CN116425869A - 一种抗柯萨奇病毒a6型的单克隆抗体及其制备方法和应用 - Google Patents
一种抗柯萨奇病毒a6型的单克隆抗体及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及抗体技术领域，具体涉及一种抗柯萨奇病毒A6型的单克隆抗体及其制备方法和应用。本发明的抗体或其抗原结合片段的重链互补决定区CDR1、CDR2、CDR3具有如SEQ ID NO.1‑3所示的氨基酸序列，轻链互补决定区CDR1、CDR2、CDR3具有如SEQ ID NO.4‑6所示的氨基酸序列。该抗体或其抗原结合片段兼具CV‑A6特异性和型内广谱性，能够交叉结合并中和CV‑A6不同亚型毒株，对CV‑A6感染动物具有较好的保护作用，对CV‑A6的检测、疫苗的研发、评价及临床诊断、CV‑A6感染及其相关疾病的治疗具有重要意义。
Description
技术领域
本发明涉及抗体技术领域，具体涉及一种抗柯萨奇病毒A6型的单克隆抗体及其制备方法和应用。
背景技术
近年来，柯萨奇病毒A组6型(Cox-sackievirus A6，CV-A6)引起的手足口病在全球呈上升趋势，在部分国家，CV-A6甚至已取代EV71及CV-A16，成为引发手足口病最主要的病原体。感染CV-A6的手足口病(Hand，foot and mouth disease，HFMD)儿童主要表现为发热、皮疹和脱甲。且有研究发现，感染CV-A6的患者出现发热的比例要明显高于感染EV71和CV-A16的患者，平均体温约为38.8℃。成人亦存在感染CV-A6的现象，除出现上述症状的基础外，还会表现出诸如手掌、脚底、口周等部位出疹的现象。上述症状均为常见的HFMD临床表现，并非所有患者均存在上述症状，也存在部分患者呈现无症状感染的情况。目前，对于CV-A6的研究尚不全面，也无相应的疫苗投入使用。目前全球主要流行的CV-A6是重组进化后的变异株。CV-A6也易与其他肠道病毒共同造成混合感染。重组CV-A6病毒感染可能比非重组CV-A6感染导致更广泛的皮肤损害，并且上肢、下肢和前躯干出现的皮肤损害更加频繁。
随着基因测序技术的进步，研究发现病毒基因组中的VP1段为编码病毒主要中和表位相关的基因，因此 VP1段的同源性和中和实验的结果呈现高度的相关性。因此，基于病毒基因组VP1段的同源性比对也成为了病毒鉴定分型的金标准之一。目前尚无国际公认的CV-A6基因分型标准。以VP1编码区全基因序列(915bp) 差异＞15％以及亚型间核昔酸差异＞8％为标准，Song等(Song Y,Zhang Y,Ji T,et al.Persistent circulation ofCoxsackievirus A6 of genotype D3 in mainland of China between 2008and 2015[J].Scientific reports,2017,7(1): 1-11.)将CV-A6分为A、B、C、D四个基因型以及Bl和B2、C1和C2、D1、D2和D3基因亚型。其中基因型A包含一个单一菌株，即1949年在美国分离的CVA6原型菌株Gdula。近年来，CV-A6流行株主要为D2和D3亚型，其中D3亚型及其D3a进化分支更为普遍。
研究表明，免疫球蛋白能够较为显著地降低如γ-干扰素、白介素-6、白介素-8等细胞因子的水平。但免疫球蛋白亦会存在诸如广谱性不高、无法中和所有血清型、可能导致感染增强等局限性。目前治疗药物正着力于抗特定病毒的单克隆抗体、对病毒的进入或复制产生抑制的小分子药物等方向的研究。
单克隆抗体具有高度靶向性、低毒性等特点，是病毒感染临床诊断和治疗的重要手段，也是现代生命科学的重要工具，广泛应用于临床诊断、治疗及疫苗评价等方面。因此，开发针对CV-A6的单克隆抗体对于该病毒感染的诊断、治疗和疫苗生产具有重要意义。
发明内容
本发明的目的是提供一种抗柯萨奇病毒A6型的抗体及其抗原结合片段以及该抗体及其抗原结合片段的制备方法和应用。
具体地，本发明提供以下技术方案：
第一方面，本发明提供抗体或其抗原结合片段，所述抗体或其抗原结合片段的重链互补决定区CDR1、 CDR2、CDR3具有如SEQ ID NO.1-3所示的氨基酸序列，和/或，所述抗体或其抗原结合片段的轻链互补决定区 CDR1、CDR2、CDR3具有如SEQ ID NO.4-6所示的氨基酸序列。
本发明中，抗原结合片段是指包含全长抗体的片段的多肽，其保持特异性结合全长抗体所结合的相同抗原的能力，或者可与全长抗体竞争对抗原的特异性结合。
在本发明的一些实施方式中，所述抗体或其抗原结合片段的重链互补决定区CDR1、CDR2、CDR3具有如 SEQ ID NO.1-3所示的氨基酸序列，轻链互补决定区CDR1、CDR2、CDR3具有如SEQ ID NO.4-6所示的氨基酸序列。
在本发明的一些实施方式中，所述抗体或其抗原结合片段的重链互补决定区CDR1、CDR2、CDR3的氨基酸序列如SEQ ID NO.1-3所示，轻链互补决定区CDR1、CDR2、CDR3的氨基酸序列如SEQ ID NO.4-6所示。
本发明提供的上述抗体或其抗原结合片段同时具有CV-A6特异性和型内广谱性，能够交叉结合及中和 CV-A6不同亚型的毒株。
优选地，所述抗体或其抗原结合片段的重链可变区具有如SEQ ID NO.7所示的氨基酸序列或具有与如SEQ ID NO.7所示的氨基酸序列具有至少80％同源性的氨基酸序列；和/或，所述抗体或其抗原结合片段的轻链可变区具有如SEQ ID NO.8所示的氨基酸序列或具有与如SEQ ID NO.8所示的氨基酸序列具有至少80％同源性的氨基酸序列。
在本发明的一些实施方式中，所述抗体或其抗原结合片段的重链可变区具有如SEQ ID NO.7所示的氨基酸序列，轻链可变区具有如SEQ ID NO.8所示的氨基酸序列。
在本发明的一些实施方式中，在具有上述重链和轻链互补决定区CDR1、CDR2、CDR3的情况下，所述抗体或其抗原结合片段的重链可变区具有与如SEQ ID NO.7所示的氨基酸序列具有至少80％、至少85％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％或至少99％的序列同源性的氨基酸序列，轻链可变区具有与如SEQ ID NO.8所示的氨基酸序列具有至少80％、至少85％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％或至少99％的序列同源性的氨基酸序列。
在本发明的一些实施方式中，所述抗体或其抗原结合片段在重链可变区的N端还包含信号肽。
在本发明的一些实施方式中，在重链可变区的N端的信号肽具有如SEQ ID NO.9所示的氨基酸序列。
