CN113150125A - 一种带状疱疹单克隆抗体及其应用 - Google Patents
一种带状疱疹单克隆抗体及其应用 Download PDFInfo
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- CN113150125A CN113150125A CN202110085548.0A CN202110085548A CN113150125A CN 113150125 A CN113150125 A CN 113150125A CN 202110085548 A CN202110085548 A CN 202110085548A CN 113150125 A CN113150125 A CN 113150125A
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Abstract
一种带状疱疹单克隆抗体,包括重链可变区和轻链可变区,所述重链可变区中HCDR1、HCDR2、HCDR3的氨基酸序列依次如SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11所示,所述轻链可变区中LCDR1、LCDR2、LCDR3的氨基酸序列依次如SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14所示;或者,所述重链可变区中HCDR1、HCDR2、HCDR3的氨基酸序列依次如SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17所示,所述轻链可变区中LCDR1、LCDR2、LCDR3的氨基酸序列依次如SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20所示。经试验证明,该抗体能特异性的结合带状疱疹重组蛋白,能够中和带状疱疹重组蛋白,可用于制备相关药物和带状疱疹检测产品。
Description
技术领域
本发明涉及一种单克隆抗体,特别涉及一种带状疱疹单克隆抗体及其应用。
背景技术
带状疱疹是由水痘-带状疱疹病毒(VZV)引起的急性感染性皮肤病,发病率随年龄增大而呈显著上升。由于病毒具有亲神经性,感染后可长期潜伏于脊髓神经后根神经节的神经元内,当抵抗力低下或劳累、感染、感冒时,病毒可再次生长繁殖,因此其治疗困难,危害大。发病期间,患者会出现多种不适症状,神经疼痛最明显,使人寝食难安。一般机构无特效疗法,加上高额费用,更使人难以承受。如治疗不当或体质虚弱诸多因素所致,会转为后遗神经痛,少则年余,多则数年,患者将长期忍受痛苦折磨。
在目前医疗条件下,50岁以上带状疱诊患者约有百分之三十以上会留下后遗神经痛,年龄越大,患后遗症的机会越大,疼痛得也越严重。近年来,随着国内人口结构的老龄化趋势日益加重,带状疱疹的发病率有明显上升的趋势,且引起的后遗神经痛使用抗病毒药物治疗无明显疗效。带状疱疹的防治现已成为重要的公共卫生问题。
如果能够更早的发现水痘-带状疱疹病毒,进而可以进行及时的治疗,因此如何有效检测出水痘-带状疱疹病毒,就显得尤为重要。目前VZV诊断包括血清学诊断、PCR检测等。PCR检测特异性较高,但是在早期实用性有限,对仪器及实验条件要求很高,在县级以下医院无法普及。对于血清学检测来说,一是针对抗体的检测,但是感染前两周无法检测到抗体,二是针对抗原的检测,抗原检测可在感染早期即可检测出,具有快速、灵敏、便捷、低成本、不易污染等优点,可替代PCR检测用于急性感染的诊断。
发明内容
有鉴于此,本发明的目的是提供一种带状疱疹单克隆抗体及其应用。
本发明采取的技术方案是:
