CN110343174B - 一种高亲和力的黄热病毒人源单克隆抗体及其应用 - Google Patents
一种高亲和力的黄热病毒人源单克隆抗体及其应用 Download PDFInfo
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本发明公开了一种高亲和力的黄热病毒人源单克隆抗体及其应用,属于医药技术领域。本发明以大肠杆菌表达的黄热病毒E蛋白作为抗原,通过流式分选,从一例康复期患者的PBMCs中筛选到可以特异结合黄热病毒E蛋白的记忆B细胞,进一步获得抗体的可变区片段,并与恒定区连接至表达载体中,经哺乳动物细胞表达、纯化后,进行一系列的功能检测,获得了1株具有保护黄热病毒感染的人源单克隆抗体。此株抗体和抗原亲和力为1.49pM,同时,具有有很强的中和黄热病毒活性,IC50为4ng/ml,并且,可以完全保护小鼠免受致死剂量的黄热病毒的攻击。这株人源抗体具有临床治疗和预防黄热病毒的应用价值。
Description
技术领域
本发明涉及一种高亲和力的黄热病毒人源单克隆抗体及其应用,属于医药技术领域。
背景技术
黄热病毒(yellow fever virus,YFV),单股正链RNA病毒,属于黄病毒科黄病毒属,是一种蚊媒传播的可引起人类致病的病原体,同一科病毒还包括寨卡病毒(zikavirus,ZIKV)、登革病毒(dengue virus,DENV)、西尼罗病毒(west nile virus,WNV)等。YFV是引起黄热病的重要病原,严重时会引起出血热伴随多器官衰竭,尤其是肝、脾、淋巴结、心、肾。
在1996年时,科学家曾估计每年在非洲和南美洲黄热病毒可引起20万人感染,30万人死亡。近两年,巴西、安哥拉和刚果民主共和国等地发生了黄热病暴发,已造成数百人死亡,死亡率达14%,中国在2016年有11例输入病例。目前,临床上已有减毒疫苗(YFV17D),但疫苗短缺和接种率不足导致疾病频繁爆发,非免疫个体仍处于危险之中。在YFV感染后,临床上没有可用于治疗该疾病的有效的特异性药物。
迄今为止,中和抗体已被证明是治疗病毒性疾病的有效方法,包括人免疫缺陷病毒(HIV)、流感病毒和其它黄病毒等。黄病毒表面的E蛋白(Envelope)识别细胞表面的受体,进而促进病毒膜与细胞膜发生膜融合,由三个不同的结构域(DI,DII和DIII)完成这些过程。因此,E蛋白是机体免疫系统产生的中和抗体作用的重要表位。
已有研究发现有一些人源抗体具有中和活性,可以中和2001年之前的部分黄热病毒毒株,如:5A、7A、R3(27)等可以中和Central African Republic(CAR)1986、Ethiopia1961、Senegal1990、Nigeria1987、Ghana 1927(Asibi)和疫苗株YFV 17D。然而,RNA病毒在抗体压力下,具有高突变的特性,尽管已经有些中和抗体被鉴定,但是更多的针对不同表位的新的抗体对于治疗是必不可少的。本发明的目的是鉴定特异的具有保护作用的新的YFV中和抗体。
发明内容
为了解决上述问题,本发明首先以大肠杆菌表达的YFV-E蛋白作为抗原,通过流式分选,从一例康复期YFV患者的PBMCs中筛选到可以特异结合YFV-E蛋白的记忆B细胞,然后对筛选的单一B细胞进行RT-PCR和PCR扩增,获得1株抗体的可变区片段,并进一步与恒定区连接至表达载体中。测序正确后,经哺乳动物细胞表达、纯化,进行一系列的功能检测,包括与YFV-E蛋白的结合力,体外中和效果,体内保护能力等检测。
本发明的第一个目的是提供一种抗体,重链可变区含有SEQ ID NO:1所示的氨基酸序列,轻链可变区含有SEQ ID NO:3所示的氨基酸序列,将该抗体命名为YD6。
在本发明的一种实施方式中,所述抗体的重链包括重链可变区和重链恒定区,其中重链恒定区含有如SEQ ID NO:5所示的氨基酸序列。
在本发明的一种实施方式中,所述抗体YD6的轻链为λ链;轻链包括轻链可变区和轻链恒定区;轻链恒定区含有SEQ ID NO:7所示的氨基酸序列。
在本发明的一种实施方式中,所述抗体可靶向黄热病毒特有的囊膜蛋白E蛋白,通过抑制E蛋白介导的受体结合和/或膜融合过程,抑制病毒对细胞的感染。
本发明的第二个目的是提供所述抗体在制备治疗和/或预防黄热病毒的药物方面的应用。
本发明的第三个目的是提供一种药物组合物,所述药物组合物含有所述抗体YD6。
在本发明的一种实施方式中,所述药物组合物还含有医学上可接受的载体。
本发明的第四个目的是提供一种用于免疫诊断或检测的试剂盒,所述试剂盒中含有所述抗体的抗原,或者编码所述抗原的DNA分子,或者表达所述抗原的重组载体/表达盒/转基因细胞系/重组菌。
本发明的第五个目的是提供编码所述人源单克隆抗体YD6的基因。
在本发明的一种实施方式中,所述YD6的重链可变区的核苷酸序列为SEQ ID NO:2,轻链可变区的核苷酸序列为SEQ ID NO:4。
在本发明的一种实施方式中,所述抗体的重链包括重链可变区和重链恒定区,编码重链恒定区的核苷酸序列如SEQ ID NO:6所示。
在本发明的一种实施方式中,编码所述抗体的轻链恒定区的核苷酸序列如SEQ IDNO:8所示。