在本发明的一些实施方式中，所述抗体或其抗原结合片段在轻链可变区的N端还包含信号肽。
在本发明的一些实施方式中，在轻链可变区的N端的信号肽具有如SEQ ID NO.10所示的氨基酸序列。
本发明中，所述抗体可为单克隆抗体、双特异抗体或多特异抗体。
其中，所述单克隆抗体可为鼠源抗体、嵌合抗体或人源化抗体。
本发明中，所述抗原结合片段可为Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段或单链抗体。
在本发明的一些实施方式中，所述抗体还包含重链恒定区。
在本发明的一些实施方式中，所述抗体的重链为IgG2b。
在本发明的一些实施方式中，所述重链恒定区的氨基酸序列如SEQ ID NO.11所示。
在本发明的一些实施方式中，所述抗体还包含轻链恒定区。
在本发明的一些实施方式中，所述抗体的轻链为Kappa。
在本发明的一些实施方式中，所述轻链恒定区的氨基酸序列如SEQ ID NO.12所示。
第二方面，本发明提供一种标记抗体，其为以上所述的抗体或其抗原结合片段被酶、生物素、荧光染料、化学发光染料和/或放射性同位素标记得到。
第三方面，本发明提供一种核酸分子，其编码所述抗体或其抗原结合片段。
根据上述抗体或其抗原结合片段的氨基酸序列，本领域技术人员可获得编码上述抗体或其抗原结合片段的核酸分子的核苷酸序列。由于密码子的简并性，编码上述抗体或其抗原结合片段的核酸分子的核苷酸序列并不唯一，所有能够编码产生上述抗体或其抗原结合片段的核酸分子均在本发明的保护范围内。
在本发明的一些实施方式中，编码上述抗体的重链的核酸分子的核苷酸序列如SEQ ID NO.13所示，编码上述抗体的轻链的核酸分子的核苷酸序列如SEQ ID NO.14所示。
第四方面，本发明提供一种生物材料，其含有以上所述的核酸分子；所述生物材料为表达盒、载体或宿主细胞。
上述表达盒可为由所述核酸分子与启动子可操作性地连接得到的重组DNA。
上述载体包括但不限于质粒载体、噬菌体载体、病毒载体、人工染色体载体等。
上述宿主细胞包括微生物细胞、动物细胞或细胞系。其中微生物细胞包括但不限于大肠杆菌、酵母等，动物细胞包括但不限于昆虫细胞，细胞系包括但不限于CHO细胞、293T细胞等。
第五方面，本发明提供所述抗体或其抗原结合片段的制备方法，所述方法包括：培养能够表达所述抗体或其抗原结合片段的宿主细胞，经分离得到所述抗体或其抗原结合片段。
第六方面，本发明提供所述抗体或其抗原结合片段或所述标记抗体或所述核酸分子或所述生物材料的以下任一种应用：
(1)在制备用于检测柯萨奇病毒A6型在样品中的存在或其水平的产品中的应用；
(2)在制备用于诊断柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病的产品中的应用；
(3)在制备用于中和样品中的柯萨奇病毒A6型毒力的产品中的应用；
(4)在制备用于预防或治疗柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病的药物中的应用；
(5)在检测柯萨奇病毒A6型疫苗的抗原性和免疫原性中的应用；
(6)在柯萨奇病毒A6型疫苗生产的质量控制中的应用；
(7)在检测柯萨奇病毒A6型抗原的特异性中的应用。
上述(1)所述的应用中，检测柯萨奇病毒A6型在样品中的存在是指检测样品中是否含有柯萨奇病毒A6 型，检测柯萨奇病毒A6型的水平是指检测样品中柯萨奇病毒A6型的含量。
上述(1)、(3)所述的应用中，所述样品可以是来自有生命的人或动物的样品(包括血液、排泄物、口鼻分泌物等)，也可以是体外培养的细胞样品。
上述(1)、(2)所述的应用中，所述产品可为检测试剂或试剂盒。
上述(2)、(4)所述的应用中，由柯萨奇病毒A6型感染导致疾病包括手足口病等。
上述(5)所述的应用中，免疫原性检测具体为检测柯萨奇病毒A6型疫苗引起动物机体免疫应答的性能，包括免疫动物体液免疫功能(例如：中和抗体及其水平、抗体的亲和力)的评价等。
上述(6)所述的应用中，柯萨奇病毒A6型疫苗的质量控制具体为检测柯萨奇病毒A6型疫苗中抗原质量、含量、稳定性等是否合格。
上述应用中，检测的方法可以使用酶联免疫吸附(ELISA)、化学发光免疫检测、放射免疫检测、荧光免疫检测、免疫色谱法等。本发明提供的抗体或其抗原结合片段可作为上述检测方法中的结合抗体，用于柯萨奇病毒A6型疫苗抗原的检测。
第七方面，本发明提供一种试剂盒，其包含所述抗体或其抗原结合片段或所述标记抗体。
上述试剂盒具有以下任一种用途：
(1)检测柯萨奇病毒A6型在样品中的存在或其水平；
(2)诊断柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病；
(3)检测柯萨奇病毒A6型疫苗的抗原性和免疫原性；
(4)柯萨奇病毒A6型疫苗生产的质量控制；
(5)检测柯萨奇病毒A6型抗原的特异性。
上述试剂盒除包含所述抗体或其抗原结合片段或所述标记抗体外，还可包含携带可检测的标记的第二抗体以检测本发明的抗体或其抗原结合片段。其中，可检测的标记包括但不限于酶、放射性同位素，荧光染料等。
第八方面，本发明提供一种药物，其包含所述抗体或其抗原结合片段。
上述药物具有以下任一种用途：
(1)预防柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病；
(2)治疗柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病。
上述药物除包含所述抗体或其抗原结合片段外，还可包含药学上可接受的载体、赋形剂或其他活性成分。
第九方面，本发明提供检测柯萨奇病毒A6型在样品中的存在或其水平的方法，所述方法包括，使用本发明的抗体或其抗原结合片段检测柯萨奇病毒A6型在样品中的存在或其水平。所述方法可以用于诊断目的(样品来自有生命的人或动物)，或者非诊断目的(样品是体外培养的细胞样品，而非来自有生命的人或动物的样品)。
第十方面，本发明提供诊断柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病的方法，所述方法包括：使用本发明的抗体或其抗原结合片段诊断柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病。
第十一方面，本发明提供用于中和样品中柯萨奇病毒A6型毒力的方法，所述方法包括，将包含柯萨奇病毒A6型的样品与本发明的抗体或其抗原结合片段接触。所述方法可以用于治疗目的或非治疗目的(样品是体外培养的细胞样品，而非来自有生命的人或动物的样品)。