第一方面,本发明提供了一种带状疱疹单克隆抗体,包括重链可变区和轻链可变区,所述重链可变区中HCDR1、HCDR2、HCDR3的氨基酸序列依次如SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11所示,所述轻链可变区中LCDR1、LCDR2、LCDR3的氨基酸序列依次如SEQ IDNO:12、SEQ ID NO:13、SEQ ID NO:14所示;或者,所述重链可变区中HCDR1、HCDR2、HCDR3的氨基酸序列依次如SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17所示,所述轻链可变区中LCDR1、LCDR2、LCDR3的氨基酸序列依次如SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20所示。
优选地,所述重链可变区包括如SEQ ID NO:1所示的氨基酸序列,所述轻链可变区包括如SEQ ID NO:2所示的氨基酸序列;或者,所述重链可变区包括如SEQ ID NO:3所示的氨基酸序列,所述轻链可变区包括如SEQ ID NO:4所示的氨基酸序列。
优选地,所述抗体与带状疱疹抗原之间的解离常数KD小于10nM,优选小于1nM。
第二方面,本发明提供了分离的多核苷酸,其编码上述的带状疱疹单克隆抗体。
优选地,所述重链可变区编码序列包括如SEQ ID NO:5所示的核苷酸序列,所述轻链可变区编码序列包括如SEQ IDNO:6所示的核苷酸序列;或者,所述重链可变区编码序列包括如SEQ ID NO:7所示的核苷酸序列,所述轻链可变区编码序列包括如SEQ IDNO:8所示的核苷酸序列。
第三方面,本发明提供了一种含有上述分离的多核苷酸的表达载体。
第四方面,本发明提供一种含有上述表达载体的宿主细胞,所述宿主细胞优选Expi293细胞。
第五方面,本发明提供了一种药物组合物,所述药物组合物包含上述的带状疱疹单克隆抗体和药学上可接受的赋形剂、稀释剂或载体。
第六方面,本发明提供了如下任一所示应用:
(1)前文所述抗体在前文所述的药物组合物中的应用;
(2)前文分离的多核苷酸在制备前文所述的抗体或前文所述的药物组合物中的应用;
(3)前文所述的抗体或分离的核苷酸或表达载体或宿主细胞或药物组合物在制备用于预防和/或治疗由VZV感染所致疾病的产品中的应用;
(4)前文所述的抗体或分离的核苷酸或表达载体或宿主细胞或药物组合物在制备用于检测VZV的产品中的应用;所述产品优选双抗体夹心ELISA检测试剂盒,其内还含有带状疱疹抗原标准品和酶标二抗;
(5)前文所述的抗体或分离的核苷酸或表达载体或宿主细胞或药物组合物在制备用于抑制VZV感染的产品中的应用。
第七方面,本发明还提供了一种制备前文所述带状疱疹单克隆抗体的方法,包括以前文所述的表达载体转染细胞,并对所述细胞进行培养;或者包括如下步骤:
1)以自行设计的带状疱疹人工抗原免疫小鼠,在所述小鼠中产生针对带状疱疹的免疫反应;
2)取所述小鼠的脾脏细胞与骨髓瘤细胞融合,并对获得的杂交瘤细胞进行筛选,得到特异识别带状疱疹抗原的阳性克隆;
3)对所述阳性克隆进行亚克隆,以获得稳定的杂交瘤细胞株;
4)对所述杂交瘤细胞株进行基因测序,获得带状疱疹抗体的轻链和重链的可变区编码序列;
5)用带状疱疹抗体的轻链和重链的可变区编码序列进行重组抗体生产,获得功能性带状疱疹单克隆抗体。
有益效果:本发明制备了一种带状疱疹单克隆抗体,经试验证明,该抗体能特异性的结合带状疱疹重组蛋白,能够中和带状疱疹重组蛋白,可用于制备相关药物和带状疱疹检测产品。
附图说明
图1显示了经带状疱疹抗原免疫后的小鼠的血清ELISA效价检测结果;NO.1-NO.4分别代表鼠1-鼠4;
图2显示了重组抗体的SDS-PAGE的还原电泳检测条带;
图3显示了重组抗体的SEC-HPLC的检测结果;
