CN114859042A - 一种鉴别结合突变型抗原的抗体的方法及试剂 - Google Patents
一种鉴别结合突变型抗原的抗体的方法及试剂 Download PDFInfo
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- CN114859042A CN114859042A CN202111208160.1A CN202111208160A CN114859042A CN 114859042 A CN114859042 A CN 114859042A CN 202111208160 A CN202111208160 A CN 202111208160A CN 114859042 A CN114859042 A CN 114859042A
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Abstract
本发明提供了一种鉴别结合突变型抗原的抗体的方法及试剂。利用本发明方法即能够快速、准确地鉴别结合突变型抗原的抗体，保证了检测时效性，且检测效率高、成本低，对于指导疫情爆发、抗原变异快的现阶段新冠疫情防控具有重要意义。
Description
技术领域
本发明属于免疫检测领域。更具体地，涉及一种鉴别结合突变型抗原的抗体的方法及试剂。
背景技术
新型冠状病毒(SARS-CoV-2)自2019年爆发以来，陆续发现了多种类型的突变株。2020年12月14日，英国首次向WHO通报新冠病毒变异株，并命名为新冠病毒B.1.1.7突变株。虽然初步评估显示新冠病毒B.1.1.7突变株不会增加疾病严重性，但其会导致更高的发病率，产生更多住院及死亡病例。2020年10月中旬首次在南非发现新冠病毒B1.351突变株，该变异株除了与新冠病毒B.1.1.7突变株在S抗原上有相同的N501Y突变外，不同之处在于还包含了对病毒感染能力有潜在重要影响的S蛋白E484K和K417N两个关键位点的突变。不同位点突变带来的差异对于指导疾病预防有着重要意义，因此能快速鉴别不同突变型抗原的诊断产品在目前尤为重要。
发明内容
本发明目的是提供一种鉴别结合突变型抗原的抗体的方法及试剂。利用本发明方法即能够快速、准确地鉴别结合突变型抗原的抗体，保证了检测时效性。
在一些实施方案中，本发明可以包括下述一项或多项：
1、一种方法，其中，利用包括ACE2或其片段的蛋白、第一抗原和第二抗原对样品进行免疫检测，所述方法用于鉴别结合突变型抗原的抗体；其中，所述第一抗原和所述第二抗原均包括RBD或其片段；所述第一抗原与所述第二抗原之间存在至少一个位点不同。
2、根据项目1所述的方法，其中，包括ACE2或其片段的蛋白用可检测标记物进行直接或间接标记，第一抗原和第二抗原分别直接或间接结合至固相；或；
包括ACE2或其片段的蛋白直接或间接结合至固相，第一抗原和第二抗原分别用可检测标记物进行直接或间接标记。
3、根据项目1所述的方法，其中，所述抗原为病原体抗原；
可选地，所述病原体为SARSr-CoV；
可选地，所述SARSr-CoV为SARS-CoV-2或其变体；
可选地，所述抗原包括SARS-CoV-2或其变体的RBD或其片段。
4、根据项目1-3任一项所述的方法，其中，所述位点包括SARS-CoV-2刺突蛋白第455位、第456位、第484位、第485位、第486位、第490位或第494位氨基酸。
5、根据项目1-3任一项所述的方法，其中，第一抗原包括SARS-CoV-2的刺突蛋白第484位突变为非谷氨酸的其它氨基酸，第二抗原包括SARS-CoV-2的刺突蛋白第484位为谷氨酸；
可选地，第一抗原包括SARS-CoV-2的刺突蛋白第484位突变为赖氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第484位为谷氨酸。
6、根据项目1-3任一项所述的方法，其中，第一抗原包括SARS-CoV-2的刺突蛋白第456位突变为非苯丙氨酸的其它氨基酸，第二抗原包括SARS-CoV-2的刺突蛋白第456位为苯丙氨酸；
可选地，第一抗原包括SARS-CoV-2的刺突蛋白第456位突变为丙氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第456位为苯丙氨酸。
7、根据项目1所述的方法，其中，所述免疫检测为免疫层析检测、ELISA检测、免疫比浊法或化学发光法检测。
8、一种鉴别结合突变型抗原的抗体的试剂，其中，包括项目1-7任一项所述的包括ACE2或其片段的蛋白、第一抗原和第二抗原。
9、一种鉴别结合突变型抗原的抗体的层析试剂，其中，包括项目1-7任一项所述的包括ACE2或其片段的蛋白、第一抗原和第二抗原、结合垫、第一检测线和第二检测线；其中，包括ACE2或其片段的蛋白用可检测标记物进行直接或间接标记，并设于结合垫上；第一检测线上设有第一抗原，所述第二检测线上设有第二抗原；或；第一检测线上设有第二抗原，所述第二检测线上设有第一抗原；其中，所述第一检测线较所述第二检测线靠近结合垫。
10、项目1-7任一项所述的方法、项目8所述的试剂或项目9所述的层析试剂在鉴别结合突变型抗原的抗体中的应用。
具体实施方式
本发明提供了一种方法，利用包括ACE2或其片段的蛋白、第一抗原和第二抗原对样品进行免疫检测，所述方法用于鉴别结合突变型抗原的抗体；其中，所述第一抗原和所述第二抗原均包括RBD或其片段；所述第一抗原与所述第二抗原之间存在至少一个位点不同。
突变型抗原是指与参考抗原相比某一位点或多个位点发生突变。
所述结合突变型抗原的抗体包括中和抗体。
本领域技术人员应该理解，本发明以待检抗体与包括ACE2或其片段的蛋白竞争结合所述抗原的免疫反应进行，通过检测结果鉴别待检样品中是否存在结合突变型抗原的抗体。
所述“包括ACE2或其片段的蛋白”可以是例如能与RBD或其片段结合的ACE2片段，例如是ACE2全长。在一些实施方案中，ACE2或其片段可以包含胞外结构域，或由胞外结构域构成。
所述第一抗原、所述第二抗原包括RBD或其片段。在一些实施方案中，其可以是例如能与ACE2或其片段结合的RBD片段，例如是受体结合基序(RBM)，例如是RBD全长，例如包括RBD的S1蛋白，例如包括RBD的刺突蛋白全长。
“所述第一抗原与所述第二抗原之间存在至少一个位点不同”是指所述第一抗原与所述第二抗原在至少一个位点上氨基酸不同。本领域技术人员应该理解，第一抗原、第二抗原可以长度不同。在一些实施方案中，其可以是例如第一抗原包括SARS-CoV-2的刺突蛋白第501位为酪氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第501位为天冬酰胺。
在一些实施方案中，包括ACE2或其片段的蛋白用可检测标记物进行直接或间接标记，第一抗原和第二抗原分别直接或间接结合至固相；在一些实施方案中，包括ACE2或其片段的蛋白直接或间接结合至固相，第一抗原和第二抗原分别用可检测标记物进行直接或间接标记。
