CN108727490B - 一种单克隆抗体zk2b10及应用 - Google Patents
一种单克隆抗体zk2b10及应用 Download PDFInfo
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Abstract
本发明公开了一种单克隆抗体ZK2B10及应用。本发明提供了一种IgG抗体,命名为ZK2B10,由轻链和重链组成;所述重链中的重链可变区中的CDR1、CDR2和CDR3依次为序列表的序列3自N末端第45‑58位氨基酸残基、第76‑83位氨基酸残基和第122‑142位氨基酸残基;所述轻链中的轻链可变区中的CDR1、CDR2和CDR3依次为序列表的序列5自N末端第45‑52位氨基酸残基、第70‑72位氨基酸残基和第109‑120位氨基酸残基。本发明还保护所述IgG抗体在制备用于抑制寨卡病毒的药物中的应用。本发明对于寨卡病毒病的防控具有重大的应用价值,将产生深远的社会意义。
Description
技术领域
本发明属于生物技术领域,具体涉及一种单克隆抗体ZK2B10及应用。
背景技术
寨卡病毒、登革热病毒、西尼罗河病毒及黄热病毒同属黄病毒属病毒。寨卡病毒病是由寨卡病毒引起的一种蚊媒传播感染性疾病,其临床表现轻微或不出现症状。主要表现为轻微发热、红疹(多数为斑丘疹)、头痛、关节痛、肌肉痛、无力以及非化脓性结膜炎等。近年来寨卡病毒先后在法国波利尼西亚及巴西爆发流行,并继续在全世界范围内特别是拉丁美洲及加勒比海区域迅速传播,已成为国际公共卫生紧急事件。
寨卡病毒感染仅引起轻微的症状。但在波利尼西的流行中成人出现了严重的神经系统并发症-格林巴利综合征(Guillain-Barrésyndrome,GBS),其发生率达1/4000。更为引人关注的是,随着寨卡病毒感染在巴西的出现,严重出生缺陷小头畸型也明显增加。据估计母亲感染寨卡病毒其胎儿小头畸型发生率高于成人神经系统并发症的几率。我国也有输入病例报道。目前针对寨卡病这一新发感染性疾病尚无有效的疫苗,更缺乏早期诊断及有效的治疗方法。
进入21世纪相继出现导致人类严重感染的几种RNA病毒,如SARS、MERS冠状病毒,以及最近的埃博拉病毒和寨卡病毒。面对这些新发的传染性疾病凸现的主要问题是缺乏有效的医疗应对措施包括抗病毒治疗。抗病毒治疗依赖于广谱抗病毒药物的研发或从已有的药物中筛选出有效的治疗药物以快速应对这些新发的传染性疾病。
单克隆抗体可大量生产,其与抗原结合的高亲和性和高特异性,大大减少了临床应用时的不良反应。同时可以对抗体分子进行改造以增加其抗病毒效力。抗体以其特异性和使用的灵活性成为感染性疾病治疗中非常有前景的手段。
寨卡病毒与同属黄病毒属的登革病毒是经同一蚊媒传播的,常在同一地区流行。有研究表明人先后感染不同血清型的登革病毒,有加重疾病严重性的风险即预先感染的血清型登革病毒产生的抗体,可以结合再次感染的不同血清型登革病毒,但不能中和病毒,反而增加病毒的进入,加重病情。因此,寨卡病毒病的治疗或预防用抗体研制需要避免抗体与登革病毒的交叉反应。
发明内容
本发明的目的是提供一种单克隆抗体ZK2B10及应用。
本发明提供了一种IgG抗体,命名为ZK2B10,由轻链和重链组成;所述重链中的重链可变区中的CDR1、CDR2和CDR3依次为序列表的序列3自N末端第45-58位氨基酸残基、第76-83位氨基酸残基和第122-142位氨基酸残基;所述轻链中的轻链可变区中的CDR1、CDR2和CDR3依次为序列表的序列5自N末端第45-52位氨基酸残基、第70-72位氨基酸残基和第109-120位氨基酸残基。
所述重链可变区可由序列表的序列3自N末端第20至153位氨基酸残基组成。
所述轻链可变区可由序列表的序列5自N末端第20至130位氨基酸残基组成。
所述重链具体可为如下(a)或(b):(a)序列表的序列3自N末端第20-483位氨基酸残基组成的蛋白质;(b)序列表的序列3所示的蛋白质。
所述轻链具体可为如下(c)或(d):(c)序列表的序列5自N末端第20-236位氨基酸残基组成的蛋白质;(d)序列表的序列5所示的蛋白质。
本发明还保护编码所述IgG抗体的基因。
编码所述重链的基因具体可为如下(1)或(2)或(3):
(1)序列表的序列4自5’末端第889-2340位核苷酸所示的DNA分子;
(2)序列表的序列4自5’末端第946-2340位核苷酸所示的DNA分子;
(3)序列表的序列4所示的DNA分子。
编码所述轻链的基因具体可为如下(4)或(5)或(6):
(4)序列表的序列6自5’末端第889-1599位核苷酸所示的DNA分子;
(5)序列表的序列6自5’末端第946-1599位核苷酸所示的DNA分子;
(6)序列表的序列6所示的DNA分子。
本发明还保护所述IgG抗体在制备用于抑制寨卡病毒的药物中的应用。
本发明还保护一种用于抑制寨卡病毒的药物,其活性成分为所述IgG抗体。
本发明还保护所述IgG抗体在制备用于中和寨卡病毒的药物中的应用。
本发明还保护一种用于中和寨卡病毒的药物,其活性成分为所述IgG抗体。
本发明还保护所述IgG抗体在制备用于预防和/或治疗寨卡病毒病的药物中的应用。
本发明还保护一种用于预防和/或治疗寨卡病毒病的药物,其活性成分为所述IgG抗体。
以上任一所述寨卡病毒具体可为寨卡病毒GZ01株。
本发明利用寨卡病毒的E蛋白作为钓饵,从感染者的外周血单个核细胞中筛选抗体生成的记忆B细胞,得到可同E蛋白特异结合的单克隆抗体。通过寨卡病毒蚀斑减少实验模型,筛选得到了具有中和活性同时具有良好的特异性的的单克隆抗体。
本发明对于寨卡病毒病的防控具有重大的应用价值,将产生深远的社会意义。
附图说明
图1为ZK2B10抗体对寨卡病毒的中和活性结果。
图2为ZK2B10抗体的特异性结果。
图3为ZK2B10抗体对动物的保护活性结果。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到的。以下实施例中的定量试验,均设置三次重复实验,结果取平均值。
质粒pcDNA3.1(+):Invitrogen公司,产品目录号V790-20。293T细胞:盖德,CRL-11268。PMD18T载体:Takara,产品目录号D101A。Vero细胞:ATCC公司,产品目录号CCL-81。C6/36细胞:ATCC公司,产品目录号CRL-1660。