在本发明的一种实施方式中,编码所述抗体的重链的序列,依次包括CMV启动子序列、第一酶切位点序列、前导序列、编码重链可变区的序列、编码重链恒定区的序列、第二酶切位点序列。
在本发明的一种实施方式中,编码所述抗体的轻链的序列,依次包括CMV启动子序列、第一酶切位点序列、前导序列、编码轻链可变区的序列、编码轻链恒定区的序列、第二酶切位点序列。
在本发明的一种实施方式中,所述第一酶切位点序列和第二酶切位点序列包括但不限于EcoR I或Xho I的酶切位点序列。
在本发明的一种实施方式中,所述前导序列的氨基酸序列如SEQ ID NO:9所示,核苷酸序列如SEQ ID NO:10所示。
本发明还要求保护含有编码所述人源单克隆抗体YD6基因的载体,或者表达所述抗体YD6的细胞。
本发明的有益效果:
本发明获得了1株人源高中和活性的抗YFV抗体——YD6。这株抗体与已经报道的YFV抗体序列完全不同,是新发现的抗体。这株人源抗体YD6抗体可以与YFV-E蛋白结合,亲和力为1.49pM;中和病毒YFV CNYF01/2016毒株时,IC50为0.0044ug/mL可以完全保护保护小鼠免受致死剂量的YFV China的攻击。本发明的这株人源抗体有着临床预防和治疗YFV的应用价值。
附图说明
图1:YFV China-E蛋白纯化分子筛与SDS-PAGE结果;
图2:Protein A纯化后,抗体SDS-PAGE结果;
图3:抗体与YFV China-E的动力学曲线结果;
图4:抗体对YFV China的中和曲线结果;
图5:抗体对感染YFV China小鼠的保护效果;A、B为小鼠在感染病毒24h后注射不同剂量抗体时,小鼠存活率(A)与体重变化(B);C、D为小鼠在感染病毒不同时间点注射同一剂量抗体后,小鼠存活率(C)与体重变化(D),。
具体实施方式
实施例1:黄热病毒E蛋白的表达与纯化
YFV CNYF01/2016(YFV-China)毒株膜蛋白E蛋白(氨基酸序列如SEQ ID NO:11所示、核苷酸序列如SEQ ID NO:12所示)胞外区DNA片段通过NdeI和XhoI酶切后,连接到pET21a载体上。其中YFV E蛋白编码区的3’端连上6个组氨酸标签(hexa-His-tag)的编码序列及翻译终止密码子。再将连接产物转化到BL21大肠杆菌感受态细胞。单克隆接种到40mLLB培养基中,培养6-8小时。接种到4L的LB培养基中,37℃培养至OD600=0.4-0.6,加入IPTG至终浓度1mM,37℃继续培养4-6小时。收获包涵体,通过稀释法复性包涵体。复性液浓缩后换成20mM Tris,150mM NaCl,pH8.0缓冲液,10%甘油。将浓缩后的蛋白溶液进一步以分子排阻层析纯化,使用AKTA-purifier(GE)和superdex200Hiload 16/60柱子(GE),使用缓冲液A(20mM Tris,150mM NaCl,pH8.0,10%甘油),同时监测280nm的紫外吸收值,收取目的蛋白,并通过SDS-PAGE鉴定蛋白纯度。经鉴定,可获得高纯度E单体蛋白,大小为43kDa。结果如图1。
实施例2:与YFV China-E蛋白结合的特异性记忆B细胞的分离
在病人的知情同意下,采集20mL的血液,分离PBMCs。将分离的PBMCs以107/mL的密度与终浓度是400nM的YFV-E蛋白冰上孵育结合半小时,然后用PBS洗2次,再与下列抗体孵育:anti-human CD3/PE-Cy5,anti-human CD16/PE-Cy5,anti-human CD235a/PE-Cy5,anti-human CD19/APC-Cy7,anti-human CD27/Pacific Blue,anti-human CD38/APC,anti-human IgG/FITC,以及anti-His/PE。抗体冰上孵育半小时后,用PBS洗2次。
经FACSAria III分选收集PE-Cy5-APC-APC-Cy7+Pacific Blue+FITC+PE+的细胞,直接收集到96孔板内,1细胞/孔。
实施例3:单一B细胞PCR、序列分析及人源抗体设计
将实施例2获得的B细胞通过Superscript III reverse transcriptase(Invitrogen)逆转录,逆转录引物如表1(序列如SED ID NO.13至SED ID NO.20所示),55℃反应60min。
表1.逆转录反应引物
将此逆转录产物作为模板,用HotStar Tap Plus酶(QIAgen)进行PCR,扩增抗体可变区序列(PCRa)。设计相应的引物,反应条件如下:95℃,5min;95℃30s,55℃(重链/κ链)/50℃(λ链)30s,72℃90s,35个循环;72℃,7min。将此作为模板再进行第二轮PCR(PCRb),条件如下:95℃,5min;95℃30s,58℃(重链)/60℃(κ链)/64℃(λ链)30s,72℃90s,35个循环;72℃,7min。
1.2%的琼脂糖凝胶电泳,分离PCR产物。条带大小在400-500bp的切胶回收后送测序公司测序。测序结果用NCBI在线软件进行分析。
分析正确的可变区序列与相应的重链与λ链的恒定区通过搭桥PCR连接,以EcoRI和XhoI连接克隆至表达载体pCAGGS中。B细胞测序及表达质粒构建策略如下:
