CN110028579A - 一种抗尼帕病毒包膜糖蛋白的单克隆抗体及其应用 - Google Patents
一种抗尼帕病毒包膜糖蛋白的单克隆抗体及其应用 Download PDFInfo
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- CN110028579A CN110028579A CN201910369352.7A CN201910369352A CN110028579A CN 110028579 A CN110028579 A CN 110028579A CN 201910369352 A CN201910369352 A CN 201910369352A CN 110028579 A CN110028579 A CN 110028579A
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Abstract
本发明公开了一种抗尼帕病毒包膜糖蛋白的单克隆抗体14F8，所述抗体具有独特的CDR区，其与尼帕病毒包膜糖蛋白的结合效价为0.47ng/mL，在抗体浓度大于9.14ng/mL时，ELISA OD值大于2.0，显示了优异的抗原结合活性。所述抗体对于亨德拉病毒包膜糖蛋白的结合效价为129.66ng/mL，在抗体浓度为20000ng/mL时OD值为仅为0.29，显示14F8可以用于尼帕病毒包膜糖蛋白的检测，且能有效区分尼帕病毒和亨德拉病毒的包膜糖蛋白。本发明还公开了14F8单抗在制备尼帕病毒病治疗药物中的应用，所述抗体能有效抑制尼帕病毒包膜糖蛋白与其细胞受体EFNB2的结合，IC50值为50ng/mL，且中和活性随着抗体浓度增加而增强，当抗体浓度超过1μg/ml时，其抑制率趋于达到100％，显示了14F8单抗作为尼帕病毒病的候选治疗性抗体的前景。
Description
技术领域
本发明公开了一种抗体，属于多肽技术领域。
背景技术
尼帕病毒(Nipah virus，NiV)是一种近年来在南亚地区新出现的高致病性新发传染病病原体，它与雪松病毒(Cedar virus，CedPV)、亨德拉病毒(Hendra virus，HeV)同属于亨尼帕病毒属(genus Henipavirus)副粘病毒科(family Paramyxoviridae)。2015-2018年，世界卫生组织连续四年将其与埃博拉病毒、马尔堡病毒等病原体共同列为当今最有可能引发严重疫情且难以应对的烈性病原体。尼帕病毒病传染性强，死亡率高，自然宿主分布广泛，严重影响全球公共卫生，危胁人类生命健康。
1998年，马来西亚和新加坡的养猪户中发生一种新型传染病，表现为脑炎和呼吸***症状。并在病人的脑脊液中首次分离到一种新型病毒，其可以与亨德拉病毒抗体发生交叉反应，在对其基因组进行分析后确认这是一种新型亨尼帕病毒属病毒，由于病毒分离自马来西亚霹雳州(state of perak)的尼帕镇(town of Nipah)，故将这种病毒命名为尼帕病毒。马来西亚的尼帕病毒病爆发中，首先在猪中发生轻度呼吸道炎症和脑炎，人接触病猪的感染性分泌物后感染尼帕病毒，随后发病。马来西亚和新加坡疫情爆发中有276例确诊病例和105例死亡病例，病死率为38％。
在首次爆发之后，马来西亚和新加坡没有新增疫情。自2001年以来，印度和孟加拉国发生了多起疫情爆发，孟加拉国的疫情比马来西亚的疫情更分散，病例数更少，导致病死率升高(平均75％)，孟加拉和印度的爆发中，病人临床表现与马来西亚疫情相似，但导致更多的严重呼吸***疾病。2001年到2017年，共有超过300例确诊病例，最近的一次爆发在2015年，导致9人死亡。由于疫情发生地比较贫困，没有完善的公共卫生体系，实际病例数可能更多。现有研究表明，孟加拉国爆发疫情的主要原因是患者食用了被蝙蝠污染的椰枣树汁，此外还出现了人传人的病例，人与人之间传播的机制尚不清楚，但可能主要是通过与病人体液及分泌物接触感染病毒。2018年5月，印度南部喀拉拉邦爆发尼帕病毒疫情，导致至少17人死亡，尼帕病毒的防控再次引发广泛关注与重视。
