CN107033242B - 一种人源抗埃博拉病毒包膜糖蛋白的单克隆抗体及应用 - Google Patents
一种人源抗埃博拉病毒包膜糖蛋白的单克隆抗体及应用 Download PDFInfo
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Abstract
本发明公开了一种人源抗埃博拉病毒包膜糖蛋白GP的单克隆抗体,所述抗体具有独特的CDR区,并具有独特的作用位点,计算机模拟分析及生物学实验结果证实所述抗体既作用于GP的NPC1受体结合区,同时也作用于GP的聚糖帽区域,通过与GP两个结构域的共同作用发挥独特的中和机制,起到抗埃博拉病毒感染的作用。所述抗体显示了较高的抗原结合活性和中和活性,仅需要约0.3μg/ml的抗体就可以保护50%的受病毒攻击的细胞,在抗体浓度为100μg/ml时,保护率达到100%,因此,本发明提供的抗体在制备埃博拉病毒病治疗药物中具有广泛的应用前景。
Description
技术领域
本发明公开了一种抗埃博拉病毒包膜糖蛋白的单克隆抗体及应用,属于微生物和免疫学领域。
背景技术
埃博拉病毒(Ebola virus,EBOV)能在人类和非人灵长类体内引发急性严重出血热病,是迄今发现的致死率最高的病毒之一,致死率高达90%,可直接通过接触传播,具有极强的传染性和致死率。埃博拉病毒被美国NIH(National Institutes of Health)和CDC(Centers for Disease Control)列为A类生物剂/生物恐怖剂(Biological agents),将其归为对国家安全和公众健康存在重大隐患和风险的病原体之一,目前仍没有获批的预防或治疗埃博拉病毒的药物。1967年埃博拉病毒被发现后,共经历了12次较大规模的传播。2014年西非爆发了历史上最大规模、最难控制的埃博拉疫情,经鉴定为扎伊尔型埃博拉病毒,此次疫情造成1万多例死亡和2.5万多例感染(根据WHO[World Health Organization]2016年2月17日发布的埃博拉疫情报告),疫情首次传播到非洲大陆以外,在世界范围内引起了极大的恐慌。公众和当局的高度关注快速推进了埃博拉疫苗和抗病毒药物的研究。
国内外迅速开展了几个有前景的埃博拉疫苗临床试验:大猩猩腺病毒3型载体疫苗、腺病毒5型载体疫苗、水疱性口炎病毒载体疫苗等。发展有效的预防类药物不可否认地是一个重要的目标,并且预防措施被认为可以挽救大量的生命,然而疫苗在某些情况下难以发挥作用,比如:1)宿主个体可能存在差异(如年长者、年幼者及免疫受损者的免疫能力薄弱);2)疫苗长时间免疫后免疫效果逐渐递减;3)疫苗激发宿主的免疫无法抵抗高剂量的埃博拉病毒暴露;4)大部分病人仅在出现埃博拉病毒感染信号后才寻求药物帮助,疫苗在短暂的治疗窗口期内难以激发宿主有效的免疫应答。因此,在开发疫苗的进程中埃博拉治疗药物的研发同样不容忽视。尽管目前没有批准的埃博拉治疗药物,但是有一些实验型抗埃博拉病毒药物正在研究当中,包括小干扰RNA、反义寡核苷酸类药物、核苷酸类似物、抗体药物等。其中,由三株单克隆抗体混合而成的抗体药物“Zmapp”及其优化株“MIL77”在埃博拉疫情爆发期间,成功挽救了多人的生命,其效果和治疗窗口期长度远超于其他种类的抗病毒药物,大大提高了药物安全性和患者治愈率,给了人们极大的鼓舞。应用抗体药物治疗丝状病毒引起了世界范围内的关注,成为埃博拉药物研究领域的热点。
