CN112961222A - 2019新型冠状病毒n蛋白线性表位肽和单克隆抗体及应用 - Google Patents
2019新型冠状病毒n蛋白线性表位肽和单克隆抗体及应用 Download PDFInfo
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- Oncology (AREA)
Abstract
本发明提供了2019新型冠状病毒N蛋白线性表位肽和单克隆抗体及应用。本发明提供的2019新型冠状病毒N蛋白线性表位肽的氨基酸序列如SEQ ID NO.1‑5任一所示。将含有前述线性表位肽的多肽载体蛋白偶联免疫小鼠制备获得多株杂交瘤细胞分泌可以特异性识别2019新型冠状病毒N蛋白且具有生物活性的单克隆抗体。
Description
本申请要求申请日为2020年2月4日,申请号2020100799132,发明名称为《2019新型冠状病毒N蛋白线性表位肽和单克隆抗体及应用》的在先申请的优先权。
技术领域
本发明涉及免疫学领域及抗体制备技术,具体地说,涉及2019新型冠状病毒N蛋白线性表位肽和单克隆抗体及应用。
背景技术
冠状病毒是一个大型病毒家族,已知可引起感冒以及中东呼吸综合征(MERS)和严重急性呼吸综合征(SARS)等较严重疾病。新型冠状病毒是以前从未在人体中发现的冠状病毒新毒株,人感染了冠状病毒后常见体征有呼吸道症状、发热、咳嗽、气促和呼吸困难等。在较严重病例中,感染可导致肺炎、严重急性呼吸综合征、肾衰竭,甚至死亡。
目前对于新型冠状病毒所致疾病没有特异治疗方法。但许多症状是可以处理的,因此需根据患者临床情况进行治疗。此外,对感染者的辅助护理比较有效。研制针对该病毒的特异性抗体,有助于2019-nCoV所引起肺炎的诊断和治疗。
发明内容
本发明的目的是提供2019新型冠状病毒N蛋白线性表位肽和单克隆抗体及其应用。
本发明提供的2019-nCoV N蛋白表位肽,其氨基酸序列含有以下任一所示的多肽序列:
多肽1:SDNGPQSNQRNAPRITFG;
多肽2:PSDSTGSNQNGERSGARSKQ;
多肽3:PGSSRGTSPARMAGNGGDAALA;
多肽4:PKKDKKKKADETQALPQRQKK;
多肽5:SADSTQA。
本发明提供的多肽1是位于2019-nCoV N蛋白氨基酸序列第2-19的多肽;多肽2是位于氨基酸序列第20-39的多肽;多肽3是位于氨基酸序列第199-220的多肽;多肽4是位于氨基酸序列第368-388的多肽;多肽5是位于氨基酸序列第413-419的多肽。偶联到载体蛋白,例如KLH,作为免疫原免疫小鼠后,制备杂交瘤细胞,筛选能够稳定分泌特异性识别2019-nCoV N蛋白且具有生物学活性单克隆抗体的杂交瘤细胞株。
本发明提供了2019-nCoV N蛋白表位肽在制备2019-nCoV N蛋白单克隆抗体或双特异性抗体中的应用,所述2019-nCoV N蛋白表位肽的氨基酸序列如SEQ ID NO.1-5任一所示,或SEQ ID NO.1-5任一所示的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
本发明提供了2019-nCoV N蛋白表位肽在制备2019-nCoV多肽疫苗中的应用,所述2019-nCoV N蛋白表位肽的氨基酸序列如SEQ ID NO.1-5任一所示,或SEQ ID NO.1-5任一所示的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
本发明提供了2019-nCoV N蛋白表位肽在制备以2019-nCoV所引起的疾病治疗药物中的应用所述2019-nCoV N蛋白表位肽的氨基酸序列如SEQ ID NO.1-5任一所示,或SEQID NO.1-5任一所示的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
本发明提供了含有所述2019-nCoV N蛋白表位肽或所述表位肽的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列的多肽疫苗。