人源抗体设计策略如下:
重链:CMV promoter-EcoR I-Leader sequences-重链可变区-CH-Xho I;
轻链(λ):CMV promoter-EcoR I-Leader sequences-轻链可变区-CL(λ)-Xho I。
其中,Leader sequences的氨基酸序列如SEQ ID NO:9(核苷酸序列如SEQ ID NO:10)。
实施例4:抗体的表达及纯化
用含10%FBS的DMEM培养293T细胞。用含有实施例3中构建的特定抗体轻、重链编码基因的质粒共转染293T。转染4-6小时后换液成无血清的DMEM继续培养7天,收集上清。
收集的上清经过5000rpm离心30min后,与含有20mM磷酸钠(pH 8.0)的缓冲液等体积混合,经过0.22μm滤膜过滤后,与protein A预装柱结合(5mL,GE Healthcare)。以0.1M甘氨酸(pH 3.0)洗脱结合的蛋白。收集此蛋白浓缩后进行分子筛层析。目的峰通过SDS-PAGE确定,结果如图2,说明目标蛋白得到正常表达。
最终,得到了能与YFV China-E蛋白结合且中和活性较强的抗体——YD6,其具体基因重排方式如下表2
表2抗体基因重排
实施例5:人源抗体的性能检测
(1)表面等离子共振技术检测与YFV-E的结合能力
表面等离子共振分析利用Biacore T100(Biacore Inc.)进行。具体步骤如下:
首先,将anti-human IgG的抗体以氨基偶联的方式固定在CM5芯片的通道(flowcell,Fc)。固定量控制在10,000响应值(response units,RU)左右。以抗体捕获的方式结合纯化的抗体,此时,液流速度控制在10μL/min,进样1min,抗体捕获量在60RU左右。再以10mMHEPES,150mM NaCl,pH 7.4溶液倍比稀释YFV China-E蛋白,流速调至30μL/min,依次通过各通道,从低浓度开始逐一上样YFV-E蛋白。曲线组成图如图3所示的动力学曲线。结果如表3所示。结合动力学常数的计算是利用BIAevaluation software T100(Biacore,Inc.)软件进行。SPR的结果显示,YD6抗体可以与YFV-E蛋白结合,亲和力为1.49pM。
表3抗体与YFV China-E蛋白结合的动力学常数
(2)中和试验
将纯化的抗体3倍倍比稀释,与1:60稀释的YFV(C6/36扩增)混合,37℃共孵育60分钟。然后将混合液加入到已铺满Vero细胞的24孔板中,300μL/孔。37℃孵育1小时后,每孔补充培养基(DMEM,10%FBS)0.7mL,继续培养40小时后染色。收集细胞,用含4%多聚甲醛,0.05%的soponin的PBS处理细胞,冰上避光静置30min。然后以solution溶液(PBS,1%BSA,0.01%soponin)洗涤细胞2次,与2μg/mL的Z6-FITC抗体冰上孵育30min后,solution溶液洗涤细胞2次,用FACSCanto检测细胞阳性比例。根据不同浓度下阳性比例,计算抗体对YFV的中和能力,结果如图4,YD6可以中和病毒YFV China,IC50为0.0044ug/ml。
(3)动物保护试验
3周龄雌性Balb/c小鼠(维通利华公司),以4-5只分组。每只小鼠颅内注射80PFU病毒YFV China,记录14天内小鼠的存活与体重变化,体重变化超过25%或是出现瘫痪症状的小鼠处死。感染24小时后,注射不同剂量的抗体,5mg/kg的剂量对小鼠保护率为100%(图5A、B)。在小鼠感染48h、72h、96h、120h后,注射25mg/kg剂量,对感染病毒96h小鼠的保护率为100%(图5C、D和表4)。注射对照抗体在第7天开始死亡,第9天全部死亡。
表4不同剂量YD6在不同时间点注射后对小鼠的保护效果
目前,已发现的抗黄热病毒的人源抗体已有5A、7A、R3(27),1A,2A,R3(9),基因重排方式为:VH4-59,VH3-11,VK1-12,VL1-19(GenBank中序列号分别为:AY661699,AY661700,AY661701,AY661702,AY661703和AY661704):其中5A、7A、R3(27)可以中和2001年前的部分毒株和疫苗株YFV 17D。中和活性IC50约1-10ug/ml。无体内动物实验验证其功能。本实验中YD6抗体的IC50 0.0044μg/Ml,远远高于已报道的抗体。并且,在动物保护实验中,本发明使用的抗体剂量为5mg/kg,可以完全保护致死剂量攻击24h的小鼠。使用的抗体剂量为25mg/kg时,可以完全保护致死剂量攻击96h的小鼠。
综上,本发明通过筛选康复病人的YFV China-E特异结合的记忆B细胞,获得的人源高中和活性的YFV抗体YD6与已经报道的黄热抗体序列完全不同,是新发现的抗体,与抗原结合的能力很强,亲和力为1.49pM,同时,具有有很强的中和黄热病毒活性,IC50为4ng/ml。并且,可以完全保护小鼠免受致死剂量的黄热病毒的攻击。结果提示,这株人源抗体在临床治疗和预防黄热方面有应用价值。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