埃博拉病毒包膜表面上的GP几乎介导了病毒进入细胞的所有环节,是一个重要的病毒中和抗体作用靶点。埃博拉病毒GP基因被加工成两种蛋白,一种是分泌的非结构型GP(secreted glycoprotein,sGP);另一种是结构型GP。埃博拉GP首先作为一个多肽被合成,接着被Furin酶酶切成为GP1(1-501位氨基酸)和GP2(502-676位氨基酸)亚基,两个亚基通过二硫键相连接,形成的三聚体由GP2内部的跨膜区固定在于包膜表面,GP1包含黏蛋白(Mucin)、聚糖帽(Glycan cap)、头部(Head)、基部(Base)等结构域。然而,简单的Furin酶切过程仍然不足以激发埃博拉GP膜融合过程的发生。
埃博拉病毒进入体内后,与细胞膜表面受体结合,但是这些宿主细胞膜表面的粘附因子,并不是真正的埃博拉病毒发生膜融合进入宿主细胞的受体。病毒结合于细胞表面粘附因子后,由网格蛋白介导了胞吞和胞饮,发生了初级和次级核内体的运输。GP在核内体中被组蛋白酶B和组蛋白酶L酶切,去除了GP1上包括黏蛋白(Mucin)和聚糖帽(Glycan cap)在内的60%的氨基酸,形成激活态GP(primed GP,GPcl),此时激活了决定性的膜融合过程的发生。GPcl与内体膜蛋白Niemann-Pick C1(NPC1)结合发生膜融合,从而使病毒RNA进入胞质完成病毒基因组复制和转录,新病毒蛋白合成后组装成子代病毒颗粒,并从宿主细胞表面出芽。
Zmapp是由烟草***表达的三株人鼠嵌合单抗(c2G4、c4G7、c13C6)组成的鸡尾酒治疗策略,其中c2G4(表位为C511,N550,G553,C556)和c4G7(表位为C511,D552,C556)结合于埃博拉病毒包膜表面上的糖蛋白GP的GP2亚基,表位存在交叠;c13C6(表位为T270,K272)以近似垂直的角度结合于聚糖帽区域。MIL77是优化于Zmapp的抗体组合,MIL77-1/-2/-3分别含有c2G4、c4G7和c13C6的可变区,其骨架区经人源化改造后表达于糖基工程改造的CHO细胞。MIL77-1和ML77-3两株抗体的鸡尾酒组合疗法在感染72小时后能够对非人灵长类起到100%的保护活性。
Zmapp的成功应用提示抗埃博拉病毒包膜糖蛋白的单克隆抗体的多重互补的作用位点是治疗埃博拉病毒感染的关键因素,获得具有这种独特作用位点的抗体成为现有技术一个亟待解决的技术需求,因此,本发明的目的是提供一种全人源的,具有独特CDR区的、并经实验验证具有独特作用位点和中和机制,由此显示出优异抗原结合活性、中和活性的埃博拉单克隆抗体,为埃博拉病毒感染提供一种更为有效的候选治疗手段。
发明内容
基于上述发明目的,本发明首先提供了一种全人源抗埃博拉病毒包膜糖蛋白的单克隆抗体,所述抗体的重链可变区的CDR1、CDR2和CDR3区的氨基酸序列如SEQ ID NO:1第26-33、51-58、97-116位氨基酸序列所示,所述轻链可变区的CDR1、CDR2和CDR3区如SEQ IDNO:5第27-32、50-52、89-99位氨基酸序列所示。
在一个优选的技术方案中,所述抗体的重链可变区的氨基酸序列如SEQ ID NO:1所示,所述轻链可变区的氨基酸序列如SEQ ID NO:5所示。
在一个更为优选的技术方案中,所述抗体的重链恒定区的氨基酸序列如SEQ IDNO:3所示,所述轻链恒定区的氨基酸序列如SEQ ID NO:7或9所示。
第二,本发明还提供了一种编码上述单克隆抗体重链和轻链的碱基编码序列,所述抗体的重链可变区的碱基编码序列由SEQ ID NO:2所示,所述抗体的轻链可变区的碱基编码序列由SEQ ID NO:6所示。
在一个优选的技术方案中,所述抗体的重链恒定区的碱基编码序列由SEQ ID NO:4所示,所述抗体的轻链恒定区的碱基编码序列由SEQ ID NO:8或者10所示。
第三,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功能元件,这种功能元件可以是传统的表达载体。
在一个优选的技术方案中,所述功能元件为线性表达框。