在一些实施方案中，所述标记蛋白用可检测标记物进行直接或间接标记。在一些实施方案中，可检测标记物例如金属粒子，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，可检测标记物例如可以是罗丹明，荧光素，荧光微球，胶体金，吖啶酯，乳胶微球，彩色微球，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，所述包被蛋白直接或间接结合至固相。在一些实施方案中，固相没有特别限制，其可以是例如磁性颗粒，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，所述抗原为病原体抗原；在一些实施方案中，所述病原体为SARSr-CoV(严重急性呼吸综合征相关冠状病毒)；在一些实施方案中，所述SARSr-CoV为SARS-CoV-2或其变体；在一些实施方案中，所述抗原包括SARS-CoV-2或其变体的RBD或其片段。
在一些实施方案中，“所述第一抗原与所述第二抗原之间存在至少一个位点不同”，所述位点包括SARS-CoV-2刺突蛋白第455位、第456位、第484位、第485位、第486位、第490位或第494位氨基酸。
在一些实施方案中，第一抗原包括SARS-CoV-2的刺突蛋白第484位突变为非谷氨酸的其它氨基酸，第二抗原包括SARS-CoV-2的刺突蛋白第484位为谷氨酸。在一些实施方案中，第一抗原包括SARS-CoV-2的刺突蛋白第484位突变为赖氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第484位为谷氨酸；在一些实施方案中，第一抗原包括SARS-CoV-2的刺突蛋白第484位突变为谷氨酰胺，第二抗原包括SARS-CoV-2的刺突蛋白第484位为谷氨酸；在一些实施方案中，第一抗原包括SARS-CoV-2的刺突蛋白第484位突变为脯氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第484位为谷氨酸。
在一些实施方案中，第一抗原包括SARS-CoV-2的刺突蛋白第456位突变为非苯丙氨酸的其它氨基酸，第二抗原包括SARS-CoV-2的刺突蛋白第456位为苯丙氨酸；在一些实施方案中，第一抗原包括SARS-CoV-2的刺突蛋白第456位突变为丙氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第456位为苯丙氨酸。
在一些实施方案中，第一抗原包括SARS-CoV-2的刺突蛋白第485位突变为精氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第485位为甘氨酸。在一些实施方案中，第一抗原包括SARS-CoV-2的刺突蛋白第494位突变为脯氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第494位为丝氨酸。
在一些实施方案中，“所述第一抗原与所述第二抗原之间存在至少一个位点不同”，所述位点还可以包括例如SARS-CoV刺突蛋白第442位、第472位、第479位、第480位或第487位氨基酸。
本发明所述免疫检测应做广义理解，其指通过抗原抗体特异性结合而进行的检测方法，包括例如免疫层析检测、例如ELISA检测、例如免疫比浊法检测、例如化学发光法检测，但不限于此。
本发明还提供了一种鉴别结合突变型抗原的抗体的试剂，包括所述的包括ACE2或其片段的蛋白、第一抗原和第二抗原。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。
在一些实施方案中，所述试剂为免疫层析试剂，包括以上任一实施方案所述的包括ACE2或其片段的蛋白、第一抗原和第二抗原、结合垫、第一检测线和第二检测线；其中，包括ACE2或其片段的蛋白用可检测标记物进行直接或间接标记，并设于结合垫上；第一检测线上设有第一抗原，所述第二检测线上设有第二抗原；或；第一检测线上设有第二抗原，所述第二检测线上设有第一抗原；其中，所述第一检测线较所述第二检测线靠近结合垫。
在一些实施方案中，所述第一检测线为T1线，所述第二检测线为T2线。
在一些实施方案中，包括ACE2或其片段的蛋白例如为人ACE2，第一抗原例如包括SARS-CoV-2变体(例如其刺突蛋白第484位为谷氨酸突变的其它氨基酸)的RBD或其片段的蛋白(例如氨基酸序列如SEQ ID NO:2所示)，第二抗原例如包括SARS-CoV-2(例如其刺突蛋白第484位为谷氨酸)的RBD或其片段的蛋白(例如氨基酸序列如SEQ ID NO:1所示)。在一些实施方案中，所述T1线上设有第一抗原、所述T2线上设有第二抗原。在一些实施方案中，当待检样品中无待检抗体时人ACE2会与第一抗原和第二抗原均发生结合，则T1线显色、T2线显色，二者显色相当。在一些实施方案中，当待检样品中存在不结合某位点突变型抗原(例如刺突蛋白第484位为谷氨酸突变的其它氨基酸)的抗体时，该抗体基本不与人ACE2竞争结合第一抗原，但会与人ACE2竞争结合第二抗原；则T1线显色不受影响、T2线显色减弱，T1线显色强于T2线显色。在一些实施方案中，当待检样品中存在结合某位点突变型抗原(例如刺突蛋白第484位为谷氨酸突变的其它氨基酸)的抗体时，该抗体会与人ACE2竞争结合第一抗原，但基本不与人ACE2竞争结合第二抗原；则T1线显色减弱、T2线显色不受影响，T1线显色弱于T2线显色。利用本发明两种抗原，设定双重检测线，可以快速简便地鉴定出突变型抗原，在一些实施方案中，可以更加优越地检测灵敏度。
在一些实施方案中，包括ACE2或其片段的蛋白例如为人ACE2，第一抗原例如包括SARS-CoV-2变体(例如其刺突蛋白第456位为苯丙氨酸突变的其它氨基酸)的RBD或其片段的蛋白(例如氨基酸序列如SEQ ID NO:3所示)，第二抗原例如包括SARS-CoV-2(例如其刺突蛋白第456位为苯丙氨酸)的RBD或其片段的蛋白(例如氨基酸序列如SEQ ID NO:1所示)。在一些实施方案中，所述T1线上设有第一抗原、所述T2线上设有第二抗原。
本发明还提供了以上任一实施方案所述方法、试剂及层析试剂在鉴别结合突变型抗原的抗体中的应用。
利用本发明方法同样也能鉴别SARSr-CoV其它冠状病毒的突变型抗原。该类病毒通过受体结合结构域RBD与ACE2的结合入侵细胞。
本发明中，待测样品包括健康或病理状态的血液(包括血清、血浆或全血)样本、淋巴样本、唾液样本或关节滑液。
本发明方案不限于SARSr-CoV突变型的鉴别，根据本发明原理，其它抗原突变型的鉴别也可以采用本发明方案，本发明方案在目前新冠病毒变异迅速的现状下，能发挥更大的优势，本发明方案也为未来一些新型病原体突变型的鉴定提供新的思路。
实施例1胶体金平台鉴别突变型
H83抗原的氨基酸序列如SEQ ID NO:1所示，H84抗原的氨基酸序列如SEQ ID NO:2所示，Ab13抗体为结合参考抗原(例如H83抗原)的抗体；Ab13抗体、人ACE2可购自菲鹏生物；其它试剂和材料均为市购。
1.标记
(1)胶体金制备：采用传统柠檬酸钠还原法，首先将氯金酸溶液加热至沸腾，迅速加入一定比例的柠檬酸三钠溶液，搅拌均匀，待溶液颜色变为酒红色且不再变化时停止加热，冷却至室温，得到浓度为万分之四的胶体金溶液；
(2)标记：向胶体金溶液中加入0.2M K2CO3溶液调节pH至6.0-7.5；
(3)离心：向调节pH后的胶体金溶液中加入人ACE2并混匀，后加入BSA封闭，终止标记，离心10000rpm/7min/4℃，去上清；
(4)复溶：重悬至100uL，超声2-3次；
(5)铺金：将重悬得到的浓缩金稀释并铺于玻璃纤维素膜，然后放入冻干机冻干(1-2h)或者放入37℃干燥房干燥过夜，制得结合垫。
