CN114106165A - 一种靶向甲型流感病毒n1亚型na蛋白的抗体 - Google Patents
一种靶向甲型流感病毒n1亚型na蛋白的抗体 Download PDFInfo
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Abstract
本发明公开了一种靶向甲型流感病毒N1亚型NA蛋白的抗体。本发明还公开了抗甲型流感病毒的抗体的编码核酸、载体、宿主细胞。另外,本发明还公开了用于检测甲型流感病毒的免疫缀合物以及检测试剂盒。本发明的抗体能够识别H5N1以及H1N1 N1亚型的NA抗原,且具有抑制H5N1假病毒释放从而限制细胞间传播的作用。
Description
技术领域
本发明属于细胞免疫学、基因工程领域,涉及一种靶向甲型流感病毒N1亚型NA蛋白的抗体。
背景技术
流感是由呼吸道感染的流感病毒引起的疾病,常常在冬季发生。已知流感具有非常高的传染性,会影响所有年龄组的人、尤其是老年人。流感病毒是负链且被包膜的RNA(核糖核酸) 病毒,属于正黏液病毒(Orthomyxoviridae)科。流感病毒具有单链RNA的8 个节段,且被分类为甲型(A)、乙型(B)和丙型(C)。甲型流感病毒根据它们主要的表面蛋白血凝素(HA)和神经氨酸酶(NA)进一步分成多种亚型。迄今为止,已鉴定出16种HA和9种NA(Cheung TK和Poon LL 2007,AnnNY Acad Sci.1102:1-25)。流感病毒根据它们的类型而具有广泛的感染范围(包括 鸟、猪和人),且流感病毒具有由分段的RNA组成的基因组。因为这一原因, 流感病毒可持续地突变和重组,从而产生新的遗传变异体。因为这一原因,难以获得抗流感病毒的长期免疫。当前使用的最有效的预防方法是抗每次预期要流行的特定流感病毒的疫苗。
通常使用蛋生产流感疫苗,但这是需要很长时间的低效率的方法。因此, 该方法具有难以每年在有限的时间范围内生产足够量的疫苗的问题。为了解决这一问题,在多家制药公司(GSK、Baxter等)中正积极进行对通过细胞培养生产疫苗的方法的研究。此外,当出现大范围流行的传染时,很难迅速开发出抗该大范围流行的流感病毒的疫苗。另外由于与具有抗性的突变病毒的出现相关的问题,抗病毒药物并不是完全可靠的。
为了解决这一问题,最近已积极开发了抗流感病毒的抗体以用于治疗目的。
发明内容
本发明的一个特征是提供一种抗甲型流感病毒的抗体或其抗原结合部分。
本发明的另一个特征是提供包含能够预防或治疗甲型流感病毒感染的抗体或其抗原结合部分的药物。
本发明的另外的特征和优点部分将在以下说明中阐明,并且部分从该说明可显而易见,或者可以通过实施本发明而认识到。根据说明书和所附的权利要求书中特别指出的要素和组合,本发明的目的和其它优点将被实现和获得。
本发明的解决方案
本发明提供了一种抗甲型流感病毒的抗体或其抗原结合部分,其包含:SEQ IDNO.1所示的重链可变区CDR1、SEQ ID NO.2所示的重链可变区CDR2、SEQ ID NO.3所示的重链可变区CDR3、SEQ ID NO.5所示的轻链可变区CDR1、SEQ ID NO.6所示的轻链可变区CDR2、SEQ ID NO.7所示的轻链可变区CDR3中的至少一个。
优选地,所述抗体或其抗原结合部分包含:SEQ ID NO.1所示的重链可变区CDR1、SEQ ID NO.2所示的重链可变区CDR2、SEQ ID NO.3所示的重链可变区CDR3、SEQ ID NO.5所示的轻链可变区CDR1、SEQ ID NO.6所示的轻链可变区CDR2、SEQ ID NO.7所示的轻链可变区CDR3。
进一步,所述重链可变区还包括重链可变区框架区FR1、FR2、FR3和FR4;轻链可变区还包括轻链可变区框架区FR1、FR2、FR3和FR4,其中,重链可变区框架区FR1、FR2、FR3和FR4的氨基酸序列如SEQ ID NO.9、10、11、12所示;轻链可变区框架区FR1、FR2、FR3和FR4的氨基酸序列如SEQ ID NO.13、14、15、16所示。
本发明的抗体或其抗原结合部分,其包含:
1)重链可变区,其氨基酸序列如SEQ ID NO.4所示;
2)轻链可变区,其氨基酸序列如SEQ ID NO.8所示。
自然产生的抗体结构单元通常包含四聚体。每个这样的四聚体都可由两对相同的多肽链组成,每对多肽链具有一条全长“轻”链( 如:约25000 道尔顿分子量(25kDa)) 和一条全长“重”链( 如:约50000~70000 道尔顿分子量(50~ 70kDa))。每条链的氨基末端部分通常包含大约100~110个或更多氨基酸的可变区,其通常负责抗原识别。每条链的羧基末端部分通常限定可能负责效应子功能的恒定区。人轻链通常被归类为K 和λ轻链。
重链通常被归类为μ,δ,γ,α 或ε,并分别限定抗体的同种型为IgM、IgD、IgG、IgA和IgE。IgG 有几个亚类,包括但不限于:IgG1、IgG2、IgG3 和IgG4。IgM 有亚类,包括但不限于:IgM1 和IgM2。相似地,IgA 细分为亚类,包括但不限于:IgA1 和IgA2。在轻链和重链内,可变区和恒定区可通过约12 个或更多氨基酸的“J”区连接,且重链还包括约10个或更多氨基酸的“D”区。参见,例如Fundamental Immunology Ch.7(Paul,W.,ed.,2nd ed.RavenPress,N.Y.(1989))(为所有的目的通过援引将其全部内容并入)。每条轻链/ 重链对的可变区通常形成抗原结合位点。
可变区通常显示相同的基本结构,由三个超变区( 也称为互补决定区或CDR) 连接相对保守的框架区(FR)。通常,来自每一对的两条链的CDRs 由框架区对齐,其能结合特异性表位。从氨基端到羧基端,轻链和重链的可变区通常都包含FRl、CDRl、FR2、CDR2、FR3、CDR3 和FR4 结构域。通常根据Kabat Sequences of Proteins of ImmunologicalInterest(National Institutes of Health,Bethesda,Md.(1987and1991)) ;或
Chothia&Lesk J.MoI.Biol.196:901-917(1987) ;Chothia 等,Nature342:878-883(1989)中的限定将氨基酸分配到每个结构域。
抗原结合部分的例子包括:Fab、Fab1、F(ab')2 和Fv 片段;双价抗体;线性抗体(Zapata 等,Protein Eng.8(10):1057-1062[1995]) ;单链抗体分子;和由抗体片段形成的多特异性抗体。抗体的木瓜蛋白酶消化产生两个相同的抗原结合部分,称为“Fab”片段,每个片段都有一个单个抗原结合位点,和一个残余“Fc”片段,其名称反映了其易于结晶的性能。胃蛋白酶处理产生F(ab')2 片段,它具有两个抗原结合位点且还能够交联抗原。“Fv”是含有完整的抗原识别和结合位点的抗体片段。该区包括紧密、非共价结合的一个重链可变结构域和一个轻链可变结构域的二聚体。单个可变结构域( 或仅包含对抗原特异性的三个CDRs 的Fv 的一半) 能够识别和结合抗原。“单链Fv”或“sFv”抗体片段包含抗体的VH 和VL 结构域,其中,这些结构域存在于单个多肽链。Fv 多肽还可包含VH 和VL 结构域之间的多肽接头,能够使得sFv 形成抗原结合所需的结构。关于sFv 的综述,参见Pluckthun,ThePharmacology of Monoclonal Antibodies,vol.113,Rosenburg 和Moore eds.,Springer-Verlag,New York,pp.269-315(1994)。
进一步,本发明的所述抗体是人源化抗体。
本发明还提供了编码前面所述的抗体或其抗原结合部分的核酸分子。
本发明还提供了包含所述核酸分子的表达载体。
本发明还提供了包含所述核酸分子或所述表达载体的宿主细胞。