第四,本发明还提供了一种含有上述线性表达框的宿主细胞。
在一个优选的技术方案中,所述细胞为293T细胞。
最后,本发明还提供了上述单克隆抗体在制备埃博拉病毒病治疗药物中的应用。
本发明提供的人源抗埃博拉病毒包膜糖蛋白的单克隆抗体具有独特的CDR区,并具有独特的作用位点,计算机模拟分析及生物学实验结果证实所述抗体既作用于GP的NPC1受体结合区,同时也作用于GP的聚糖帽区域,通过与GP两个结构域的共同作用发挥独特的中和机制,起到抗埃博拉病毒感染的作用。基于这种独特的中和机制,本发明提供的抗体显示了优异的抗原结合活性和中和活性,仅需要约0.3μg/ml的抗体就可以保护50%的受病毒攻击的细胞,在抗体浓度为100μg/ml时,保护率达到100%。因此本发明的结果显示,所述抗体具有在制备埃博拉病毒病治疗药物中广泛应用的前景。
附图说明
图1.流式分选细胞仪分选细胞流程及分选图谱;
图2.线性表达框示意图;
图3.ELISA检测单抗与GP结合特异性示意图;
图4.假病毒中和实验检测抗体的中和活性曲线图;
图5.ELISA验证单抗与GP及其截短抗原的结合示意图;
图6.计算机模拟分析1B3和GP结合的最佳模式;
图7A.Western Blot分析1B3与GP突变体的结合示意图;
图7B.流式分析1B3与GP突变体的结合示意图;
图8.竞争结合ELISA分析1B3的作用于聚糖帽区域示意图
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人源抗埃博拉病毒包膜糖蛋白的单克隆抗体的筛选和制备
1.血液样品采集
在获得知情同意书后,采集重组埃博拉疫苗临床试验受试者第一次免疫14天后血液样品5mL,用于后续实验。
2.流式分选单细胞
将采集的血样利用Ficoll密度梯度离心法分离PBMC,过程如下:
1)取新鲜抗凝全血,EDTA抗凝。用等体积PBS或0.09%NaCl稀释全血。
2)在离心管中加入一定体积的分离液,将稀释后的血样平铺到分离液液面上方,保持两液面界面清晰。分离液、抗凝未经稀释全血、PBS(或生理盐水)体积为1:1:1。
3)配平,室温,水平转子700-800g(2000-2500rpm),加速度3~4acc,离心20-30min。
4)离心结束后,管底是红细胞,中间层是分离液,最上层是血浆/组织匀浆层,血浆层与分离液层之间是一层薄且较致密的白膜,即:单个核细胞(包括淋巴细胞和单核细胞)层。小心吸取白膜层到另一离心管中。
5)用PBS/1640稀释到一定体积,颠倒混匀。室温,水平转子250-400g(1000-1500rpm),离心5-10min,弃上清。重复洗涤1-2次。
6)用PBS或合适的培养基将淋巴细胞重悬备用。
将PBMC使用流式抗体染色:anti-CD3-FITC,anti-CD20-FITC,anti-CD19-PE-Alexa 610,anti-CD27-PE,anti-CD38-PE-Cy5,每5×106个PBMC细胞各加入5μL上述抗体,孵育30分钟后,使用含2%FBS的PBS重复洗涤2-3次。利用MoFlo XDP流式分选细胞仪,选择浆细胞特异的细胞表面标记物(CD3neg/CD20low/CD19high/CD27high/CD38high)分选浆细胞(如图1所示),直接将单个浆细胞分选至96孔板中,96孔板中每孔含有5U RNA酶抑制剂及19.8μL去RNA酶的水中,-80℃保存。
3.单细胞PCR扩增全人源单抗基因
1)反转录PCR
具体参考说明书(QIAGEN,210212),程序简单介绍如下:
通过流式分选了2112个单细胞,因此有2112个反转录反应体系。向每个反应体系中同时加入以下全部的针对重链(H)、κ轻链、λ轻链各亚型的特异引物(引物序列见表1)。
