CN113234154B - 类风湿因子IgG、IgM、IgA复合质控品及其制备方法、应用 - Google Patents
类风湿因子IgG、IgM、IgA复合质控品及其制备方法、应用 Download PDFInfo
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Abstract
本发明公开了类风湿因子IgG、IgM、IgA复合质控品及其制备方法、应用，制备方法为通过用类风湿因子抗原免疫小鼠获得小鼠RF抗体，通过抗体氨基酸序列测序得到小鼠RF抗体的可变区氨基酸序列，通过序列设计和全基因合成RF抗体可变区‑人IgA恒定区‑人IgM恒定区并联碱基序列，并将序列引入含有人IgG Fc片段基因表达序列的pFUSE‑hIgG1‑Fc2载体中，制备同时含有人IgG、IgM、IgA Fc段和RF抗体可变区的重组质粒，将该重组质粒转染HEK293哺乳细胞，获取同时含有人IgG、IgM、IgA Fc段和RF抗体可变区的重组抗体，将该重组抗体配制为质控品，可同时用于RF‑IgG、RF‑IgM、RF‑IgA及RF‑IgG/M/A四类检测试剂盒，其均一性、精密性和稳定性较好，既方便了临床操作，又极大的节约了成本，也极大的控制了质控品间的批间差。
Description
技术领域
本发明涉及体外诊断技术领域，具体涉及类风湿因子IgG、IgM、IgA复合质控品及其制备方法、应用。
背景技术
类风湿因子(rheumatoid factor，RF)是一种抗人或动物IgG分子Fc片段抗原决定簇的抗体，是以变性IgG为靶抗原的自身抗体。类风湿因子一般分为IgM型、IgG型和IgA型。类风湿因子(RF)是美国风湿病学会1987规定的经典诊断类风湿关节炎(RA)的标准之一。类风湿因子阳性患者较多伴有关节外表现，如皮下结节及血管炎等。到目前为止，对疑似RA患者最常用的血清学检测除了常规炎症参数外，主要是类风湿因子RF。RA患者中有70％～80％可以检测到RF，RF阴性的RA占20％～30％。通常与高浓度的类风湿因子相关疾病有类风湿关节炎(RA),Sjogren综合征。此外，它还被发现与系统性红斑狼疮(SLE)，多肌炎，系统性硬化症，混合性结缔组织病(MCTD)，冷球蛋白血症，干燥综合症(SS)有关。
目前市场上检测RF的试剂盒主要有四个大类，RF抗体IgG试剂盒、RF抗体IgM检测试剂盒、RF抗体IgA检测试剂盒和RF抗体IgG/M/A检测试剂盒，临床上常规检查的RF主要是IgM-RF，其敏感性高，但是对RA的诊断特异性较低，正常人亦可出现2％-5％的阳性率。IgG-RF在关节软骨表面的沉积可激活补体引起关节的炎性损伤，因此RF IgG在RA患者血清或滑膜液中出现与患者的滑膜炎、血管炎的症状密切相关。IgA-RF是RA临床活动的一项指标，效价与患者关节炎症状和严重程度以及骨质破坏程度有显著的相关性。临床上3种RF同时检测较一般单一IgM-RF检测更能全面反映RA的临床情况，对诊断RA、判断RA活动程度，治疗效果和预后具有重要意义。
RF常用的免疫检测方法有酶联免疫吸附分析技术(ELISA)和化学发光免疫分析技术(CLIA)，磁微粒化学发光技术是以化学发光剂为底物的酶免疫技术，同时应用了纳米级磁性微粒做固相载体，增加了吸附面积，使抗原、抗体最大限度结合，并使其结合反应在近似液相的条件下进行，兼具化学发光与酶免疫技术的优点，是近几年快速发展的非放射性检测方法。质控品作为化学发光试剂的重要组成部分，主要作用是监控整个检测系统的状态，确认样本检测在检测系统正常状态下进行，对检测结果是否准确提供非常重要的参考作用。
而现有的RF质控品多为动物源性血清，在现有的技术条件下的质控品中IgG、IgM和IgA批间差较难控制，且生产及储存成本更高。
发明内容