SEQUENCE LISTING
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<212> PRT
<213> 人工序列
<400> 5
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 6
<211> 990
<212> DNA
<213> 人工序列
<400> 6
gccagcacca aaggcccgag cgtgtttccg ctggcgccga gcagcaaaag caccagcggc 60
ggcaccgcgg cgctgggctg cctggtgaaa gattattttc cggaaccggt gaccgtgagc 120
tggaacagcg gcgcgctgac cagcggcgtg catacctttc cggcggtgct gcagagcagc 180
ggcctgtata gcctgagcag cgtggtgacc gtgccgagca gcagcctggg cacccagacc 240
tatatttgca acgtgaacca taaaccgagc aacaccaaag tggataaacg cgtggagccc 300
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960
cagaagagcc tctccctgtc tccgggtaaa 990
<210> 7
<211> 104
<212> PRT
<213> 人工序列
<400> 7
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
1 5 10 15
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
20 25 30
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
35 40 45
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
50 55 60
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
65 70 75 80
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
85 90 95
Thr Val Ala Pro Thr Glu Cys Ser
100
<210> 8
<211> 312
<212> DNA
<213> 人工序列
<400> 8
cccaaggctg ccccctccgt gacactgttc cctccatcta gcgaagaact gcaagctaac 60
aaagccacac tcgtgtgcct cattagcgac ttctaccctg gcgccgtgac cgtggcctgg 120
aaagcggact cctctccagt gaaggccggc gtggagacaa ccaccccatc caagcagtct 180
aacaacaagt acgccgcctc ttcctacctg agcctcacac ctgagcagtg gaagtctcac 240
aggtcctact cttgccaggt gacccacgag ggctccacag tggaaaaaac cgtggcccca 300
accgagtgca gc 312
<210> 9
<211> 21
<212> PRT
<213> 人工序列
<400> 9
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp
20
<210> 10
<211> 63
<212> DNA
<213> 人工序列
<400> 10
atggagacgg atacgctgct cctgtgggtt ttgctgctgt gggttccagg ttccactggt 60
gac 63
<210> 11
<211> 405
<212> PRT
<213> 人工序列
<400> 11
Met Ala His Cys Ile Gly Ile Thr Asp Arg Asp Phe Ile Glu Gly Val
1 5 10 15
His Gly Gly Thr Trp Val Ser Ala Thr Leu Glu Gln Asp Lys Cys Val
20 25 30
Thr Val Met Ala Pro Asp Lys Pro Ser Leu Asp Ile Ser Leu Gln Thr
35 40 45
Val Ala Ile Asp Gly Pro Ala Glu Ala Arg Lys Val Cys Tyr Ser Ala
50 55 60
Val Leu Thr His Val Lys Ile Asn Asp Lys Cys Pro Ser Thr Gly Glu
65 70 75 80