本发明中的表达载体通常指本领域熟知的各种市售表达载体等,例如可以是细菌质粒、噬菌体、酵母质粒、植物细胞病毒、哺乳动物细胞病毒如腺病毒、逆转录病毒或其他载体。所述载体还可以包括与这所述多核苷酸序列操作性连接的一个或多个调控序列,所述调控序列可以包括合适的启动子序列。启动子序列通常与待表达氨基酸序列的编码序列操作性连接。启动子可以是在所选择的宿主细胞中显示转录活性的任何核苷酸序列,包括突变的、截短的和杂合启动子,并且可以从编码与该宿主细胞同源或异源的胞外或胞内多肽的基因获得。调控序列还可以包括合适的转录终止子序列,由宿主细胞识别以终止转录的序列。终止子序列与编码该多肽的核苷酸序列的3’末端相连,在选择的宿主细胞中有功能的任何终止子都可用于本发明。
任何适用于表达载体进行表达的细胞都可以作为宿主细胞,例如,所述宿主细胞可以是原核细胞,如细菌细胞;或是低等真核细胞,如酵母细胞;或是高等真核细胞,如哺乳动物细胞,具体可以是包括但不限于大肠杆菌,链霉菌属;鼠伤寒沙门氏菌的细菌细胞;真菌细胞如酵母、丝状真菌、植物细胞;果蝇S2或Sf9的昆虫细胞;CHO、COS、HEK293细胞、或Bowes黑素瘤细胞的动物细胞等中的一种或多种的组合。构建所述表达系统的方法对于本领域技术人员来说应该是已知的,例如,可以是包括但不限于显微注射法、基因枪法、电穿孔法、病毒介导的转化法、电子轰击法、磷酸钙沉淀法等中的一种或多种的组合。
本发明还提供了产品,所述产品包括免疫缀合物,试剂盒、药物组合物。
在本发明的具体实施方案中,本发明还提供了免疫缀合物或免疫偶联物,所述免疫缀合物或免疫偶联物是由本发明的抗体或其抗原结合部分偶联到官能剂上形成的。
官能剂可以是细胞毒素剂如化学治疗剂、毒素( 例如,细菌、真菌、植物或动物来源的酶活性毒素或其片段)、或放射性同位素( 即放射性偶联物)、抗生素、溶核酶、或它们的任意组合。化学治疗剂可以用于产生免疫偶联物,例如,甲氨喋呤(methotrexate)、阿霉素(adriamicin)、长春花生物碱(vinca alkaloid)( 长春新碱(vincristine),长春碱(vinblastine),依托泊苷(etoposide))、阿霉素(doxorubicin)、美法仑(melphalan)、丝裂霉素C(mitomycin C)、苯丁酸氮芥(chlorambucil)、柔红霉素(daunorubicin) 或其它嵌入剂、酶、和/ 或它们的片段,如溶核酶、抗生素、和毒素如小分子毒素或细菌、真菌、植物或动物来源的酶活性毒素,包括其片段和/ 或变体,以及以下公开的各种抗肿瘤剂或抗癌剂。可使用的酶活性毒素及其片段包括:例如,白喉A 链(diphtheria A chain)、白喉毒素的非结合活性片段、外毒素A 链(exotoxin A chain)( 来自绿脓杆菌(Pseudomonasaeruginosa))、蓖麻毒素A 链(ricin A chain)、相思豆毒素A 链(abrin A chain)、蒴莲根毒素A 链(modeccin A chain),α- 八叠球菌(alpha-sarcin)、油桐(Aleuritesfordii) 蛋白,石竹素蛋白(dianthin protein),美洲商陆(Phytolacca americana) 蛋白(PAPI,PAPII 和PAP-S)、苦瓜(momordica charantia) 抑制剂、麻疯树毒素(curcin)、巴豆毒素(crotin)、石碱草(saponaria officinalis) 抑制剂、白树毒素(gelonin)、丝裂蛋白(mitogellin)、局限曲菌素(restrictocin)、酚霉素(phenomycin)、依诺霉素(enomycin)、和单端孢霉烯族毒素类(tricotheeenes)。本领域已知或可用的任何合适的放射性核苷酸或放射性试剂均可用于产生放射性偶联的单克隆抗体。
所述免疫缀合物还可以是本发明的抗体或其抗原结合部分直接或间接偶联至可检测标记物形成的复合物。
