CN106380517A - 一种对中东呼吸综合征冠状病毒具有中和活性的小分子抗体及其应用 - Google Patents
一种对中东呼吸综合征冠状病毒具有中和活性的小分子抗体及其应用 Download PDFInfo
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- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
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Abstract
本发明公开了一种对MERS冠状病毒具有中和活性的小分子抗体及其应用。该小分子抗体Nano‑Anti‑MRBD是如下(a)或(b)或(c)的蛋白质：(a)由序列表中序列1所示的氨基酸序列组成的蛋白质；(b)将序列表中序列1的氨基酸序列经过一个或几个氨基酸残基的取代和/或缺失和/或添加且具有相同活性的由(a)衍生的蛋白质；(c)基于序列表中序列1所示的氨基酸序列进行人源化改造的由(a)衍生的蛋白质。间接ELISA实验表明，小分子抗体Nano‑Anti‑MRBD与MERS冠状病毒RBD具有很好的反应性；中和试验表明，小分子抗体Nano‑Anti‑MRBD对MERS冠状病毒具有良好的中和活性。
Description
技术领域
本发明涉及生物技术领域，尤其涉及一种对中东呼吸综合征冠状病毒(MERS冠状病毒)具有中和活性的小分子抗体及其应用。
背景技术
MERS冠状病毒致病性强、病死率高、且具有人-人传播的能力，是继SARS冠状病毒之后又一种对人具有高致病性的冠状病毒。而发展对MERS冠状病毒具有保护作用的中和抗体对于该病的防治具有十分重要的意义。
重链抗体的可变区(variable domain of heavy-chain of heavy-chainantibody，VHH)是能够结合抗原的单一结构域。基于重链抗体可变区发展的单域重链抗体，具有分子量小、免疫原性弱、易于生产制备等优点，在免疫实验、疾病诊断和治疗领域具有广阔的应用前景。
发明内容
本发明的一个目的是提供一种对中东呼吸综合征冠状病毒具有中和活性的小分子抗体。
本发明所提供的小分子抗体，名称为Nano-Anti-MRBD；所述Nano-Anti-MRBD是如下1)或2)或3)的蛋白质：
1)由序列表中序列1所示的氨基酸序列组成的蛋白质；
2)将序列表中序列1的氨基酸序列经过一个或几个氨基酸残基的取代和/或缺失和/或添加且具有相同活性的由1)衍生的蛋白质；
3)基于序列表中序列1所示的氨基酸序列进行人源化改造的由1)衍生的蛋白质。
为使1)中的蛋白便于纯化，可在其N末端或C末端连接如表1所示的标签。
表1.标签的序列
| 标签 | 残基 | 序列 |
| Poly-Arg | 5-6(通常为5个) | RRRRR |
| Poly-His | 2-10(通常为6个) | HHHHHH |
| FLAG | 8 | DYKDDDDK |
| Strep-tag II | 8 | WSHPQFEK |
| c-myc | 10 | EQKLISEEDL |
上述2)中的Nano-Anti-MRBD的编码基因可通过将1)中的蛋白编码基因的DNA序列中缺失一个或几个氨基酸残基的密码子，和/或进行一个或几个碱基对的错义突变，和/或在其5′端和/或3′端连上表1所示的标签的编码序列得到。
上述3)中的Nano-Anti-MRBD的编码基因可通过对1)中的蛋白编码基因进行人源化改造得到。
为了便于蛋白的分泌表达，还可在所述蛋白的氨基末端添加上信号肽序列。
编码上述蛋白质的DNA分子也属于本发明的保护范围。
上述DNA分子是如下1)-4)中任一种的DNA分子：
1)编码区为序列表中序列2所示的DNA分子；
2)编码区为序列表中序列2第7-399位所示的DNA分子；
3)在严格条件下与1)或2)限定的DNA序列杂交且编码具有相同功能蛋白质的DNA分子；
4)与1)或2)限定的DNA序列至少具有70％、至少具有75％、至少具有80％、至少具有85％、至少具有90％、至少具有95％、至少具有96％、至少具有97％、至少具有98％或至少具有99％同源性且编码具有相同功能蛋白质的DNA分子。
上述严格条件可为在6×SSC、0.5％SDS的溶液中，在65℃下杂交，然后用2×SSC、0.1％SDS和1×SSC、0.1％SDS各洗膜一次。
含有上述DNA分子的重组载体、表达盒、转基因细胞系或重组菌也属于本发明的保护范围。
