CN114409767A - 一种鉴别新冠突变型抗原的抗体、试剂及方法 - Google Patents
一种鉴别新冠突变型抗原的抗体、试剂及方法 Download PDFInfo
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Abstract
本发明提供了一种鉴别新冠突变型抗原的抗体、试剂及方法。利用本发明抗体、试剂或方法能够快速、准确地鉴别新冠突变型抗原,且检测效率高、成本低。
Description
技术领域
本发明属于蛋白检测领域。更具体地,涉及一种鉴别新冠突变型抗原的抗体、试剂及方法。
背景技术
新型冠状病毒(SARS-CoV-2)属于冠状病毒科,为不分节段的单股正链RNA病毒。它编码4种结构蛋白(S、E、M和N蛋白),其中,N蛋白是病毒粒子的核心成分,其蛋白全长419个氨基酸,大小为43-50kDa。N蛋白有三个相对保守的结构域,其中一域可与病毒基因组RNA相互缠绕形成病毒核衣壳,在病毒RNA的合成过程中发挥着重要的作用,与病毒基因组复制和调节细胞信号通路有关。N蛋白是一个磷酸化蛋白,磷酸化能够调节N蛋白的构象,增强与病毒蛋白的构象,增强与病毒RNA的亲和力。在核衣壳包装过程中,N蛋白可与M蛋白相互作用,促进核衣壳包装成病毒粒子。
N抗原检测呈阳性可作为新冠早期感染的直接证据。然而,新冠病毒N蛋白上出现的各种突变意味着抗原逃逸检测抗体对的几率上升,导致试剂盒面临无法检出突变株病毒的风险。因此,开发一种能够鉴别新冠突变株的试剂盒具有重要意义。
发明内容
本发明的目的是提供一种鉴别新冠突变型抗原的抗体、试剂及方法。
在一些实施方案中,本发明可以包括下述一项或多项:
一种抗体,其中,所述抗体抗体结合新冠病毒野生株N抗原第28-36位氨基酸片段。
本发明还提供了一种抗体偶联物,其包括上述抗体及偶联部分;其中,所述偶联部分选自标记物,固相载体,结合配偶体之一。
本发明还提供了编码抗体的核酸分子。
本发明的另一目的是提供了一种方法,其利用抗体1、抗体2和抗体3对待测样本进行免疫检测,所述抗体1能与M种新冠病毒抗原结合;所述抗体2能与除Omicron突变株外的M-1种新冠病毒抗原结合,所述抗体2选自前述抗体;所述抗体3能与M种新冠病毒抗原结合。
本发明还提供了一种鉴别新冠突变型抗原的检测试剂。
本发明还提供了一种鉴别新冠突变型抗原的免疫层析试纸,其中,所述免疫层析试纸包括底板、样品垫、结合垫、硝酸纤维素膜和吸水垫,所述硝酸纤维素膜上设置检测线1和检测线2,所述结合垫上设置有前述抗体3,所述检测线1上包被前述抗体1、所述检测线2上包被前述抗体2;所述抗体3用标记物进行标记;可选地,所述硝酸纤维素膜上还设置有质控线。
本发明还提供了上述抗体、抗体偶联物、方法、试剂或试纸在检测新冠病毒Omicron突变株的应用。
利用本发明抗体、试剂或方法能够快速、准确地鉴定或鉴别新冠突变型抗原,且检测效率高、成本低。
具体实施方式
本发明涉及一种抗体,所述抗体结合新冠病毒野生株N抗原第28-36位氨基酸片段。在一些实施方案中,所述新冠病毒野生株N抗原第28-36位氨基酸片段如SEQ ID NO:5所示。本发明新冠病毒野生株N抗原的描述特指最先发现的野生株新冠病毒N抗原。
在一些实施方案中,所述抗体不结合新冠病毒野生株N抗原第31-33位发生缺失的氨基酸片段;在一些实施方案中,所述抗体不结合SEQ ID NO:3或4所示的氨基酸片段;在一些实施方案中,所述抗体不结合新冠病毒Omicron突变株N抗原。其中,新冠病毒Omicron突变株N抗原存在E31del、R32del、S33del。
在本发明中,术语“抗体”在最广义上使用,其可以包括全长单克隆抗体,双特异性或多特异性抗体,以及嵌合抗体,只要它们展示所需的生物学活性。在一些实施方案中,可以采用本领域已知的方法制备本发明的抗体,例如利用其全长抗原或者已知表位的抗原片段(如本发明所述的28-36位氨基酸片段)作为免疫原免疫动物,获得结合所述抗原片段的抗体。为了增加免疫原性,可以将载体蛋白(包括但不限于BSA、卵清蛋白、KLH等)与免疫反应性物质(例如表位肽)偶联。载体蛋白可以包括蛋白质或多肽,其可以起免疫原载体的作用。这些类型的多肽包括白蛋白、血清蛋白、球蛋白、晶状体蛋白、脂蛋白和/或其片段。
本发明杂交瘤细胞由免疫原免疫的B淋巴细胞与骨髓瘤细胞融合得到。
本发明还涉及抗体偶联物,包括上述抗体及偶联部分;所述偶联部分选自标记物,固相载体,结合配偶体之一;在一些实施方案中,所述标记物选自金属粒子,荧光标记,发色团标记,电子致密标记,化学发光标记,电化学标记,放射性标记,核酸标记,或酶标记;在一些实施方案中,所述标记物选自罗丹明,荧光素,荧光微球,胶体金,吖啶酯,胶乳微球,三联钌、鲁米诺类、Eu螯合物,荧光素酶,辣根过氧化物酶,碱性磷酸酶,β-半乳糖苷酶,葡糖淀粉酶,溶菌酶,糖氧化酶,葡萄糖氧化酶,半乳糖氧化酶或葡萄糖-6-磷酸脱氢酶标记;在一些实施方案中,所述固相载体选自磁性颗粒、胶乳粒子、微量滴定板、硝酸纤维素膜,玻璃纤维素膜,尼龙膜或微流控芯片;在一些实施方案中,结合配偶体选自生物素/抗生物素蛋白,生物素/链霉抗生物素蛋白;在一些实施方案中,根据应用场景对抗体进行标记物偶联或者固相载体偶联。
本发明还涉及一种核酸分子,所述核酸分子编码上述抗体。
本发明还涉及一种鉴别新冠突变型抗原的方法,利用抗体1、抗体2和抗体3对待测样本进行免疫检测,所述抗体1能与M种新冠病毒抗原结合;所述抗体2能与除Omicron突变株外的M-1种新冠病毒抗原结合,所述抗体2选自前述抗体;所述抗体3能与M种新冠病毒抗原结合,M为大于等于2的整数。本发明所述“M种新冠病毒抗原”包括野生株和突变株新冠病毒的抗原,其中突变株不限于Omicron突变株,还可以是B.1.1.7突变株、B1.351突变株或B.1.1.28突变株。本发明所述“除Omicron突变株外的M-1种新冠病毒抗原”包括野生株,可选地还包括除Omicron突变株外的其他突变株,如B.1.1.7突变株、B1.351突变株或B.1.1.28突变株。相关检测原理见专利申请202110315361.5。