可检测标记物是一种例如通过光谱学、光化学、生物化学、免疫化学或化学手段可检测的试剂。有用的可检测标记物包括,但不限于,荧光染料、化学发光化合物、放射性同位素、电子密集试剂、酶、有色颗粒、生物素或地高辛(dioxigenin)。可检测标记物往往会产生可测量的信号,如放射性、荧光、颜色或酶活性。与可检测试剂偶联的抗体可用于诊断或治疗目的。可检测试剂的例子包括各种酶、辅基、荧光材料、发光材料、生物发光材料、放射性材料、使用各种正电子发射断层摄影术的正电子发射金属、和非放射性顺磁金属离子。可检测物质可以采用本领域已知技术直接地与抗体、或间接地通过中间体如本领域已知的接头,连接或偶联。参见,美国专利第4,741,900 号,记载了金属离子与抗体的偶联用于诊断。合适的酶的实例包括辣根过氧化物酶、碱性磷酸酶、β- 半乳糖苷酶和乙酰胆碱酯酶;合适的辅基复合物的实例包括链霉亲和素/生物素和抗生物素蛋白/ 生物素;合适的荧光材料的实例包括伞形酮、荧光素、异硫氰酸荧光素、罗丹明、二氯三嗪氨(dichlorotriazinylamine) 荧光素、丹磺酰氯和藻红蛋白;发光材料的一个实例包括发光氨;生物发光材料的实例包括虫荧光素和发光蛋白质。
本发明的抗体包括人源化抗体、完全人源化抗体、部分人源化抗体。非人抗体可以使用本领域中已知的任何适用的方法进行人源化。人源化抗体可使用免疫系统已经被部分或完全人源化的转基因动物来制备。
术语 “人源化抗体” 指具有基本来自非人物种免疫球蛋白的抗原结合位点的分子,其中所述分子其余的免疫球蛋白结构是基于人免疫球蛋白的结构和/或序列。所述抗原结合位点可包含融合到恒定结构域上的完整可变结构域,或者仅包含移植到可变结构域中适当构架区的互补性决定区(CDR)。抗原结合位点可以是野生型的,或者通过一个或多个氨基酸替换进行修饰,例如进行修饰以与人免疫球蛋白更为相近。某些形式的人源化抗体保留了全部CDR序列。其他形式具有一个或多个相对于原始抗体而言发生了改变的CDR。
本发明的抗体是单克隆抗体,单克隆抗体也可以通过使用重组DNA 方法,例如美国专利第4816567 号所述的那些方法进行制备。可用常规程序( 例如,通过使用能够特异性结合编码鼠抗体重链和轻链的基因的寡核苷酸探针) 容易地分离并测序编码本发明的单克隆抗体的DNA。本发明的杂交瘤细胞可作为此类DNA 的优选来源。一旦分离,所述DNA可置于表达载体中,然后将该载体转染到不会以其它方式产生免疫球蛋白的宿主细胞如猴COS 细胞、中国仓鼠卵巢(CHO) 细胞或骨髓瘤细胞中,以在重组宿主细胞中合成单克隆抗体。也可通过,例如,用人重链和轻链恒定结构域的编码序列代替同源鼠序列,或者通过将免疫球蛋白编码序列共价结合于非免疫球蛋白多肽的全部或部分编码序列来对DNA 进行修饰。此类非免疫球蛋白多肽可替代本发明抗体的恒定结构域,或可替代本发明抗体的一个抗原结合位点的可变结构域,以产生嵌合二价抗体。采用重组DNA 方法例如噬菌粒展示方法(phagemid display method) 制备抗体可使用市售的试剂盒来完成,例如,从Pharmacia(Uppsala,Sweden)可得的重组噬菌粒抗体体系,或SurfZAPTM 噬菌体展示系统(Stratagene Inc.,LaJolla,Califorinia)。
本发明的抗体可以是双价抗体。术语“双价抗体(diabody)”是指含有两个抗原结合位点的小抗体片段,片段包含一条与同一多肽链中的轻链可变结构域(VL) 相连的重链可变结构域(VH)(Vn-VL)。通过使用太短的连接物以致无法允许相同链上的两个结构域之间进行配对,能够迫使结构域与另一条链上的互补结构域配对,形成两个抗原结合位点。例如在欧洲专利EP 404,097、W093/11161 和Hollinger 等,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993) 中对双价抗体有更为全面的论述。
本发明的抗体可包括单链抗体。该抗体可以是单价抗体。制备单价抗体的方法是本领域熟知的。例如,一种方法涉及重组表达免疫球蛋白轻链和修饰重链。一般来说,可在Fc区的任何一点将重链截断,以防止重链交联。或者,以另一氨基酸残基替代相关的半胱氨酸残基或去掉相关的半胱氨酸残基以防止交联。体外方法也是合适用于产生单价抗体。可使用本领域已知常规技术来实现抗体消化,以产生抗体片段,特别是Fab 片段。