尼帕病毒是一种有包膜的单股负链RNA病毒，包膜糖蛋白GP在其感染中发挥重要作用。尼帕病毒侵染细胞时，GP首先与细胞膜上的肝配蛋白受体结合，随后引发融合蛋白(Fusion protein，FP)的构象变化形成刺突，介导病毒包膜与细胞膜的融合，导致病毒核衣壳递送到细胞质中。因此阻断GP与细胞受体的结合是尼帕病毒疫苗及抗体药物的主要保护机制。GP与宿主细胞膜蛋白Ephrin-B2和Ephrin-B3结合，Ephrin-B2和Ephrin-B3分子属于与Eph结合的表面糖蛋白配体家族，并且在已知的敏感宿主中具有高度的序列保守性，氨基酸同源性95％至98％。Ephrin-B2表达在多个器官和组织中的动脉、小动脉和毛细血管中。在病毒附着于含有Ephrin受体的宿主细胞后，F蛋白发生构象变化，从而驱动病毒粒子和宿主细胞之间的膜融合过程，导致将病毒核衣壳递送到细胞质中。
当前有多种尼帕病毒候选疫苗在研发中，包括使用亨德拉病毒GP制备的重组亚单位疫苗、携带NIV-GP基因的重组病毒载体疫苗等。使用噬菌体表面展示文库技术筛选得到的M102.4单克隆抗体对尼帕病毒表现出了良好的中和活性，有望成为候选治疗性抗体。目前尚未有疫苗或抗体药物进入临床试验阶段。
尼帕病毒是一种新出现的、高度危险的烈性病原体，有传入我国并引发严重疫情的风险，有必要筛选制备抗尼帕病毒GP的单克隆抗体，为制备尼帕病毒检测试剂和候选治疗抗体提供基础。因此本发明的目的就提供一种具有优异的抗原结合活性的抗尼帕病毒GP的单克隆抗体，并且能够有效抑制尼帕病毒GP与其受体的结合，从而提供一种其在制备尼帕病毒病治疗药物中的应用。
发明内容
基于上述目的，本发明首先提供了一种抗尼帕病毒包膜糖蛋白的单克隆抗体，所述抗体轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.1的第27-37、55-57和94-102位氨基酸序列所示，所述抗体重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.5的第26-33、51-57和96-105位氨基酸序列所示。
在一个优选的实施方案中，所述抗体轻链可变区的氨基酸序列如SEQ ID NO.1所示，所述抗体重链可变区的氨基酸序列如SEQ ID NO.5所示。
更为优选地，所述抗体轻链恒定区的氨基酸序列如SEQ ID NO.3所示，所述抗体重链恒定的氨基酸序列如SEQ ID NO.7所示。
其次，本发明还提供了一种编码上述单克隆抗体轻链和重链的基因编码序列，所述抗体的轻链可变区的基因编码序列由SEQ ID NO.2所示，所述抗体的重链可变区的基因编码序列由SEQ ID NO.6所示。
在一个优选的实施方案中，所述抗体的轻链恒定区的基因编码序列由SEQ IDNO.4所示，所述抗体的重链恒定区的基因编码序列由SEQ ID NO.8所示。
再次，本发明还提供了一种能够表达上述编码单克隆抗体重链和/或轻链的核苷酸编码序列的表达载体。
在一个优选的实施方案中，所述表达载体为pcDNA3.4。
又次，本发明还提供了一种含有上述表达载体的宿主细胞。
在一个优选的实施方案中，所述细胞为Expi293细胞。
最后，本发明提供了上述的单克隆抗体在制备尼帕病毒病治疗药物中的应用。
本发明提供的抗体具有独特的CDR区，其与尼帕病毒包膜糖蛋白的结合效价为0.47ng/mL，在抗体浓度大于9.14ng/mL时，ELISA的OD值大于2.0，显示了优异的抗原结合活性。所述抗体对于亨德拉病毒包膜糖蛋白的结合效价为129.66ng/mL，在抗体浓度为20000ng/mL时OD值仅为0.29，显示14F8可以用于尼帕病毒包膜糖蛋白的检测，且能有效区分尼帕病毒和亨德拉病毒的包膜糖蛋白。所述抗体能有效抑制尼帕病毒包膜糖蛋白与其细胞受体EFNB2的结合，IC50值为50ng/mL，且中和活性随着抗体浓度增加而增强，当抗体浓度超过1μg/ml时，其抑制率趋于达到100％，显示了14F8单抗作为尼帕病毒病的候选治疗性抗体的前景。
附图说明
图1. 14F8嵌合抗体表达载体构建示意图；
图2.ELISA检测14F8与尼帕病毒包膜糖蛋白的结合；
图3.ELISA检测14F8与亨德拉病毒包膜糖蛋白的结合；
图4.液相芯片实验评价14F8单抗中和活性。
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的保护范围构成任何限制。
实施例1.抗体制备
1.免疫动物
1)将纯化的NIV-GP重组蛋白与等量弗氏完全佐剂混合，在每只小鼠腹股沟皮下多点注射，每只小鼠注射的蛋白计量为20μg，共免疫3只。
2)2周和4周后注射PSCA重组蛋白与弗氏不完全佐剂混合物，方法及用量同第1次。
3)第3次免疫2周后，取小鼠尾静脉血测免疫效价，达1∶1600以上准备融合，融合前3d加强免疫(20μg/只)。
2.细胞融合和克隆化