Ala His Leu Ala Glu Glu Asn Asp Gly Asp Asn Ala Cys Lys Arg Thr
85 90 95
Tyr Ser Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys Gly
100 105 110
Ser Ile Val Ala Cys Ala Lys Phe Thr Cys Ala Lys Ser Met Ser Leu
115 120 125
Phe Glu Val Asp Gln Thr Lys Ile Gln Tyr Val Ile Arg Ala Gln Leu
130 135 140
His Val Gly Ala Lys Gln Glu Asn Trp Asn Thr Asp Ile Lys Thr Leu
145 150 155 160
Lys Phe Asp Ala Leu Ser Gly Ser Gln Glu Ala Glu Phe Thr Gly Tyr
165 170 175
Gly Lys Ala Thr Leu Glu Cys Gln Val Gln Thr Ala Val Asp Phe Gly
180 185 190
Asn Ser Tyr Ile Ala Glu Met Glu Lys Asp Ser Trp Ile Val Asp Arg
195 200 205
Gln Trp Ala Gln Asp Leu Thr Leu Pro Trp Gln Ser Gly Ser Gly Gly
210 215 220
Ile Trp Arg Glu Met His His Leu Val Glu Phe Glu Pro Pro His Ala
225 230 235 240
Ala Thr Ile Arg Val Leu Ala Leu Gly Asn Gln Glu Gly Ser Leu Lys
245 250 255
Thr Ala Leu Thr Gly Ala Met Arg Val Thr Lys Asp Glu Asn Asp Asn
260 265 270
Asn Leu Tyr Lys Leu His Gly Gly His Val Ser Cys Arg Val Lys Leu
275 280 285
Ser Ala Leu Thr Leu Lys Gly Thr Ser Tyr Lys Met Cys Thr Asp Lys
290 295 300
Met Ser Phe Val Lys Asn Pro Thr Asp Thr Gly His Gly Thr Val Val
305 310 315 320
Met Gln Val Lys Val Pro Lys Gly Ala Pro Cys Lys Ile Pro Val Ile
325 330 335
Val Ala Asp Asp Leu Thr Ala Ala Val Asn Lys Gly Ile Leu Val Thr
340 345 350
Val Asn Pro Ile Ala Ser Thr Asn Asp Asp Glu Val Leu Ile Glu Val
355 360 365
Asn Pro Pro Phe Gly Asp Ser Tyr Ile Ile Val Gly Thr Gly Asp Ser
370 375 380
Arg Leu Thr Tyr Gln Trp His Lys Glu Gly Ser Ser Ile Gly Lys His
385 390 395 400
His His His His His
405
<210> 12
<211> 1215
<212> DNA
<213> 人工序列
<400> 12
atggcacatt gcatcggcat taccgaccgc gatttcatcg agggtgtgca tggtggtaca 60
tgggtgagtg caaccctgga acaggataaa tgcgtgaccg tgatggcccc ggataagcct 120
agtctggata ttagcctgca gaccgtggcc attgatggtc cggcagaagc ccgtaaagtg 180
tgctacagcg ccgttctgac ccacgtgaag atcaacgaca agtgccctag cacaggcgaa 240
gcccatctgg cagaggagaa cgacggtgat aacgcctgta aacgcaccta cagcgaccgt 300
ggctggggta atggctgcgg cctgtttggc aagggtagca ttgtggcctg cgcaaaattc 360
acctgcgcca agagcatgag tctgttcgag gtggaccaga ccaagattca gtatgtgatc 420
cgcgcccagc tgcacgtggg cgcaaagcag gagaactgga acaccgacat caagaccctg 480
aagttcgatg ccctgagcgg cagccaagaa gccgagttta caggttacgg caaggcaacc 540