实施例中所用的寨卡病毒为寨卡病毒GZ01株(Zika virus isolate GZ01):参考文献:GenBankACCESSION NO.KU820898。
实施例中所用的登革1型病毒为Hawaii株。参考文献:Complete GenomeSequences of Dengue Virus Type 1to 4StrainsUsed for the Development of CBER/FDA RNA Reference Reagentsand WHO International Standard Candidates forNucleic Acid Testing;Genome Announcements;January/February 2016Volume 4Issue1e01583-15。
实施例中所用的登革2型病毒为New Guinea株。参考文献:Complete GenomeSequences of Dengue Virus Type 1to 4StrainsUsed for the Development of CBER/FDA RNA Reference Reagentsand WHO International Standard Candidates forNucleic Acid Testing;Genome Announcements;January/February 2016Volume 4Issue1e01583-15。
AG6小鼠(AG6mice):AG6小鼠为干扰素α、干扰素β和干扰素γ的受体缺陷型的小鼠,攻毒一定剂量的寨卡病毒后几天内死亡。参考文献:Flavivirus NS1protein ininfected host sera enhances viral acquisition by mosquitoes;JianyingLiu,etc;Nature microbiology.2016;1(9):16087。
实施例1、抗体的发现
一、蛋白的制备
1、构建重组质粒
(1)合成序列表的序列2所示的双链DNA分子。
序列表的序列2所示的双链DNA分子编码序列表的序列1所示的蛋白质,其中开放阅读框为序列2自5’末端第13-1296位核苷酸。
序列表的序列1中,自N末端第1至19位氨基酸残基组成信号肽,第20-421位氨基酸残基组成寨卡病毒的E蛋白,第422至427位氨基酸残基组成His6标签。将序列表的序列1所示的蛋白质命名为E-His6融合蛋白,预期分子量为50kDa。
(2)用限制性内切酶BamHI和NotI双酶切步骤1得到的双链DNA分子,回收酶切产物。
(3)用限制性内切酶BamHI和NotI双酶切质粒pcDNA3.1(+),回收约5400bp的载体骨架。
(4)将步骤(2)回收的酶切产物和步骤(3)回收的载体骨架连接,得到重组质粒pcDNA3.1-ZIKV-E。根据测序结果,对重组质粒pcDNA3.1-ZIKV-E进行结构描述如下:在质粒pcDNA3.1(+)的BamHI和NotI酶切位点之间插入了序列表的序列2自5’末端第7至1299位核苷酸所示的双链DNA分子。
2、制备蛋白
(1)将重组质粒pcDNA3.1-ZIKV-E转染293T细胞,然后在含2%胎牛血清的DMEM培养基培养72h,然后4000rpm离心30min,收集上清液。
(2)亲和层析
亲和层析的层析柱规格:长度3cm,内径1cm;
亲和层析的柱填料:镍柱beads(购自Qiagen公司,产品目录号为30230);
依次进行如下操作步骤:①将300mL步骤(1)得到的上清液上样于亲和层析柱,4℃孵育3小时;②用100mL含20mM咪唑的上样缓冲液洗涤柱子;③用30mL含500mM咪唑的洗脱缓冲液洗脱目的蛋白,收集过柱后溶液。
上样缓冲液即HEPEs buffer(pH7.2、1M)。
(3)取步骤(2)得到的过柱后溶液,用30kD浓缩管(购自Merck公司,产品目录号为UFC800396)进行浓缩,得到体积为1mL的浓缩液。
(4)凝胶过滤层析
凝胶过滤层析的层析柱规格:长度24cm,内径2cm;
凝胶过滤层析的柱填料:superdex200increase 10/300GL(购自GEHealthcare公司,产品目录号为28-9909-44);
操作步骤:上样0.5mL步骤(3)得到的浓缩液,用流速为0.5mL/min的PBS缓冲液(pH7.2、10mM)洗脱,收集保留体积为11mL的峰对应的过柱后溶液,即为E-His6融合蛋白溶液。
二、感染者记忆B细胞的识别、分选和培养,培养上清抗体的筛选
1、外周血单个核细胞分离:取寨卡感染者恢复期外周静脉EDTA抗凝血,利用密度梯度离心方法分离外周血单个核细胞,分装5×106/管,置于液氮中冻存。
2、荧光标记抗体染色:外周血单个核细胞放置于37℃中水浴溶化,使用PBS缓冲液洗涤3次,接着加入荧光标记的抗体进行染色(设9个分析管,1-7管加入相应的单个荧光标记的抗体,第9管加入7种混合的荧光标记的抗体,第8管为只有细胞的空白管),室温避光孵育15min,使用PBS缓冲液洗涤,然后加入400μl PBS缓冲液悬浮细胞上样流式仪(贝克曼库尔特MoFloAstrios EQ超高速流式细胞分选系统)。
3、记忆B细胞的分选:样品管上机分析,依据7-AAD及CD45圈出活的CD45阳性的白细胞。依据CD19圈出B细胞。在IgM和IgD双阴的B细胞群体里定义IgD-IgM-CD27+CD38low群体为记忆B细胞。将记忆B细胞分选至含细胞培养液的96孔细胞培养板中,25-50个细胞/每孔。
4、记忆B细胞培养及培养上清抗体的筛选:向含记忆B细胞的96孔细胞培养板中加入CpG、IL21、IL2、放射照射过的健康人PBMC及含有EBV的B95.8细胞培养上清培养7-10天。用步骤一中得到的E-His6融合蛋白作为包被蛋白,用ELISA方法筛选B细胞培养上清中针对寨卡病毒E蛋白抗体的存在。
三、抗体序列的获得