本发明的抗体可以是双特异性的。双特异性抗体(bispecific antibody) 特异性结合一个蛋白质,并特异性结合与病理和/ 或治疗相关的其它抗原,可使用文献中记载的标准程序制备、分离和测试双特异性抗体。( 参见:例如,Pluckthun 和Pack,Immunotechnology,3:83-105(1997) ;Carter 等,J.Hematotherapy,4:463-470(1995) ;Renner 和Pfreundschuh,Immunological Reviews,1995,No.145,pp.179-209 ;Pfreundschuh 的美国专利第5643759 号;Segal 等,J.Hematotherapy,4:377-382(1995) ;Segal 等,Immunobiology,185:390-402(1992) ;和Bolhuis 等,Cancer Immunol.Immunother.,34:1-8(1991))。
本发明的抗体可构建为免疫脂质体。包含抗体的脂质体可用本领域已知的方法制备,如Epstein 等,Proc.Natl.Acad.Sci.USA,82:3688(1985) ;Hwang 等,Proc.Natl.Acad.Sci.USA 77:4030(1980) 以及美国专利第4,485,045 和4,544,545 号所描述的。美国专利第5,013,556 号公开了循环时间延长的脂质体。可利用包含磷脂酰胆碱、胆固醇和PEG衍生的磷脂酰乙醇胺(PEG-PE) 的脂质组合物通过反相蒸发法制备特别有用的脂质体。可以通过确定孔径的滤膜挤出以得到具有理想直径的脂质体。本发明抗体的Fab' 片段可通过二硫化物互换反应偶联到脂质体上,如Martin 等,J.Biol.Chem.257:286-288(1982) 所述。可选地,化学治疗剂( 如阿霉素(Doxorubicin)) 可以包裹到脂质体内。参见,Gabizon,J.National Cancer Inst.,81(19):1484(1989)。
本发明提供了一种预防或治疗甲型流感病毒感染的方法,包括:将有效治疗量的本发明的抗体或其抗原结合部分给药予受试者。该方法还包括:诊断感染甲型流感病毒的患者。可在诊断患者感染病毒之前、当中、和/ 或之后施用本发明的抗体或其抗原结合部分。
该方法还包括:监测至少一种甲型流感病毒感染症状的减轻。
本发明提供了一种检测甲型流感病毒的方法,包括:将来自受试者的样品与本发明的抗体或其抗原结合部分接触。该方法还可包括:根据抗体是否结合甲型流感病毒,检测受试者中存在或不存在甲型流感病毒。
本发明前面所述的产品可以是一种用于甲型流感病毒检测的试剂盒,所述试剂盒包含本发明前面所述的抗体或其抗原结合部分、前面所述的核酸分子、前面所述的表达载体、前面所述的宿主细胞。
本发明前面所述的产品可以是一种用于防治于甲型流感病毒感染的药物组合物,所述药物组合物包含本发明前面所述的抗体或其抗原结合部分。
进一步,所述药物组合物还包括药学可接受载体。
术语 “药物组合物” 指其形式使得其中含有的活性成分的生物学活性有效,且不含对会接受该组合物施用的受试者有不可接受的毒性的别的成分的制剂。
术语“药学可接受载体”指药物组合物中活性成分以外对受试者无毒的成分。药学可接受载体包括但不限于缓冲剂、赋形剂、稳定剂或防腐剂。
本发明还提供了前面所述的抗体或其抗原结合部分在制备甲型流感病毒检测产品或感染诊断产品中的应用。
本发明还提供了前面所述的抗体或其抗原结合部分在制备防治甲型流感病毒感染的药物组合物中的应用。
本发明还提供了前面所述的核酸分子在制备防治甲型流感病毒感染的药物组合物中的应用。
本发明还提供了前面所述的表达载体在制备防治甲型流感病毒感染的药物组合物中的应用。
本发明还提供了前面所述的宿主细胞在制备防治甲型流感病毒感染的药物组合物中的应用。
本发明还提供了前面所述的药物组合物在制备防治甲型流感病毒感染疾病的药物中的应用。
本发明还提供了前面所述的免疫缀合物在制备甲型流感病毒检测产品或感染诊断产品中的应用。
本发明的所述流感病毒为H1N1、H5N1。
