Pro Leu Ser Asn Ser Leu Leu Arg Tyr His Asn Lys
2465 2470 2475
Val Tyr Cys Thr Thr Thr Lys Ser Ala Ser Leu Arg Ala Lys Lys
2480 2485 2490
Val Thr Phe Asp Arg Met Gln Val Leu Asp Ser Tyr Tyr Asp Ser
2495 2500 2505
Val Leu Lys Asp Ile Lys Leu Ala Ala Ser Lys Val Thr Ala Arg
2510 2515 2520
Leu Leu Thr Met Glu Glu Ala Cys Gln Leu Thr Pro Pro His Ser
2525 2530 2535
Ala Arg Ser Lys Tyr Gly Phe Gly Ala Lys Glu Val Arg Ser Leu
2540 2545 2550
Ser Gly Arg Ala Val Asn His Ile Lys Ser Val Trp Lys Asp Leu
2555 2560 2565
Leu Glu Asp Ser Glu Thr Pro Ile Pro Thr Thr Ile Met Ala Lys
2570 2575 2580
Asn Glu Val Phe Cys Val Asp Pro Thr Lys Gly Gly Lys Lys Ala
2585 2590 2595
Ala Arg Leu Ile Val Tyr Pro Asp Leu Gly Val Arg Val Cys Glu
2600 2605 2610
Lys Met Ala Leu Tyr Asp Ile Thr Gln Lys Leu Pro Gln Ala Val
2615 2620 2625
Met Gly Ala Ser Tyr Gly Phe Gln Tyr Ser Pro Ala Gln Arg Val
2630 2635 2640
Glu Phe Leu Leu Lys Ala Trp Ala Glu Lys Lys Asp Pro Met Gly
2645 2650 2655
Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val Thr Glu Arg
2660 2665 2670
Asp Ile Arg Thr Glu Glu Ser Ile Tyr Arg Ala Cys Ser Leu Pro
2675 2680 2685
Glu Glu Ala His Thr Ala Ile His Ser Leu Thr Glu Arg Leu Tyr
2690 2695 2700
Val Gly Gly Pro Met Phe Asn Ser Lys Gly Gln Thr Cys Gly Tyr
2705 2710 2715
Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Met Gly Asn
2720 2725 2730
Thr Ile Thr Cys Tyr Val Lys Ala Leu Ala Ala Cys Lys Ala Ala
2735 2740 2745
Gly Ile Ile Ala Pro Thr Met Leu Val Cys Gly Asp Asp Leu Val
2750 2755 2760
Val Ile Ser Glu Ser Gln Gly Thr Glu Glu Asp Glu Arg Asn Leu
2765 2770 2775
Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly
2780 2785 2790
Asp Pro Pro Arg Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys
2795 2800 2805
Ser Ser Asn Val Ser Val Ala Leu Gly Pro Gln Gly Arg Arg Arg
2810 2815 2820
Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Ile Ala Arg Ala Ala
2825 2830 2835
Trp Glu Thr Val Arg His Ser Pro Val Asn Ser Trp Leu Gly Asn
2840 2845 2850
Ile Ile Gln Tyr Ala Pro Thr Ile Trp Ala Arg Met Val Leu Met
2855 2860 2865
Thr His Phe Phe Ser Ile Leu Met Ala Gln Asp Thr Leu Asp Gln
2870 2875 2880
Asn Leu Asn Phe Glu Met Tyr Gly Ala Val Tyr Ser Val Ser Pro
2885 2890 2895
Leu Asp Leu Pro Ala Ile Ile Glu Arg Leu His Gly Leu Asp Ala
2900 2905 2910
Phe Ser Leu His Thr Tyr Thr Pro His Glu Leu Thr Arg Val Ala
2915 2920 2925
Ser Ala Leu Arg Lys Leu Gly Ala Pro Pro Leu Arg Ala Trp Lys
2930 2935 2940
Ser Arg Ala Arg Ala Val Arg Ala Ser Leu Ile Ser Arg Gly Gly
2945 2950 2955
Arg Ala Ala Val Cys Gly Arg Tyr Leu Phe Asn Trp Ala Val Lys
2960 2965 2970
Thr Lys Leu Lys Leu Thr Pro Leu Pro Glu Ala Arg Leu Leu Asp
2975 2980 2985
Leu Ser Ser Trp Phe Thr Val Gly Ala Gly Gly Gly Asp Ile Tyr
2990 2995 3000
His Ser Val Ser Arg Ala Arg Pro Arg Leu Leu Leu Phe Gly Leu
3005 3010 3015
Leu Leu Leu Phe Val Gly Val Gly Leu Phe Leu Leu Pro Ala Arg
3020 3025 3030
<210> 6
<211> 28
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 6
cacaagcttc gcacccatac tgttgggg 28
<210> 7
<211> 32
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 7
gctctagatt accatcggac gatgtatttt gt 32
<210> 8