引物:
H:5′L-VH 1、L-VH 3、L-VH 4/6,5′L-VH 5、HuIgG-const-anti、3′CμCH1
κ:5′L Vκ1/2、5′L Vκ3、5′L Vκ4、3′Cκ543–566
λ:5′L Vλ1、5′L Vλ2、5′L Vλ3、5′L Vλ4/5、5′L Vλ6、5′L Vλ7、5′L Vλ8、3′Cλ
表1反转录PCR引物
PCR反应体系中包含:5×缓冲液6μL、dNTP 1.2μL、反转录酶1.2μL、引物如上、模板为单细胞,水补齐至30μL。
PCR反应条件为:50℃反转录30min,95℃预变性15min,接着95℃40s,55℃30s,72℃1min,40个循环,最后72℃延伸10min。
2)巢式PCR
以反转录产物为模板,分别进行3次巢式PCR反应扩增H、κ、λ,具体过程如下:
引物:
H:VH3a-sense、VH3b-sense、MuD、PW-Cgamma
κ:5′Pan Vκ、3′Cκ494–516
λ:5′AgeI Vλ1、5′AgeI Vλ2,、5′AgeI Vλ3、5′AgeI Vλ4/5、5′AgeI Vλ6、5′AgeI Vλ7/8、3′XhoI Cλ
表2巢式PCR引物
PCR反应体系中包含:10×缓冲液2.5μL、10mM dNTP 0.5μL、DNA聚合酶0.25μL、引物如上、模板为反转录产物1μL、水补齐至25μL。
PCR反应条件为:94℃预变性4min,接着94℃30s,57℃30s,72℃45min,40个循环,最后72℃延伸10min。
3)琼脂糖凝胶电泳
一个单细胞中重链和轻链基因均扩增成功的克隆,被认为是配对成功的克隆。取5μL巢式PCR扩增产物经1%琼脂糖凝胶电泳后,取配对的阳性克隆进行测序,测序获得的抗体可变区序列用Vector NTI软件及IMGT网站进行分析,并进行抗体蛋白表达和功能验证。
4.线性表达框表达抗体
通过上述反转录反应,单细胞克隆中获得了462个配对的抗体序列,如果采用传统的克隆表达方法费时费力,通过构建线性表达框的方法可以快速表达抗体。该方法的基本原理是直接通过重叠延伸PCR将启动子序列(GENBANK登记号:X03922.1)、抗体前导肽的编码序列(由SEQ ID NO:11所示)、抗体可变区(从单细胞中扩增获得)、抗体恒定区(生工生物合成,重链恒定区序列由SEQ ID NO:3所示,DNA编码序列由SEQ ID NO:4所示,Kappa型轻链恒定区序列由SEQ ID NO:7所示,DNA编码序列由SEQ ID NO:8所示,Lamda型轻链恒定区序列由SEQ ID NO:9所示,DNA编码序列由SEQ ID NO:10所示)、多聚A尾(GENBANK登记号:X03896.1)连接起来,将该线性形式的DNA转染进入细胞中进行抗体表达。
具体过程如下:
1)以pSec Tag2(Invitrogen)为模板,扩增启动子-前导序列片段、多聚A尾片段。
扩增启动子-前导序列片段的PCR反应体系中包括:模板质粒pSec Tag2(Invitrogen)1ng,10×缓冲液5μL、10mM dNTP 1μL、DNA聚合酶0.5μL、引物5'CMV-FORWARD(CGATGTACGGGCCAGATATACGCGTTG)、引物3'leader-sequence(GTCACCAGTGGAACCTGGAACCCA)、水补齐至50μL。
扩增多聚A尾片段的PCR反应体系中包括:模板质粒pSec Tag2(Invitrogen)1ng,10×缓冲液5μL、10mM dNTP 1μL、DNA聚合酶0.5μL、引物5'POLY(A)(GCCTCGACTGTGCCTTCTAGTTGC)、引物3'POLY(A)(TCCCCAGCATGCCTGCTATTGTCT)、水补齐至50μL。