在一些实施方案中,所述抗体1和抗体3夹心检测新冠病毒抗原;所述抗体2和抗体3夹心检测新冠病毒抗原;这里所述的新冠病毒抗原不限于N抗原,或者也可以是S抗原,不限于野生株,也可以是突变株。在一些实施方案中,所述新冠病毒抗原为新冠病毒抗原N抗原。
利用本发明的抗体,任何免疫检测方法均可适用。在一些实施方案中,所述方法可以是免疫层析法、酶联免疫吸附法、化学发光法、胶乳免疫比浊法。
例如在一些实施方案中,采用免疫层析法,制备一种鉴别新冠突变型抗原的免疫层析试纸,所述免疫层析试纸包括底板、样品垫、结合垫、硝酸纤维素膜和吸水垫,所述硝酸纤维素膜上设置检测线1和检测线2,所述结合垫上设置有前述抗体3,所述检测线1上包被前述抗体1、所述检测线2上包被前述抗体2;所述抗体3用标记物进行标记,例如金属粒子,荧光标记,例如胶体金,荧光素,荧光微球,胶乳微球。在一些实施方案中,将免疫层析试纸与待测样本接触,当检测线1和检测线2同时显色或检测线1和2显色基本一致(例如相差1个色卡以内),则判定为样品中不含有新冠病毒Omicron突变株;当检测线1显色,检测线2不显色时或者检测线1和2显色存在明显差异(例如相差3个色卡以上),则判定为样品中含有新冠病毒Omicron突变株。
在一些实施方案中,所述硝酸纤维素膜上还设置有质控线。所述质控线包被有捕获内参的试剂;所述内参可以是配对抗体,或其他抗原或抗体类物质;所述内参用可检测标记物进行直接或间接标记;在一些实施方案中,所述内参用胶体金标记;在一些实施方案中,所述胶体金标记的内参设于结合垫上;在一些实施方案中,所述内参为特定物种来源的抗体或抗原;在一些实施方案中,所述特定物种来源可以是牛、马、乳牛、猪、绵羊、山羊、大鼠、小鼠、狗、猫、兔、骆驼、驴、鹿、貂、鸡、鸭、鹅、火鸡、斗鸡或人;在一些实施方案中,所述内参为小鼠来源的抗体或抗原(例如配对抗体为鼠源),所述质控线包被有抗小鼠IgG;例如质控线包被有羊抗小鼠IgG。
本发明还涉及一种鉴别新冠突变型抗原的检测试剂,所述试剂包含前述抗体或前述抗体1、抗体2和抗体3。本发明所述试剂应做广义理解,其主要指承载免疫检测相关试剂的工具;在一些实施方案中,还可以进一步包括一些配套试剂,其可以是例如工作液,但不限于此。
前述抗体,抗体偶联物、方法,试剂或试纸在检测新冠病毒Omicron突变株或制备新冠病毒Omicron突变株检测产品中的应用。
一种检测新冠病毒Omicron突变株的方法,包括将待测样本分别与抗体1、抗体2和抗体3接触,检测免疫反应,当抗体1和抗体3夹心反应结果和抗体2和抗体3夹心反应结果均为阳性时,则待测样本中不含新冠病毒Omicron突变株。当抗体1和抗体3夹心反应结果为阳性,抗体2和抗体3夹心反应结果为阴性时,则待测样本中含新冠病毒Omicron突变株。在一些实施方案中,待测样本采用稀释液进行稀释后进行测定,例如稀释液为PBS。
在一些实施方案中,也可以采取酶联免疫吸附方法进行测定,例如将抗体1和抗体2分别用HRP进行标记,抗体3用ELISA板固定。
本发明中,待测样本包括健康或病理状态的鼻咽拭子、痰、唾液、下呼吸道分泌物、血液(包括血清、血浆或全血)、尿液或粪便。
下面将结合实施例对本发明的实施方案进行详细描述。
实施例1单克隆抗体的制备
1、免疫动物
取8~12周龄与骨髓瘤细胞同种系的BALB/c小鼠,以含蛋白质100μg/只的2019-nCoV N蛋白重组抗原(SEQ ID NO:1,全长1-419aa,下称2019-nCoVN)与等量福氏完全佐剂充分混匀,注入小鼠腹腔内,每隔2周100μg/只的2019-nCoVN与等量福氏不完全佐剂充分混匀,多次注入小鼠腹腔内加强免疫。经检测小鼠血清(间接ELISA法),滴度在1∶2000以上者可用于融合,融合前3天经小鼠腹腔内再次加强免疫,剂量为50μg/只。
2、饲养细胞的制备
以BALB/c鼠腹腔巨噬细胞作饲养细胞。在融合前1天,BALB/c鼠拉颈处死,75%酒精全身浸泡,超净台内,无菌操作下用剪刀剪开腹部皮肤,暴露腹膜,用注射器腹腔注入RPMI 1640基础培养液5mL,反复冲洗,回收冲洗液,1000rpm,离心5分钟,留沉淀,用RPMI1640筛选培养液(含HAT的RPMI 1640完全培养液中)重悬,调整细胞浓度1×105个/mL,加入96孔板,150μL/孔,37℃,5%CO2培养过夜。
3、免疫脾细胞的制备
小鼠末次免疫后三天,在无菌条件下取出脾脏,置于平皿中,RPMI 1640基础培养液冲洗一次,放于小烧杯的尼龙网上磨碎过滤,制成细胞悬液。离心,弃上清,RPMI 1640基础培养液重悬,如此重复三次,计数。
4、细胞融合
(1)取40mL HAT培养液,15mL DMEM无血清培养液和1mL50%PEG(M12000)分别置于37℃水浴中预温;
(2)分别取小鼠骨髓瘤细胞Sp2/0(菲鹏生物股份有限公司保存)(2~5×107)、上述免疫脾细胞(108)悬液加入50mL离心管中混匀,并加DMEM无血清培养液至40mL。离心10分钟,倒尽上清液,混匀;
(3)将离心管置于37℃预温的水中,取0.7mL预温的50%PEG溶液,静置90秒钟。立即滴加37℃15mL预温的无血清培养液;
(4)补加DMEM无血清培养液至40mL,离心10分钟,倒尽上清液。加40mL含15%~20%胎牛血清的HAT培养液。用吸管混匀,滴加到已含有饲养细胞的4块96孔细胞培养板的小孔中,每孔2滴,置37℃、7%CO2的培养箱中培养。