<211> 28
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 8
cacaagcttc gcacccatac tgttgggg 28
<210> 9
<211> 30
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 9
acaggatccc atcggacgat gtattttgtg 30
<210> 10
<211> 28
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 10
cacaagcttg gcaccaccac cgttggag 28
<210> 11
<211> 33
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 11
acaggatcct cccatcgaac gacgtatttt gtg 33
<210> 12
<211> 32
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 12
caaagcttgc gacctacgtg acgggggggt cg 32
<210> 13
<211> 43
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 13
cctctagatt atggatccca tttgattgca taggagacaa ccg 43
<210> 14
<211> 34
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 14
caaagcttgg aacctatgtg acagggggga cgat 34
<210> 15
<211> 41
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 15
cctctagatt atggatccca tttgattgca aaggagacaa c 41
<210> 16
<211> 33
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 16
caaagcttca tacccgcgtg acgggggggg tgc 33
<210> 17
<211> 42
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 17
cctctagatt atggatccca cttgatggca atggagacga cc 42
<210> 18
<211> 31
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 18
caaagcttga aacccacgtc accgggggaa a 31
<210> 19
<211> 41
<212> DNA
<213> 人工的
<220>
<223> 引物
<400> 19
cctctagatt atggatccca cttaatggcc caggacgcga t 41
<210> 20
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 20
Asp Arg Leu Gly Ala Pro Thr Tyr Thr Trp
1 5 10
<210> 21
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 21
Gly Ala Pro Thr Tyr Thr Trp Gly Glu Asn
1 5 10
<210> 22
<211> 13
<212> PRT
<213> 丙型肝炎病毒
<400> 22
Asp Arg Leu Gly Ala Pro Thr Tyr Thr Trp Gly Glu Asn
1 5 10
<210> 23
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 23
Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys
1 5 10
<210> 24
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 24
Asn Glu Thr Asp Val Phe Leu Leu Asn Ser
1 5 10
<210> 25
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 25
Asp Val Phe Leu Leu Asn Ser Thr Arg Pro
1 5 10
<210> 26
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 26
Leu Leu Asn Ser Thr Arg Pro Pro Leu Gly
1 5 10
<210> 27
<211> 19
<212> PRT
<213> 丙型肝炎病毒
<400> 27
Trp Gly Glu Asn Glu Thr Asp Val Phe Leu Leu Asn Ser Thr Arg Pro
1 5 10 15
Pro Leu Gly
<210> 28
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 28
Phe Arg Val Gly Trp Gly Ala Leu Gln Tyr
1 5 10
<210> 29
<211> 13
<212> PRT
<213> 丙型肝炎病毒
<400> 29
Phe Arg Val Gly Trp Gly Ala Leu Gln Tyr Glu Asp Asn
1 5 10
<210> 30
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 30
Gly Ala Pro Pro Cys Arg Thr Arg Ala Asp
1 5 10
<210> 31
<211> 13
<212> PRT
<213> 丙型肝炎病毒
<400> 31
Lys Thr Cys Gly Ala Pro Pro Cys Arg Thr Arg Ala Asp
1 5 10
<210> 32
<211> 10
<212> PRT
<213> 丙型肝炎病毒
<400> 32
Ile Phe Lys Ile Arg Met Tyr Val Gly Gly
1 5 10
<210> 33
<211> 13
<212> PRT
<213> 丙型肝炎病毒
<400> 33
Asn Tyr Thr Ile Phe Lys Ile Arg Met Tyr Val Gly Gly
1 5 10
Claims (12)
1.一种抗体,其特异性结合基因型2a的丙型肝炎病毒的包膜蛋白2,但是不与基因型1a的丙型肝炎病毒的包膜蛋白2免疫反应。
2.根据权利要求1的抗体,其将序列表中SEQ ID NO:1所示的氨基酸序列识别为表位。