1、cDNA合成:对于筛选出上清中有针对寨卡病毒E蛋白抗体存在的B细胞,先提RNA再逆转录成cDNA。cDNA合成为试剂盒(SuperScript III First Strand SynthesisSystem,invitrogen,#18080051)。
2、巢式PCR扩增抗体的重链可变区基因和轻链可变区基因:PCR引物序列参考文献(J Immunol Methods.2008Jan 1;329(1-2):112-24.),反应使用Phusion超保真DNA聚合酶(Phusion High-Fidelity PCR Master Mix with GC Buffer,NEB,#M0532s)。
3、将重链可变区上游与CMV片段、重链可变区下游与人IgG1的恒定区以及ployA片段,进行overlapping PCR,得到可以表达完整重链的DNA片段。将轻链可变区上游与CMV片段、轻链可变区下游与轻链κ/λ的恒定区以及ployA片段,进行overlapping PCR,得到可以表达完整轻链的DNA片段。
基于以上步骤,得到了多种IgG,将其中一种命名为ZK2B10。
ZK2B10的全长重链的氨基酸序列如序列表的序列3所示,ZK2B10的全长轻链的氨基酸序列如序列表的序列5所示。
序列表的序列3中,第1至19位氨基酸残基组成信号肽(引导蛋白分泌到细胞外),第20至153位氨基酸残基组成重链可变区(CDR1、CDR2和CDR3依次为序列3第45-58位氨基酸残基、第76-83位氨基酸残基和第122-142位氨基酸残基),第154至483位氨基酸残基组成重链恒定区。
序列表的序列5中,第1至19位氨基酸残基组成信号肽(引导蛋白分泌到细胞外),第20至130位氨基酸残基组成轻链可变区(CDR1、CDR2和CDR3依次为序列5第45-52位氨基酸残基、第70-72位氨基酸残基和第109-120位氨基酸残基),第131位至236位氨基酸残基组成轻链恒定区。
实施例2、ZK2B10抗体的制备
一、重组质粒的构建
将序列表的序列4所示的双链DNA分子插入PMD18T载体,得到重链表达载体。序列表的序列4中,第1至888位核苷酸组成CMV启动子,第889至2340位核苷酸编码序列表的序列3所示的全长重链,第2393至2538位核苷酸为ployA片段。
将序列表的序列6所示的双链DNA分子插入PMD18T载体,得到轻链表达载体。序列表的序列6中,第1至888位核苷酸组成CMV启动子,第889至1599位核苷酸编码序列表的序列5所示的全长轻链,第1600至1745位核苷酸为ployA片段。
二、抗体的制备
1、将重链表达载体和轻链表达载体共转染293T细胞,然后在含2%胎牛血清的DMEM培养基培养72h,然后4℃、4000rpm离心30min,收集上清液。
2、亲和层析
亲和层析的层析柱规格:长度3cm,内径1cm;
亲和层析的柱填料:protein A beads(Thermo,产品目录号10006D);
依次进行如下操作步骤:①将300mL步骤1得到的上清液上样于亲和层析柱,4℃孵育16小时;②用60mL结合缓冲液洗涤柱子;③用30mL洗脱缓冲液洗脱目的蛋白,收集过柱后溶液。
结合缓冲液:取甘氨酸112.6g、氯化钠175.2g,溶于水并用水定容至1L,用氢氧化钠调pH至8.0。
洗脱缓冲液:取甘氨酸7.5g,溶于水并用水定容至500mL,用盐酸调pH至3.0。
3、取步骤2得到的过柱后溶液,用超滤浓缩管浓缩并将体系置换为PBS缓冲液(pH7.2、10mM),得到1mL抗体浓度为2mg/mL的抗体溶液(抗体浓度均以蛋白浓度计),将其命名为ZK2B10溶液。
实施例3、ZK2B10抗体对病毒的中和活性
一、病毒的制备
将寨卡病毒接种C6/36细胞(采用含10%FBS的DMEM培养基),置于28℃、5%CO2条件下静置培养4天,然后3000rpm离心5min,收集上清液,即为寨卡病毒液。
二、单克隆抗体的中和活性检测
1、取实施例2制备的ZK2B10溶液,用PBS缓冲液(pH7.2、10mM)进行稀释,得到抗体稀释液。
2、将Vero细胞接种至六孔板(每孔4×105个细胞),静置培养过夜,细胞密度长至90%且均匀铺满孔板。
3、将步骤一制备的寨卡病毒液与步骤1制备的抗体稀释液混合,得到各个混合液(每毫升混合液中,病毒含量为100pfu,抗体浓度为8μg/mL、2.67μg/mL、0.89μg/mL、0.30μg/mL、0.099μg/mL、0.033μg/mL、0.011μg/mL或0.0037μg/mL);将步骤一制备的寨卡病毒液与pH7.2、10mM的PBS缓冲液混合,得到病毒浓度为100pfu/mL的混合液(空白对照);37℃静置孵育1小时。
4、取完成步骤2的六孔板,吸弃上清,每孔加入1mL完成步骤3的混合液(每种混合液设置2个复孔),37℃静置孵育1小时。
5、取完成步骤4的六孔板,吸弃上清,用PBS缓冲液(pH7.2、10mM)洗涤两遍,然后加入含有1%低熔点琼脂糖和2%FBS的DMEM培养基,待培养基凝固后置于37℃静置培养6天。
6、取完成步骤5的六孔板,加入多聚甲醛终止反应,然后加入1%结晶紫染色,统计病毒蚀斑个数。
中和百分比=(空白对照组的病毒蚀斑个数-试验组的病毒蚀斑个数)/空白对照组的病毒蚀斑个数×100%。
结果见表1和图1。
表1
中和百分比为50%时的抗体浓度,即抗体的IC50值,ZK2B10的IC50值为0.04μg/mL。
实施例4、ZK2B10抗体的特异性
一、病毒的制备
将登革1型病毒接种C6/36细胞,置于28℃、5%CO2条件下静置培养6天,然后3000rpm离心5min,收集上清液,即为登革1型病毒液。
将登革2型病毒接种C6/36细胞,置于28℃、5%CO2条件下静置培养6天,然后3000rpm离心5min,收集上清液,即为登革2型病毒液。
二、中和活性检测
分别用登革1型病毒液和登革2型病毒液作为待测病毒液。
1、取实施例2制备的ZK2B10溶液,用PBS缓冲液(pH7.2、10mM)进行稀释,得到抗体稀释液。
2、将Vero细胞接种至六孔板(每孔4×105个细胞),静置培养过夜,细胞密度长至90%且均匀铺满孔板。