第十二方面，本发明提供用于预防或治疗柯萨奇病毒A6型感染由柯萨奇病毒A6型感染导致疾病(包括手足口病等)的方法，所述方法包括：给予受试者预防或治疗有效量的本发明的抗体或其抗原结合片段或包含所述抗体或其抗原结合片段的药物。
第十三方面，本发明提供一种柯萨奇病毒A6型疫苗生产的质量控制方法，所述方法包括使用本发明的抗体或其抗原结合片段检测柯萨奇病毒A6型的步骤。
本发明的有益效果至少包括以下几方面：
(1)本发明提供的抗体或其抗原结合片段兼具CV-A6特异性和型内广谱性，能够特异性结合CV-A6，而与其他型别抗原和Vero宿主细胞蛋白无交叉反应；而且还能够交叉结合CV-A6不同亚型的毒株。
(2)本发明提供的抗体或其抗原结合片段具有广谱中和活性，能够交叉中和CV-A6不同亚型的毒株。
(3)本发明提供的抗体或其抗原结合片段可以竞争抑制人自然感染血清。
(4)本发明提供的抗体或其抗原结合片段对CV-A6感染动物具有较好的保护作用，保护效果与抗体剂量呈现效应关系。
本发明提供的抗体或其抗原可应用于CV-A6的存在或其含量水平的检测，CV-A6疫苗抗原性及免疫原性的评价，对CV-A6的检测、CV-A6疫苗的研发、评价及临床诊断具有重要意义；还可应用于CV-A6预防或治疗药物的开发，对于CV-A6感染及其相关疾病的治疗具有重要意义。
附图说明
图1为本发明实施例1中蔗糖密度梯度离心分离后电镜鉴定实心病毒颗粒和空心病毒颗粒，其中，左图为空心颗粒，右图为实心颗粒，图中的标尺为100nm。
图2为本发明实施例3中单克隆抗体的SDS-PAGE检测结果。
图3为本发明实施例3中单克隆抗体与人血清的竞争抑制试验。
图4为本发明实施例5中酶标抗体的反应曲线。
图5为本发明实施例7中抗原检测方法的线性范围的三次评价结果。
图6为本发明实施例7中抗原检测方法的专属性评价结果。
图7为本发明实施例8中各组的生存曲线。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例1CV-A6抗原的制备
病毒培养：取1支CV-A6毒株，按MOI＝0.001，接种至4个长满单层Vero细胞的10层细胞工厂，每个工厂2L，置于35℃恒温箱内培养3～5天。待病变达到100％时收获病毒液。将病毒收获液分装至离心杯，6000rpm，离心40min，收获离心上清，得到CV-A6离心上清液。
超滤浓缩：将离心上清液用300KD膜包进行超滤浓缩。用10mmol/L PBST溶液连续洗滤，洗膜2次，洗膜液与未滤过液合并为超滤产物。
蔗糖密度梯度离心：将超滤产物用10mmol/L PBS溶液(0.15mol/L NaCl)稀释3.5倍，进行梯度离心。蔗糖浓度为40％～55％。30000rpm，离心15～18h，每管35ml，收集24管。取样进行SDS-PAGE检测，根据检测结果合并空心颗粒和实心颗粒，用电镜鉴定空实心颗粒。
蔗糖密度梯度离心分离后电镜鉴定的实心病毒颗粒、空心病毒颗粒电镜比较图见图1。
实施例2单克隆抗体的制备
杂交瘤细胞株制备：将实施例1制得的空心颗粒和实心颗粒收集后脱糖处理，按1:1体积合并，即得到 CV-A6病毒纯化液。采用上述CV-A6病毒纯化液免疫NIH小鼠，免疫5只；在0，2，4，6，8周共5针背部皮下多点免疫；免疫剂量：第1针为30μg/只，弗氏完全佐剂；第2、3针为15μg/只，弗氏不完全佐剂；第4 针不加佐剂，15μg/只，尾静脉注射；采血检测：分别于免疫第2针和第3针后1周采血检测间接酶联免疫法效价，对抗体效价达到10 4以上的小鼠进行第4针腹腔注射进行加强免疫。
细胞融合：采用电融合方法进行细胞融合。平均融合效率是用大约2500个脾细胞能融合产生1个杂交瘤细胞。
筛选验证：用间接ELISA方法初步筛选融合细胞的上清液，挑选出对免疫原阳性的上清。对初筛阶段得到的所有阳性克隆，采用间接ELISA方法确认筛选。采用中和抗体测定的方法对确认筛选的阳性克隆进行中和活性验证。筛选具有中和活性且结合效价高的阳性克隆。
亚克隆、扩大培养和冻存：将阳性母克隆细胞转到24孔板扩大培养，收集细胞上清进行再次验证。最终用采用有限稀释法对阳性母克隆进行两次亚克隆，用间接ELISA方法和中和抗体测定方法进行筛选。二次亚克隆后确认的阳性克隆株进行扩大培养，免疫小鼠制备腹水。
实施例3单克隆抗体的纯化及鉴定
抗体纯化：将实施例2中免疫小鼠制备的腹水2～8℃、4000～8000r/min离心5～15分钟，取上清经采用 0.45μm滤膜过滤，采用Protein A/G亲和层析方法纯化抗体，用透析方法将纯化抗体保存在磷酸盐缓冲液(PBS) 中。采用Lowry法检测蛋白质含量为4.15mg/ml。对纯化后的单克隆抗体进行纯度检测和效价的测定。
SDS-PAGE纯度测定：分析显示单克隆抗体3A9(以下简称单抗3A9)的重链和轻链分别为50KD和25KD 左右，如图2所示。
结合抗体效价测定：分别将EV-A71、CV-A16、CV-A6、CV-A10病毒纯化液及Vero细胞宿主蛋白用碳酸盐缓冲液稀释至1.0μg/ml，包被96孔酶标板于4℃过夜。加入终浓度为0.05％吐温20的0.01M磷酸盐缓冲液 (PBST)洗3～5遍，再每孔加入150μl含有3～6％BSA的PBST于37℃封闭1～2小时，弃去封闭液并拍干。待检单抗和阴性对照(样品稀释液)按照10倍梯度法进行系列梯度稀释至108倍，依次加入10-2至10-8稀释度样品于上述96孔板，每孔加入100μl，37℃孵育1小时，每孔加入300μl PBST，洗涤2～5遍，加入1:5000 稀释的羊抗小鼠IgG-HRP，每孔100μl，于37℃孵育45分钟，PBST洗板2-5遍后，拍干，加入底物显色液于室温避光显色10～15分钟，1M H2SO4终止反应，于酶标仪波长450nm处读数。阴阳性临界值判定标准：应≥阴性对照均值×2.1。结果表明，单抗3A9只特异性与CV-A6抗原结合，其结合抗体效价为1.6*10 5，而不与其他型别和Vero细胞宿主蛋白结合，表明其具有良好的特异性。
中和抗体效价测定：待测样品(1:8稀释)，加至96孔细胞培养板中，进行2倍系列稀释，0.05ml/孔，再分别与100CCID50(半数细胞感染量)的CV-A6病毒悬液于37℃中和2h；加入1～2×105个/ml的RD细胞悬液，0.1ml/孔，置35±0.5℃,5％CO2培养箱中培养7天。将能抑制50％细胞病变的最高稀释度定为中和抗体效价，并以稀释倍数的倒数表示。每次试验均设病毒回滴试验，回滴结果在32～320 CCID50/孔时试验判为成立。以中和效价≥8判为中和抗体阳性，＜8则为阴性，阴性抗体的几何平均滴度(geometric mean titer，GMT) 均按4计算。单抗3A9的中和抗体效价为1:4096，表明该单克隆抗体具有很高的体外中和活性。