PCR反应条件为:94℃预变性4min,接着94℃30s,60℃30s,72℃1min,30个循环,最后72℃延伸10min。
2)扩增抗体恒定区。
H链恒定区PCR体系中包含:重链恒定区模板10ng、10×缓冲液5μL、10mM dNTP 1μL、DNA聚合酶0.5μL、引物5'CH(ACCAAGGGCCCATCGGTCTTCCCC)、引物3'CH(GCAACTAGAAGGCACAGTCGAGGCTTTACCCGGAGACAGGGA)、水补齐至50μL。
κ链恒定区PCR体系中包含:κ链恒定区模板10ng、10×缓冲液5μL、10mM dNTP 1μL、DNA聚合酶0.5μL、引物5'Cκ(ACTGTGGCTGCACCATCTGTCTTC)、引物3'Cκ(GCAACTAGAAGGCACAGTCGAGGCACACTCTCCCCTGTTGAAGCT)、水补齐至50μL。
λ链恒定区PCR体系中包含:λ链恒定区模板10ng、10×缓冲液5μL、10mM dNTP 1μL、DNA聚合酶0.5μL、引物5'Cλ(GAGGAGCTTCAAGCCAACAAGGCCACA)、引物3'Cλ(GCAACTAGAAGGCACAGTCGAGGCTGAACATTCTGTAGGGGCCAC)、水补齐至50μL。
PCR反应条件为:94℃预变性4min,接着94℃30s,60℃60s,72℃3min,30个循环,最后72℃延伸10min。
3)扩增抗体可变区。
PCR体系中包含:模板为反转录PCR产物10ng,10×缓冲液5μL、10mM dNTP 1μL、DNA聚合酶0.5μL、引物如表3中所示(将重链和轻链引物分别混合后加入体系中)、水补齐至50μL。
PCR反应条件为:94℃预变性4min,接着94℃30s,60℃30s,72℃3min,30个循环,最后72℃延伸10min。
表3.线性表达框构建PCR引物
4)PCR产物回收纯化:将以上PCR产物经1%的琼脂糖凝胶电泳后,切胶并使用OMEGA公司回收试剂盒回收。
5)分别扩增重链和轻链的线性表达框。
线性表达框的拼接顺序示意图如图2所示。图2中,A为H链线性表达框,B为κ链线性表达框,C为λ链线性表达框。
PCR反应体系中包括:
模板:纯化后的启动子-前导序列片段10ng、重链/轻链可变区片段10ng、重链/轻链恒定区片段10ng、多聚A尾片段10ng,10×缓冲液2.5μL、10mM dNTP 0.5μL、DNA聚合酶0.25μL、引物5'CMV-FORWARD(CGATGTACGGGCCAGATATACGCGTTG)和3'POLY(A)(TCCCCAGCATGCCTGCTATTGTCT)、水补齐至25μL。
PCR反应条件为:94℃预变性4min,接着94℃30s,60℃30s,72℃3min,30个循环,最后72℃延伸10min。
6)PCR产物回收纯化:PCR反应产物直接用OMEGA公司回收试剂盒回收。
7)DNA定量:用Nano(GE Healthcare)对PCR回收产物进行定量。
8)细胞接种:将293T细胞以2×105/mL接种于24孔细胞培养板中,在含有5%CO2的细胞温箱中,37℃培养过夜。
9)细胞共转染:次日,向200μL无血清的MEM培养基中,加入构建成功的重链和轻链线性表达框PCR产物各1μg,混匀后加入4μL转染试剂Turbofect(Thermo Scientific,R0531),共同孵育15-20min后逐滴加至过夜培养的293T细胞培养孔中。在含有5%CO2的细胞温箱中,37℃培养48h后收细胞培养上清备用。
5.ELISA筛选具有结合活性的抗体