5、杂交瘤细胞的选择培养
免疫小鼠脾细胞与小鼠骨髓瘤细胞,经PEG处理后,形成多种细胞成分的混合体,其中包括未融合的骨髓瘤细胞和免疫脾细胞;骨髓瘤细胞的共核体和免疫脾细胞的共核体,以及骨髓瘤细胞和免疫脾细胞的异核体。仅后者才能形成杂交瘤细胞。为此,在这多种细胞混合体中必须除去未融合的细胞和同种融合的共核体,并选择出真正的杂交细胞。因此,在细胞融合后第1,3,5,7天用前述的HAT培养液换液培养。
6、特异性抗体的检测及杂交瘤细胞克隆化
吸取每个培养孔的上清液,用间接ELISA法检测出培养液中含特异性识别2019-nCoVN的抗体的培养孔。采用间接ELISA法鉴定细胞培养上清的交叉反应性,用2019-nCoVN包被96孔板,封闭,加入杂交瘤细胞培养液上清孵育,加二抗,测405nm反应值,挑选反应值(0.5以上)比较高的细胞株制备抗体进行下一轮筛选实验。筛选得到以下有较好反应性的抗体。
实施例2抗体结合片段确认
将实施例2筛选得到的抗体,进一步进行特异性表位筛选,用新冠抗原野生株N抗原1-43位对应的氨基酸片段(SEQ ID NO:2)、及新冠抗原野生株N抗原1-419位,且31-33位缺失的氨基酸片段(SEQ ID NO:3)筛选抗体,获得与SEQ ID NO:2结合,但不与SEQ ID NO:3结合的抗体,进一步将抗体与1-419,且E31del、G204R、P13L、R32del、R203K、S33del(SEQ IDNO:4)结合,看其与新冠病毒Omicron突变株N抗原的反应,具体反应值如下:
注:OD450大于0.5为强反应,OD450小于0.1为不反应。
可见以上抗体对新冠病毒Omicron突变株N抗原不反应,对新冠病毒野生株N抗原强反应,采用ELISA方法,可以实现新冠病毒Omicron突变株的鉴定。
对获得的抗体进一步鉴定结合片段,最终确认其结合片段为新冠抗原野生株N抗原28-36位对应氨基酸片段(SEQ ID NO:5)。
注:“+”表示OD450大于1。
因此,本发明提供了一类结合新冠抗原野生株N抗原28-36位的抗体,且不结合新冠抗原野生株N抗原31-33位缺失的片段。
以上结合实验是将0.2ug/ml待结合的氨基酸片段分别包被微孔,以PBS+20%NBS为稀释液,稀释单抗为一抗浓度到1ug/ml,以羊抗鼠IgG-HRP为二抗,鉴定抗体的反应情况。
实施例3鉴定突变型抗原
本实施例的标记抗体为15C8或Mb117(菲鹏自产)能结合新冠病毒野生株N抗原和新冠病毒Omicron突变株N抗原,T1线包被抗体为Mb30(菲鹏自产)能结合新冠病毒野生株N抗原和新冠病毒Omicron突变株N抗原,T2线包被实施例1获得的抗体237或548。
1、抗体标记:取5ml浓度为4/万的胶体金,加入30-40ul 0.2M K2CO3,搅拌5min,加入标记抗体(所加抗体体积=50μg/抗体浓度),搅拌5min,再加入50ul 10%BSA封闭终止标记;离心10000rpm,7min,去上清,沉淀用金子复溶液复溶,最后用金子复溶液定容到0.5ml(即1/10胶体金溶液体积)。
2、配制金子工作液:用金子复溶液将标记抗体浓缩金以20%的稀释比例配制成金子工作液,铺于玻璃纤维上。
3、制备干燥好的金子:将铺好的金子放入冻干机冻干(1-2h)或者放37℃干燥房干燥过夜。
4、抗体包被:将硝酸纤维素膜与PVC底板组装好备用;将Mb30抗体稀释至1.0-1.5mg/ml,用喷金画膜仪在NC膜上均匀地划T1线;再将237或548抗体稀释至1.0-1.5mg/ml,用喷金画膜仪在NC膜上均匀地划T2线;放37℃恒温箱60min。
5、制备金标条:用切条机将金标条按需要的宽度切条,组装后加样进行检测。
6、检测
(1)检测品:5ng/mL的新冠病毒Omicron突变株N抗原(SEQ ID NO:4),和新冠病毒野生株N抗原(2019-nCoVN);
(2)检测方法:根据色卡比对,肉眼判读显色读值。
7、结果:
注:数字代表显色,数字越大,显色越弱(活性越低),B为阴性。
以上结果可以看出,237和548抗体对Omicron突变株N抗原不反应,对新冠病毒野生株N抗原反应,由此可以实现对Omicron突变株的快速鉴定。
利用新冠抗原野生株N抗原28-36位氨基酸片段作为免疫原,可以快速筛选到结合28-36位氨基酸片段的抗体,如抗体28D3和28E11,对31-33位缺失的氨基酸片段无反应,利用这些抗体按前述方法进行Omicron突变株的快速鉴定,具有预期的检测结果。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
序列表如下:
SEQ ID NO:1
SEQ ID NO:2
SEQ ID NO:3
SEQ ID NO:4
SEQ ID NO:5
SEQUENCE LISTING
<110> 广东菲鹏生物有限公司
<120> 一种鉴别新冠突变型抗原的抗体、试剂及方法
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<170> PatentIn version 3.5
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Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu
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Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro
65 70 75 80
Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly
85 90 95
Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr
100 105 110
Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp
115 120 125
Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp
130 135 140
His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln
145 150 155 160
Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser
165 170 175
Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn
180 185 190
Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala
195 200 205
Arg Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu
210 215 220
Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln
225 230 235 240
Gln Gln Gly Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys
245 250 255
Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln
260 265 270
Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp
275 280 285
Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile
290 295 300
Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile
305 310 315 320
Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Ala Ala
325 330 335
Ile Lys Leu Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu
340 345 350
Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro
355 360 365
Lys Lys Asp Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln
370 375 380
Arg Gln Lys Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu
385 390 395 400
Asp Asp Phe Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser
405 410 415
Thr Gln Ala
<210> 2
<211> 43
<212> PRT
<213> 人工序列
<400> 2
Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr
1 5 10 15
Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Glu Arg
20 25 30
Ser Gly Ala Arg Ser Lys Gln Arg Arg Pro Gln
35 40
<210> 3
<211> 416
<212> PRT
<213> 人工序列
<400> 3
Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr
1 5 10 15
Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Gly Ala
20 25 30
Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn Thr Ala Ser
35 40 45
Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu Lys Phe Pro
50 55 60
Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro Asp Asp Gln
65 70 75 80
Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly Gly Asp Gly
85 90 95
Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr Leu Gly Thr
100 105 110
Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp Gly Ile Ile
115 120 125
Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp His Ile Gly
130 135 140
Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln Leu Pro Gln
145 150 155 160
Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser Arg Gly Gly
165 170 175
Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn Ser Ser Arg
180 185 190
Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala Arg Met Ala
195 200 205
Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu Asp Arg Leu
210 215 220
Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln Gln Gln Gly
225 230 235 240
Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys Lys Pro Arg
245 250 255
Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln Ala Phe Gly
260 265 270
Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp Gln Glu Leu
275 280 285
Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile Ala Gln Phe
290 295 300
Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile Gly Met Glu
305 310 315 320
Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Ala Ala Ile Lys Leu
325 330 335
Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu Leu Asn Lys
340 345 350
His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro Lys Lys Asp
355 360 365
Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln Arg Gln Lys
370 375 380
Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu Asp Asp Phe
385 390 395 400
Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser Thr Gln Ala
405 410 415
<210> 4
<211> 416
<212> PRT
<213> 人工序列
<400> 4
Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Leu Arg Ile Thr
1 5 10 15
Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Gly Ala
20 25 30
Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn Thr Ala Ser
35 40 45
Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu Lys Phe Pro
50 55 60
Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro Asp Asp Gln
65 70 75 80
Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly Gly Asp Gly
85 90 95
Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr Leu Gly Thr
100 105 110
Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp Gly Ile Ile
115 120 125
Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp His Ile Gly
130 135 140
Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln Leu Pro Gln
145 150 155 160
Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser Arg Gly Gly
165 170 175
Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn Ser Ser Arg
180 185 190
Asn Ser Thr Pro Gly Ser Ser Lys Arg Thr Ser Pro Ala Arg Met Ala
195 200 205
Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu Asp Arg Leu
210 215 220
Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln Gln Gln Gly
225 230 235 240
Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys Lys Pro Arg
245 250 255
Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln Ala Phe Gly
260 265 270
Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp Gln Glu Leu
275 280 285
Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile Ala Gln Phe
290 295 300
Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile Gly Met Glu
305 310 315 320
Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Ala Ala Ile Lys Leu
325 330 335
Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu Leu Asn Lys
340 345 350
His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro Lys Lys Asp
355 360 365
Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln Arg Gln Lys
370 375 380
Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu Asp Asp Phe
385 390 395 400
Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser Thr Gln Ala
405 410 415
<210> 5
<211> 9
<212> PRT
<213> 人工序列
<400> 5
Gln Asn Gly Glu Arg Ser Gly Ala Arg
1 5
Claims (10)
1.一种抗体,其特征在于,所述抗体结合新冠病毒野生株N抗原第28-36位氨基酸片段。
2.权利要求1所述的抗体,其特征在于,所述抗体不结合新冠病毒野生株N抗原第31-33位发生缺失的氨基酸片段;
可选地,所述抗体不结合SEQ ID NO:3或4所示的氨基酸片段;
可选地,所述抗体不结合新冠病毒Omicron突变株N抗原;
可选地,所述新冠病毒野生株N抗原第28-36位氨基酸片段如SEQ ID NO:5所示。
3.抗体偶联物,包括权利要求1或2所述的抗体及偶联部分;其特征在于,所述偶联部分选自标记物,固相载体,结合配偶体之一;
可选地,所述标记物选自金属粒子,荧光标记,发色团标记,电子致密标记,化学发光标记,电化学标记,放射性标记,核酸标记,或酶标记;
可选地,所述标记物选自罗丹明,荧光素,荧光微球,胶体金,吖啶酯,胶乳微球,三联钌、鲁米诺类、Eu螯合物,荧光素酶,辣根过氧化物酶,碱性磷酸酶,β-半乳糖苷酶,葡糖淀粉酶,溶菌酶,糖氧化酶,葡萄糖氧化酶,半乳糖氧化酶或葡萄糖-6-磷酸脱氢酶标记;
可选地,所述固相载体选自磁性颗粒、胶乳粒子、微量滴定板、硝酸纤维素膜,玻璃纤维素膜,尼龙膜或微流控芯片;
可选地,结合配偶体选自生物素/抗生物素蛋白,生物素/链霉抗生物素蛋白。
4.一种核酸分子,其特征在于,所述核酸分子编码权利要求1或2所述的抗体。
5.一种鉴别新冠突变型抗原的方法,其特征在于,利用抗体1、抗体2和抗体3对待测样本进行免疫检测,所述抗体1能与M种新冠病毒抗原结合;所述抗体2能与除Omicron突变株外的M-1种新冠病毒抗原结合,所述抗体2选自权利要求1或2所述的抗体;所述抗体3能与M种新冠病毒抗原结合,M为大于等于2的整数。
6.根据权利要求5所述的方法,其特征在于,所述抗体1和抗体3夹心检测新冠病毒抗原;所述抗体2和抗体3夹心检测新冠病毒抗原;
可选地,所述新冠病毒抗原为新冠病毒的N抗原。
7.根据权利要求5所述的方法,其特征在于,所述方法选自免疫层析法、酶联免疫吸附法、化学发光法、胶乳免疫比浊法。
8.一种鉴别新冠突变型抗原的检测试剂,其特征在于,所述试剂包含权利要求1或2所述的抗体或权利要求5-7任一项所述的抗体1、抗体2和抗体3。
9.一种鉴别新冠突变型抗原的免疫层析试纸,其特征在于,所述免疫层析试纸包括底板、样品垫、结合垫、硝酸纤维素膜和吸水垫,所述硝酸纤维素膜上设置检测线1和检测线2,所述结合垫上设置有权利要求5-7任一项所述的抗体3,所述检测线1上包被权利要求5-7任一项所述的抗体1、所述检测线2上包被权利要求5-7任一项所述的抗体2;所述抗体3用标记物进行标记;可选地,所述硝酸纤维素膜上还设置有质控线。
10.权利要求1或2所述的抗体,权利要求3所述的抗体偶联物、权利要求5-7任一项所述的方法,权利要求8所述的试剂或权利要求9所述的试纸在检测新冠病毒Omicron突变株或制备新冠病毒Omicron突变株检测产品中的应用。
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