亚型鉴定：将纯化抗体用PBST稀释至200ng/ml，50μl/孔加入预包被酶标板(厂家：Proteintech)中，再将1x羊抗鼠IgM+IgG-HRP加入样品孔中，50μl/孔，轻轻混匀，室温孵育1小时。弃去孔内液体，PBST洗板 3次，拍干。加入显色液，100μl/孔。室温避光10～20min。每孔加入100μl终止液终止反应。通过酶标仪读取 OD450nm，OD值最深孔对应的即为相应的亚型。单抗3A9的亚型检定结果见表1。重链为IgG2b，轻链为 Kappa。
表1亚型鉴定结果
| 亚型分类 | IgG1 | IgG2a | IgG2b | IgG2c | IgG3 | IgM | Kappa | Lambda |
| 吸光值450nm | 0.72 | 0.696 | 3.208 | 0.062 | 0.117 | 0.088 | 1.755 | 0.214 |
体外中和活性：采用微量细胞病变法对单抗3A9的体外中和活性进行检测，方法如下：取96孔板，将 1mg/ml的单克隆抗体3A9以1:8～1:16384进行2倍系列稀释后，分别与100CCID50的CV-A6毒株Gdula(A 基因型，genbankNo.AY421764)和11株D基因型毒株(2014-2019年中国临床患者分离获得的毒株，其中， R01170631已于2021年7月13日保藏在中国微生物菌种保藏管理委员会普通微生物中心(简称CGMCC，地址：北京市朝阳区北辰西路1号院3号，中国科学院微生物研究所，邮编100101)，分类命名为柯萨奇病毒 A6型，保藏编号为CGMCCNo.19532，该毒株已在专利申请CN113564131A中公开；交叉中和检测委托中国食品药品检定研究院进行，其余所用毒株均来自中国食品药品检定研究院并用于测试)进行37℃中和2h；加入浓度为(1～2)×105个/mL的RD细胞悬液，100μL/孔，35℃，CO2培养箱培养7d；观察细胞病变效应(cytopathic effect，CPE)，以可抑制50％CPE最高稀释度的倒数判为中和抗体效价。试验同时设细胞对照和病毒回滴，仅有细胞对照无CPE，且病毒回滴在30～300CCID50/孔时，试验方可成立。包括原型株在内的 12个病毒株测定的中和效价在48～3072之间，MAX/MIN为64，表现出了较均一的广谱中和能力。结果见表 2，表明单抗3A9对CV-A6具有广谱的交叉中和能力，选择3A9作为检测单克隆抗体。
表2中和能力研究
与人血清(健康人血清、人自然混合感染血清及人自然感染血清1)的竞争抑制研究：将CV-A6的抗原稀释至0.01μg/ml包被至96孔酶标板上，人血清用样品稀释液从1:4起稀释，连续2倍倍比稀释，100μL/孔， 37℃孵育1h；用抗体稀释液将HRP标记的单抗3A9进行1:200稀释，100μL/孔，37℃孵育1h；以对照孔吸光值均值作为B0，待测样品组吸光值均值作为B1，抑制率％＝(B0-B1)/B0*100。以抑制率作为纵坐标，待测血清稀释度(以log2为底取对数)作为横坐标，四参数法拟合确定反应曲线(图3，R2依次为0.9842、0.9801、 0.9801)。
以上结果表明，健康人血清与单抗3A9无明显竞争抑制。而人自然混合感染血清和人自然感染血清与单抗3A9有明显的竞争抑制。证明单抗3A9所对应表位在人体感染引起的免疫应答中占有重要地位。
单克隆抗体3A9的基因序列分离及鉴定：从生长良好的杂交瘤细胞株用Trizol试剂提取总RNA，逆转录合成cDNA，然后PCR扩增出轻、重链可变区基因，进行氨基酸序列测定。测序结果显示，单克隆抗体3A9 的重链互补决定区CDR1、CDR2、CDR3的氨基酸序列如SEQ IDNO.1-3所示，轻链互补决定区CDR1、CDR2、 CDR3的氨基酸序列如SEQ ID NO.4-6所示；重链可变区的氨基酸序列如SEQ ID NO.7所示，轻链可变区的氨基酸序列如SEQ ID NO.8所示，重链的氨基酸序列如SEQ ID NO.15所示，编码基因序列如SEQ ID NO.13所示，轻链的氨基酸序列如SEQ ID NO.16所示，编码基因序列如SEQ ID NO.14所示。
实施例4单克隆抗体3A9可特异结合CV-A6病毒颗粒抗原
夹心ELISA实验：用包被液碳酸盐缓冲液(CBS pH9.6)稀释抗CV-A6的兔多克隆抗体(1:1000、1： 5000、1:10000、1:20000)，加入酶标板(康宁可拆卸)，每孔100μl，2～8℃包被过夜；PBST洗涤3次，拍干；用3％BSA PBST封闭，每孔150μl，37℃孵育2h；PBST洗涤3次，拍干；用样品稀释液(0.5BSA PBS溶液) 稀释抗原标准品至100ng/ml作为阳性对照，样品稀释液作为阴性对照，每孔100μl，37℃孵育2h；PBST洗涤3次，拍干；用抗体稀释液(10％FBSPBST)稀释单克隆抗体至适当浓度(1:1000、1：5000、1:10000、1:20000)，每孔100μl，于37℃作用1h；PBST洗涤3次，拍干；用抗体稀释液稀释羊抗小鼠-HRP至1:8000，每孔100μl，于37℃作用30～60min；PBST洗涤4次，拍干；每孔加入TMB底物显色液100μl，于室温下避光显色15min；加入1mol/L H2SO4每孔加入50μl。于450nm/630nm读值。结果显示包被多抗稀释倍数为1:5000，单克隆抗体 3A9作为检测抗体1:1000稀释时，P/N值最大，表明该单克隆抗体可以作为检测抗体。
实施例5辣根过氧化物酶标记单克隆抗体3A9
取HRP 5mg溶于0.2mol/L，pH 5.6醋酸盐缓冲液0.5ml中；加入新鲜配置的0.1mol/L NaIO4 0.25ml，此时溶液由原棕色变为墨绿色，置4℃放置30min，此时溶液由原棕色变为墨绿色；加入2.5％乙二醇0.5ml，室温下轻微搅拌1h，终止反应；加入待标记的抗体10mg，用1.0mol/L，pH 9.5CBS，调节pH值至9.0；混匀，置 4℃过夜；加入硼氢化钠溶液0.1ml，混匀，4℃放置3h；用0.15mol/L，pH7.4 PBS溶液，4℃透析过夜，换液 3次；3000r/min离心30min，去除沉淀物；收集上清液即为酶标记抗体。加入等体积60％甘油，小量分装，于-20℃以下保存。
酶标记抗体的效价测定：先将CV-A6抗原用0.05mol/L pH9.6包被缓冲液稀释为10μg/ml左右，于聚苯乙烯板孔内加100μl，4℃过夜，用PBST洗涤3次。采用3％BSA-PBST封闭板子，150μl/孔，37℃孵育2小时，用PBST洗涤3次。酶标记抗体用0.5％BSA-PBST液从1:100起始稀释，2倍系列稀释至12800，分别加入反应孔中，每个稀释度二孔，每孔100μl，37℃孵育1小时后洗涤。然后加显色液，每孔100μl，室温避光10分钟。以1mol/L H2SO4终止反应，每孔50μl。