3、将待测病毒液与步骤1制备的抗体稀释液混合,得到各个混合液(每毫升混合液中,病毒含量为100pfu,抗体浓度为0.064μg/mL、0.32μg/mL、1.6μg/mL、8μg/mL或40μg/mL);将待测病毒液与pH7.2、10mM的PBS缓冲液混合,得到病毒浓度为100pfu/mL的混合液(空白对照);37℃静置孵育1小时。
4、取完成步骤2的六孔板,吸弃上清,每孔加入1mL完成步骤3的混合液(每种混合液设置2个复孔),37℃静置孵育1小时。
5、取完成步骤4的六孔板,吸弃上清,用PBS缓冲液(pH7.2、10mM)洗涤两遍,然后加入含有1%低熔点琼脂糖和2%FBS的DMEM培养基,待培养基凝固后置于37℃静置培养6天。
6、取完成步骤5的六孔板,加入多聚甲醛终止反应,然后加入1%结晶紫染色,统计病毒蚀斑个数。
抗体对登革1型病毒的中和百分比的结果见图2的A。抗体对登革2型病毒的中和百分比的结果见图2的B。结果表明,ZK2B10对登革1型病毒和登革2型病毒的中和活性均为30%以下,说明ZK2B10不对黄病毒属的登革病毒1型与登革病毒2型具有交叉中和活性。
实施例5、ZK2B10抗体对动物的保护活性
AG6小鼠分成两组,每组4只,分别处理如下:
第一组:试验第1天,腹腔注射实施例3的步骤一制备的寨卡病毒液(每只小鼠的攻毒剂量为1.5×104pfu);试验第2天,腹腔注射实施例2制备的ZK2B10溶液(每只小鼠的给药剂量为300μg抗体);每天记录小鼠的体重与存活情况。
第二组:用等体积PBS缓冲液(pH7.2、10mM)代替ZK2B10溶液,其他同第一组。
从试验起始时刻开始计时,第1个24小时为第1天,第2个24小时为第2天,依次类推。第2天的存活率结果和相对体重结果即第48小时终止时刻的测量结果,依次类推。
相对体重=第n天的体重/试验起始时刻的体重×100%。
存活率结果见图3的A。相对体重结果见图3的B。试验第6天,第二组有1只小鼠死亡,试验第7天,第二组剩下的3只小鼠死亡。一直到试验第14天,第一组都没有小鼠死亡。结果表明,ZK2B10能100%保护AG6小鼠免受寨卡病毒致死,且小鼠体重基本稳定。
SEQUENCE LISTING
<110> 清华大学
广州市第八人民医院
<120> 一种单克隆抗体ZK2B10及应用
<130> CGGNQAY-176049
<160> 6
<170> PatentIn version 3.5
<210> 1
<211> 427
<212> PRT
<213> 人工序列
<400> 1
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Arg Cys Ile Gly Val Ser Asn Arg Asp Phe Val Glu Gly
20 25 30
Met Ser Gly Gly Thr Trp Val Asp Val Val Leu Glu His Gly Gly Cys
35 40 45
Val Thr Val Met Ala Gln Asp Lys Pro Thr Val Asp Ile Glu Leu Val
50 55 60
Thr Thr Thr Val Ser Asn Met Ala Glu Val Arg Ser Tyr Cys Tyr Glu
65 70 75 80
Ala Ser Ile Ser Asp Met Ala Ser Asp Ser Arg Cys Pro Thr Gln Gly
85 90 95
Glu Ala Tyr Leu Asp Lys Gln Ser Asp Thr Gln Tyr Val Cys Lys Arg
100 105 110
Thr Leu Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys
115 120 125
Gly Ser Leu Val Thr Cys Ala Lys Phe Ala Cys Ser Lys Lys Met Thr
130 135 140
Gly Lys Ser Ile Gln Pro Glu Asn Leu Glu Tyr Arg Ile Met Leu Ser
145 150 155 160
Val His Gly Ser Gln His Ser Gly Met Ile Val Asn Asp Thr Gly His
165 170 175
Glu Thr Asp Glu Asn Arg Ala Lys Val Glu Ile Thr Pro Asn Ser Pro
180 185 190
Arg Ala Glu Ala Thr Leu Gly Gly Phe Gly Ser Leu Gly Leu Asp Cys
195 200 205
Glu Pro Arg Thr Gly Leu Asp Phe Ser Asp Leu Tyr Tyr Leu Thr Met
210 215 220
Asn Asn Lys His Trp Leu Val His Lys Glu Trp Phe His Asp Ile Pro
225 230 235 240
Leu Pro Trp His Ala Gly Ala Asp Thr Gly Thr Pro His Trp Asn Asn
245 250 255
Lys Glu Ala Leu Val Glu Phe Lys Asp Ala His Ala Lys Arg Gln Thr
260 265 270
Val Val Val Leu Gly Ser Gln Glu Gly Ala Val His Thr Ala Leu Ala
275 280 285
Gly Ala Leu Glu Ala Glu Met Asp Gly Ala Lys Gly Arg Leu Ser Ser
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Gly His Leu Lys Cys Arg Leu Lys Met Asp Lys Leu Arg Leu Lys Gly
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Val Ser Tyr Ser Leu Cys Thr Ala Ala Phe Thr Phe Thr Lys Ile Pro