1)无菌摘取小鼠脾脏，制备脾细胞悬液，按常规方法与Sp2/0骨髓瘤细胞融合，用HAT选择培养基培养。
2)融合后第4天更换培养液为200μl新鲜含HAT的培养液，观察细胞克隆生长至培养孔面积1/3～1/2时，对细胞培养上清液用ELISA进行检测，筛选阳性克隆，初次克隆时换HT培养液，用有限稀释法进行亚克隆化，连续亚克隆3次以上，阳性率达100％。
3.腹水制备
1)按常规方法制备腹水。
2)用ELISA法检测腹水和杂交瘤细胞培养上清液的抗体效价。
4.杂交瘤细胞测序
1)Trizol法提取RNA；
2)将RNA反转录后获得cDNA；
3)扩增并获得重链和轻链可变区；
4)克隆至pMD18-T载体，测序；
5)使用IMGT/V-QUEST数据库进行测序结果比对，进一步分析。
5. 14F8单抗可变区序列说明
轻链可变区的氨基酸序列如SEQ ID NO.1所示，轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.1的第27-37、55-57和94-102位氨基酸序列所示，轻链可变区的基因编码序列由SEQ ID NO：2所示，轻链恒定区的氨基酸序列如SEQ ID NO.3所示，轻链恒定区的基因编码序列由SEQ ID NO：4所示。
重链可变区的氨基酸序列如SEQ ID NO.5所示，重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.5的第26-33、51-57和96-105位氨基酸序列所示，重链可变区的基因编码序列由SEQ ID NO.6所示，重链恒定的氨基酸序列如SEQ ID NO.7所示，重链恒定区的基因编码序列由SEQ ID NO.8所示。
6. 14F8单抗嵌合抗体重组表达
1)将14F8单抗轻、重链可变区氨基酸序列与人IgG1恒定区氨基酸序列按顺序组合，密码子优化后合成嵌合抗体基因。
2)在合成的嵌合抗体基因5’端加入tPA信号肽，构建进pcDNA3.4真核表达质粒(图1为14F8嵌合抗体表达载体构建示意图)。
3)取pcDNA3.4-14F8H和pcDNA3.4-14F8L各15μg，转染至30mL Expi293悬浮细胞中，125rpm，5％CO2培养72h。
4)3000×g，离心10min收取表达上清，经0.22μm针头滤器抽滤后，使用rProtein A层析柱进行亲和层析纯化。
5)用PBS对收集的抗体进行换液，然后用BCA蛋白定量试剂盒测定抗体浓度。
实施例2.ELISA实验检测14F8单抗与尼帕病毒G蛋白的结合活性
1)实验前一天96孔酶联板，包被1μg/mL的NIV-GP，每孔200μL包被。将包被的酶联板放入湿盒，4℃过夜。
2)实验当天用洗板机洗5次。
3)每孔加入100μL封闭液，室温下放置1小时。
4)洗板机洗3次。
5)首孔加入150μL浓度为20μg/mL的14F8单抗，其余孔加入100μL的稀释液。从首孔吸出50μL加入到次孔，以此类推，按1:3梯度稀释每孔终体积为100μL。室温静置1小时。
6)洗板机洗5次。
7)将HPR标记的羊抗鼠IgG二抗以1:10000用稀释液进行稀释，每孔100μL加入到ELISA板对应孔中，室温孵育1小时。
8)洗板机洗5次。
9)每孔加入100μL的TMB单组份显色液，显色6min，室温避光，之后每孔加入50μL终止液终止反应。
10)使用酶标仪检测450-630nm处的OD值，保存记录原始数据。
11)使用GraphPad Prism7.0软件对所得数据进行四参数非线性拟合，以阴性孔的2.1倍作为cutoff值计算抗体结合效价。最终计算14F8抗体的结合效价为0.47ng/mL，结果如图2所示，14F8单抗具有良好的结合尼帕病毒GP的活性。
实施例3.ELISA实验检测14F8单抗与亨德拉病毒包膜糖蛋白的结合活性
1)实验前一天96孔酶联板，包被1μg/mL的亨德拉病毒G蛋白HEV-GP，每孔200μL包被。将包被的酶联板放入湿盒，4℃过夜。
2)实验当天用洗板机洗5次。
3)每孔加入100μL封闭液，室温下放置1小时。
4)洗板机洗3次。
5)首孔加入150μL浓度为20μg/mL的14F8单抗，其余孔加入100μL的稀释液。从首孔吸出50μL加入到次孔，以此类推，按1:3梯度稀释每孔终体积为100μL。室温静置1小时。
6)洗板机洗5次。
7)将HPR标记的羊抗鼠IgG二抗以1:10000用稀释液进行稀释，每孔100μL加入到ELISA板对应孔中，室温孵育1小时。
8)洗板机洗5次。