3.根据权利要求1或2的抗体,其由具有临时登记号FERM ABP-11181的杂交瘤细胞系产生。
4.根据权利要求1的抗体,其不与基因型1b的丙型肝炎病毒的包膜蛋白2免疫反应。
5.根据权利要求4的抗体,其将序列表中SEQ ID NO:2所示的氨基酸序列识别为表位。
6.根据权利要求4的抗体,其将序列表中SEQ ID NO:3所示的氨基酸序列识别为表位。
7.根据权利要求4或5的抗体,其由具有临时登记号FERM ABP-11180的杂交瘤细胞系产生。
8.根据权利要求4或6的抗体,其由具有临时登记号FERM ABP-11179的杂交瘤细胞系产生。
9.根据权利要求4的抗体,其特异性地结合J6CF株的包膜蛋白2,但是不与JFH1毒株的包膜蛋白2免疫反应。
10.根据权利要求9的抗体,其将序列表中SEQ ID NO:4所示的氨基酸序列识别为表位。
11.根据权利要求9或10的抗体,其由具有临时登记号FERM ABP-11183的杂交瘤细胞系产生。
12.一种鉴定丙型肝炎病毒基因型的方法,其中:
如果病毒结合根据权利要求3的抗体,但是不与根据权利要求7和8的任一抗体结合,所述丙型肝炎病毒的基因型被确定为基因型1b;
如果病毒结合根据权利要求3的抗体,并且结合根据权利要求7和8的抗体,所述丙型肝炎病毒的基因型被确定为基因型2a;以及
如果所述病毒结合由具有临时登记号FERM ABP-11182的杂交瘤细胞系产生的抗体,但是不结合根据权利要求3、7和8的任一抗体,所述丙型肝炎病毒的基因型被确定为基因型1a。
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JP2008-254338 | 2008-09-30 | ||
JP2008254338 | 2008-09-30 | ||
PCT/JP2009/067051 WO2010038789A1 (ja) | 2008-09-30 | 2009-09-30 | C型肝炎ウイルスのエンベロープタンパク質2に結合する抗体及びそれを用いたc型肝炎ウイルスの遺伝子型の同定方法 |
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CN102227445A true CN102227445A (zh) | 2011-10-26 |
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US (1) | US8993228B2 (zh) |
EP (2) | EP2336173A4 (zh) |
JP (1) | JP5608087B2 (zh) |
CN (1) | CN102227445B (zh) |
CA (1) | CA2738982C (zh) |
DK (1) | DK2862876T3 (zh) |
ES (1) | ES2564586T3 (zh) |
HK (1) | HK1159650A1 (zh) |
WO (1) | WO2010038789A1 (zh) |
Cited By (1)
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CN109160942A (zh) * | 2018-09-26 | 2019-01-08 | 广州市第八人民医院 | Hcv包膜蛋白高度保守区域的肽段502-518及其用途 |
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HUE046865T2 (hu) | 2009-02-27 | 2020-03-30 | Toray Industries | Immunogén készítmény |
US8592559B2 (en) | 2009-10-30 | 2013-11-26 | Toray Industries, Inc. | Antibody having activity of inhibiting hepatitis C virus (HCV) infection and use thereof |
US10117463B2 (en) | 2014-01-03 | 2018-11-06 | Robert P Thomas, Jr. | Vapor delivery device |
CN109738648B (zh) * | 2018-12-29 | 2021-09-17 | 山东莱博生物科技有限公司 | 稳定高效表达丙型肝炎病毒核心抗原抗体的工程细胞株及其应用 |
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US6924362B2 (en) | 2000-12-01 | 2005-08-02 | The United States Of America As Represented By The Department Of Health & Human Services | Monoclonal antibodies specific for the E2 glycoprotein of hepatitic C virus and their use in the diagnosis, treatment, and prevention of hepatitis C |
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CN109160942A (zh) * | 2018-09-26 | 2019-01-08 | 广州市第八人民医院 | Hcv包膜蛋白高度保守区域的肽段502-518及其用途 |
CN109160942B (zh) * | 2018-09-26 | 2021-06-29 | 广州市第八人民医院 | Hcv包膜蛋白高度保守区域的肽段502-518及其用途 |
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CA2738982A1 (en) | 2010-04-08 |
ES2564586T3 (es) | 2016-03-23 |
US8993228B2 (en) | 2015-03-31 |
EP2862876A1 (en) | 2015-04-22 |
DK2862876T3 (en) | 2016-05-23 |
EP2336173A1 (en) | 2011-06-22 |
US20110201014A1 (en) | 2011-08-18 |
EP2336173A4 (en) | 2012-07-25 |
EP2862876B1 (en) | 2016-03-02 |
CN102227445B (zh) | 2014-12-17 |
WO2010038789A1 (ja) | 2010-04-08 |
JP5608087B2 (ja) | 2014-10-15 |
HK1159650A1 (zh) | 2012-08-03 |
CA2738982C (en) | 2016-05-24 |
JPWO2010038789A1 (ja) | 2012-03-01 |
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