2.包被
(1)将硝酸纤维素膜与底板组装好备用；
(2)将H84抗原和H83抗原稀释至0.1-1.0mg/mL，用喷金画膜仪，在硝酸纤维素膜上均匀的画T1和T2线(间距6mm)，然后放入37℃恒温箱中进行干燥，至少干燥45min以上。
T1线较T2线靠近结合垫，将样品垫、结合垫、硝酸纤维素膜、吸水垫依次搭接组装于底板上，组装切条，加样检测。
3.检测
(1)待检样品：阴性血清、Ab13、抗体阳性血清等。
(2)检测方法：使用试纸条进行检测。
4.实验结果
表1、H83和H84对阴性血清和Ab13抗体的检测结果
表2、H83和H84对阴性血清和23#、25#血清的检测结果
| 包被抗原 | 阴性血清 | 23# | 25# |
| T1：H83 | C4+ | C6 | C6 |
| T2：H84 | C4 | C4 | C4 |
表1、2中，字母B代表不显色，字母C后的数字代表显色强度，数字越大，显色越弱。
表1结果显示，检测阴性血清时，T1和T2的显色基本相当，而加入Ab13抗体后，H83对应的检测线的显色明显降低，而H84对应的检测线显色无明显降低，可见Ab13抗体结合包括刺突蛋白第484位谷氨酸的非突变型抗原；阳性血清23#、25#的检测结果见表2，结果显示，加入该样本时，H83对应的检测线T1的显色明显降低，而T2线显色无明显降低，可见阳性血清中存在结合刺突蛋白第484位谷氨酸的非突变型抗原的抗体。
实施例2彩色微球鉴别突变型
1.标记
取彩色微球，300W超声后，取0.1ml乳胶颗粒加入0.9ml 100mM MES中，涡旋混匀；15000rmp 15min离心，后去上清；加入1.0ml 100mM MES超声，加入适量MES和NHS活化微球10min；15000rmp 15min离心，后去上清；加入1.0ml 100mM MES超声，加入适量ACE2，37℃涡旋反应过夜；15000rmp 15min离心，后去上清，加入BSA封闭，超声，37℃反应4h；15000rmp15min离心，后去上清并清洗，超声；15000rmp 15min离心，后去上清重悬；将重悬得到的浓缩液稀释并铺于玻璃纤维素膜，然后放入冻干机冻干(1-2h)或者放入37℃干燥房干燥过夜，制得结合垫。
2.包被
(1)将硝酸纤维素膜与底板组装好备用；
(2)将H84抗原和H83抗原稀释至0.1-1.0mg/mL，用喷金画膜仪，在NC膜上均匀的画T1和T2线(间距6mm)，然后放入37℃恒温箱中进行干燥，至少干燥45min以上。
T1线较T2线靠近结合垫，将样品垫、结合垫、NC膜、吸水垫依次搭接组装于底板上，组装切条，加样检测。
3.检测
(1)待检样品：生理盐水、阴性血清、Ab13、抗体阳性血清等。
(2)检测方法：使用试纸条进行检测。
4.实验结果
表3、H84和H83对生理盐水、阴性血清和Ab13抗体的检测结果
| 包被抗原 | 生理盐水 | 阴性血清 | Ab13(20ug/ml) | Ab13(5ug/ml) |
| T2：H83 | C4 | C4 | C9 | C7+ |
| T1：H84 | C4 | C4+ | C3 | C3 |
表4、H83和H84对阴性血清和Ab13抗体的检测结果
| 包被抗原 | 阴性血清 | Ab13(20ug/ml) |
| T2：H84 | C4- | C5+ |
| T1：H83 | C3 | B+ |
表3、表4结果显示，检测生理盐水、阴性血清时，T1和T2的显色基本相当，而加入Ab13抗体后，H83对应的检测线的显色明显降低，而H84对应的检测线显色无明显降低，可见Ab13抗体结合包括刺突蛋白第484位谷氨酸的非突变型抗原；阳性血清1#等16份样本的检测结果见表5，结果显示，加入此16份样本时，检测线T2的显色明显降低，而T1线显色无明显降低，可见阳性血清中存在结合包括刺突蛋白第484位谷氨酸的非突变型抗原的抗体。阳性血清36#、47#检测结果见表6，结果显示，检测线T1显色降低，且降低相比表5更为明显(血清样本均经过稀释)，T1线显色无明显降低，可见，阳性血清中存在结合包括刺突蛋白第484位赖氨酸的突变型抗原的抗体；并且相比检测结合非突变型抗原的抗体，检测结合突变型抗原的抗体具有更高的灵敏度，在新冠病毒变异多的现阶段具有提高指示结合突变株抗原的抗体的作用。
表5、H84和H83对抗体阳性血清的检测结果
表6、H84和H83对36#、47#阳性血清的检测结果
a：稀释比例
表3、4、5、6中，字母B代表不显色，字母C后的数字代表显色强度，数字越大，显色越弱。
实施例3彩色微球鉴别突变型
H85抗原氨基酸序列如SEQ ID NO:3所示。H85抗原包被于T1检测线，H83抗原包被于T2检测线，其它标记、包被、检测过程同实施例2。当检测样品为阴性血清时，T1、T2检测线显色相当；当检测样品中含有结合包括刺突蛋白第456位苯丙氨酸的非突变型抗原的抗体时，T2检测线显色减弱，T1检测线显色强于T2至少2个色卡；当检测样品中含有包括结合刺突蛋白第456位丙氨酸的抗体时，T1检测线显色减弱、几乎消线，T2检测线显色强于T1至少2个色卡。
H86抗原氨基酸序列如SEQ ID NO:4所示。H86抗原包被于T1检测线，H83抗原包被于T2检测线，其它标记、包被、检测过程同实施例2。当检测样品为阴性血清时，T1、T2检测线显色相当；当检测样品中含有结合包括刺突蛋白第484位谷氨酸的非突变型抗原的抗体时，T2检测线显色减弱，T1检测线显色强于T2至少2个色卡；当检测样品中含有包括结合刺突蛋白第484位谷氨酰胺的抗体时，T1检测线显色减弱、几乎消线，T2检测线显色强于T1至少2个色卡；通过双重检测线，可以更准确、灵敏地识别突变型抗原。
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
SEQ ID NO:1：
RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNF
SEQ ID NO:2：
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVKGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRAR
SEQ ID NO:3：
RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLARKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNF
SEQ ID NO:4：
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVQGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRAR
SEQUENCE LISTING
<110> 广东菲鹏生物有限公司
<120> 一种鉴别结合突变型抗原的抗体的方法及试剂
<130>
<150> CN202110147628.4
<151> 2021-02-03
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 223
<212> PRT
<213> SARS-COV-2
<400> 1
