CN113880947B - 小分子抗体及其编码基因和制备方法及应用和药物组合物 - Google Patents
小分子抗体及其编码基因和制备方法及应用和药物组合物 Download PDFInfo
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Abstract
本发明涉及生物技术领域,具体涉及一种小分子抗体及其编码基因和制备方法及应用和药物组合物。本发明提供的小分子抗体能够高效特异性结合SARS冠状病毒受体结合区,且对SARS冠状病毒具有良好的中和活性,这说明本发明提供的小分子抗体具有用于SARS冠状病毒防治的潜力。
Description
技术领域
本发明涉及生物技术领域,具体涉及一种小分子抗体及其编码基因和制备方法及应用和药物组合物。
背景技术
严重急性呼吸综合征(severe acute respiratory syndrome,SARS)又称为“非典型肺炎”,是由SARS冠状病毒(SARS-CoV)引起的急性呼吸道传染病,开发抗SARS冠状病毒产品对于SARS的预防和治疗具有十分重要的意义。
一般而言,疫苗是对于病毒性传染病而言最有效的预防手段之一,然而,迄今为止仍然没有SARS冠状病毒疫苗上市推广,这使得目前针对SARS的防治手段十分匮乏。研究表明,SARS疫苗研发进展困难不仅是因为自2003年后再未出现SARS疫情导致对该疫苗的需求和研发必要性的下降造成的,更是由于SARS冠状病毒本身的一些特性导致了疫苗开发困难造成的。因此,研发其他类型的抗病毒产品用于SARS防治就显得尤为迫切。
发明内容
本发明的目的是为了克服现有技术存在的缺少针对SARS冠状病毒的抗病毒产品,从而使得对SARS的防治手段匮乏的问题,提供一种小分子抗体及其编码基因和制备方法及应用和药物组合物。本发明提供的小分子抗体能够特异性结合SARS冠状病毒受体结合区,对SARS冠状病毒具有良好的中和性,可以在SARS预防和治疗工作中发挥重要作用。
为了实现上述目的,本发明一方面提供一种小分子抗体,所述抗体包括:
(1)氨基酸序列如SEQ ID NO:1所示的蛋白质;
(2)氨基酸序列如SEQ ID NO:1所示的蛋白质经改造获得的与改造前具有相同活性的衍生蛋白质。
本发明第二方面提供编码前述小分子抗体的基因。
本发明第三方面提供一种制备如前所述的小分子抗体的方法,所述方法包括:将含有前述基因的重组载体导入宿主细胞,表达获得所述小分子抗体。
本发明第四方面提供含有如前所述的基因的重组载体、表达盒和表达载体。
本发明第五方面提供扩增如前所述的基因或其片段的引物。
本发明第六方面提供如前所述的小分子抗体、基因、重组载体、表达盒和表达载体或引物在制备针对严重急性呼吸综合征冠状病毒的抗病毒产品中的应用。
本发明第七方面提供一种药物组合物,所述药物组合物包括如前所述的小分子抗体、基因或重组载体、表达盒和表达载体。
本发明提供的小分子抗体通过分子生物学方法构建获得,经实验验证,其与SARS冠状病毒的受体结合区(receptor-binding domain,RBD)具有很强的反应性,且对SARS冠状病毒具有良好的中和活性。这表明该小分子抗体能够(单独或与其他抗体配合)作为活性组分,发挥对SARS冠状病毒的防治作用。
附图说明
图1为本发明实施例1中获得的表达载体pCold I-Nano-Anti-SRBD的测序结果。
图2为本发明实施例1中获得的纯化样品的SDS-PAGE结果。
图3为本发明实施例1中获得的浓缩Nano-Anti-SRBD蛋白样品的SDS-PAGE结果。
图4为本发明实施例2中获得的ELISA检测结果示意图。
图5为本发明实施例3中获得的对SARS冠状病毒假病毒的中和活性检测结果示意图。
具体实施方式
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
本发明中,“SARS”为“严重急性呼吸综合征”的简写形式,其二者含义相同,可以互换使用。
单域重链抗体(the variable domain of the heavy-chain of heavy-chainantibody,VHH)是由重链可变区结合抗原的单一结构域构成的小分子抗体,是具有完整的抗原结合活性的单一折叠单元。单域重链抗体的制备方法简单,能够采用大肠杆菌等工程菌进行表达生产,而且与具有轻链和重链的完整结构的抗体相比,单域重链抗体的分子(量)小,更易通过血管壁,更利于发挥治疗作用,而且能与分布于病毒表面凹槽的抗原结合,更利于病毒性疾病的防治。
本发明的发明人在研究的过程中巧妙地通过分子生物学方法构建了一种针对SARS冠状病毒的单域重链抗体(氨基酸序列如SEQ ID NO:1所示),该抗体能够与SARS冠状病毒的受体结合域特异性结合,并且具有良好的SARS冠状病毒中和性,从而具有应用于SARS冠状病毒防治相关产品研发的潜力。
本发明一方面提供一种小分子抗体,所述抗体包括:
(1)氨基酸序列如SEQ ID NO:1所示的蛋白质;
(2)氨基酸序列如SEQ ID NO:1所示的蛋白质经改造获得的与改造前具有相同活性的衍生蛋白质。
本发明提供的小分子抗体可以是在活性相同的情况下,将上述蛋白质(1)进行任意本领域现有方式的改造获得的衍生蛋白质,对于其改造方法和改造后的衍生蛋白质的具体序列和特性没有特别限定。
根据本发明的优选实施方式,其中,所述改造可以包括:
i、将SEQ ID NO:1所示的氨基酸序列中的一个或几个氨基酸残基进行取代、缺失和添加中的至少一种;和/或
ii、在SEQ ID NO:1所示的氨基酸序列的N末端和/或C末端连接便于纯化的标签和/或利于蛋白分泌表达的信号肽序列;和/或
iii、将SEQ ID NO:1所示的氨基酸序列进行人源化改造。
本发明中,改造方式iii可以采用任意本领域现有的对蛋白质(尤其是单域重链抗体)进行人源化改造的方式。优选地,可以通过将SEQ ID NO:1所示的氨基酸序列的编码基因进行人源化改造实现。
本发明提供的小分子抗体可以通过将SEQ ID NO:1所示的氨基酸序列经过上述改造方式i、ii和iii中的任意一种或几种的组合处理获得,只要改造后的衍生蛋白质具有与SEQ ID NO:1所示的氨基酸序列相同的活性即可。
任意本领域现有的能够方便蛋白质纯化的标签均可适用于本发明提供的小分子抗体。优选地,所述便于纯化的标签选自Poly-Arg、Poly-His、FLAG、Strep-tag II和c-myc中的至少一种。上述标签的具体氨基酸序列没有特别限制,例如可以为如下表1中所示的序列。
表1便于纯化的标签序列
*Poly-Arg可以由5-6个精氨酸残基组成,表1中仅列出了通常采用的5个精氨酸残基组成的Poly-Arg标签,但是6个精氨酸残基组成的Poly-Arg标签也可适用于本发明。
**Poly-His可以由2-10个组氨酸残基组成,表1中仅列出了通常采用的6个组氨酸残基组成的Poly-His标签,但是2-10个组氨酸组成的Poly-His标签均可适用于本发明。
任意本领域现有的能够利于蛋白分泌表达的信号肽序列均可适用于本发明提供的小分子抗体。优选地,所述信号肽序列选自人IL-2SP、CD5 SP、人IgG2 H SP、人胰凝乳蛋白酶原SP、人胰蛋白酶原-2SP、人胰岛素SP。
本发明第二方面提供编码如上所述的小分子抗体的基因。
任意能够编码如上所述的小分子抗体的基因均属于本发明的内容。根据本发明的优选实施方式,其中,所述基因包括:
a、编码区核苷酸序列如SEQ ID NO:2所示的DNA分子;和/或
b、编码区核苷酸序列如SEQ ID NO:3所示的DNA分子;和/或
c、与DNA分子a或b具有至少70%同源性,并编码具有相同功能的蛋白质的DNA分子;和/或
d、DNA分子a或b经突变或改造获得的编码具有相同功能的蛋白质的DNA分子。
本发明中,上述DNA分子a可以仅包含SEQ ID NO:2所示的序列,也可以是以SEQ IDNO:2所示的序列为编码区,并额外添加其他组件的DNA分子。所述其他组件可以包括任意本领域用于人工合成基因序列并通过表达载体进行表达时所需的组件,例如启动子、增强子、Kozak序列等。
本发明中,上述DNA分子b可以仅包含SEQ ID NO:3所示的序列,也可以是以SEQ IDNO:3所示的序列为编码区,并额外添加其他组件的DNA分子。所述其他组件可以包括任意本领域用于人工合成基因序列并通过表达载体进行表达时所需的组件,例如启动子、增强子、Kozak序列等。
优选地,上述DNA分子c与DNA分子a或b具有至少75%、至少80%、至少85、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同源性,并且编码具有相同功能的蛋白质。所述“具有相同功能的蛋白质”的氨基酸序列与DNA分子a或b所编码的蛋白质的氨基酸序列可以相同,也可以不同。
本发明中,上述DNA分子d可以经过任意本领域现有的基因突变或改造方式获得,只要最终获得的DNA分子d所表达的蛋白质与DNA分子a或b所表达的蛋白质的功能相同即可。
根据本发明的一种优选实施方式,其中,所述DNA分子d可以通过将其他DNA分子在严格杂交条件下与DNA分子a或b杂交获得。
优选地,所述其他DNA分子可以为任意不影响DNA分子a或b功能,且杂交获得的DNA分子d的表达产物仅为与DNA分子a或b表达产物具有相同功能的蛋白质的DNA分子。
优选地,所述严格杂交条件可以为在60-70℃(最优选65℃)的温度下,于杂交溶液中进行杂交,然后用洗膜溶液进行洗膜。
更优选地,所述杂交溶液为含有0.1-1重量%十二烷基硫酸钠(SDS)的柠檬酸钠缓冲液(SSC缓冲液),优选所述SCC缓冲液为氯化钠和柠檬酸钠的水溶液,其中氯化钠浓度为0.8-1M,柠檬酸钠浓度为0.08-0.1M。
优选地,所述洗膜采用分步操作的方式进行,且每步采用不同的洗膜溶液。优选采用如下方式进行分步洗膜:
第一洗膜:采用含有0.01-0.2重量%SDS的SCC缓冲液作为第一洗膜溶液洗膜一次,所述SCC缓冲液中氯化钠浓度为0.2-0.4M,柠檬酸钠的浓度为0.02-0.04M。
第二洗膜:采用含有0.01-0.2重量%SDS的SCC缓冲液作为第二洗膜溶液洗膜一次,所述SCC缓冲液中氯化钠浓度为0.1-0.2M,柠檬酸钠的浓度为0.01-0.02M。
更优选地,第一洗膜溶液和第二洗膜溶液中的SDS含量相同。
更优选地,第一洗膜溶液采用的SCC缓冲液浓度高于第二洗膜溶液,优选第一洗膜溶液采用的SCC缓冲液的浓度是第二洗膜溶液采用的SCC缓冲液浓度的1.5-2.5倍。
本发明第三方面提供一种制备如前所述的小分子抗体的方法,其特征在于,所述方法包括:将含有如上所述的基因的重组载体导入宿主细胞,表达获得所述小分子抗体。
任意本领域中能够插入上述基因,并在宿主细胞中表达所述小分子抗体的重组载体均可适用于本发明。根据本发明的优选实施方式,其中,所述重组载体选自pCold I载体、pQE30载体、pET32a载体、pcDNA3.1载体和pPICZ载体中的至少一种。优选为pCold I载体。
任意本领域用于表达外源性基因的宿主细胞均可适用于本发明。根据本发明的优选实施方式,其中,所述宿主细胞选自大肠杆菌、293T细胞和酵母菌中的至少一种。
根据本发明的优选实施方式,其中,所述方法还包括对表达获得的小分子抗体进行纯化的方法。
任意本领域用于纯化宿主细胞表达的外源性蛋白的方法均可适用于本发明。例如,可以利用载体中或所述小分子抗体中带有的便于纯化的标签(如表1中的标签)进行纯化。
本发明第四方面提供含有如前所述的基因的重组载体、表达盒和表达载体。
本发明中,任意含有如前所述的基因的重组载体或表达盒均属于本发明的保护范围,本领域技术人员可以根据实际情况对其进行具体选择和调整。
本发明中,任意含有如前所述的基因的表达载体均属于本发明的保护范围。优选地,所述表达载体包括(含有如前所述的基因的)转基因细胞系、重组菌和重组酵母中的至少一种。
本发明第五方面提供扩增如前所述的基因或其片段的引物。
本发明中,所述引物用于扩增如前所述的基因(例如前述DNA分子a、DNA分子b、DNA分子c和DNA分子d)的全长序列,或用于扩增如前所述的基因中的任意长度的片段(例如扩增其中的编码区,即核苷酸序列如SEQ ID NO:2或SEQ ID NO:3所示的DNA分子,或扩增其中含有编码区和部分非编码区的片段)。
本发明第六方面提供如前所述的小分子抗体、基因、重组载体、表达盒和表达载体或引物在制备针对SARS冠状病毒的抗病毒产品中的应用。
本发明中,所述在制备针对SARS冠状病毒的抗病毒产品中的应用可以包括利用如前所述的小分子抗体、基因、重组载体、表达盒和表达载体或引物进行所述抗病毒产品的研发和/或生产。
本发明第七方面提供一种药物组合物,所述药物组合物包括如前所述的小分子抗体、基因或重组载体、表达盒和表达载体。
优选地,所述药物组合物还包括药学上可接受的辅料。所述辅料可以为任意本领域现有的用于药物组合物制备的辅料,只要该辅料不影响活性组分(即如前所述的小分子抗体、基因或重组载体、表达盒和表达载体)的功能和作用即可。
本发明提供的药物组合物中,可以仅以如前所述的小分子抗体(或其编码基因或重组载体、表达盒和表达载体)作为活性组分,也可以将其与其他抗体(或药物)配合作为活性组分。所述其他抗体(或药物)可以是本领域中任意抗SARS冠状病毒的抗体(或药物),也可以是本领域中任意能够调节前述小分子抗体功能的抗体(或药物),还可以是与SARS相关的衍生疾病防治有关的抗体(或药物)。
以下将通过实施例对本发明进行详细描述。应当能够理解的是,以下实施例仅用于示例性地解释和说明本发明的内容,而不用于限制本发明的范围。
以下实施例中采用的基因片段均为委托金斯瑞公司合成。未经特殊说明的情况下,采用的试剂均购自正规化学或生物试剂供应商,纯度为分析纯。
实施例1
本实施例用于说明小分子抗体Nano-Anti-SRBD的表达和鉴定。
(一)表达载体构建
发明人设计了SEQ ID NO:2所示的核苷酸序列作为小分子抗体Nano-Anti-SRBD(氨基酸序列如SEQ ID NO:1所示)的编码基因,其中,5’末端第1-6位为BamH I的识别位点,第7-375位(即SEQ ID NO:3所示的核苷酸序列)为Nano-Anti-SRBD编码序列,第376-381位为Xba I的识别位点。
采用BamH I和Xba I(均购自Thermofisher公司,牌号分别为FD0055和FD0685)分别对小分子抗体Nano-Anti-SRBD的编码基因和pCold I载体(购自TAKARA公司,牌号为D3361,其表达蛋白带有Poly-His标签(该标签的氨基酸序列如SEQ ID NO:8所示)进行双酶切,并将酶切产物连接,获得表达载体pCold I-Nano-Anti-SRBD。