所述重组载体具体可为在pCold I的多克隆位点间插入上述任一种融合蛋白的编码基因得到的pCold I-Nano-Anti-MRBD。
所述重组菌具体可为将所述pCold I-Nano-Anti-MRBD转入大肠杆菌BL21(DE3)得到的重组大肠杆菌。
扩增上述DNA分子全长或其任意片段的引物对也是本发明保护的范围。
上述蛋白、上述DNA分子或上述重组载体、表达盒、转基因细胞系或重组菌在制备抗MERS冠状病毒产品中的应用也是本发明保护的范围。
上述应用中，所述抗MERS冠状病毒产品为抗MERS冠状病毒抗体。
上述蛋白在作为抗MERS冠状病毒抗体中的应用也是本发明保护的范围。
本发明第二个目的是提供一种抗MERS冠状病毒产品。
本发明提供的产品，其活性成分为上述蛋白。
上述产品中，所述抗MERS冠状病毒产品为抗MERS冠状病毒抗体。
本发明还提供了一种表达所述Nano-Anti-MRBD的方法。
本发明所提供的表达所述Nano-Anti-MRBD的方法，是将含有所述Nano-Anti-MRBD编码基因的重组表达载体导入宿主细胞，表达得到所述蛋白。
所述重组表达载体具体可为上述pCold I-Nano-Anti-MRBD，所述宿主细胞具体可为将所述pCold I-Nano-Anti-MRBD转入大肠杆菌BL21(DE3)(全式金公司)得到的重组大肠杆菌细胞。
本发明还提供了Nano-Anti-MRBD的纯化方法。
本发明的实验证明了，本发明通过分子生物学的方法构建了小分子抗体Nano-Anti-MRBD，ELISA实验表明，Nano-Anti-MRBD与MERS冠状病毒的受体结合区(RBD)具有很强的反应性；中和试验表明，Nano-Anti-MRBD对MERS冠状病毒具有良好的中和活性，表明Nano-Anti-MRBD是一种对MERS冠状病毒具有中和活性的小分子抗体，在MERS冠状病毒的防治中将发挥重要作用。
附图说明
图1为重组表达载体pCold I-Nano-Anti-MRBD的PCR鉴定图谱。
图2为Nano-Anti-MRBD小量诱导表达SDS-PAGE鉴定图。
图3为Nano-Anti-MRBD表达形式SDS-PAGE鉴定图。
图4为Nano-Anti-MRBD纯化SDS-PAGE鉴定图。
图5为Nano-Anti-MRBD浓缩后SDS-PAGE鉴定图。
图6为Nano-Anti-MRBD与MERS冠状病毒RBD反应性检测结果。
图7为Nano-Anti-MRBD对MERS冠状病毒中和活性检测结果。
具体实施方式
下述实施例中所使用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材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1、Nano-Anti-MRBD的表达及鉴定
1、小分子抗体Nano-Anti-MRBD及表达载体pCold I-Nano-Anti-MRBD的构建
根据大肠杆菌的偏爱密码子，人工合成序列表中序列2所示的Nano-Anti-MRBD(其氨基酸序列是序列表中的序列1)的编码基因，序列2的自5′末端第1-6位为BamHI的识别位点，序列2的自5′末端第7-399位(共393个核苷酸)为Nano-Anti-MRBD的编码序列，序列2的自5′末端第400-405位为终止密码子，序列2的自5′末端第406-411位为SalI的识别位点。
以BamHI和SalI双酶切Nano-Anti-MRBD的编码基因，与经相同酶切的pCold I载体(TAKARA公司D3361)连接，并转化大肠杆菌BL21(DE3)(全式金公司CD601)感受态细胞，挑选氨苄青霉素抗性克隆，提取质粒进行PCR鉴定及测序鉴定，将鉴定正确的重组质粒命名为pCold I-Nano-Anti-MRBD。
pCold I-Nano-Anti-MRBD的PCR鉴定图谱如图1所示，得到长度为411bp的Nano-Anti-MRBD条带(箭头示)。图1中，1泳道为PCR扩增的Nano-Anti-MRBD，2泳道为Trans 2KPlus DNA Marker(全式金公司BM111)，可以看出，得到411bp的Nano-Anti-MRBD的编码基因，表明载体构建成功。
pCold I-Nano-Anti-MRBD为将序列表中序列2所示的Nano-Anti-MRBD的编码基因替换pCold I载体的BamHI和SalI双酶切位点间DNA片段的载体。