1)实验前一天96孔酶联板,分别包被lectin和Goat anti-human IgG-Fc抗体。用ELISA包被液分别将Lectin和Goat anti-human IgG-Fc抗体稀释至终浓度为10μg/mL,每孔100μL包被。并包被PA、LF、EF等其他抗原,将包被的酶联板放入湿盒,4℃过夜。
2)实验当天甩弃孔内液体,用ELISA洗涤液洗2次。
3)每孔加入100μL封闭液,室温下放置1小时。
4)甩弃孔内液体,用洗涤液洗2次。
5)捕捉GP抗原,将GP蛋白表达上清与样品稀释液1:1稀释,加入至包被了lectin的孔内,室温放置1小时。
6)甩弃孔内液体,用洗涤液洗6次。
7)加入100μL的单抗稀释液,将MIL77-2作为阳性对照,以其他非特异抗体作为阴性对照。
8)室温静置1小时。
9)甩弃孔内液体,用洗涤液洗6次。
10)将HPR标记的羊抗人IgG二抗以1:20000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;
11)甩弃孔内液体,用洗涤液洗6次,最后一次弃掉洗涤液后,将残留液体在吸水纸上尽量轻柔拍干;
12)每孔加入100μL的TMB单组份显色液,显色5分钟,室温避光,之后每孔加入50μL终止液终止反应;
13)用酶标仪上检测450-630nm处的OD值,保存记录原始数据;
结果:将462株单抗进行筛选,并对埃博拉GP的结合抗体进行特异性鉴定。如图3,具有结合活性的24株抗体中,有17株与埃博拉GP能够特异结合,包括1B3、1D8、2G10、4C4、4F2、5C3、5D2、5G1、10B7、17B5、17C2、17F3、19A8、19G9、20A10、20E8、20H7,而其他几株抗体则与PA或其他抗原有非特异结合。
6.假病毒中和实验筛选具有中和活性的抗体
1)将假病毒按1:6用1640培养基稀释,用假病毒稀释液稀释单抗,并依次进行两倍稀释,以加入MIL77-2抗体的孔作为阳性对照,不加假病毒仅加入培养基的孔作为全活对照,以仅加入假病毒不加入抗体的孔作为全死对照。
2)将假病毒和抗体混合物放置37℃培养箱孵育1小时。
3)另取一块96孔板,将293细胞计数后每孔铺2×104细胞,每孔100μL。
4)将孵育的96孔板中的抗体病毒溶液转移至对应细胞板的孔中,每孔转移100μL;全活对照孔加入100μL的培养基,全死对照孔加入100μL的假病毒溶液。
5)将96孔细胞培养板放入温箱中培养36~48小时后,取出细胞培养板,小心吸出培养液弃掉。
6)各孔加入100μL细胞裂解液,震荡机上350rpm震荡15min。之后,3000rpm离心10min。
7)将Luciferase Assay Substrate(lyophilized,检测底物冻干剂)和Luciferase Assay Buffer(检测缓冲液)混合吹匀后,充盈整个检测管路。
8)吸取20μL上清读值,读取荧光值,计算抗体对细胞的保护率。
结果:如图4,17株埃博拉GP特异结合的单抗中,有一株具有中和活性的单抗1B3,仅需要约0.3μg/ml的抗体就可以保护50%的细胞,在抗体浓度为100μg/ml时,保护率达到100%。而其他单抗,如4F2所在孔中细胞与全死对照无差异,还有一种单抗,如20E8所在孔中细胞存活率低于全死对照。通过序列分析,单抗1B3的重链可变区的氨基酸序如SEQ IDNO:1所示,轻链可变区的氨基酸序列如SEQ ID NO:3所示,通过进一步分析,抗体的重链可变区的CDR1、CDR2和CDR3区的氨基酸序列如SEQ ID NO:1第26-33、51-58、97-116位氨基酸序列所示,所述轻链可变区的CDR1、CDR2和CDR3区如SEQ ID NO:3第27-32、50-52、89-99位氨基酸序列所示。
实施例2:中和单抗1B3与GP结合的抗原表位分析
1.1B3与GP及其截短抗原的结合作用分析