利用表达载体pCold I-Nano-Anti-SRBD转化大肠杆菌BL21(DE3)(购自博迈德公司,牌号为BC201)感受态细胞,获得重组大肠杆菌pCold I-Nano-Anti-SRBD/BL21(DE3),利用含100μg/mL氨苄青霉素的LB固体培养基进行培养,挑选氨苄青霉素抗性克隆,提取质粒进行测序鉴定(委托诺赛公司完成)。测序结果如图1所示,其中用方框圈出了BamH I和XbaI的酶切位点。
理论而言,表达载体pCold I-Nano-Anti-SRBD的序列应为将pCold I载体中BamHI和Xba I的酶切位点间的DNA片段替换为Nano-Anti-SRBD的编码基因(SEQ ID NO:2)的核苷酸序列。经比对,该测序结果与理论序列完全一致,说明表达载体构建成功。
(二)小分子抗体的表达和纯化
取含有正确重组质粒的重组大肠杆菌pCold I-Nano-Anti-SRBD/BL21(DE3)接种于5mL LB液体培养基(含100μg/mL氨苄青霉素)中,37℃震荡培养10h,获得种子液。
将上述种子液以1:100的体积比接种于新鲜的500mL LB液体培养基(含100μg/mL氨苄青霉素)中,37℃振荡培养3h,至OD600达到0.5±0.1。加入异丙基-β-D-硫代半乳糖苷(IPTG),加入量使得IPTG的终浓度为0.4mM,15℃诱导培养24h。
诱导培养结束后12000rpm离心10min收集菌体沉淀,使用25mL结合缓冲液BufferA(50mM HEPES,500mM NaCl,pH 7.5)重悬菌体沉淀。超声破碎重悬的菌体(超声破碎条件:240W,处理总时长60min,期间每隔10s间歇超声处理5s)。
超声破碎后在4℃下13000rpm离心15min,将离心上清转入新的离心管;再次在4℃下13000rpm离心15min,彻底去除沉淀。使用0.22μm滤器(购自PALL公司,牌号为PN4612)过滤离心上清于50mL细离心管中,即获得了超声上清样品。
利用pCold I载体表达蛋白所带的Poly-His标签,采用Ni亲和层析的方法需超声上清样品进行纯化。所用的Ni柱为HisTrap HP层析柱(购自GE Healthcare公司,牌号为17524701),其为5mL柱体积的预装柱,按照以下方法进行纯化: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Buffer A再洗5个柱体积,流速为5mL/min;分别使用5%、10%、100%(对应含25mM、50mM、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(即为纯化样品),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。
将收集获得的纯化样品进行SDS电泳鉴定,结果如图2所示。图2中,M泳道为蛋白Marker(购自全式金公司,牌号为DM101),1-3泳道分别为25mM、50mM和500mM咪唑洗脱的纯化样品,由图2可看出,500mM咪唑洗脱的纯化样品纯度最高。
使用3kDa超滤管(购自Merck Millipore公司,牌号为UFC900396)对Nano-Anti-SRBD蛋白进行浓缩,具体步骤如下:取4mL 500mM咪唑洗脱的纯化样品与8mL PBS缓冲液混合获得稀释液,将稀释液转入3kDa超滤管,在4℃下4000×g离心60min;将被截留的液体(约0.5mL)与12mL PBS缓冲液混合,而后再于4℃下4000×g离心60min,获得的被截留的液体即为浓缩Nano-Anti-SRBD蛋白样品,体积约0.5mL。取少量浓缩Nano-Anti-SRBD蛋白样品进行浓度测定及SDS电泳鉴定,其余分装后于-70℃冻存。
蛋白浓度检测结果显示浓缩Nano-Anti-SRBD蛋白样品的浓度为1.48mg/mL。
SDS电泳鉴定结果如图3所示,其中,M泳道为蛋白Marker(购自Thermo公司,牌号为26616),1泳道为浓缩Nano-Anti-SRBD蛋白样品。
实施例2
本实施例用于说明小分子抗体Nano-Anti-SRBD与SARS冠状病毒的结合特性。
采用间接ELISA法检测Nano-Anti-SRBD与SARS冠状病毒RBD的反应性,具体方法如下:
实验组:SARS冠状病毒RBD-Fc蛋白(SARS冠状病毒S蛋白RBD功能区与人IgG Fc片段的融合蛋白,其氨基酸序列如SEQ ID NO:4所示)
对照组I: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,其氨基酸序列如SEQ ID NO:5所示)
对照组II:新型冠状病毒RBD-Fc蛋白(新型冠状病毒S蛋白RBD功能区与人IgG Fc片段的融合蛋白,其氨基酸序列如SEQ ID NO:6所示)