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Ala Glu Thr Leu His Gly Thr Val Thr Val Glu Val Gln Tyr Ala Gly
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Thr Asp Gly Pro Cys Lys Val Pro Ala Gln Met Ala Val Asp Met Gln
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Thr Leu Thr Pro Val Gly Arg Leu Ile Thr Ala Asn Pro Val Ile Thr
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Glu Ser Thr Glu Asn Ser Lys Met Met Leu Glu Leu Asp Pro Pro Phe
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Gly Asp Ser Tyr Ile Val Ile Gly Val Gly Glu Lys Lys Ile Thr His
405 410 415
His Trp His Arg Ser His His His His His His
420 425
<210> 2
<211> 1307
<212> DNA
<213> 人工序列
<400> 2
ggatccacca ccatgggatg gtcatgtatc atcctttttc tagtagcaac tgcaaccggt 60
gtacattcca ggtgcatagg agtcagcaat agggactttg tggaaggtat gtcaggtggg 120
acttgggttg atgttgtctt ggaacatgga ggttgtgtca ccgtaatggc acaggacaaa 180
ccgactgtcg acatagagct ggttacaaca acagtcagca acatggcgga ggtaagatcc 240
tactgctatg aggcatcaat atcagacatg gcttcggaca gccgctgccc aacacaaggt 300
gaagcctacc ttgacaagca atcagacact caatatgtct gcaaaagaac gttagtggac 360
agaggctggg gaaatggatg tggacttttt ggcaaaggga gcctggtgac atgcgctaag 420
tttgcatgct ccaagaaaat gaccgggaag agcatccagc cagagaatct ggagtaccgg 480
ataatgctgt cagttcatgg ctcccagcac agtgggatga tcgttaatga cacaggacat 540
gaaactgatg agaatagagc gaaagttgag ataacgccca attcaccaag agccgaagcc 600
accctggggg gttttggaag cctaggactt gattgtgaac cgaggacagg ccttgacttt 660
tcagatttgt attacttgac tatgaataac aagcactggt tggttcacaa ggagtggttc 720
cacgacattc cattaccttg gcacgctggg gcagacaccg gaactccaca ctggaacaac 780
aaagaagcac tggtagagtt caaggacgca catgccaaaa ggcaaactgt cgtggttcta 840
gggagtcaag aaggagcagt tcacacggcc cttgctggag ctctggaggc tgagatggat 900
ggtgcaaagg gaaggctgtc ctctggccac ttgaaatgtc gcctgaaaat ggataaactt 960
agattgaagg gcgtgtcata ctccttgtgt actgcagcgt tcacattcac caagatcccg 1020
gctgaaacac tgcacgggac agtcacagtg gaggtacagt acgcagggac agatggacct 1080
tgcaaggttc cagctcagat ggcggtggac atgcaaactc tgaccccagt tgggaggttg 1140
ataaccgcta accccgtaat cactgaaagc actgagaact ctaagatgat gctggaactt 1200
gatccaccat ttggggactc ttacattgtc ataggagtcg gggagaagaa gatcacccac 1260
cactggcaca ggagtcatca tcaccatcac cattaatgag cggccgc 1307
<210> 3
<211> 483
<212> PRT
<213> 人工序列
<400> 3
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Gly His Thr Phe Pro Ser Tyr Asp Ile Asn Trp Val Arg Gln
50 55 60
Ala Thr Gly Gln Gly Leu Glu Trp Met Gly Trp Met Asn Pro Asn Arg
65 70 75 80
Gly Asn Thr Gly Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr
85 90 95
Arg Asn Thr Ser Ile Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg
100 105 110