主要以ELISA酶标仪读取各孔OD450nm/630nm值，并以OD(450nm-630nm)为纵坐标，酶标抗体稀释度为横坐标，绘制滴定曲线(图4)。由曲线上查得OD值为1.0左右，且曲线斜率最大时的酶标抗体稀释度，即为该标记物的抗体效价。结果见表3，显示该酶标抗体的效价为600。
表3酶标抗体反应吸光值
| 稀释度 | 吸光值1 | 吸光值2 | 均值 |
| 100 | 2.422 | 2.084 | 2.253 |
| 200 | 1.758 | 1.538 | 1.648 |
| 400 | 1.259 | 1.232 | 1.2455 |
| 800 | 0.841 | 0.691 | 0.766 |
| 1600 | 0.563 | 0.461 | 0.512 |
| 3200 | 0.309 | 0.269 | 0.289 |
| 6400 | 0.169 | 0.137 | 0.153 |
| 12800 | 0.097 | 0.081 | 0.089 |
实施例6抗原检测方法的建立
将兔多抗作为包被抗体，单克隆抗体3A9作为检测抗体建立双抗体夹心酶联免疫检测方法，用来检测CV-A6抗原。采用棋盘法进行试验，具体方法如下：将兔多抗用碳酸盐缓冲液(pH 9.6)稀释至1.6μg/ml、0.32μg/ml、 0.16μg/ml，包被96孔酶标板，100μl/孔，37℃包被2小时。用PBST洗板3次，用封闭液(0.01M PBS含3％BSA，0.5‰吐温20)封闭非特异性结合位点，150μl/孔，37℃封闭2小时。将CV-A6疫苗抗原用PBS(含0.5％BSA) 稀释至100ng/ml，按100μl/孔加入酶标板，同时以样品稀释液为阴性对照，同时设置空白对照，各2孔，37℃孵育2小时。PBST洗板4次，加入HRP标记的3A9单抗(1:1000、1:5000)，37℃孵育30～45min。PBST洗板5次，每孔加入100μl TMB显色液显色室温避光显色15min，再每孔加入50μl终止液(1M硫酸溶液)终止反应，于酶标仪450/630nm读值。检测结果见表4，P/N值最高时，包被抗体以0.32μg/ml包被，酶标抗体以 1:1000稀释，该组合最优。说明以单抗3A9为检测抗体的双抗体夹心方法，可以用于CV-A6抗原的检测。
表4棋盘法
注：P代表待测样品均值，N代表阴性对照均值
实施例7抗原检测方法的评价
对实施例6建立的抗原检测方法进行评价，具体如下：
线性范围：按照已确定的抗原检测方法，将抗原参考品从150ng/ml起，连续2倍稀释8个稀释度(300ng/ml、 150ng/ml、75ng/ml、37.5ng/ml、18.75ng/ml、9.375ng/ml、4.6875ng/ml、2.34375ng/ml)，每个稀释度均做复孔。独立测定6次。以标准品含量取对数作为横坐标，吸光值取对数作为纵坐标，绘制标准曲线，考察6次结果的 R2的一致性。以2.1*阴性均值作为阴阳性判定标准。
6次试验结果的R2＞0.98，见图5，表明该方法的线性和平行性良好，并且参考品在150～9.375ng/ml内，线性良好。
专属性评价：参照实施例6方法，选择CV-A6同为微小核糖核酸病毒科的EV-A71、CV-A16、CV-A10抗原及生产用细胞基质Vero细胞宿主蛋白分别稀释至1000ng/mL作为待测样品(以蛋白含量计算)，以及脊髓灰质炎病毒(Poliovirus，PV)抗原和CV-A6抗原样品中的可能存在的其他成分M199、DMEM、PEG6000、58％蔗糖、10mmol/L PBST(1M NaCL，0.1％吐温80)作为待测样品(简写为S)，以CV-A6抗原作为阳性对照，样品稀释液作为阴性对照，以阴性对照的2.1倍作为CUT-OFF值(简写为CO)，验证该抗原检测系统对肠道病毒检测的专属性。
结果见图6，该抗原评价系统对CV-A6病毒检测具有很好的专属性，对其它型别的肠道病毒均不反应。
抗原检测试剂盒对空实心颗粒结合能力的评价：按照已确定的抗原检测方法，分别将空心病毒颗粒和实心病毒颗粒按照一定的浓度系列稀释，按照达到相同OD值的条件下，加入空心、实心病毒蛋白的浓度比值的倒数即为该抗原检测试剂盒对空心病毒颗粒和实心病毒颗粒的反应能力的比值。
结果如表5所示，空、实心颗粒反应能力为1:2，该抗原检测试剂盒可以很好地对空心颗粒和实心颗粒进行检测。
表5对空心颗粒和实心颗粒反应能力比较
实施例8单克隆抗体3A9在小鼠体内治疗CV-A6感染实验
用致死剂量R01170631/CV-A6(38CCID50/鼠)感染1日龄BALB/c乳鼠，设置包括病毒对照组在内共8组， 0.5h后实验组分别注射16.0μg/只、4.0μg/只、1.0μg/只、0.25μg/只、0.0625μg/只、0.015625μg/只的单克隆抗体 3A9，空白对照组注射相同剂量的MEM，连续21d观察记录乳鼠的生存状态，做生存曲线。
结果如图7所示，MEM对照组全部存活，病毒对照组小鼠在攻毒后8天100％死亡。结果显示：0.25μg组别的乳鼠可全部存活，不表现消瘦、四肢麻痹的临床症状；0.0625μg和0.015625μg组别的乳鼠全部死亡。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
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<110> 北京民海生物科技有限公司
<120> 一种抗柯萨奇病毒A6型的单克隆抗体及其制备方法和应用
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<213> 人工序列(Artificial Sequence)
<400> 4
Ser Ala Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 6
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Gln Arg Ser Thr Tyr Pro Pro Tyr Ala
1 5 10
<210> 7
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Thr Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ala Arg Lys Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Thr Thr Thr Val Val Val Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Leu Thr Val Ser Ser
