CN114773461A - 乙型脑炎病毒抗体1d11及其应用 - Google Patents
乙型脑炎病毒抗体1d11及其应用 Download PDFInfo
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- CN114773461A CN114773461A CN202210708971.6A CN202210708971A CN114773461A CN 114773461 A CN114773461 A CN 114773461A CN 202210708971 A CN202210708971 A CN 202210708971A CN 114773461 A CN114773461 A CN 114773461A
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Abstract
本发明涉及抗体技术领域，具体涉及乙型脑炎病毒抗体1D11及其应用。本发明提供一种乙型脑炎病毒抗体，其重链可变区的互补决定区CDR1、CDR2、CDR3分别具有如SEQ ID NO.1‑3所示的氨基酸序列，轻链可变区的互补决定区CDR1、CDR2、CDR3分别具有如SEQ ID NO.4‑6所示的氨基酸序列。该抗体能够与乙型脑炎病毒结合，具有高度特异性和高结合能力，可用于乙型脑炎病毒的免疫荧光染色和流式细胞染色等检测。同时，该抗体对乙型脑炎病毒具有高效的中和能力。该抗体为乙型脑炎病毒的防治、检测和诊断提供了有效的工具。
Description
技术领域
本发明涉及抗体技术领域，具体涉及一种乙型脑炎病毒抗体及其应用。
背景技术
日本脑炎病毒（Japanese encephalitis virus, JEV）又称乙型脑炎病毒，属于黄病毒科黄病毒属。JEV经库蚊叮咬传播，引起日本脑炎（Japanese encephalitis, JE），即流行性乙型脑炎（简称乙脑）。
目前，JEV是亚洲病毒性脑炎最重要的病原体，乙脑仍然是一个不容忽视的公共卫生问题。尽管目前已经有成熟的疫苗用于预防，但是仍有散发乙脑疫情不断出现，因此，仍需要开发具有高特异性、结合能力和中和能力的JEV抗体，以满足诊断、预防和治疗的需要。
发明内容
本发明的目的之一是提供一种JEV抗体。本发明的另一目的是提供该抗体的应用及其相关产品。
为实现上述目的，本发明以人乙脑减毒活疫苗为免疫原免疫小鼠，通过杂交瘤技术筛选到一株JEV特异性的杂交瘤（克隆号记为1D11），制备小鼠腹水并纯化抗体，得到能够特异性结合JEV的鼠源性单克隆抗体（mAb）1D11，该抗体对JEV具有较高的亲和力，同时具有中和JEV的能力。
具体地，本发明提供以下技术方案：
本发明提供JEV抗体或其抗原结合片段，其重链可变区的互补决定区CDR1具有如SEQ ID NO.1所示的氨基酸序列，CDR2具有如SEQ ID NO.2所示的氨基酸序列，CDR3具有如SEQ ID NO.3所示的氨基酸序列。轻链可变区的互补决定区CDR1具有如SEQ ID NO.4所示的氨基酸序列，CDR2具有如SEQ ID NO.5所示的氨基酸序列，CDR3具有如SEQ ID NO.6所示的氨基酸序列。
优选地，所述JEV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。
进一步优选地，所述JEV抗体为鼠源单克隆抗体，其重链恒定区具有如SEQ IDNO.11所示的氨基酸序列，其轻链恒定区具有如SEQ ID NO.12所示的氨基酸序列。
本发明中，所述抗原结合片段可选自Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体、人源化抗体、嵌合抗体、双特异抗体或多特异抗体。
本发明提供含有所述JEV抗体或其抗原结合片段的双特异抗体或多特异抗体。
基于上述抗体，本发明提供一种核酸分子，其编码所述JEV抗体或其抗原结合片段。
根据上述提供的JEV抗体或其抗原结合片段的氨基酸序列，本领域技术人员可以确定编码所述JEV抗体或其抗原结合片段的核酸分子的核苷酸序列，并根据宿主细胞的密码子偏好性选择不同的核酸分子的核苷酸序列。