分别使用以上实验组、对照组I和对照组II的蛋白包被96孔酶标板,包被浓度为1μg/mL,每孔50μL。用封闭液(含3重量%BSA的PBS溶液)将实施例1获得的浓缩Nano-Anti-SRBD蛋白样品配制成不同浓度的蛋白溶液作为一抗,使用HRP-His鼠单克隆抗体(购自康为世纪公司,牌号为CW0285M)作为二抗。
ELISA检测结果如图4所示,图中SARS-CoV RBD、MERS-CoV RBD和SARS-CoV-2RBD对应的曲线分别代表实验组、对照组I和对照组II的检测结果。由图中可以看出,小分子抗体Nano-Anti-SRBD与SARS冠状病毒RBD-Fc蛋白反应性很好,说明其能够很好地结合,进一步的结果显示其EC50值为4.76ng/mL;相比之下,小分子抗体Nano-Anti-SRBD与MERS冠状病毒RBD-Fc蛋白和新型冠状病毒RBD-Fc蛋白基本没有反应,说明该小分子抗体几乎不与这两个对照蛋白结合。由此说明了本发明提供的小分子抗体Nano-Anti-SRBD能够很好地特异性结合SARS冠状病毒RBD。
实施例3
本实施例用于说明小分子抗体Nano-Anti-SRBD对SARS冠状病毒假病毒的中和活性。
本实施例中采用的Huh-7细胞购自ATCC,采用的SARS冠状病毒假病毒(含萤火虫荧光素酶报告基因)的制备方法参照:A safe and convenient pseudovirus-basedinhibition assay to detect neutralizing antibodies and screen for viral entryinhibitors against the novel human coronavirus MERS-CoV.Zhao G,Du L,Ma C,etal.Virol J.2013;10:266.doi:10.1186/1743-422X-10-266。
实验抗体:实施例1获得的浓缩Nano-Anti-SRBD蛋白样品
对照抗体:Anti-MERS-NbMS10(抗MERS冠状病毒中和抗体,制备方法参照:A NovelNanobody Targeting Middle East Respiratory Syndrome Coronavirus(MERS-CoV)Receptor-Binding Domain Has Potent Cross-Neutralizing Activity and ProtectiveEfficacy against MERS-CoV.Zhao G,He L,Sun S,et al.J Virol.2018;92(18):e00837-18.doi:10.1128/JVI.00837-18。
实验组:采用不同浓度的抗体(利用DMEM高糖培养基对实验抗体或对照抗体进行稀释获得)进行处理
对照组I:以等体积DMEM高糖培养基替代抗体进行处理,其他操作与实验组相同,即病毒对照组
对照组II:以等体积DMEM高糖培养基替代抗体和假病毒(溶液),其他操作与实验组相同,即细胞对照组
使用96孔板,分别将50μL/孔不同浓度的实验抗体和对照抗体与500TCID50的SARS冠状病毒假病毒(加入量为100μL/孔)混合,于37℃孵育1小时。向孵育后的混合液中加入100μL的Huh-7细胞(约4×104个细胞/孔),即培养体系为250μL/孔,37℃培养48小时。
而后吸弃部分培养基(150μL/孔),加入显色底物(购自Perkin Elmer,牌号为6066761),加入量为100μL/孔,反应2分钟,然后将反应混合物(200μL/孔)转移至96孔白板中,测定其相对光单位(Relative Light Unit,RLU)的强度,采用以下公式计算抗体对SARS冠状病毒假病毒进入细胞的抑制率:
抑制率=(病毒对照孔RLU-样品孔RLU)/(病毒对照孔RLU-细胞对照孔RLU)×100%
式中,样品孔RLU即为实验组RLU。
结果如图5所示,图中S14和NbMS10对应的曲线分别代表实验抗体和对照抗体的检测结果。从图中可以看出,小分子抗体Nano-Anti-SRBD对SARS冠状病毒假病毒具有较好的中和活性,能够有效抑制SARS冠状病毒假病毒进入Huh-7细胞,进一步的结果显示其IC50为4.93ng/mL。相比之下,对照抗体则基本对SARS冠状病毒假病毒不产生抑制作用。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于此。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,包括各个技术特征以任何其它的合适方式进行组合,这些简单变型和组合同样应当视为本发明所公开的内容,均属于本发明的保护范围。
SEQUENCE LISTING
<110> 中国人民解放军军事科学院军事医学研究院微生物流行病研究所
<120> 小分子抗体及其编码基因和制备方法及应用和药物组合物
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ggatcccagg tgcagctggt ggagtctgga ggaggcttgg tgcaggctgg ggagtctctg 60