图4显示了本发明的带状疱疹单克隆抗体与带状疱疹重组蛋白特异性结合的曲线图;
图5显示了针对带状疱疹的抗体的存在情况;
图6显示了针对带状疱疹的抗体的存在情况。
具体实施方式
除非另有说明,本发明所用的技术和科学术语具有与本发明所属领域的普通技术员通常所理解的含义。
本文所用的术语“抗体”指免疫球蛋白分子,其通常为由2个相同重链和2个相同轻链通过二硫键相互连接组成的四聚体。根据氨基酸序列的保守性差异,将重链和轻链分为位于氨基端的可变区(V)和位于羧基端的恒定区(C)。在重链和轻链的可变区内,分别有三个局部区域的氨基酸组成和排列顺序具有更高的变异程度,为抗体与抗原结合的关键位置,因而也称为互补决定区(CDR)。在本文中,三个重链互补决定区分别称为HCDR1、HCDR2和HCDR3,三个轻链互补决定区分别称为LCDR1、LCDR2和LCDR3。一条重链和一条轻链的可变区相互作用形成了抗原结合部位(Fv)。根据它们重链恒定区的氨基酸序列,可将抗体分为不同类别。有五种主要类型的完整抗体:IgA、IgD、IgE、IgG和IgM,并且这些中的一些可进一步分为亚类,例如,IgG1、IgG2、IgG3、IgG4、IgA和IgA2。不同类别的免疫球蛋白的亚单位结构和三维构象在本领域内是已知的。本发明旨在包括任何前述类或亚类的抗体。
本文使用的术语“抗体”还旨在涵盖其消化片段或功能性变体,例如,能够结合带状疱疹抗原或其部分的抗体片段,包括但不限于Fab(例如,抗体经木瓜蛋白酶消化而得到)、F(ab)2 (例如,通过胃蛋白酶消化得到)、Fv或scFv(例如通过分子生物学技术得到)。
本文使用的术语“单克隆抗体”指均一的、仅针对某一特定抗原表位的抗体。与典型地包括针对不同抗原决定簇(表位)的不同抗体的普通多克隆抗体制剂相比,每种单克隆抗体针对抗原上的单个抗原决定簇。修饰语“单克隆”表示抗体的均一特征,不解释为需要通过任何特定方法产生的抗体。本发明的单克隆抗体优选通过重组DNA方法产生,或通过本文其它地方描述的筛选方法获得。
本文使用的术语“分离的多核苷酸”指非自然界中天然存在状态的多核苷酸,包括通过生物学技术从自然界(包括生物体内)分离出的多核苷酸,也包括人工合成的多核苷酸。分离的多核苷酸可以是基因组DNA、cDNA、mRNA或合成的其它RNA,或者它们的组合。本文提供了多个用于编码带状疱疹单克隆抗体的重链可变区和轻链可变区的核苷酸序列,需要指出的是,本领域技术人员可以根据本文所提供的重链可变区和轻链可变区的氨基酸序列,基于密码子简并性,设计出与以上提供的核苷酸序列不完全相同的核苷酸序列,但都编码相同的氨基酸序列。这些经改动的核苷酸序列也包括在本发明的范围内。
当涉及多核苷酸时,本文所用的术语“载体”指用于将核苷酸编码信息转移到宿主细胞内的任一种分子(例如,核酸、质粒、或病毒等)。术语“表达载体”或“表达盒”指适于在宿主细胞内表达目的基因(待表达核苷酸序列)的载体,通常包括目的基因、启动子、终止子、标记基因等部分。
本文所用的术语“宿主细胞”指已经或者能够用核酸序列转化并从而表达所选的目的基因的细胞。该术语包括亲本细胞的后代,无论该后代与原来的亲本细胞在形态或基因组成上是否相同,只要后代存在所选目的基因即可。常用的宿主细胞包括细菌、酵母、哺乳动物细胞等。
本文所用的术语“转染”指外来或外源DNA被细胞摄入,该技术可用于将一种或多种外源DNA部分导入适宜的宿主细胞。可通过理化方法(例如通过氯化钙处理)诱导细胞,使其处于最适摄取和容纳外来DNA的生理状态,即“感受态”。
下面将结合具体实施例对本发明的一些方面进行详细描述。除非另有说明,下文描述的实施例的方法和材料均为可以通过市场购买获得的常规产品。
实施例1:带状疱疹杂交瘤细胞株的获得
1)动物免疫