作为本发明的一种实施方式，编码所述重链可变区的核酸分子具有如SEQ IDNO.9所示的核苷酸序列，编码所述轻链可变区的核酸分子具有如SEQ ID NO.10所示的核苷酸序列。
编码所述重链恒定区的核酸分子具有如SEQ ID NO.13所示的核苷酸序列，编码所述轻链恒定区的核酸分子具有如SEQ ID NO.14所示的核苷酸序列。
本发明还提供一种生物材料，其含有编码所述JEV抗体或其抗原结合片段的核酸分子，所述生物材料为表达盒、载体或宿主细胞。
以上所述的表达盒是指将所述核酸分子的上游或下游连接用于转录、翻译的调控元件得到的重组核酸分子。
以上所述的载体是指可将核酸分子插入其中的一种核酸运载工具，包括但不限于质粒、人工染色体、噬菌体、动物病毒等，可以为表达载体，也可以为克隆载体或非复制型载体。
以上所述的宿主细胞可以为微生物细胞（如：大肠杆菌、酵母细胞等）或动物细胞（如：昆虫细胞、CHO细胞、BHK细胞，HEK293细胞等用于表达、制备抗体的细胞），其中，动物细胞为不能够繁殖成为动物个体的细胞。
基于上述JEV抗体或其抗原结合片段的功能，本发明提供所述JEV抗体或其抗原结合片段、所述核酸分子或所述生物材料的如下任一种应用：
（1）在制备用于检测JEV的试剂或试剂盒中的应用；
（2）在制备用于预防或治疗JEV感染或JEV感染引起疾病的药物中的应用；
（3）在制备用于中和JEV毒力的产品中的应用。
以上（1）中所述的检测JEV包括检测JEV的存在或其水平。
以上（2）中所述的JEV感染引起疾病包括流行性乙型脑炎及其相关疾病。
基于上述JEV抗体或其抗原结合片段，本发明提供一种抗体偶联物，其为由所述JEV抗体或其抗原结合片段与载体或药物偶联得到，或者由所述JEV抗体或其抗原结合片段与经化学或生物标记得到。
以上所述的载体可为任意可与蛋白质偶联的载体或药物载体。
以上所述的化学标记包括同位素、胶体金、荧光素、生物素标记等。
以上所述的生物标记包括蛋白标记、酶标记等。
本发明提供一种检测试剂，其含有所述JEV抗体或其抗原结合片段或含有所述抗体偶联物。
以上所述的试剂盒还可包含免疫学检测、流式细胞检测等所需的其它试剂。
本发明提供一种药物组合物，其含有所述JEV抗体或其抗原结合片段或含有所述抗体偶联物。
以上所述的药物组合物还可包含药学上可接受的载体或赋形剂。所用载体或赋形剂的类型可根据药物组合物的剂型和给药方式进行选择。所述药物组合物还可包含具有其它功效的抗体或药物活性成分。
本发明的有益效果在于：本发明提供一种针对JEV的单克隆抗体1D11，该抗体能够与JEV特异性结合，具有高度特异性和高结合能力，可用于JEV的免疫荧光染色和流式细胞染色等检测，即使在较高稀释度时，仍然具有较好的检测效果。同时，该抗体对JEV具有高效的中和能力。该抗体为JEV的检测和诊断提供了有效的工具。
附图说明
图1为本发明实施例2中抗体1D11用于间接免疫荧光检测，设灭活病毒感染对照及4G2阳性对照，1D11（1:10000）和1D11（1:20000）分别为抗体1D11经1: 10000和1:20000稀释后染色结果。
图2为本发明实施例2中通过间接免疫荧光检测抗体1D11与其他黄病毒抗原的反应性，其中，4G2为阳性对照。
图3为本发明实施例2中抗体1D11用于流式细胞检测，设灭活病毒感染对照及4G2阳性对照，1D11染色分别为1:20000和1:40000稀释。
图4为本发明实施例2中抗体1D11的中和曲线（其半数中和浓度为0.00047μg/ml）。
图5为本发明实施例2中抗体1D11 Fab的中和曲线（其半数中和浓度为0.0082μg/ml）。
图6为本发明实施例2中抗体1D11对小鼠JEV感染的预防效果，其中A为体重监测，B为生存曲线。
图7为本发明实施例2中抗体1D11对小鼠JEV攻毒后的治疗效果，其中A为体重监测，B为生存曲线。
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1 杂交瘤细胞和单克隆抗体的筛选和制备