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Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val
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Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp
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Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln
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Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr
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Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly
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Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys
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Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr
145 150 155 160
Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser
165 170 175
Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val
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Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly
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Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe
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Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
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Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
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Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
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Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
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Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
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Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
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Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
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Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
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Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
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Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
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Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
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Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
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Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
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Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
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Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
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Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
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Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
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Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
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Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
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Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
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Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
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Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
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Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
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Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
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Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
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Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
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Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
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Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
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Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
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Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
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Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
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Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
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Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
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Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
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His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
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Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg
675 680 685
<210> 3
<211> 223
<212> PRT
<213> SARS-COV-2
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Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn
1 5 10 15
Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val
20 25 30
Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser
35 40 45
Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val
50 55 60
Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp
65 70 75 80
Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln
85 90 95
Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr
100 105 110
Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly
115 120 125
Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Ala Arg Lys Ser Asn Leu Lys
130 135 140
Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr
145 150 155 160
Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser
165 170 175
Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val
180 185 190
Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly
195 200 205
Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe
210 215 220
<210> 4
<211> 685
<212> PRT
<213> SARS-COV-2
<400> 4
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
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Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
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Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
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Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
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Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
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Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
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Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
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Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
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Asn Gly Val Gln Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
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Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
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Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
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Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
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Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
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Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
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Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
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Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
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His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
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Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
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Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
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Claims (10)
1.一种方法，其特征在于，利用包括ACE2或其片段的蛋白、第一抗原和第二抗原对样品进行免疫检测，所述方法用于鉴别结合突变型抗原的抗体；其中，所述第一抗原和所述第二抗原均包括RBD或其片段；所述第一抗原与所述第二抗原之间存在至少一个位点不同。
2.根据权利要求1所述的方法，其特征在于，包括ACE2或其片段的蛋白用可检测标记物进行直接或间接标记，第一抗原和第二抗原分别直接或间接结合至固相；或；
包括ACE2或其片段的蛋白直接或间接结合至固相，第一抗原和第二抗原分别用可检测标记物进行直接或间接标记。
3.根据权利要求1所述的方法，其特征在于，所述抗原为病原体抗原；
可选地，所述病原体为SARSr-CoV；
可选地，所述SARSr-CoV为SARS-CoV-2或其变体；
可选地，所述抗原包括SARS-CoV-2或其变体的RBD或其片段。
4.根据权利要求1-3任一项所述的方法，其特征在于，所述位点包括SARS-CoV-2刺突蛋白第455位、第456位、第484位、第485位、第486位、第490位或第494位氨基酸。
5.根据权利要求1-3任一项所述的方法，其特征在于，第一抗原包括SARS-CoV-2的刺突蛋白第484位突变为非谷氨酸的其它氨基酸，第二抗原包括SARS-CoV-2的刺突蛋白第484位为谷氨酸；
可选地，第一抗原包括SARS-CoV-2的刺突蛋白第484位突变为赖氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第484位为谷氨酸。
6.根据权利要求1-3任一项所述的方法，其特征在于，第一抗原包括SARS-CoV-2的刺突蛋白第456位突变为非苯丙氨酸的其它氨基酸，第二抗原包括SARS-CoV-2的刺突蛋白第456位为苯丙氨酸；
可选地，第一抗原包括SARS-CoV-2的刺突蛋白第456位突变为丙氨酸，第二抗原包括SARS-CoV-2的刺突蛋白第456位为苯丙氨酸。
7.根据权利要求1所述的方法，其特征在于，所述免疫检测为免疫层析检测、ELISA检测、免疫比浊法或化学发光法检测。
8.一种鉴别结合突变型抗原的抗体的试剂，其特征在于，包括权利要求1-7任一项所述的包括ACE2或其片段的蛋白、第一抗原和第二抗原。
9.一种鉴别结合突变型抗原的抗体的层析试剂，其特征在于，包括权利要求1-7任一项所述的包括ACE2或其片段的蛋白、第一抗原和第二抗原、结合垫、第一检测线和第二检测线；其中，包括ACE2或其片段的蛋白用可检测标记物进行直接或间接标记，并设于结合垫上；第一检测线上设有第一抗原，所述第二检测线上设有第二抗原；或；第一检测线上设有第二抗原，所述第二检测线上设有第一抗原；其中，所述第一检测线较所述第二检测线靠近结合垫。
10.权利要求1-7任一项所述的方法、权利要求8所述的试剂或权利要求9所述的层析试剂在鉴别结合突变型抗原的抗体中的应用。
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