选择6-8周龄的BALB/c雌鼠用含100μg带状疱疹抗原蛋白的250μl弗氏完全佐剂的1:1乳液皮下免疫;随后,每二周一次皮下注射含50μg 带状疱疹抗原蛋白的弗氏不完全佐剂的1:1乳液,最多达3次,从而对小鼠进行加强免疫。骨髓瘤融合前3天,选择表现出最高抗体滴度(参见图1,采用血清ELISA法测定抗体效价)的一只小鼠进行50μg 带状疱疹抗原(不含佐剂)腹腔加强免疫。
2)杂交瘤融合和筛选
提取脾脏并进行均质化以产生单细胞悬液,同时准备骨髓瘤细胞(SP2/0)单细胞悬液。使用PEG1500融合,将SP2/0小鼠骨髓瘤细胞与小鼠的脾脏细胞进行融合。将融合的细胞重悬于100ml含杂交瘤细胞选择剂胸腺核苷嘧啶、次黄嘌呤和氨基喋呤的IMDM/ 15%FBS培养基中,并移至96孔板中。将板在37℃下在5%CO2中孵育。每隔2天换液,孵育10天之后,开始使用下文所述的ELISA结合来测试针对带状疱疹的抗体的存在情况。如图5所示,OD值大于0.2的为阳性孔,表示该孔细胞为所需的杂交瘤细胞。
ELISA结合检测方法:用间接ELISA法来评估上清液中抗体对于带状疱疹抗原的结合能力。将抗原用包被液稀释至适合的包被浓度,每孔100ul,4℃下包被过夜。用PBST(0.05%吐温)洗涤酶标板,并将其用200μl/孔的含1%BSA的PBST在室温下封闭2小时。随后弃去封闭液,向每个酶标板中加入100μl杂交瘤细胞培养上清液,然后在室温下孵育1小时。将酶标板用PBST洗涤三次,并用100μl /孔的结合辣根过氧化物酶的山羊抗小鼠IgG,37℃孵育1小时。将板用PBST洗涤五次,然后加入TMB显色液并在37℃下孵育10分钟。通过加入50μl的1MHCl溶液终止液终止反应。使用酶标仪测定450nm处各孔的吸光值。
3)杂交瘤亚克隆
使用有限稀释法进行亚克隆。使用血球细胞计数器并在含H(次黄嘌呤)T(胸腺嘧啶核苷)的培养基中对细胞进行系列稀释来确定细胞数量,直至细胞密度达到5-15个细胞/ml。对于每个杂交瘤,将200μl的细胞溶液用移液管移至96孔中,密度为1个细胞/孔。将培养物在37℃下在5%CO2中培养1周后,观察细胞生长情况,挑出只有一个细胞团的细胞孔,即为单克隆细胞孔。然后换液200ul/孔含HT的培养基,1周后对上清液进行上述ELISA结合测试,来评估针对带状疱疹抗原的抗体的存在情况。如图6,OD值大于0.2的为阳性孔,表示该孔细胞可分泌针对带状疱疹的抗体,为所需要的单克隆细胞株。
实施例2:单克隆抗体的可变区测序及抗体重组生产
使用快速ELISA小鼠抗体亚型鉴定试剂盒对杂交瘤细胞培养上清中的抗体进行亚型鉴定后,使用总RNA提取试剂盒从杂交瘤细胞提取总RNA,并利用抗体亚型特异性引物和通用引物将其逆转录为cDNA。随后通过PCR试剂盒扩增鼠免疫球蛋白重链和轻链V-区域片段,将所得的PCR片段亚克隆至pMD19-T载体系统中,并使用载体特异性引物对插入片段进行测序。最终获得了克隆005:12-20E7、005:27-30C1的独特V-区域核苷酸/氨基酸序列。其中,重链可变区氨基酸序列如SEQ ID NO:1或SEQ ID NO:3所示,轻链可变区氨基酸序列如SEQ ID NO:2或SEQ ID NO:4所示;重链可变区核苷酸序列如SEQ ID NO:5或SEQ ID NO:7所示,轻链可变区核苷酸序列如SEQ ID NO:6或SEQ ID NO:8所示。
在重链可变区和轻链可变区的氨基酸序列中,CDR1区加有实心下划线,CDR2区加有虚线下划线,CDR3区加有波浪下划线。
重链可变区氨基酸序列:SEQ ID NO:1
QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDVKRYNPALKSRLTISKDTSSSQVFLKIASVDTADTATYYCARIRGTMILPYFDYWGQGTTLTVSS
轻链可变区氨基酸序列:SEQ ID NO:2