本发明提供了一种抗体,其为所述2019-nCoV N蛋白表位肽或所述表位肽的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列的多肽,与载体蛋白偶联后作为免疫原,免疫动物,制备免疫血清得到抗体;或对所述抗体进行改造得到的嵌合抗体。
所述的抗体,其为多克隆抗体、单克隆抗体。
具体的说,本发明以偶联了载体蛋白的多肽分别作为免疫原分别免疫小鼠,采用杂交瘤技术经过细胞融合并筛选得到能持续、稳定分泌特异性识别新冠病毒N蛋白的小鼠单克隆抗体的杂交瘤细胞株,由各细胞株分泌得到2个单克隆抗体,其中由多肽2作为免疫原免疫小鼠获得了单克隆抗体Clone 4G1,由多肽4作为免疫原免疫小鼠获得了单克隆抗体11D5。本发明提供的单克隆抗体分别命名为Clone 4G1和Clone 11D5。
所述单克隆抗体Clone 4G1的轻链可变区和重链可变区的氨基酸序列分别如SEQID No.6和7所示;
所述单克隆抗体Clone 11D5的轻链可变区和重链可变区的氨基酸序列分别如SEQID No.8和9所示;
本发明还提供能稳定分泌上述单克隆抗体的杂交瘤细胞,其为所述2019-nCoV N蛋白表位肽或所述表位肽的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列的多肽,与载体蛋白偶联后作为免疫原免疫动物所得的杂交瘤细胞。
上述杂交瘤细胞所分泌产生的单克隆抗体属于本发明的保护范围。
本发明提供一种药物,其含有上述的抗体。
本发明提供一种2019-nCoV检测试剂盒,其含有所述的2019-nCoV N蛋白表位肽或含有所述的2019-nCoV N蛋白表位肽产生的抗体。
本发明提供一种免疫毒素,包含以各种形式连接于细胞毒性剂的本发明所述的抗体或所述杂交瘤细胞分泌产生的单克隆抗体;优选所述的各种连接形式为抗体被标记、体外交联或分子偶联。
本发明提供一种双特异性或多特异性分子,包含所述2019-nCoV N蛋白表位肽或所述的抗体或所述杂交瘤细胞分泌产生的单克隆抗体。
本发明还提供一种抗体与其他蛋白和/或多肽的融合蛋白,包含本发明所述的抗体或所述杂交瘤细胞分泌产生的单克隆抗体和具有某种功能的其他蛋白或多肽分子的复合物。
本发明提供了所述的抗体或所述杂交瘤细胞分泌产生的单克隆抗体在制备2019-nCoV所引起的疾病的治疗药物中的应用。
本发明提供了含有所述的抗体或所述杂交瘤细胞分泌产生的单克隆抗体的药物、检测试剂或试剂盒。
本发明提供了所述的2019-nCoV N蛋白表位肽、或所述的多肽疫苗、或所述的抗体、或所述的单克隆抗体、或所述的药物、或所述的免疫毒素、或所述的融合蛋白在治疗或预防2019新型冠状病毒肺炎中的应用。
本发明提供了2019-nCoV N蛋白表位肽、或所述的抗体、或所述的单克隆抗体、或所述的检测试剂盒在诊断2019新型冠状病毒肺炎中的应用。
将含有前述线性表位肽的多肽载体蛋白偶联免疫小鼠制备获得多株杂交瘤细胞分泌可以特异性识别2019新型冠状病毒N蛋白且具有生物活性的单克隆抗体。本发明中由多肽2作为免疫原免疫小鼠获得了单克隆抗体Clone 4G1,由多肽4作为免疫原免疫小鼠获得了单克隆抗体11D5显示了良好的病原特异性亲和力和反应原性,可用于制备2019新型冠状病毒诊断试剂盒等相关检查试剂。
附图说明
图1是单克隆抗体的SDS-PAGE电泳图,其中M是蛋白分子量标准(kDa),本发明获得的2个单克隆抗体,泳道1-4分别是4G1还原抗体、4G1非还原抗体、11D5还原抗体、11D5非还原抗体。
图2所示单克隆抗体Clone 4G1的免疫印迹结果。
图3所示单克隆抗体Clone 4G1的ELISA结合力结果。
图4所示单克隆抗体Clone 4G1的BIAcore亲和力测试结果,图中检测抗原使用的是重组表达的新冠病毒N蛋白,采用1:1binding的模型,Clone 4G1的亲和力(KD)计算结果为1.55×10-10M。图中1为25nM,2为12.5nM,3为6.25nM,4为3.125nM,5为1.5625nM。
图5所示单克隆抗体Clone 4G1的免疫组化结果。
图6所示单克隆抗体Clone 11D5的免疫印迹结果。
图7所示单克隆抗体Clone 11D5的ELISA结合力结果。