以人乙脑减毒活疫苗（SA 14-14-2）为免疫原，通过双后肢足垫免疫BALB/c小鼠，剂量为成人剂量的1/10；间隔三周，共计免疫三次。末次免疫1周后，取小鼠脾脏，分离脾细胞与SP2/0细胞进行融合，制备杂交瘤细胞。
克隆化后，经ELISA初筛，筛选到一株对JEV具有高结合能力的单克隆抗体，其杂交瘤克隆号记为1D11，其抗体亚型为IgG2a。
将1D11杂交瘤注射入经降植烷致敏的小鼠腹腔内，约10天后收获小鼠腹水，采用Protein G进行纯化，获得纯化单克隆抗体，浓度为2mg/ml。
培养1D11杂交瘤细胞，提取细胞总RNA，RT-PCR扩增抗体重链（1.4kb）及轻链基因（0.7kb），并将正确DNA条带经内切酶消化后与载体pcomb3连接，进而转化x-blue感受态细胞，最后选择阳性克隆进行测序，得到抗体重链及轻链全长序列。
经测序，单克隆抗体1D11的重链可变区的互补决定区CDR1、CDR2、CDR3的氨基酸序列分别如SEQ ID NO.1-3所示，轻链可变区的互补决定区CDR1、CDR2、CDR3的氨基酸序列分别如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。重链恒定区的氨基酸序列如SEQ ID NO.11所示，轻链恒定区的氨基酸序列如SEQ ID NO.12所示。
实施例2 单克隆抗体1D11的性能验证
1、间接免疫荧光技术（indirect immunofluorescent assay, IFA）检测抗体1D11对JEV病毒抗原的反应性
1.1利用IFA检测抗体1D11对JEV病毒抗原的反应性，具体方法如下：
采用5% MEM 培养Vero细胞，传代至24孔板；次日细胞融合度约为50%，感染JEVBeijing-1株 （MOI=1）（JEV Beijing-1株已在下述文献中公开：Sheng ZY, et al.Electroporation enhances protective immune response of a DNA vaccine againstJapanese encephalitis in mice and pigs. Vaccine. 2016 Nov 11;34(47):5751-5757.；Chen H, et al. Suppressive Effects on the Immune Response andProtective Immunity to a JEV DNA Vaccine by Coadministration of a GM-CSF-Expressing Plasmid in Mice. PLoS One. 2012;7(4):e34602.），同时设置灭活病毒感染为阴性对照。感染24h 后，细胞以PBS漂洗2-3遍，加入4%多聚甲醛固定15-20min；PBS漂洗2-3遍；Triton X-100 通透5 min， PBS漂洗2-3遍；1% BSA室温封闭1-2h；加入不同稀释度的纯化单克隆抗体1D11 （原浓度为2mg/ml，稀释度为1:5000, 1:10000, 1:20000, 1:40000,1:80000），4℃孵育过夜，同时设置4G2抗体（广谱黄病毒抗体，其杂交瘤细胞信息参见https://www.atcc.org/products/hb-112）染色作为阳性对照；次日PBS漂洗2-3遍，加入驴抗488二抗，室温孵育30-60min，PBS漂洗2-3遍；加入DAPI染料孵育5-10min染核；PBS 漂洗2-3遍，倒置荧光显微镜下观察。
结果显示，上述各个稀释度的1D11抗体与JEV病毒抗原均有特异性结合反应，但染色荧光强度随抗体稀释度升高而逐渐减弱。其中，1:10000和1:20000稀释度的检测效果更为理想（图1）。以上结果表明，1D11抗体在10-4稀释度，仍可用于JEV的IFA检测。
1.2利用IFA检测抗体1D11对其他黄病毒抗原的反应性