agactctcct gtgcagtctc tggaggcacc ttcagtagct tgagcatggg ctggttccgc 120
caggctccag ggaagcagcg tgagttggtc gcacagatta gtagtggtgg tagcacaaac 180
tatgcaggct ccgtgaaggg ccgattcacc atctccagag acaacgccaa gaacacggtg 240
tatctgcgaa tgaacagcct gaaacctgag gacacggccg tctattactg taacgcagtt 300
ccgtctgacg actatagtgc tagtttctac tattcgcact actggggcca ggggacccag 360
gtcatcgtct cctcatctag a 381
<210> 3
<211> 369
<212> DNA
<213> 人工序列
<400> 3
caggtgcagc tggtggagtc tggaggaggc ttggtgcagg ctggggagtc tctgagactc 60
tcctgtgcag tctctggagg caccttcagt agcttgagca tgggctggtt ccgccaggct 120
ccagggaagc agcgtgagtt ggtcgcacag attagtagtg gtggtagcac aaactatgca 180
ggctccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
cgaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaacgc agttccgtct 300
gacgactata gtgctagttt ctactattcg cactactggg gccaggggac ccaggtcatc 360
gtctcctca 369
<210> 4
<211> 451
<212> PRT
<213> 人工序列
<400> 4
Arg Val Val Pro Ser Gly Asp Val Val Arg Phe Pro Asn Ile Thr Asn
1 5 10 15
Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Lys Phe Pro Ser Val
20 25 30
Tyr Ala Trp Glu Arg Lys Lys Ile Ser Asn Cys Val Ala Asp Tyr Ser
35 40 45
Val Leu Tyr Asn Ser Thr Phe Phe Ser Thr Phe Lys Cys Tyr Gly Val
50 55 60
Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser Asn Val Tyr Ala Asp
65 70 75 80
Ser Phe Val Val Lys Gly Asp Asp Val Arg Gln Ile Ala Pro Gly Gln
85 90 95
Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Met
100 105 110
Gly Cys Val Leu Ala Trp Asn Thr Arg Asn Ile Asp Ala Thr Ser Thr
115 120 125
Gly Asn Tyr Asn Tyr Lys Tyr Arg Tyr Leu Arg His Gly Lys Leu Arg
130 135 140
Pro Phe Glu Arg Asp Ile Ser Asn Val Pro Phe Ser Pro Asp Gly Lys
145 150 155 160
Pro Cys Thr Pro Pro Ala Leu Asn Cys Tyr Trp Pro Leu Asn Asp Tyr
165 170 175
Gly Phe Tyr Thr Thr Thr Gly Ile Gly Tyr Gln Pro Tyr Arg Val Val
180 185 190
Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr Val Cys Gly Pro
195 200 205
Lys Leu Ser Thr Asp Leu Ile Lys Asn Gln Cys Val Asn Phe Arg Ser
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 5
<211> 441
<212> PRT
<213> 人工序列
<400> 5