115
<210> 8
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Tyr Pro Pro Tyr
85 90 95
Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 9
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Met Asn Phe Gly Leu Ser Leu Ile Phe Leu Val Leu Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 10
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly
20
<210> 11
<211> 336
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly
1 5 10 15
Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Ser Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Ser Val His Thr Phe Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val
65 70 75 80
Thr Cys Ser Val Ala His Pro Ala Ser Ser Thr Thr Val Asp Lys Lys
85 90 95
Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys
100 105 110
Lys Glu Cys His Lys Cys Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser
115 120 125
Val Phe Ile Phe Pro Pro Asn Ile Lys Asp Val Leu Met Ile Ser Leu
130 135 140
Thr Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro
145 150 155 160
Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala
165 170 175
Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Ile Arg Val Val
180 185 190
Ser Thr Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe
195 200 205
Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ser Pro Ile Glu Arg Thr
210 215 220
Ile Ser Lys Ile Lys Gly Leu Val Arg Ala Pro Gln Val Tyr Ile Leu
225 230 235 240
Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys Asp Val Ser Leu Thr Cys
245 250 255
Leu Val Val Gly Phe Asn Pro Gly Asp Ile Ser Val Glu Trp Thr Ser
260 265 270
Asn Gly His Thr Glu Glu Asn Tyr Lys Asp Thr Ala Pro Val Leu Asp
275 280 285
Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Met Lys Thr Ser
290 295 300
Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys Asn Val Arg His Glu Gly
305 310 315 320
Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile Ser Arg Ser Pro Gly Lys
325 330 335
<210> 12
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
1 5 10 15
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
20 25 30
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
35 40 45
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
65 70 75 80
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
85 90 95
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
100 105
<210> 13
<211> 1422
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
atgaactttg ggctgagctt gattttcctt gtcctaattt taaaaggtgt ccagtgtgaa 60
gtgaagctgg tggagtctgg gggaggctta gtgaagcctg gagggtccct gaaactctcc 120
tgtgcagcct ctggattcgt tttcagtagc tatgacatgt cttgggttcg ccagactccg 180
gagacgaggc tggagtgggt cgcaaccatt agtagtggtg gtacttacac ctactatcca 240
gacagtgtga agggccgatt caccatctcc agagacactg ccaggaagac cctgtacctg 300
caaatgagca gtctgaggtc tgaggacacg gccttgtatt actgtgcaac tactacggta 360