9)每孔加入100μL的TMB单组份显色液，显色6min，室温避光，之后每孔加入50μL终止液终止反应。
10)使用酶标仪检测450-630nm处的OD值，保存记录原始数据。
11)使用GraphPad Prism7.0软件对所得数据进行四参数非线性拟合，以阴性孔的2.1倍作为cutoff值计算抗体结合效价。
结果如图3所示，所述抗体对于亨德拉病毒包膜糖蛋白的结合效价为129.66ng/mL，在抗体浓度为20000ng/mL时OD值为仅为0.29，显示14F8可以用于区分尼帕病毒和亨德拉病毒的包膜糖蛋白。
实施例4.液相芯片实验评价14F8单抗中和活性
Ephrinb2、ephrinb3是GP的细胞受体，抑制GP与细胞受体的结合是阻断病毒感染细胞的关键所在，根据国内外多篇文献报道，保护性血清或中和抗体可以抑制GP和受体的结合，抑制效果和保护性相关。尼帕、亨德拉病毒的实毒实验必须在4级生物安全实验室进行，而通过受体竞争抑制实验，可以在体外和普通生物安全条件下评价疫苗或抗体的保护效果。
1)向黑色96孔板中加入不同稀释倍数的14F8单抗。
2)向96孔板中加入包被尼帕病毒GP的磁性微球，每孔加入微球量约为1000个。
3)将Ephrinb2受体稀释为25ng/mL，每孔加入10μL。
4)将SAPE稀释为12μg/mL，每孔加入10μL；800rpm震荡孵育30分钟。
5)将96孔板置于磁力架上30秒，吸去孔内液体，加入100μL PBS缓冲液(含1％BSA)。
6)静置30秒后吸去孔内液体。重复以上步骤，共洗两次。
7)加入100μL PBS缓冲液(含1％BSA)重悬微球，使用luminex xmap仪器进行检测。
8)使用GraphPad Prism7.0软件对所得数据进行四参数非线性拟合，计算IC50值为50ng/mL。结果如图4所示，14F8单抗能有效抑制NIV-GP与其细胞受体EFNB2的结合，且中和活性随着抗体浓度增加而增强，当抗体浓度超过1μg/ml时(此处表示浓度的横坐标为log10数值)时，其抑制率趋于达到100％，显示了14F8单抗作为尼帕病毒病的候选治疗性抗体的前景。说明14F8单抗可以作为一种尼帕病毒病的候选治疗性抗体。
序 列 表
<110> 中国人民解放军军事科学院军事医学研究院
<120> 一种抗尼帕病毒包膜糖蛋白的单克隆抗体及其应用
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Claims (10)
1.一种抗尼帕病毒包膜糖蛋白的单克隆抗体，其特征在于，所述抗体轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.1的第27-37、55-57和94-102位氨基酸序列所示，所述抗体重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.5的第26-33、51-57和96-105位氨基酸序列所示。
2.根据权利要求1所述的单克隆抗体，其特征在于，所述抗体轻链可变区的氨基酸序列如SEQ ID NO.1所示，所述抗体重链可变区的氨基酸序列如SEQ ID NO.5所示。
3.根据权利要求2所述的单克隆抗体，其特征在于，所述抗体轻链恒定区的氨基酸序列如SEQ ID NO.3所示，所述抗体重链恒定的氨基酸序列如SEQ ID NO.7所示。
4.一种编码权利要求1-3任一所述单克隆抗体轻链和重链的基因编码序列，其特征在于，所述抗体的轻链可变区的基因编码序列由SEQ ID NO.2所示，所述抗体的重链可变区的基因编码序列由SEQ ID NO.6所示。
5.根据权利要求4所述的序列，其特征在于，所述抗体的轻链恒定区的基因编码序列由SEQ ID NO.4所示，所述抗体的重链恒定区的基因编码序列由SEQ ID NO.8所示。
6.一种能够表达权利要求5所述编码单克隆抗体重链和/或轻链的核苷酸编码序列的表达载体。
7.根据权利要求6所述的表达载体，其特征在于，所述表达载体为pcDNA3.4。
8.一种含有权利要求7所述表达载体的宿主细胞。
9.根据权利要求8所述的宿主细胞，其特征在于，所述细胞为Expi293细胞。
10.权利要求1-3任一所述的单克隆抗体在制备尼帕病毒病治疗药物中的应用。
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| CN113372454A (zh) * | 2021-06-16 | 2021-09-10 | 军事科学院军事医学研究院军事兽医研究所 | 尼帕病毒受体结合糖蛋白及其应用 |