Gln Ala Glu Gly Val Glu Cys Asp Phe Ser Pro Leu Leu Ser Gly Thr
1 5 10 15
Pro Pro Gln Val Tyr Asn Phe Lys Arg Leu Val Phe Thr Asn Cys Asn
20 25 30
Tyr Asn Leu Thr Lys Leu Leu Ser Leu Phe Ser Val Asn Asp Phe Thr
35 40 45
Cys Ser Gln Ile Ser Pro Ala Ala Ile Ala Ser Asn Cys Tyr Ser Ser
50 55 60
Leu Ile Leu Asp Tyr Phe Ser Tyr Pro Leu Ser Met Lys Ser Asp Leu
65 70 75 80
Ser Val Ser Ser Ala Gly Pro Ile Ser Gln Phe Asn Tyr Lys Gln Ser
85 90 95
Phe Ser Asn Pro Thr Cys Leu Ile Leu Ala Thr Val Pro His Asn Leu
100 105 110
Thr Thr Ile Thr Lys Pro Leu Lys Tyr Ser Tyr Ile Asn Lys Cys Ser
115 120 125
Arg Leu Leu Ser Asp Asp Arg Thr Glu Val Pro Gln Leu Val Asn Ala
130 135 140
Asn Gln Tyr Ser Pro Cys Val Ser Ile Val Pro Ser Thr Val Trp Glu
145 150 155 160
Asp Gly Asp Tyr Tyr Arg Lys Gln Leu Ser Pro Leu Glu Gly Gly Gly
165 170 175
Trp Leu Val Ala Ser Gly Ser Thr Val Ala Met Thr Glu Gln Leu Gln
180 185 190
Met Gly Phe Gly Ile Thr Val Gln Tyr Gly Thr Asp Thr Asn Ser Val
195 200 205
Cys Pro Lys Leu Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
210 215 220
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 6
<211> 429
<212> PRT
<213> 人工序列
<400> 6
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg
1 5 10 15
Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn
50 55 60
Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile
65 70 75 80
Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp
100 105 110
Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys
115 120 125
Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln
130 135 140
Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe
145 150 155 160
Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln
165 170 175
Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala
180 185 190
Thr Val Ala Ala Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
195 200 205
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
210 215 220
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
225 230 235 240
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
245 250 255
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
260 265 270