DIQMTQTTSSLSASLGDRVTISCRASQDISNDLNWYQQKPDGTVKALIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFGGGTKLEIK
重链可变区氨基酸序列:SEQ ID NO:3
EVHLQQSGPELVKPGASVKISCKTSGYTFTEYIMHWVKQSHGKSLEWIGGINPNNGDTSYNQKFKGKATLTVDKSSSTAYMELRSLTSEDSAVYYCARSGVVFDVYGAQGTLVTVSA
轻链可变区氨基酸序列:SEQ ID NO:4
DVAMTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSELDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPRTFGGGTKLEIK
表达质粒构建与抽提:将目标的VH,VL可变区序列分别重组到包含信号肽和鼠源IgG1和Kappa的PTT5表达载体中,得重链重组质粒和轻链重组质粒(上述质粒重组的实验原理及步骤的出处见《分子克隆实验指南(第三版)》,(美)J.萨姆布鲁克等著)并经测序验证。使用质粒抽提试剂盒抽提高纯度的重组质粒,质量为200μg以上,供转染使用。
细胞转染:将重组质粒转染至Expi293细胞中,放入摇床培养,培养完成后收集上清,离心5min,丢弃细胞,上清以供纯化。
抗体纯化:将离心好的细胞上清上柱,必要时收集流穿液。上柱完成后,使用5倍以上柱体积PBS清洗。用pH3.4的0.1M柠檬酸缓冲液进行洗脱,分管收集洗脱液,混合符合浓度要求的抗体,在1×PBS中透析过夜,避免内毒素污染。透析结束后,测定浓度,使用内毒素检测试剂盒(安度斯)检测抗体内毒素含量。
SDS-PAGE电泳检测:纯化的抗体电泳检测结果见图2。
SEC-HPLC检测:纯化的抗体SEC-HPLC检测检测结果见图3。
实施例3:单克隆抗体对带状疱疹重组蛋白的结合
将通过间接ELISA法来评估纯化抗体对于带状疱疹的结合能力。将抗原用包被液稀释至适合的包被浓度,每孔100ul,4℃下包被过夜。用PBST(0.05%吐温)洗涤酶标板,并将其用200μl/孔的含1%BSA的PBST在室温下封闭2小时。随后弃去封闭液,向首孔加入10μg/ml的纯化抗体100μl,并按照3倍梯度稀释,共计7个测试浓度梯度。然后37℃孵育1小时。将酶标板用PBST洗涤三次,并用100μl/孔的缀合辣根过氧化物酶的山羊抗小鼠IgG37℃孵育1小时。将酶标板用PBST洗涤五次,然后加入TMB显色液并在37℃孵育10分钟。通过加入50μl的1MHCl溶液终止液终止反应。使用酶标仪测定450nm处各孔的吸光值。克隆005:12-20E7、005:27-30C1对于重组蛋白带状疱疹的结合能力如图4。根据ELISA浓度梯度实验计算得到的EC50表明这些抗体对于抗原都表现出相当高的亲和力(ELISA EC50都小于25ng/ml)。说明这些抗体能特异性的结合带状疱疹重组蛋白。
尽管已经对上述各实施例进行了描述,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例做出另外的变更和修改,所以以上所述仅为本发明的实施例,并非因此限制本发明的专利保护范围,凡是利用本发明说明书及附图内容所作的等效结构或等效流程变换,或直接或间接运用在其他相关的技术领域,均同理包括在本发明的专利保护范围之内。
序列表
<110> 上海英抗生物科技有限公司
<120> 一种带状疱疹单克隆抗体及应用
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Claims (10)