gtagtcccct ttgactactg gggccaaggc acctctctca cagtctcctc agccaaaaca 420
acacccccat cagtctatcc actggcccct gggtgtggag atacaactgg ttcctccgtg 480
actctgggat gcctggtcaa gggctacttc cctgagtcag tgactgtgac ttggaactct 540
ggatccctgt ccagcagtgt gcacaccttc ccagctctcc tgcagtctgg actctacact 600
atgagcagct cagtgactgt cccctccagc acctggccaa gtcagaccgt cacctgcagc 660
gttgctcacc cagccagcag caccacggtg gacaaaaaac ttgagcccag cgggcccatt 720
tcaacaatca acccctgtcc tccatgcaag gagtgtcaca aatgcccagc tcctaacctc 780
gagggtggac catccgtctt catcttccct ccaaatatca aggatgtact catgatctcc 840
ctgacaccca aggtcacgtg tgtggtggtg gatgtgagcg aggatgaccc agacgtccag 900
atcagctggt ttgtgaacaa cgtggaagta cacacagctc agacacaaac ccatagagag 960
gattacaaca gtactatccg ggtggtcagc accctcccca tccagcacca ggactggatg 1020
agtggcaagg agttcaaatg caaggtcaac aacaaagacc tcccatcacc catcgagaga 1080
accatctcaa aaattaaagg gctagtcaga gctccacaag tatacatctt gccgccacca 1140
gcagagcagt tgtccaggaa agatgtcagt ctcacttgcc tggtcgtggg cttcaaccct 1200
ggagacatca gtgtggagtg gaccagcaat gggcatacag aggagaacta caaggacacc 1260
gcaccagtcc tggactctga cggttcttac ttcatatata gcaagctcaa tatgaaaaca 1320
agcaagtggg agaaaacaga ttccttctca tgcaacgtga gacacgaggg tctgaaaaat 1380
tactacctga agaagaccat ctcccggtct ccgggtaaat ga 1422
<210> 14
<211> 711
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
atgcattttc aagtgcagat tttcagcttc ctgctaatca gtgcctcagt cataatgtcc 60
agaggacaaa ttgttctcac ccagtctcca gcaatcatgt ctgcatctcc aggggagaag 120
gtcaccataa cctgcagtgc cagctcaagt gtaagttaca tgcactggtt ccagcagaag 180
ccaggcactt ctcccaaact ctggatttat agcacatcca acctggcttc tggggtccct 240
gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag ccgaatggag 300
gctgaagatg ctgccactta ttactgccag caaaggagta cttacccacc ctacgcgttc 360
ggagggggga ccaagctgga aataaaacgg gctgatgctg caccaactgt atccatcttc 420
ccaccatcca gtgagcagtt aacatctgga ggtgcctcag tcgtgtgctt cttgaacaac 480
ttctacccca aagacatcaa tgtcaagtgg aagattgatg gcagtgaacg acaaaatggc 540
gtcctgaaca gttggactga tcaggacagc aaagacagca cctacagcat gagcagcacc 600
ctcacgttga ccaaggacga gtatgaacga cataacagct atacctgtga ggccactcac 660
aagacatcaa cttcacccat tgtcaagagc ttcaacagga atgagtgtta g 711
<210> 15
<211> 454
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Thr Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ala Arg Lys Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Thr Thr Thr Val Val Val Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
115 120 125
Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr Val Thr Trp Asn
145 150 155 160
Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro Ala Leu Leu Gln
165 170 175
Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro Ser Ser Thr
180 185 190
Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala His Pro Ala Ser Ser
195 200 205
Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile
210 215 220
Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys Pro Ala Pro Asn
225 230 235 240
Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Ile Lys Asp
245 250 255
Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys Val Val Val Asp
260 265 270
Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn
275 280 285
Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn
290 295 300
Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile Gln His Gln Asp Trp
305 310 315 320
Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro
325 330 335
Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu Val Arg Ala
340 345 350
Pro Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys
355 360 365
Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn Pro Gly Asp Ile
370 375 380
Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu Glu Asn Tyr Lys Asp
385 390 395 400
Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys
405 410 415
Leu Asn Met Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys
420 425 430
Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile
435 440 445
Ser Arg Ser Pro Gly Lys
450
<210> 16
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Tyr Pro Pro Tyr
85 90 95
Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
Claims (10)
1.抗体或其抗原结合片段，其特征在于，所述抗体或其抗原结合片段的重链互补决定区CDR1、CDR2、CDR3具有如SEQ ID NO.1-3所示的氨基酸序列，
和/或，
所述抗体或其抗原结合片段的轻链互补决定区CDR1、CDR2、CDR3具有如SEQ ID NO.4-6所示的氨基酸序列。
2.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体或其抗原结合片段的重链可变区具有如SEQ ID NO.7所示的氨基酸序列或具有与如SEQ ID NO.7所示的氨基酸序列具有至少80％同源性的氨基酸序列；
和/或，所述抗体或其抗原结合片段的轻链可变区具有如SEQ ID NO.8所示的氨基酸序列或具有与如SEQ ID NO.8所示的氨基酸序列具有至少80％同源性的氨基酸序列。
3.根据权利要求1或2所述的抗体或其抗原结合片段，其特征在于，所述抗体为单克隆抗体、双特异抗体或多特异抗体；所述抗原结合片段为Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段或单链抗体。
4.标记抗体，其特征在于，其为权利要求1～3任一项所述的抗体或其抗原结合片段被酶、生物素、荧光染料、化学发光染料和/或放射性同位素标记得到。
5.核酸分子，其特征在于，其编码权利要求1-3任一项所述的抗体或其抗原结合片段。
6.生物材料，其特征在于，所述生物材料包含权利要求5所述的核酸分子，所述生物材料为表达盒、载体或宿主细胞。
7.权利要求1-3任一项所述的抗体或其抗原结合片段的制备方法，其特征在于，所述方法包括：培养能够表达所述抗体或其抗原结合片段的宿主细胞，经分离得到所述抗体或其抗原结合片段。
8.权利要求1-3任一项所述的抗体或其抗原结合片段或权利要求4所述的标记抗体或权利要求5所述的核酸分子或权利要求6所述的生物材料的以下任一种应用：
(1)在制备用于检测柯萨奇病毒A6型在样品中的存在或其水平的产品中的应用；
(2)在制备用于诊断柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病的产品中的应用；
(3)在制备用于中和样品中的柯萨奇病毒A6型毒力的产品中的应用；
(4)在制备用于预防或治疗柯萨奇病毒A6型感染或由柯萨奇病毒A6型感染导致疾病的药物中的应用；
(5)在检测柯萨奇病毒A6型疫苗的抗原性和免疫原性中的应用；
(6)在柯萨奇病毒A6型疫苗生产的质量控制中的应用；
(7)在检测柯萨奇病毒A6型抗原的特异性中的应用。
9.一种试剂盒，其特征在于，所述试剂盒包含权利要求1-3任一项所述的抗体或其抗原结合片段或权利要求4所述的标记抗体。
10.一种药物，其特征在于，所述药物包含权利要求1-3任一项所述的抗体或其抗原结合片段。
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| CN202210349352.2A CN116425869A (zh) | 2022-04-01 | 2022-04-01 | 一种抗柯萨奇病毒a6型的单克隆抗体及其制备方法和应用 |
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| CN202210349352.2A CN116425869A (zh) | 2022-04-01 | 2022-04-01 | 一种抗柯萨奇病毒a6型的单克隆抗体及其制备方法和应用 |
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| Country | Link |
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