2、小分子抗体Nano-Anti-MRBD在原核表达系统中的表达和纯化
1)Nano-Anti-MRBD的小量诱导表达
将pCold I-Nano-Anti-MRBD转入大肠杆菌BL21(DE3)(全式金公司CD601)，得到重组大肠杆菌pCold I-Nano-Anti-MRBD/BL21(DE3)；将pCold I(空质粒，TAKARA公司D3361)转入大肠杆菌BL21(DE3)得到重组大肠杆菌pCold I/BL21(DE3)，作为阴性对照组。从阳性重组质粒表达菌pCold I-Nano-Anti-MRBD/BL21(DE3)及阴性对照菌pCold I/BL21(DE3)挑取单克隆菌落分别接种5ml LB培养基中(含100μg/ml氨苄青霉素，全式金公司GG101-01)，37℃振荡培养10小时。将菌液以1：100的体积比转接于新鲜的5ml LB培养基中(含100μg/ml氨苄青霉素，全式金公司GG101-01)，37℃震荡培养3h，至OD600在0.5-1.0之间。加入终浓度为0.4mM的IPTG(TAKARA公司D9030A)，在15℃诱导12小时；同时设置未用IPTG进行诱导表达的对照。诱导表达12小时后，同时收集各菌液。一方面取1ml各菌液离心，收集菌体做全菌SDS-PAGE电泳样品；另一方面取3ml各菌液离心，将菌体重悬后进行超声破碎，分别收集超声上清及包涵体沉淀，对超声上清及包涵体沉淀分别做SDS-PAGE电泳样品。
2)Nano-Anti-MRBD表达的SDS-PAGE鉴定
取pCold I-Nano-Anti-MRBD/BL21(DE3)的诱导表达菌液及未诱导表达菌液各1ml，pCold I/BL21(DE3)的诱导表达菌液及未诱导表达菌液各1ml。分别移入1.5ml EP管，12000rpm，离心1min，弃上清，用生理盐水洗涤后，加入125μl生理盐水和等体积2×SDS上样缓冲液(TAKARA公司D620)，混匀，100℃煮沸10min，自然冷却后，12000rpm，离心1min，取30μl上清(约40μg)上样于凝胶加样孔内。分离胶浓度为12％(金斯瑞公司M01210)，恒定电压140V电泳1小时。电泳完毕后，考马斯亮蓝染色观察。
结果如图2所示，1泳道为蛋白Marker(Thermo公司26616)；2泳道为pCold I-Nano-Anti-MRBD/BL21(DE3)诱导表达组；3泳道为pCold I-Nano-Anti-MRBD/BL21(DE3)未诱导组；4泳道为pCold I/BL21(DE3)诱导表达组；5泳道为pCold I/BL21(DE3)未诱导组；表明pCold I-Nano-Anti-MRBD/BL21(DE3)表达得到了大小为17kDa的Nano-Anti-MRBD(箭头示)，而pCold I/BL21(DE3)不表达大小为17kDa的Nano-Anti-MRBD。
3)Nano-Anti-MRBD表达形式的鉴定
取pCold I-Nano-Anti-MRBD/BL21(DE3)的诱导表达菌液3ml，12000rpm，离心1min收集菌体于1.5ml离心管。PBS缓冲液洗涤菌体2次，而后用400μl PBS缓冲液重悬菌体。超声破碎仪冰浴破碎重悬菌体(功率100W，超声时间5s，间歇10s，总程10min)，4℃12000rpm离心10min，获得超声上清液和粗制包涵体沉淀。分别做总菌、超声上清液及粗制包涵体沉淀的SDS-PAGE电泳样品，而后进行SDS-PAGE电泳鉴定。电泳结果如图3所示，1泳道为蛋白Marker(Thermo公司26616)；2泳道为pCold I-Nano-Anti-MRBD/BL21(DE3)诱导表达组全菌样品；3泳道为pCold I-Nano-Anti-MRBD/BL21(DE3)诱导表达组粗制包涵体沉淀样品；4泳道为pCold I-Nano-Anti-MRBD/BL21(DE3)诱导表达组超声上清样品。表明Nano-Anti-MRBD在超声上清和粗制包涵体沉淀中均有存在，属部分可溶性表达。
4)Nano-Anti-MRBD的大量诱导表达