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val Arg Ser Gly Thr
115 120 125
Asn Tyr Gly Ser Tyr Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly
130 135 140
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
145 150 155 160
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
165 170 175
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
180 185 190
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
195 200 205
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
210 215 220
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
225 230 235 240
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
260 265 270
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
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His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
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Pro Gly Lys
<210> 4
<211> 2538
<212> DNA
<213> 人工序列
<400> 4
agtaatcaat tacggggtca ttagttcata gcccatatat ggagttccgc gttacataac 60
ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg acgtcaataa 120
tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa tgggtggagt 180
atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca agtacgcccc 240
ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac atgaccttat 300
gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc atggtgatgc 360
ggttttggca gtacatcaat gggcgtggat agcggtttga ctcacgggga tttccaagtc 420
tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg gactttccaa 480
aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg taggcgtgta cggtgggagg 540
tctatataag cagagctcgt ttagtgaacc gtcagatcgc ctggagacgc catccacgct 600
gttttgacct ccatagaaga caccgggacc gatccagcct ccgcggccgg gaacggtgca 660
ttggaacgcg gattccccgt gccaagagtg acgtaagtac cgcctataga gtctataggc 720
ccaccccctt ggcttcgtta gaacgcggct acaattaata cataacctta tgtatcatac 780
acatacgatt taggtgacac tatagaataa catccacttt gcctttctct ccacaggtgt 840
ccactcccag gtccaactgc acctcggttc tatcgattga attccaccat gggatggtca 900
tgtatcatcc tttttctagt agcaactgca accggtgtac attccgaggt gcagctggtg 960
cagtctggag ctgaggtgaa gaagcctggg gcctcagtga aggtctcctg caaggcttct 1020
gggtacacct tcacttctgg acacaccttc cccagttatg atatcaactg ggtgcgacag 1080
gccactggac aagggcttga gtggatggga tggatgaacc ctaacagggg taacacaggc 1140
tatgcacaga agttccaggg cagagtcacc atgactagga acacctccat aaacacagcc 1200
tacatggagc tgagcagcct gagatctgag gacacggccg tatattactg tgcgagagta 1260
agaagtggga ccaactacgg ttcctattat tactactatt acggtatgga cgtctggggc 1320
caagggacca cggtcaccgt ctcctcagcg tcgaccaagg gcccatcggt cttccccctg 1380
gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 1440