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
275 280 285
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
290 295 300
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
305 310 315 320
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
325 330 335
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
340 345 350
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
355 360 365
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
370 375 380
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
385 390 395 400
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
405 410 415
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425
<210> 7
<211> 5
<212> PRT
<213> 人工序列
<400> 7
Arg Arg Arg Arg Arg
1 5
<210> 8
<211> 6
<212> PRT
<213> 人工序列
<400> 8
His His His His His His
1 5
<210> 9
<211> 8
<212> PRT
<213> 人工序列
<400> 9
Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
<210> 10
<211> 8
<212> PRT
<213> 人工序列
<400> 10
Trp Ser His Pro Gln Phe Glu Lys
1 5
<210> 11
<211> 10
<212> PRT
<213> 人工序列
<400> 11
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
1 5 10
Claims (10)
1.一种针对严重急性呼吸综合征冠状病毒的小分子抗体,其特征在于,所述抗体为:
(1)氨基酸序列如SEQ ID NO:1所示的蛋白质;或者
(2)氨基酸序列如SEQ ID NO:1所示的蛋白质经改造获得的与改造前具有相同活性的衍生蛋白质,所述改造为:
i、在氨基酸序列如SEQ ID NO:1所示的蛋白质的N末端和/或C末端连接便于纯化的标签和/或利于蛋白分泌表达的信号肽序列;和/或
ii、将SEQ ID NO:1所示的氨基酸序列进行人源化改造。
2.根据权利要求1所述的小分子抗体,其中,所述便于纯化的标签选自Poly-Arg、Poly-His、FLAG、Strep-tag II和c-myc中的至少一种;
和/或,所述信号肽序列选自人IL-2 SP、CD5 SP、人IgG2 H SP、人胰凝乳蛋白酶原SP、人胰蛋白酶原-2 SP和人胰岛素SP中的至少一种。
3.编码权利要求1或2所述的小分子抗体的基因。
4.根据权利要求3所述的基因,其中,所述基因包括:
a、编码区核苷酸序列如SEQ ID NO:2所示的DNA分子;或
b、编码区核苷酸序列如SEQ ID NO:3所示的DNA分子。
5.一种制备权利要求1或2所述的小分子抗体的方法,其特征在于,所述方法包括:将含有权利要求3或4所述的基因的重组载体导入宿主细胞,表达获得所述小分子抗体。
6.根据权利要求5所述的方法,其中,所述重组载体选自pCold I载体、pQE30载体、pET32a载体、pcDNA3.1载体和pPICZ载体中的至少一种;
和/或,所述宿主细胞选自大肠杆菌、293T细胞和酵母菌中的至少一种。
7.含有权利要求3或4所述的基因的重组载体、表达盒和表达载体,其中,所述表达载体包括转基因细胞系、重组菌和重组酵母中的至少一种。
8.权利要求1或2所述的小分子抗体、权利要求3或4所述的基因或权利要求7所述的重组载体、表达盒和表达载体在制备针对严重急性呼吸综合征冠状病毒的抗病毒产品中的应用。
9.一种药物组合物,其特征在于,所述药物组合物包括权利要求1或2所述的小分子抗体、权利要求3或4所述的基因或权利要求7所述的重组载体、表达盒和表达载体。
10.根据权利要求9所述的药物组合物,其中,所述药物组合物还包括药学上可接受的辅料。
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