采用5% MEM 培养Vero细胞，传代至24孔板；次日细胞融合度约为50%，感染登革病毒1~4型（DENV 1~4）及寨卡病毒（ZIKV），同时设置灭活病毒感染作为阴性对照。感染后约2d，将细胞按照上述步骤处理后加入1D11（1:5000），4℃过夜，同样依上述步骤进行后续染色，最后置于倒置荧光显微镜下观察。结果如图2所示，1D11仅特异性识别JEV，对DENV1~4和ZIKV均无交叉反应。
2、流式细胞术检测抗体1D11对JEV病毒抗原的反应性
利用流式细胞术检测（单染，间接法）检测抗体1D11对JEV病毒抗原的反应性，具体方法如下：
采用5% MEM 培养Vero细胞，传代至25cm2细胞瓶；次日融合度约为50%，感染JEVBeijing-1株 （MOI=1），同时设置灭活病毒感染作为阴性对照。感染24h后，细胞以PBS漂洗1-2遍，加入0.04% EDTA消化细胞，终止消化后，将细胞悬液于1000rpm离心5min，弃上清；2%PFA固定10min，离心弃上清，PBS漂洗2-3遍；加入皂素通透液作用5min，离心弃上清，PBS漂洗2-3遍；加入1% BSA 室温封闭1-2h，离心弃上清；加入不同稀释度的纯化1D11（原浓度为2mg/ml，稀释度为1:5000, 1:10000, 1:20000, 1:40000, 1:80000），同时设置4G2抗体（广谱黄病毒抗体）染色作为阳性对照，于4℃处理30min，PBS漂洗2-3遍，离心去上清；加入驴抗488二抗；4℃孵育30min，PBS漂洗2-3遍后，以PBS重悬细胞，上机检测。
结果显示，1D11抗体与JEV病毒抗原有特异性结合反应，其中，1:20000和1:40000稀释度的检测结果如图3所示。以上结果表明，1D11抗体在10-4稀释度，仍可用于JEV的流式细胞检测。
3、中和实验评价抗体1D11的中和能力
将Vero细胞传代24孔板；次日，以2% FBS MEM分别稀释抗体1D11（原浓度为2mg/ml，从1:10开始，5倍比稀释，共设10个稀释度）和JEV病毒原液（Beijing-1）；将稀释好的抗体与病毒混匀（1:1），混合物于37℃孵育1h；无血清MEM漂洗24孔板1次；将上述混合物加入Vero细胞，37℃继续孵育1h；同时设定不加抗体的病毒对照；洗板后加入1.4%甲基纤维素，于37℃、5% CO2条件下培养，5-6 d后染色，计数噬斑，绘制中和曲线并计算半数中和浓度（Neut50）。结果如图4所示，抗体1D11的半数中和浓度（Neut50）可达到0.00047μg/ml，该抗体可高效中和JEV。
进一步研究中，将抗体1D11经木瓜蛋白酶处理后，回收并纯化得到Fab片段，同样采取上述方法，绘制中和曲线并计算半数中和浓度（Neut50）。结果如图5所示，抗体1D11Fab片段的半数中和浓度（Neut50）为0.0082μg/ml，同样可高效中和JEV。
4、抗体1D11对JEV感染的预防及治疗效果
预防作用：取3周龄BALB/c小鼠，预防组腹腔（i.p）注射抗体1D11（n=10），剂量为200μg/只，对照组注射PBS，200μl/只（n=10）；次日，实验组和对照组小鼠均通过腹腔注射致死量JEV Beijing-1株（约2~3×107pfu/只）；攻毒后逐日监测小鼠体重及状态，共监测14天；绘制体重曲线及生存曲线。结果如图6所示，1D11预防组小鼠在观察期内体重平稳上升，且未见感染症状，全部存活；对照组在感染后第5天体重开始下降，最后全部死亡。
治疗作用：取3周龄BALB/c小鼠，通过腹腔注射致死量JEV Beijing-1株（约2~3×107pfu/只）；24h后，治疗组腹腔注射抗体1D11，剂量为200μg/只（n=5），对照组注射PBS，200μl/只（n=5）；攻毒后逐日监测小鼠体重及状态， 共监测14天；绘制体重曲线及生存曲线。结果如图7所示，1D11治疗组小鼠在观察期内体重平稳上升，且未见明显的感染症状，全部存活。对照组在感染后第4天开始体重下降，最后全部死亡。
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。
序列表
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<120> 乙型脑炎病毒抗体1D11及其应用