ctggagtgtc aagtgcagac cgcagtggat ttcggtaata gctatattgc cgagatggag 600
aaagacagct ggatcgtgga tcgccagtgg gcccaagatc tgaccctgcc gtggcagagc 660
ggtagtggtg gcatttggcg cgaaatgcat catctggtgg agtttgagcc gccgcatgcc 720
gcaaccattc gtgtgctggc cctgggcaat caggaaggca gcctgaaaac cgccctgaca 780
ggcgccatgc gcgtgaccaa agacgaaaac gataataatc tgtacaagct gcatggtggc 840
cacgtgagct gccgcgtgaa gctgagcgcc ctgaccctga aaggcaccag ctacaagatg 900
tgtacagaca aaatgagctt cgttaagaat ccgaccgata ccggccacgg caccgtggtg 960
atgcaggtta aggttccgaa aggcgcaccg tgcaaaatcc cggtgattgt tgccgatgac 1020
ctgaccgccg ccgtgaataa gggcattctg gtgaccgtga acccgatcgc aagcaccaac 1080
gatgatgagg tgctgatcga agtgaacccg ccttttggcg acagttacat catcgtgggt 1140
accggcgata gccgcctgac ctatcaatgg cacaaggaag gcagtagcat cggcaaacat 1200
catcaccacc accat 1215
<210> 13
<211> 20
<212> DNA
<213> 人工序列
<400> 13
atggagtcgg gaaggaagtc 20
<210> 14
<211> 19
<212> DNA
<213> 人工序列
<400> 14
tcacggacgt tgggtggta 19
<210> 15
<211> 19
<212> DNA
<213> 人工序列
<400> 15
tcacggaggt ggcattgga 19
<210> 16
<211> 19
<212> DNA
<213> 人工序列
<400> 16
caggcgatga ccacgttcc 19
<210> 17
<211> 19
<212> DNA
<213> 人工序列
<400> 17
catgcgacga ccacgttcc 19
<210> 18
<211> 20
<212> DNA
<213> 人工序列
<400> 18
aggtgtgcac gccgctggtc 20
<210> 19
<211> 20
<212> DNA
<213> 人工序列
<400> 19
gcaggcacac aacagaggca 20
<210> 20
<211> 17
<212> DNA
<213> 人工序列
<400> 20
aggccactgt cacagct 17
Claims (9)
1.一种针对黄热病毒的抗体,其特征在于,重链可变区的氨基酸序列如SEQ ID NO:1所示,轻链可变区的氨基酸序列如SEQ ID NO:3所示。
2.根据权利要求1所述的抗体,其特征在于,所述抗体的重链包括重链可变区和重链恒定区,其中重链恒定区含有如SEQ ID NO:5所示的氨基酸序列。
3.根据权利要求1或2所述的抗体,其特征在于,所述抗体的轻链包括轻链可变区和轻链恒定区;轻链恒定区含有SEQ ID NO:7所示的氨基酸序列。
4.权利要求1~3任一所述的抗体在制备治疗和/或预防黄热病毒的药物方面的应用。
5.一种药物组合物,其特征在于,含有权利要求1~3任一所述的抗体。
6.编码权利要求1~3任一所述抗体的DNA。
7.根据权利要求6所述的DNA,其特征在于,编码抗体的重链的序列包括CMV 启动子序列、前导序列、编码重链可变区的序列、编码重链恒定区的序列;编码抗体的轻链的序列包括CMV 启动子序列、前导序列、编码轻链可变区的序列、编码轻链恒定区的序列。
8.根据权利要求7所述的DNA,其特征在于,所述前导序列的核苷酸序列如SEQ ID NO:10所示。
9.含有权利要求6或7所述DNA的载体或表达权利要求1~3任一所述抗体的细胞。
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ANC33489.1;佚名;《GenBank》;20160508;全文 * |
T Cell-Mediated Immunity towards Yellow Fever Virus and Useful Animal Models;Alan M. Watson,等;《Viruses》;20170411;第9卷(第4期);第1-14页 * |
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