| CN113391067A (zh) * | 2021-06-16 | 2021-09-14 | 军事科学院军事医学研究院军事兽医研究所 | 抗尼帕病毒g蛋白抗体的间接elisa检测方法 |
| CN113968907A (zh) * | 2020-07-22 | 2022-01-25 | 中国人民解放军军事科学院军事医学研究院 | 具有中和活性的抗尼帕病毒单克隆抗体及应用 |
| CN113968908A (zh) * | 2020-07-22 | 2022-01-25 | 中国人民解放军军事科学院军事医学研究院 | 具有广谱中和活性的抗亨尼帕病毒单克隆抗体及应用 |
| WO2023109844A1 (en) * | 2021-12-14 | 2023-06-22 | Doma Biopharmaceutical (Suzhou) Co., Ltd. | Antibodies and uses thereof |
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| CN117487005A (zh) * | 2023-12-13 | 2024-02-02 | 中国人民解放军军事科学院军事医学研究院 | 靶向亨尼帕病毒融合蛋白diii区的广谱中和抗体及应用 |
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| CN113968907A (zh) * | 2020-07-22 | 2022-01-25 | 中国人民解放军军事科学院军事医学研究院 | 具有中和活性的抗尼帕病毒单克隆抗体及应用 |
| CN113968908A (zh) * | 2020-07-22 | 2022-01-25 | 中国人民解放军军事科学院军事医学研究院 | 具有广谱中和活性的抗亨尼帕病毒单克隆抗体及应用 |
| WO2022017124A1 (zh) * | 2020-07-22 | 2022-01-27 | 中国人民解放军军事科学院军事医学研究院 | 具有广谱中和活性的抗亨尼帕病毒单克隆抗体及应用 |
| WO2022017123A1 (zh) * | 2020-07-22 | 2022-01-27 | 中国人民解放军军事科学院军事医学研究院 | 具有中和活性的抗尼帕病毒单克隆抗体及应用 |
| CN113968907B (zh) * | 2020-07-22 | 2023-05-26 | 中国人民解放军军事科学院军事医学研究院 | 具有中和活性的抗尼帕病毒单克隆抗体及应用 |
| CN113372454A (zh) * | 2021-06-16 | 2021-09-10 | 军事科学院军事医学研究院军事兽医研究所 | 尼帕病毒受体结合糖蛋白及其应用 |
| CN113391067A (zh) * | 2021-06-16 | 2021-09-14 | 军事科学院军事医学研究院军事兽医研究所 | 抗尼帕病毒g蛋白抗体的间接elisa检测方法 |
| WO2023109844A1 (en) * | 2021-12-14 | 2023-06-22 | Doma Biopharmaceutical (Suzhou) Co., Ltd. | Antibodies and uses thereof |
| CN117402238A (zh) * | 2023-12-12 | 2024-01-16 | 中国人民解放军军事科学院军事医学研究院 | 靶向亨尼帕病毒融合蛋白di和diii区的广谱中和抗体及应用 |
| CN117402238B (zh) * | 2023-12-12 | 2024-03-05 | 中国人民解放军军事科学院军事医学研究院 | 靶向亨尼帕病毒融合蛋白di和diii区的广谱中和抗体及应用 |
| CN117487005A (zh) * | 2023-12-13 | 2024-02-02 | 中国人民解放军军事科学院军事医学研究院 | 靶向亨尼帕病毒融合蛋白diii区的广谱中和抗体及应用 |
| CN117487005B (zh) * | 2023-12-13 | 2024-03-08 | 中国人民解放军军事科学院军事医学研究院 | 靶向亨尼帕病毒融合蛋白diii区的广谱中和抗体及应用 |
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