图8所示单克隆抗体Clone 11D5的BIAcore亲和力测试结果,图中检测抗原使用的是重组表达的新冠病毒N蛋白,采用1:1binding的模型,Clone 11D5的亲和力(KD)计算结果为8.13×10-8M。图中1为200nM,2为100nM,3为50nM,4为25nM,5为12.5nM。
图9所示双抗体夹心ELISA法灵敏度实验的拟合曲线。
具体实施方法
以下实施例进一步说明本发明的内容,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。
若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例1、杂交瘤细胞系的建立
一、实验材料
1、免疫原:本例分别将多肽1-5分别与载体蛋白KLH偶联,以偶联KLH的多肽分别作为免疫原来免疫动物。
2、实验动物:BALB/c小鼠,4-6周龄,雌性,SPF级。
3、其他材料:弗氏完全佐剂和弗氏不完全佐剂购于Sigma公司;HRP标记的山羊抗小鼠IgG抗体购于JacksonImmune公司;其余试剂均为国产分析纯产品。
二、杂交瘤细胞系的建立
1.动物免疫
1)基础免疫:将抗原与弗氏完全佐剂等体积混合并充分乳化,分点皮下注射,每只Balb/c小鼠每次注射量为100μg。
2)加强免疫:加强免疫采用抗原与弗氏不完全佐剂的乳化液。在进行细胞融合前3天,经腹腔注射含150ug抗原的生理盐水溶液。
2.杂交瘤细胞的制备
按常规方法收集小鼠的脾细胞与SP2/0细胞按10:1的比例以500g/L的PEG4000进行融合。用HAT培养液选择培养,融合后10~15天,取上清采用间接ELISA法筛选分泌抗每种多糖型和载体蛋白的杂交瘤细胞株。对所得阳性克隆株采用有限稀释法进行亚克隆。间接ELISA法的操作步骤如下:用100μl的重组表达的新冠病毒N蛋白分别包板,用免疫小鼠血清1:2000作为阳性对照,无克隆生长的培养基上清作为阴性对照,每孔加1:2000HRP-山羊抗小鼠IgG 100μl,最后测定450nm OD值。凡OD450值大于阴性对照2倍以上者,即可初步判定为阳性克隆。
3.应用上述杂交瘤细胞系所得单抗的效价检测
1)细胞培养液上清效价测定:间接ELISA法检测上述杂交瘤细胞培养上清效价为:1:50000-1:100000。
2)小鼠腹水效价测定:间接ELISA法检测上述杂交瘤细胞制备的腹水效价为:1:500000-1:1000000。
4.杂交瘤细胞的传代培养
将上述杂交瘤细胞系在含有10%胎牛血清的DMEM培养基中继续进行培养、传代,培养到10代后,杂交瘤细胞系仍然能够生长良好、稳定传代,培养液上清效价仍然可以达到1:10000以上。
以上结果表明,所得杂交瘤细胞系能够稳定传代,可以持续、稳定分泌抗新冠病毒N蛋白的单克隆抗体。
实施例2抗新冠病毒小鼠单克隆抗体的制备和评价
一、抗体制备
选择成年BALB/c小鼠,腹腔接种弗氏不完全佐剂,每只小鼠0.5ml。7-10天后腹腔接种第16代杂交瘤细胞,每只小鼠1×106-2×106个。间隔5天后,待腹部明显膨大,以手触摸时,皮肤有紧张感,即可用9号针头采集腹水。
将腹水离心(13000r/min 30分钟),除去细胞成分和其他的沉淀物,收集上清。用Protein G~Sepharose CL-4B进行纯化,上柱液为20mM的PBS缓冲液,柱层析洗脱液为:pH2.7,20mM的甘氨酸缓冲液,分别得到抗新冠病毒N蛋白的小鼠单克隆抗体。其中由多肽2作为免疫原免疫小鼠获得了单克隆抗体Clone 4G1,由多肽4作为免疫原免疫小鼠获得了单克隆抗体11D5。
二、抗体的鉴定
1、抗体纯度鉴定
SDS-PAGE电泳鉴定,纯度在95%以上,见图1。
2、特异识别新冠病毒N蛋白的单克隆抗体4G1和11D5的可变区序列测定。
将获得的2株单克隆细胞分别提取mRNA,反转录为cDNA,使用可变区通用引物进行高保真PCR扩增,将PCR产物片段插入到T载体内进行DNA序列测定,并将获得的序列翻译成蛋白质的氨基酸序列。将获得的序列进行比对后未显示有相同序列,说明所获得的序列为特异的序列。