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Claims (10)
1.乙型脑炎病毒抗体或其抗原结合片段，其特征在于，其重链可变区的互补决定区CDR1具有如SEQ ID NO.1所示的氨基酸序列，CDR2具有如SEQ ID NO.2所示的氨基酸序列，CDR3具有如SEQ ID NO.3所示的氨基酸序列；
和/或，
其轻链可变区的互补决定区CDR1具有如SEQ ID NO.4所示的氨基酸序列，CDR2具有如SEQ ID NO.5所示的氨基酸序列，CDR3具有如SEQ ID NO.6所示的氨基酸序列。
2.根据权利要求1所述的乙型脑炎病毒抗体或其抗原结合片段，其特征在于，其重链可变区具有如SEQ ID NO.7所示的氨基酸序列；和/或，其轻链可变区具有如SEQ ID NO.8所示的氨基酸序列。
3.根据权利要求1或2所述的乙型脑炎病毒抗体或其抗原结合片段，其特征在于，所述抗原结合片段为Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体、人源化抗体、嵌合抗体、双特异抗体或多特异抗体。
4.核酸分子，其特征在于，其编码权利要求1~3任一项所述的乙型脑炎病毒抗体或其抗原结合片段。
5.根据权利要求4所述的核酸分子，其特征在于，编码所述重链可变区的核酸分子具有如SEQ ID NO.9所示的核苷酸序列，编码所述轻链可变区的核酸分子具有如SEQ ID NO.10所示的核苷酸序列。
6.生物材料，其特征在于，其含有权利要求4或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任一项所述的乙型脑炎病毒抗体或其抗原结合片段或权利要求4或5所述的核酸分子或权利要求6所述的生物材料的如下任一种应用：
（1）在制备用于检测乙型脑炎病毒的试剂或试剂盒中的应用；
（2）在制备用于预防或治疗乙型脑炎病毒感染或乙型脑炎病毒感染引起疾病的药物中的应用；
（3）在制备用于中和乙型脑炎病毒毒力的产品中的应用。
8.一种抗体偶联物，其特征在于，其为由权利要求1~3任一项所述的乙型脑炎病毒抗体或其抗原结合片段与载体或药物偶联得到，或者由权利要求1~3任一项所述的乙型脑炎病毒抗体或其抗原结合片段与经化学或生物标记得到。
9.一种检测试剂，其特征在于，其含有权利要求1~3任一项所述的乙型脑炎病毒抗体或其抗原结合片段或权利要求8所述的抗体偶联物。
10.一种药物组合物，其特征在于，其含有权利要求1~3任一项所述的乙型脑炎病毒抗体或其抗原结合片段或权利要求8所述的抗体偶联物。
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| CN101607983A (zh) * | 2009-07-29 | 2009-12-23 | 中国农业科学院哈尔滨兽医研究所 | 乙型脑炎病毒PrM/M蛋白B细胞抗原表位多肽及应用 |
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| CN101492495A (zh) * | 2009-02-24 | 2009-07-29 | 中国农业科学院哈尔滨兽医研究所 | 一组抗原表位多肽及其应用 |
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| WO2021097024A1 (en) * | 2019-11-12 | 2021-05-20 | Vanderbilt University | Human hendra virus and nipah virus antibodies and methods of use therefor |
| CN114621343A (zh) * | 2022-05-17 | 2022-06-14 | 首都医科大学 | 乙型脑炎病毒抗体2g1及其应用 |
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