ELISA检测单抗与截短抗原的结合。构建三种GP截短抗原GP1(33~500aa)、GPdmucin(33~310aa,463~632aa)、sGP(33~294aa)的表达质粒,用Expi293哺乳细胞***表达上述三种截短抗原,用包被于ELISA板的lectin分别捕捉GP全长和截短抗原,鉴定17株特异抗体与GP及其截短抗原的结合活性。以Zmapp的优化株MIL77-1/2/3和炭疽特异单抗8A7分别作为阳性和阴性对照。
结果:如图5,MIL77-3与四种形式的GP均能结合,MIL77-1/2仅能与GP全长和GPdmucin结合,与文献报道的结合表位所在区域一致,阴性对照抗体8A7则与四种形式抗原均不能结合。17株特异抗体中,包含1B3在内的16株抗体与四种形式的GP均能结合,说明1B3单抗与GP结合的抗原表位位于GP1上的33~294aa区域。
2.1B3与GP作用位点的计算机模拟分析
使用Discovery Studio软件模拟1B3与GP蛋白作用,输入1B3可变区核酸序列,通过Macromolecules模块首先对1B3Fab进行三维建模。从PDB库中下载的埃博拉GP晶体结构文件3CXY。使用ZDock模块对1B3和GP进行对接,对抗原抗体的结合Pose打分,计算出各个氨基酸的综合评分。选择打分高的氨基酸进行筛选,获得结合界面包含关键氨基酸的抗原抗体结合Pose集合,从中分析获得最优的结合Pose。
结果:计算机模拟分析的1B3和GP结合的最佳模式如图6,1B3结合于GP的33~294aa之间,该区域位于GP1亚基,模拟结果与上述ELISA结果一致。在GP1亚基上,GP与1B3结合RCF算法打分最高的前10个氨基酸位点依次是172、112、117、119、120、118、114、58、90、54位点,其中112、114和118位点是文献报道的GPcl和NPC1结合的关键位点。说明1B3很有可能结合于GP的NPC1受体结合区。
3.1B3与GP1的NPC1受体结合区结合作用的鉴定
Western Blot和流式分析1B3与GP突变体的结合。选择计算机模拟表位分析的关键氨基酸:170、171、172、112、114、117、118、119和120位分别突变成丙氨酸,克隆至表面展示质粒pDisplay(Invitrogen)中。转染293T细胞后,于48h后,取少许细胞用于WesternBlot,剩余细胞用于流式染色分析。选择pDisplay质粒中位于***片段羧基端的HA标签作为衡量GP表达量的判断依据。
结果:Western Blot结果显示,在保证相同的GP上样量情况下,117、118和171位氨基酸分别突变后GP与1B3的结合显著降低(图7A)。流式分析结果显示118位和172位氨基酸位点突变的GP与1B3的结合活性丢失(图7B)。上述结果显示117、118、171和172位氨基酸为GP与1B3结合的关键氨基酸,这两对相邻的氨基酸位于GP受体NPC1结合区的两端。因此1B3可能以横跨的方式结合于受体结合区上的这些位点,进而通过影响GP与NPC1的结合起到保护活性。
4.1B3与GP1的聚糖帽区结合作用的鉴定
采用竞争结合ELISA分析1B3的抗原作用表位。用已知结合表位的MIL77-1/2/3和其余两株结合于sGP区域的特异抗体作为对照抗体,利用竞争ELISA考察这些抗体与GP的结合表位是否存在交叠。实验中保持检测抗体的量恒定,加入不同浓度梯度的生物素标记的竞争抗体,考察检测抗体与GP的结合是否会被同孵育的竞争抗体所阻断。