所述单克隆抗体Clone 4G1的轻链可变区和重链可变区的氨基酸序列分别为SEQID No.6和7所示。
所述单克隆抗体Clone 11D5的轻链可变区和重链可变区的氨基酸序列分别为SEQID No.8和9所示。
3、抗体的特异性验证
蛋白免疫印迹进行单克隆抗体结合新冠病毒N蛋白特异性鉴定。将新冠病毒N蛋白、SARS病毒N蛋白和MERS病毒N蛋白进行SDS-PAGE电泳,然后将通过电泳分离的N蛋白转移至杂交膜上;接下来使用5%脱脂奶粉将杂交膜进行封闭,再分别使用单克隆抗体与杂交膜进行孵育反应,再加上HRP标记的山羊抗小鼠IgG二抗孵育,然后显色。
免疫印迹实验表明,Clone 4G1能够特异性识别新冠病毒N蛋白,不与SARS和MERS病毒的N蛋白由交叉反应,见图2;Clone 11D5识别新冠病毒N蛋白,与SARS和MERS病毒N蛋白的交叉反应大于100倍,见图6。
4、抗体的ELISA结合能力验证
使用ELISA方法鉴定单克隆抗体结合新冠病毒N蛋白的能力。将新冠病毒N蛋白包被酶联板,然后使用5%脱脂奶粉将杂交膜进行封闭,再加上梯度稀释的单克隆抗体反应,然后加入HRP标记的山羊抗小鼠IgG二抗孵育,然后加入TMB底物显色,最后在酶标仪中读取OD450的数值。
ELISA实验表明,单克隆抗体Clone 4G1和11D5均能够与新冠病毒N蛋白有良好的结合反应,见图3和图7。
5、抗体与抗原的亲和力鉴定
使用BIAcore仪器测试单克隆抗体Clone 4G1和11D5与抗原的亲和力,其中Clone4G1的亲和力为1.55×10-10M,Clone 11D5的亲和力为8.13×10-8M,结果见图4和图8。
6、抗体在免疫组化实验的应用
使用免疫组化实验验证单克隆抗体能够应用于病理组织的鉴定。结果见图5。
实施例3、应用纯化抗体Clone 4G1和Clone 11D5制备新冠病毒N蛋白检测试剂
应用Clone 4G1和Clone 11D5抗体做配对检测实验,确定以Clone4G1作为捕获抗体,使用HRP标记Clone 11D5作为检测抗体,确定了ELISA检测方法,检测灵敏度达到2.5ng/mL,见图9。
序列表
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<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ile Val Met Thr Gln Ser Thr Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Ala His Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Ala Asp Ala Ala Pro Thr Val Ser
115 120
<210> 9
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala Leu
1 5 10 15
Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr Tyr
20 25 30
Ile Tyr Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly
35 40 45
Trp Ile Asp Pro Glu Asn Gly Tyr Thr Ile Tyr Asp Pro Lys Phe Gln
50 55 60
Gly Lys Ala Ser Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu
65 70 75 80
Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Gly Ser Ser Phe Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser
115
Claims (18)
1.2019-nCoV N蛋白表位肽,其特征在于,其氨基酸序列含有以下任一所示的多肽序列:
多肽1:SDNGPQSNQRNAPRITFG;
多肽2:PSDSTGSNQNGERSGARSKQ;