取重组大肠杆菌pCold I-Nano-Anti-MRBD/BL21(DE3)甘油菌接种5ml LB培养基中(含100μg/ml氨苄青霉素)，37℃振荡培养10小时。将菌液以1：100的体积比转接于新鲜的500ml LB培养基中(含100μg/ml氨苄青霉素)，37℃震荡培养3h，至OD600在0.5-1.0之间。加入终浓度为0.4mM的IPTG，在15℃诱导12小时。12000rpm离心10分钟收集菌体沉淀，使用25ml结合缓冲液Buffer A(50mM HEPES，500mM NaCl，pH7.5)重悬菌体沉淀。加入适量的蛋白酶抑制剂(Roche公司4693132001)，超声破碎重悬的菌体(240W，超声5s，间歇10s，总程25min)。4℃，13000rpm离心15分钟，将离心上清转入新的离心管；4℃，13000rpm再次离心15分钟，彻底去除沉淀。使用0.22μm滤器(PALL公司PN4612)过滤离心上清于50ml细心管，即获得了超声上清样品。
5)Nano-Anti-MRBD的纯化
pCold I载体表达蛋白带有组氨酸标签，利用这一特性可以采用Ni亲和层析的方法进行纯化，具体操作按照HisTrap HP说明书进行(GE Healthcare公司17524701)。使用Ni柱为5ml柱体积的预装柱，纯化方法简述如下：使用结合缓冲液Buffer A平衡镍柱5个柱体积，平衡流速为5ml/min；将超声上清样品上样，上样流速为1ml/min；用结合缓冲液BufferA再洗5个柱体积，流速为5ml/min；使用10％、20％、100％(对应含50、100、500mM咪唑)浓度的洗脱缓冲液Buffer B(50mM HEPES，500mM NaCl，500mM咪唑，pH7.5)洗脱蛋白，流速为2ml/min，分别对应收集各洗脱峰1管、1管和4管，最后用纯水洗5个柱体积，再用20％的乙醇洗5个柱床体积，流速为5ml/min，柱子置于4℃环境中保存。
将纯化过程中的样品进行SDS电泳鉴定，结果如图4所示，1泳道为蛋白Marker(Thermo公司26616)；2泳道为全菌样品；3泳道为粗制包涵体沉淀样品；4泳道为超声上清样品；5泳道为穿柱液样品；6泳道500mM咪唑洗脱样品-1；7泳道500mM咪唑洗脱样品-2；8泳道500mM咪唑洗脱样品-3；9泳道500mM咪唑洗脱样品-4。表明500mM咪唑洗脱样品-2中Nano-Anti-MRBD蛋白很纯，选其用于后续实验。
5)Nano-Anti-MRBD蛋白的浓缩
使用3kDa超滤管(Merck Millipore公司UFC900396)浓缩Nano-Anti-MRBD蛋白，具体步骤如下：取4ml 500mM咪唑洗脱样品-2稀释于8ml PBS缓冲液中，将稀释液转入3kDa超滤管，4℃，4000×g离心60分钟；将被截留的液体(约0.5ml)用12ml PBS缓冲液稀释，4℃，4000×g离心60分钟；浓缩后蛋白终体积约0.5ml，取少量浓缩蛋白进行浓度测定及SDS电泳鉴定，其余分装冻存于-70℃。SDS电泳鉴定结果如图5所示，1泳道为蛋白Marker(Thermo公司26616)；2泳道为浓缩后的Nano-Anti-MRBD蛋白。Nano-Anti-MRBD蛋白浓度测定为1.1mg/ml。
实施例2、小分子抗体Nano-Anti-MRBD与MERS冠状病毒RBD的反应性检测
间接ELISA方法检测Nano-Anti-MRBD与MERS冠状病毒RBD的反应性，具体步骤如下：分别使用MERS冠状病毒RBD-Fc蛋白(MERS冠状病毒S蛋白RBD功能区与人IgG Fc片段的融合蛋白,其氨基酸序列为序列3：)及EDIII-Fc对照蛋白(乙型脑炎病毒E蛋白DIII功能区与人IgG Fc片段的融合蛋白，其氨基酸序列为序列4：)包被96孔酶标板，包被浓度为2μg/ml，每孔50μl；使用不同浓度的实施例1获得的蛋白Nano-Anti-MRBD作为一抗；使用HRP-His鼠单克隆抗体(康为世纪公司CW0285M)作为二抗。
ELISA检测结果如图6所示，当Nano-Anti-MRBD浓度为0.08μg/ml时，依然和MERS冠状病毒RBD-Fc蛋白具有很好的反应性；而Nano-Anti-MRBD基本不和对照蛋白反应。表明Nano-Anti-MRBD与MERS冠状病毒RBD具有很好的反应性，可作为其小分子抗体。
实施例3、小分子抗体Nano-Anti-MRBD对MERS冠状病毒的中和活性检测