术语“治疗/预防”或“防治”指试图改变治疗个体中疾病的自然进程,并且可以是为了预防或在临床病理学的过程期间实施的临床干预。治疗的期望效果包括但不限于预防疾病的发生或复发、缓解症状、降低疾病的任何直接或间接病理学后果、预防转移、减缓疾病进展的速率、改善或减轻疾病状态、及免除或改善预后。在一些实施方案中,本发明的抗体用于延迟疾病的形成或延缓病症的进展。
附图说明
图1是FNA1抗体的SDS-PAGE电泳图,A:非还原;B:还原;
图2是ELISA检测FNA1抗体的抗原结合特异性图;
图3是免疫印迹检测FNA1抗体抗原结合特异性图;
图4是抑制假病毒释放实验的结果图。
具体实施方式
下面结合附图和实施例对本发明作进一步详细的说明。
以下实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1 筛选抗NA蛋白抗体
1、构建噬菌体抗体库
借助计算机辅助分子设计构建靶向甲型流感病毒N1亚型NA蛋白的抗体库,利用噬菌体展示技术筛选候选抗体。
(1)展示的噬菌体库黏附H1N1的 N1亚型NA蛋白;
(2)反复洗涤去除非特异性结合,洗脱并收集与H1N1的N1亚型NA蛋白的噬菌体;
(3)再次感染大肠杆菌,挑选单克隆展示于噬菌体表面,ELISA筛选识别H1N1 的N1亚型NA蛋白的阳性克隆。
2、抗体可变区基因序列的测定、分析
阳性克隆送到上海生工生物技术有限公司进行抗体可变区基因序列测定, 对测序结果用DNAMAN和数据库进行检索分析。
3、结果
通过上述步骤筛选出了能够同时识别结合H1N1以及H5N1 的N1亚型NA蛋白的人源化单克隆抗体FNA1,经序列比对,获得了编码FNA1单克隆抗体的轻链可变区的氨基酸序列和编码FNA1单克隆抗体的重链可变区的氨基酸序列,其中重链的CDR1-3序列如SEQ IDNO.1~3所示,重链可变区框架区FR1、FR2、FR3和FR4的氨基酸序列如SEQ ID NO.9~12所示,重链可变区序列如SEQ ID NO.4所示,轻链的CDR1-3序列如SEQ ID NO. 5~7所示,轻链可变区框架区FR1、FR2、FR3和FR4的氨基酸序列如SEQ ID NO.13~16所示,轻链可变区的氨基酸序列如SEQ ID NO.8所示。
重链可变区VH氨基酸序列:
QVKLQESGGGLVQPKGSLKLSCAASGFAFYSYAMNWVRQAPGKALEWVARIRSKSNNCATFYADSVKDRFTISRDDSQSMLYLQMHNLKTDDTAMYYCVRPSVYSYASGYLDDWGAGTTVTVSS SEQ ID NO.4
表1 VH的CDR与FR区域序列
重链可变区VH核酸序列:
CAGGTGAAACTGCAGGAAAGCGGCGGCGGCCTGGTGCAGCCGAAAGGCAGCCTGAAACTGAGCTGCGCGGCGAGCGGCTTTGCCTTTTACAGCTATGCGATGAACTGGGTGCGCCAGGCGCCGGGCAAAGCCCTGGAATGGGTGGCGCGCATTCGGAGCAAAAGCAACAACTGCGCGACCTTTTATGCGGATAGCGTGAAAGATCGCTTTACCATTAGCCGCGATGATAGCCAGAGCATGCTGTATCTGCAGATGCATAACCTGAAAACCGATGATACCGCGATGTATTATTGCGTGCGCCCGAGCGTTTATTCTTATGCGAGCGGCTATCTGGATGACTGGGGCGCGGGCACCACCGTGACCGTGAGCAGCSEQ ID NO.17
轻链可变区VL氨基酸序列:
QIVLSQSPAILSASPGEKVTMTCRTSSSVNYVHWYQQKPGSSPKPWIYATSNLASGVPFRFSGSGSGTSYSLTISRVEAEDAATYYCQQSNSSPVTFGGGTKLEIK SEQ ID NO.8
表2 VL CDR与FR区域序列
轻链可变区VL核酸序列:
CAGATTGTGCTGAGCCAGAGCCCGGCGATTCTGAGCGCGAGCCCGGGCGAAAAAGTGACCATGACCTGCCGCACCAGCAGCAGCGTGAACTATGTGCATTGGTATCAGCAGAAACCGGGCAGCAGCCCGAAACCGTGGATTTATGCGACCAGCAACCTGGCGAGCGGCGTGCCGTTTCGCTTTAGCGGCAGCGGCAGCGGCACCAGCTATAGCCTGACCATTAGCCGCGTGGAAGCGGAAGATGCGGCGACCTATTATTGCCAGCAGAGCAACAGCTCCCCGGTCACCTTTGGCGGCGGCACCAAACTGGAAATTAAA SEQ ID NO.18
实施例2 单克隆抗体FNA1的制备
1、利用PCR方法扩增抗体FNA1重链可变区序列(氨基酸序列如SEQ ID NO.4所示,核苷酸序列如SEQ ID NO.17所示)轻链可变区序列(氨基酸序列如SEQ ID NO.8,核苷酸序列如SEQ ID NO.18所示),并将其利用分子克隆的方法将片段克隆入表达载体中。
2、将同时含有单克隆抗体轻链以及重链基因的载体转染进哺乳动物细胞中,进行表达。
3、收集表达上清,利用GE公司的Protein A FF蛋白柱进行纯化。
4、用pH3.0的柠檬酸缓冲液洗脱,收集流出液,并立即用1mol/L pH 8.5 TRIS-HCL缓冲液中和,用pH7.2,0.01mol/L的PBS透析72h,0.22μm滤膜过滤除菌。
5、利用SDS-PAGE和Western Blot实验检验抗体的表达及纯化情况,以及利用BCA方法检测纯化抗体浓度,4℃保存。
6、结果如图1所示,证实得到较纯蛋白,并可清察到解链后的抗体轻、重链。
实施例3 单克隆抗体FNA1的特异性检测
一、采用ELISA法检测单克隆抗体FNA1的特异性
1、在ELISA板中包被2μg/ml的甲型流感病毒H1N1,H3N2,H5N1以及H7N9的NA抗原,4℃过夜;
2、用脱脂奶粉封闭未结合的位点,然后用含0.1%吐温的PBS 缓冲液洗涤5 次;
3、 配置不同浓度的抗体FNA1,加入步骤2中的ELISA板条中,37℃孵育1h,用含0.1%吐温的PBS 缓冲液洗涤5 次;
4、加入HRP-标记的羊抗人抗体,37℃孵育30min,用含0.1%吐温的PBS缓冲液洗涤5次;加入TMB显色,1mol/L的硫酸终止后检测OD450 的值。
5、结果
结果如图2所示,抗体FNA1能有效地结合甲型流感病毒H1N1和H5N1的NA抗原,且呈剂量依赖关系。
二、免疫印迹检测单克隆抗体FNA1的特异性
将1 μg H1N1 NA、H3N2 NA、H5N1 NA、H7N9 NA蛋白加入5×还原型上样缓冲液,沸水浴10 min。采用12%的SDS-PAGE进行电泳,室温恒流20 mA,1.5h之后冰浴转印至PVDF膜上,5%脱脂牛奶室温封闭1h,加入抗体FNA1(5 μg/mL)4℃孵育过夜。TBST清洗3遍后,加入辣根过氧化酶标记的二抗(anti-human IgG-HRP),室温孵育1h。TBST清洗3遍,ECL显色。
结果如图3所示,抗体FNA1能有效地结合甲型流感病毒H1N1和H5N1的NA抗原。
实施例4 抑制假病毒释放实验
1、步骤
将24孔板中的293T细胞培养长至80%;将H5N1 HA以及NA表达质粒与pNL-4.3-luc以1:1:2的比例利用转染试剂lipoamine3000共转染进293T细胞中;转染6 h后,换用新鲜的完全DMEM培养基,在相应培养孔添加5 μg/mL或者50 μg/mL FNA1,同时设置未加抗体孔对照,继续培养48h后,分别收集不同处理孔的细胞培养上清,3000 rpm/min离心10 min,用0.45 μm的滤膜过滤后,感染24孔板中的293T细胞。48h后,裂解细胞测荧光素酶活性(RLU)。
2、结果
病毒的检测结果如图4所示,制备的含荧光素酶报告基因的H5N1假病毒颗粒上清感染293T细胞后,293T细胞产生荧光。FNA1在低浓度下(5 mg/L)即能有效阻断细胞膜表面NA活性,从而抑制包装的假病毒从细胞表面释放,继而抑制其进一步感染靶细胞, 显示为靶细胞胞内荧光值显著降低。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