多肽3:PGSSRGTSPARMAGNGGDAALA;
多肽4:PKKDKKKKADETQALPQRQKK;
多肽5:SADSTQA。
2.含有权利要求1所述2019-nCoV N蛋白表位肽或所述表位肽的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列的多肽疫苗。
3.一种抗体,其为权利要求1所述2019-nCoV N蛋白表位肽或所述表位肽的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列的多肽,与载体蛋白偶联后作为免疫原,免疫动物,制备免疫血清得到抗体;或对所述抗体进行改造得到的嵌合抗体。
4.如权利要求3所述的抗体,其为多克隆抗体、单克隆抗体。
5.如权利要求4所述的抗体,其特征在于,其为权利要求1所述2019-nCoV N蛋白表位肽或所述表位肽的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列的多肽,与载体蛋白偶联后作为免疫原免疫动物所得的杂交瘤细胞分泌所得的单克隆抗体。
6.权利要求3-5任一所述的抗体,其特征在于,所述单克隆抗体为Clone 4G1,其轻链可变区和重链可变区的氨基酸序列分别如SEQ ID No.6和7所示;或
所述单克隆抗体为Clone 11D5的轻链可变区和重链可变区的氨基酸序列分别如SEQID No.8和9所示。
7.一种药物,其特征在于,含有权利要求3-6任一所述的抗体。
8.一种2019-nCoV检测试剂盒,其特征在于,含有权利要求1所述的2019-nCoV N蛋白表位肽或含有权利要求1所述的2019-nCoV N蛋白表位肽产生的抗体。
9.一种免疫毒素,包含以各种形式连接于细胞毒性剂的权利要求3-6任一所述的抗体;优选所述的各种连接形式为抗体被标记、体外交联或分子偶联。
10.一种双特异性或多特异性分子,其特征在于,包含权利要求1所述2019-nCoV N蛋白表位肽或权利要求3-6任一所述的抗体。
11.一种抗体与其他蛋白和/或多肽的融合蛋白,其特征在于,包含权利要求3-6任一所述的抗体和具有某种功能的其他蛋白或多肽分子的复合物。
12.2019-nCoV N蛋白表位肽在制备2019-nCoV N蛋白单克隆抗体或双特异性抗体中的应用,其特征在于,所述2019-nCoV N蛋白表位肽的氨基酸序列如SEQ ID NO.1-5任一所示,或SEQ ID NO.1-5任一所示的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
13.2019-nCoV N蛋白表位肽在制备2019-nCoV多肽疫苗中的应用,其特征在于,所述2019-nCoV N蛋白表位肽的氨基酸序列如SEQ ID NO.1-5任一所示,或SEQ ID NO.1-5任一所示的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
14.2019-nCoV N蛋白表位肽在制备以2019-nCoV所引起的疾病治疗药物中的应用,其特征在于,所述2019-nCoV N蛋白表位肽的氨基酸序列如SEQ ID NO.1-5任一所示,或SEQID NO.1-5任一所示的序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
15.权利要求3-6任一所述的抗体在制备2019-nCoV所引起的疾病的治疗药物中的应用。
16.含有权利要求3-6任一所述的抗体的药物、检测试剂或试剂盒。
17.2019-nCoV N蛋白表位肽、或权利要求2所述的多肽疫苗、或权利要求3-6任一所述的抗体、或权利要求7所述的药物、或权利要求9所述的免疫毒素、CAR-T、CAR-NK或权利要求11所述的融合蛋白在治疗或预防2019新型冠状病毒肺炎中的应用。
18.2019-nCoV N蛋白表位肽、或权利要求3-6任一所述的抗体的单克隆抗体、或权利要求8所述的检测试剂盒在诊断2019新型冠状病毒肺炎中的应用。
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