1.一种带状疱疹单克隆抗体,包括重链可变区和轻链可变区,其特征在于,所述重链可变区中HCDR1、HCDR2、HCDR3的氨基酸序列依次如SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11所示,所述轻链可变区中LCDR1、LCDR2、LCDR3的氨基酸序列依次如SEQ ID NO:12、SEQ IDNO:13、SEQ ID NO:14所示;或者,所述重链可变区中HCDR1、HCDR2、HCDR3的氨基酸序列依次如SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17所示,所述轻链可变区中LCDR1、LCDR2、LCDR3的氨基酸序列依次如SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20所示。
2.根据权利要求1所述的带状疱疹单克隆抗体,其特征在于,所述重链可变区包括如SEQ ID NO:1所示的氨基酸序列,所述轻链可变区包括如SEQ ID NO:2所示的氨基酸序列;或者,所述重链可变区包括如SEQ ID NO:3所示的氨基酸序列,所述轻链可变区包括如SEQID NO:4所示的氨基酸序列。
3.根据权利要求1所述的带状疱疹单克隆抗体,其特征在于,所述抗体与带状疱疹抗原之间的解离常数KD小于10nM,优选小于1nM。
4.分离的多核苷酸,其编码权利要求1所述的带状疱疹单克隆抗体。
5.根据权利要求4所述的分离的多核苷酸,其特征在于,所述重链可变区编码序列包括如SEQ ID NO:5所示的核苷酸序列,所述轻链可变区编码序列包括如SEQ IDNO:6所示的核苷酸序列;或者,所述重链可变区编码序列包括如SEQ ID NO:7所示的核苷酸序列,所述轻链可变区编码序列包括如SEQ IDNO:8所示的核苷酸序列。
6.一种含有权利要求4或5所述分离的多核苷酸的表达载体。
7.一种含有权利要求6所述表达载体的宿主细胞,所述宿主细胞优选Expi293细胞。
8.药物组合物,其特征在于,所述药物组合物包含权利要求1-3中任一项所述的抗体和药学上可接受的赋形剂、稀释剂或载体。
9.应用,为如下任一所示:
(1)权利要求1-3任一项所述抗体在制备权利要求8所述的药物组合物中的应用;
(2)权利要求4或5所述的分离的多核苷酸在制备权利要求1-3中任一项所述的抗体或权利要求8所述的药物组合物中的应用;
(3)权利要求1-8任一项所述的抗体或分离的核苷酸或表达载体或宿主细胞或药物组合物在制备用于预防和/或治疗由VZV感染所致疾病的产品中的应用;
(4)权利要求1-8任一项所述的抗体或分离的核苷酸或表达载体或宿主细胞或药物组合物在制备用于检测VZV的产品中的应用;所述产品优选双抗体夹心ELISA检测试剂盒,其内还含有带状疱疹抗原标准品和酶标二抗;
(5)权利要求1-8任一项所述的抗体或分离的核苷酸或表达载体或宿主细胞或药物组合物在制备用于抑制VZV感染的产品中的应用。
10.一种制备权利要求1-3任一项所述带状疱疹单克隆抗体的方法,其特征在于,包括以权利要求7所述的表达载体转染细胞,并对所述细胞进行培养;或者包括如下步骤:
1)以自行设计的带状疱疹人工抗原免疫小鼠,在所述小鼠中产生针对带状疱疹的免疫反应;
2)取所述小鼠的脾脏细胞与骨髓瘤细胞融合,并对获得的杂交瘤细胞进行筛选,得到特异识别带状疱疹抗原的阳性克隆;
3)对所述阳性克隆进行亚克隆,以获得稳定的杂交瘤细胞株;
4)对所述杂交瘤细胞株进行基因测序,获得带状疱疹抗体的轻链和重链的可变区编码序列;
5)用带状疱疹抗体的轻链和重链的可变区编码序列进行重组抗体生产,获得功能性带状疱疹单克隆抗体。
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