tacttccccg aacctgtgac ggtctcgtgg aactcaggcg ccctgaccag cggcgtgcac 1500
accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 1560
ccctccagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 1620
accaaggtgg acaagagagt tgagcccaaa tcttgtgaca aaactcacac atgcccaccg 1680
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1740
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1800
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1860
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1920
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1980
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 2040
tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 2100
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 2160
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctatagc 2220
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 2280
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtcccc gggtaaatga 2340
gtgcgacggc cggcaagccc ccgctccccg ggctctcgcg gtcgtacgag gaaagcttgg 2400
ccgccatggc ccaacttgtt tattgcagct tataatggtt acaaataaag caatagcatc 2460
acaaatttca caaataaagc atttttttca ctgcattcta gttgtggttt gtccaaactc 2520
atcaatgtat cttatcat 2538
<210> 5
<211> 236
<212> PRT
<213> 人工序列
<400> 5
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Ser Trp Ala Ser Tyr Glu Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr
20 25 30
Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile
35 40 45
Gly Asn Asn Tyr Val His Trp Tyr Gln Gln Leu Pro Gly Ser Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Gly Ser Leu Ala Ile Ser
85 90 95
Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp
100 105 110
Asp Ser Leu Ser Gly His Trp Val Phe Gly Gly Gly Thr Lys Val Thr
115 120 125
Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
130 135 140
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
145 150 155 160
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser
165 170 175
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
180 185 190
Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
195 200 205
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
210 215 220
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 6
<211> 1747
<212> DNA
<213> 人工序列
<400> 6
agtaatcaat tacggggtca ttagttcata gcccatatat ggagttccgc gttacataac 60
ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg acgtcaataa 120
tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa tgggtggagt 180
atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca agtacgcccc 240
ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac atgaccttat 300
gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc atggtgatgc 360