利用中和试验检测小分子抗体Nano-Anti-MRBD对MERS冠状病毒的中和活性，具体步骤如下：分别使用不同浓度的Nano-Anti-MRBD及对照抗体(抗SARS冠状病毒中和单抗Anti-SARS-33G4，文献出处：Receptor-Binding Domain of Severe Acute RespiratorySyndrome Coronavirus Spike Protein Contains Multiple Conformation-DependentEpitopes that Induce Highly Potent Neutralizing Antibodies.Yuxian He,Hong Lu,Pamela Siddiqui,Yusen Zhou,Shibo Jiang.The Journal of Immunology,April 15,2005；174(8):4908-4915.doi:10.4049/jimmunol.174.8.4908)同MERS冠状病毒EMC株(文献出处：Isolation of a Novel Coronavirus from a Man with Pneumonia in SaudiArabia.Ali M.Zaki,Sander van Boheemen,Theo M.Bestebroer,AlbertD.M.E.Osterhaus,Ron A.M.Fouchier.The New England journal of medicine,2012November 8；367(19):1814-1820.doi:10.1056/NEJMoa1211721.)0.1MOI于37℃孵育1小时；将混合液接种于Vero E6单层细胞(ATCC CRL-1586)72小时后观察Vero E6细胞产生的细胞病变效应(CPE)，利用ND50评价Nano-Anti-MRBD对MERS冠状病毒的中和活性。
结果如图7所示，表明小分子抗体Nano-Anti-MRBD在浓度为0.833μg/ml时，依然能够使50％以上数量的实验孔不产生CPE，Nano-Anti-MRBD对MERS冠状病毒具有良好的中和活性。
序列表
<110> 中国人民解放军军事医学科学院微生物流行病研究所
<120>一种对中东呼吸综合征冠状病毒具有中和活性的小分子抗体及其应用
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aataaagtaa ctgggccctt aggagcgaat gactactgtt cagggaattg gcgtgagtat 360
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Claims (10)
1.一种蛋白，是如下1)或2)或3)：
1)序列表中序列1所示的蛋白质；
2)将序列表中序列1所示的氨基酸序列经过一个或几个氨基酸残基的取代和/或缺失和/或添加且具有相同功能由序列1衍生的蛋白质；
3)基于序列表中序列1所示的氨基酸序列进行人源化改造的由(a)衍生的蛋白质。
2.编码权利要求1所述蛋白质的DNA分子。
3.如权利要求2所述的DNA分子，其特征在于：所述DNA分子是如下1)-3)中任一种的DNA分子：
1)编码区为序列表中序列2所示的DNA分子；
2)编码区为序列表中序列2第7-399位所示的DNA分子；
3)在严格条件下与1)或2)限定的DNA序列杂交且编码具有相同功能蛋白质的DNA分子；
4)与1)或2)限定的DNA序列至少具有70％、至少具有75％、至少具有80％、至少具有85％、至少具有90％、至少具有95％、至少具有96％、至少具有97％、至少具有98％或至少具有99％同源性且编码具有相同功能蛋白质的DNA分子。
4.含有权利要求2或3所述DNA分子的重组载体、表达盒、转基因细胞系或重组菌。
5.扩增权利要求2或3所述DNA分子全长或其任意片段的引物对。
6.权利要求1所述蛋白、权利要求2或3所述DNA分子或权利要求4所述重组载体、表达盒、转基因细胞系或重组菌在制备抗MERS冠状病毒产品中的应用；
或，权利要求1所述蛋白、权利要求2或3所述DNA分子或权利要求4所述重组载体、表达盒、转基因细胞系或重组菌在治疗或预防MERS冠状病毒中的应用。
或，权利要求1所述蛋白、权利要求2或3所述DNA分子或权利要求4所述重组载体、表达盒、转基因细胞系或重组菌在制备治疗或预防MERS冠状病毒产品中的应用。
7.根据权利要求6所述的应用，其特征在于：所述抗MERS冠状病毒产品为抗MERS冠状病毒抗体。
8.权利要求1所述蛋白在作为抗MERS冠状病毒抗体中的应用。
9.一种抗MERS冠状病毒产品或治疗或预防MERS冠状病毒产品，其活性成分为权利要求1所述蛋白。
10.根据权利要求9所述的产品，其特征在于：所述产品为抗MERS冠状病毒抗体。
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