结果:如图8,1B3抗体与MIL77-3、2G10、5C3存在竞争,说明这些抗体结合表位空间接近或存在交叠。MIL77-3是一株作用于GP1聚糖帽区的270和272位氨基酸的单抗,说明1B3不仅结合于GP的NPC1受体结合区,同时作用于GP1中靠近MIL77-3表位的聚糖帽区域,而该作用方式的埃博拉抗体目前未见报道。鉴于1B3与MIL77-3有相近的表位,又是具有较好中和活性的全人源单抗,1B3极有可能替代MIL77-3与MIL77-1组成效果更佳的鸡尾酒治疗策略。
序 列 表
<110> 中国人民解放军军事医学科学院生物工程研究所
<120> 一种人源抗埃博拉病毒包膜糖蛋白的单克隆抗体及应用
<160> 11
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Claims (10)
1.一种人源抗埃博拉病毒包膜糖蛋白的单克隆抗体,其特征在于,所述抗体的重链可变区的CDR1、CDR2和CDR3区的氨基酸序列如SEQ ID NO:1第26-33、51-58、97-116位氨基酸序列所示,所述抗体的轻链可变区的CDR1、CDR2和CDR3区如SEQ ID NO:5第27-32、50-52、89-99位氨基酸序列所示。
2.根据权利要求1所述的抗体,其特征在于,所述抗体的重链可变区的氨基酸序列如SEQ ID NO:1所示,所述抗体的轻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所述的抗体,其特征在于,所述抗体的重链恒定区的氨基酸序列如SEQ ID NO:3所示,所述抗体的轻链恒定区的氨基酸序列如SEQ ID NO:7或9所示。
4.一种编码权利要求1-3任一所述单克隆抗体重链和轻链的多核苷酸,其特征在于,编码所述抗体重链可变区的多核苷酸的序列由SEQ ID NO:2所示,编码所述抗体轻链可变区的多核苷酸的序列由SEQ ID NO:6所示。
5.根据权利要求4所述的多核苷酸,其特征在于,编码所述抗体的重链恒定区的多核苷酸的序列由SEQ ID NO:4所示,编码所述抗体的轻链恒定区的多核苷酸的序列由SEQ IDNO:8或者10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/或轻链的多核苷酸的功能元件。
7.根据权利要求要求6所述的功能元件,其特征在于,所述功能元件为线性表达框。
8.一种含有权利要求7所述线性表达框的宿主细胞。
9.根据权利要求要求8所述的宿主细胞,其特征在于,所述细胞为293T细胞。
10.权利要求1-3任一所述的单克隆抗体在制备埃博拉病毒病治疗药物中的应用。
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CN111138528B (zh) * | 2018-11-06 | 2021-07-30 | 中国人民解放军军事科学院军事医学研究院 | 特异性结合于埃博拉病毒糖蛋白聚糖帽的单克隆抗体5a8 |
CN111138526B (zh) * | 2018-11-06 | 2021-07-30 | 中国人民解放军军事科学院军事医学研究院 | 一种抗埃博拉病毒糖蛋白gp2亚基的单克隆抗体2g1及应用 |
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CN111138528B (zh) * | 2018-11-06 | 2021-07-30 | 中国人民解放军军事科学院军事医学研究院 | 特异性结合于埃博拉病毒糖蛋白聚糖帽的单克隆抗体5a8 |
CN111138526B (zh) * | 2018-11-06 | 2021-07-30 | 中国人民解放军军事科学院军事医学研究院 | 一种抗埃博拉病毒糖蛋白gp2亚基的单克隆抗体2g1及应用 |
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