序列表
<110> 中国人民解放军军事科学院军事医学研究院
<120> 一种靶向甲型流感病毒N1亚型NA蛋白的抗体
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Claims (10)
1.一种靶向甲型流感病毒N1亚型NA蛋白的抗体或其抗原结合部分,其特征在于,其包含:SEQ ID NO.1所示的重链可变区CDR1、SEQ ID NO.2所示的重链可变区CDR2、SEQ IDNO.3所示的重链可变区CDR3、SEQ ID NO.5所示的轻链可变区CDR1、SEQ ID NO.6所示的轻链可变区CDR2、SEQ ID NO.7所示的轻链可变区CDR3。
2.根据权利要求1所述的抗体或其抗原结合部分,其特征在于,所述重链可变区还包括重链可变区框架区FR1、FR2、FR3和FR4;轻链可变区还包括轻链可变区框架区FR1、FR2、FR3和FR4,其中,重链可变区框架区FR1、FR2、FR3和FR4的氨基酸序列如SEQ ID NO.9、10、11、12所示;轻链可变区框架区FR1、FR2、FR3和FR4的氨基酸序列如SEQ ID NO.13、14、15、16所示。
3.根据权利要求1所述的抗体或其抗原结合部分,其特征在于,所述抗体或其抗原结合部分包含:
1)重链可变区,其氨基酸序列如SEQ ID NO.4所示;
2)轻链可变区,其氨基酸序列如SEQ ID NO.8所示。
4.根据权利要求1-3任一项所述的抗体或其抗原结合部分,其特征在于,所述抗体是人源化抗体。
5.一种核酸分子,其特征在于,所述核酸分子包含编码权利要求1-3中任一项所述的抗体或其抗原结合部分的核酸序列。
6.根据权利要求5所述的核酸分子,其特征在于,所述编码重链可变区的核酸序列如SEQ ID NO.17所示;编码轻链可变区的核酸序列如SEQ ID NO.18所示。
7.一种表达载体,其特征在于,其包含权利要求5或6所述的核酸分子。
8.一种宿主细胞,其特征在于,其包含权利要求5或6所述的核酸分子,或权利要求7所述的表达载体。
9.一种产品,所述产品包括以下任一项所述的产品:
1)所述产品是免疫缀合物,所述免疫缀合物包括权利要求1-3中任一项所述的抗体或其抗原结合部分;
2)所述产品是药物组合物,所述药物组合物包括权利要求1-3中任一项所述的抗体或其抗原结合部分、权利要求5或6所述的核酸分子或权利要求7所述的表达载体;
3)所述产品是试剂盒,所述试剂盒包括权利要求1-3中任一项所述的抗体或其抗原结合部分、权利要求5或6所述的核酸分子、权利要求7所述的表达载体或权利要求8所述的宿主细胞。
10.如下任一项所述的应用,其特征在于,包括:
1)权利要求1-3中任一项所述的抗体或其抗原结合部分在制备甲型流感病毒检测产品或感染诊断产品中的应用;
2)权利要求1-3中任一项所述的抗体或其抗原结合部分在制备防治甲型流感病毒感染的药物组合物中的应用;
3)权利要求5或6所述的核酸分子在制备防治甲型流感病毒感染的药物组合物中的应用;
4)权利要求7所述的表达载体在制备防治甲型流感病毒感染的药物组合物中的应用;
5)权利要求8所述的宿主细胞在制备防治甲型流感病毒感染的药物组合物中的应用;
6)权利要求9中所述的药物组合物在制备防治甲型流感病毒感染疾病的药物中的应用;
7)权利要求9中所述的免疫缀合物在制备甲型流感病毒检测产品或感染诊断产品中的应用;
所述甲型流感病毒为H1N1、H5N1。
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CN114349854B (zh) * | 2022-03-17 | 2022-05-20 | 中国人民解放军军事科学院军事医学研究院 | 针对甲型流感病毒n1亚型na蛋白的抗体及其应用 |
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