ggttttggca gtacatcaat gggcgtggat agcggtttga ctcacgggga tttccaagtc 420
tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg gactttccaa 480
aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg taggcgtgta cggtgggagg 540
tctatataag cagagctcgt ttagtgaacc gtcagatcgc ctggagacgc catccacgct 600
gttttgacct ccatagaaga caccgggacc gatccagcct ccgcggccgg gaacggtgca 660
ttggaacgcg gattccccgt gccaagagtg acgtaagtac cgcctataga gtctataggc 720
ccaccccctt ggcttcgtta gaacgcggct acaattaata cataacctta tgtatcatac 780
acatacgatt taggtgacac tatagaataa catccacttt gcctttctct ccacaggtgt 840
ccactcccag gtccaactgc acctcggttc tatcgattga attccaccat gggatggtca 900
tgtatcatcc tttttctagt agcaactgca accggttcct gggcctctta tgagctgact 960
cagccaccct cagcgtctgg gacccccggg cagagggtca ccatctcttg ttctggaagc 1020
agctccaaca tcggaaataa ttatgtccac tggtaccagc agctcccagg atcggccccc 1080
aaactcctca tttataggaa taatcagcgg ccctcagggg tccctgaccg attctctggc 1140
tccaagtctg gcacctcagg ctccctggcc atcagtgggc tccggtccga agatgaggct 1200
gattattact gtgcatcatg ggatgacagc ctgagtggtc attgggtgtt cggcggaggg 1260
accaaggtga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 1320
tcgagtgagg agcttcaagc caacaaggcc acactggtgt gtctcataag tgacttctac 1380
ccgggagccg tgacagtggc ctggaaggca gatagcagcc ccgtcaaggc gggagtggag 1440
accaccacac cctccaaaca aagcaacaac aagtacgcgg ccagcagcta cctgagcctg 1500
acgcctgagc agtggaagtc ccacagaagc tacagctgcc aggtcacgca tgaagggagc 1560
accgtggaga agacagtggc ccctacagaa tgttcataga agcttggccg ccatggccca 1620
acttgtttat tgcagcttat aatggttaca aataaagcaa tagcatcaca aatttcacaa 1680
ataaagcatt tttttcactg cattctagtt gtggtttgtc caaactcatc aatgtatctt 1740
atcatgt 1747
Claims (10)
1.一种IgG抗体,由轻链和重链组成;所述重链中的重链可变区中的CDR1、CDR2和CDR3依次为序列表的序列3自N末端第45-58位氨基酸残基、第76-83位氨基酸残基和第122-142位氨基酸残基;所述轻链中的轻链可变区中的CDR1、CDR2和CDR3依次为序列表的序列5自N末端第45-52位氨基酸残基、第70-72位氨基酸残基和第109-120位氨基酸残基。
2.如权利要求1所述的IgG抗体,其特征在于:
所述重链可变区由序列表的序列3自N末端第20至153位氨基酸残基组成;
所述轻链可变区由序列表的序列5自N末端第20至130位氨基酸残基组成。
3.如权利要求2所述的IgG抗体,其特征在于:
所述重链为如下(a)或(b):(a)序列表的序列3自N末端第20-483位氨基酸残基组成的蛋白质;(b)序列表的序列3所示的蛋白质;
所述轻链为如下(c)或(d):(c)序列表的序列5自N末端第20-236位氨基酸残基组成的蛋白质;(d)序列表的序列5所示的蛋白质。
4.编码权利要求3所述IgG抗体的基因,其特征在于:
编码所述重链的基因为如下(1)或(2)或(3):
(1)序列表的序列4自5’末端第889-2340位核苷酸所示的DNA分子;
(2)序列表的序列4自5’末端第946-2340位核苷酸所示的DNA分子;
(3)序列表的序列4所示的DNA分子;
编码所述轻链的基因为如下(4)或(5)或(6):
(4)序列表的序列6自5’末端第889-1599位核苷酸所示的DNA分子;
(5)序列表的序列6自5’末端第946-1599位核苷酸所示的DNA分子;
(6)序列表的序列6所示的DNA分子。
5.权利要求1或2或3所述IgG抗体在制备用于抑制寨卡病毒的药物中的应用。
6.一种用于抑制寨卡病毒的药物,其活性成分为权利要求1或2或3所述IgG抗体。
7.权利要求1或2或3所述IgG抗体在制备用于中和寨卡病毒的药物中的应用。
8.一种用于中和寨卡病毒的药物,其活性成分为权利要求1或2或3所述IgG抗体。
9.权利要求1或2或3所述IgG抗体在制备用于预防和/或治疗寨卡病毒病的药物中的应用。
10.一种用于预防和/或治疗寨卡病毒病的药物,其活性成分为权利要求1或2或3所述IgG抗体。
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