本发明的目的在于提供类风湿因子IgG、IgM、IgA复合质控品及其制备方法，通过本发明所述方法制备的复合质控品解决现有RF质控品批间差难控制的问题，且稳定性较好。
此外，本发明还提供上述类风湿因子IgG、IgM、IgA复合质控品的应用。
本发明通过下述技术方案实现：
类风湿因子IgG、IgM、IgA复合质控品的制备方法，包括以下步骤：
S1、分别获取小鼠RF抗体的可变区基因序列、人IgM恒定区基因序列和人IgA恒定区基因序列，小鼠RF抗体的可变区基因序列如SEQ ID No.2所示，其氨基酸序列如SEQ IDNo.4所示；
S2、根据步骤S1获得的基因序列按以下排序顺序合成全基因序列：
小鼠RF抗体的可变区基因序列-Linker-人IgA恒定区基因序列-Linker-人IgM-恒定区基因序列；获得的全基因序列如SEQ ID No.1所示，其氨基酸序列如SEQ ID No.3所示；
S3、将步骤S2获得的全基因序列引入含有人IgG Fc片段基因表达序列的pFUSE-hIgG1-Fc2载体中，制备同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组质粒；
S4、将步骤S3获得的重组质粒转染哺乳细胞，获取同时含有人IgG、人IgM、人IgAFc段和小鼠RF抗体可变区的重组抗体。
本发明利用小鼠抗RF抗体可变区和人IgG、IgM、IgA Fc段融合蛋白作为RF检测试剂复合质控品的原料，极大提高原料的筛选效率，制备的重组抗体同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区，较大降低原料批间差控制的难度。
本发明制备的重组抗体同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区，可同时用于RF-IgG、RF-IgM、RF-IgA及RF-IgG/M/A四类检测试剂盒，其均一性、精密性和稳定性较好，既方便了临床操作，又极大的节约了成本，也极大的控制了质控品间的批间差。
本发明的关键在于获取小鼠RF抗体的可变区基因序列、人IgM恒定区基因序列和人IgA恒定区基因序列，并将小鼠RF抗体的可变区基因序列、人IgM恒定区基因序列和人IgA恒定区基因序列与含有人IgG Fc片段基因表达序列的pFUSE-hIgG1-Fc2载体融合，最终成功构建同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体。
进一步地，步骤S1中，小鼠RF抗体的可变区基因序列的获取过程如下：
通过类风湿因子抗原免疫小鼠获得小鼠RF抗体，通过抗体氨基酸序列测序得到小鼠RF抗体的可变区氨基酸序列，根据哺乳动物密码子偏爱性，合成小鼠RF抗体的可变区基因序列。
进一步地，小鼠RF抗体的获得过程如下：
将类风湿因子抗原通过多次免疫小鼠获得可表达RF抗体的脾细胞；提取脾细胞与Sp2/0细胞融合、筛选、验证得到可高效表达抗RF抗原单克隆抗体的细胞株；通过细胞培养，表达纯化得到高纯度的单克隆抗体。
进一步地，步骤S2中，全基因序列的合成过程如下：
针对小鼠RF抗体的可变区基因序列、人IgM恒定区基因序列和人IgA恒定区基因序列，插入刚性linker连接，N端加入蜂毒信号肽序列，在序列上游加入限制性核酸内切酶位点EcoRI，下游序列插入限制性核酸内切酶位点NcoI。
进一步地，步骤S4中采用的哺乳细胞为HEK293哺乳细胞。
进一步地，还包括以下步骤：
将获得的同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体制备成缓冲溶液。
一种同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体。
一种类风湿因子IgG、IgM、IgA复合质控品，包括如权利要求1-6任一项所述的制备方法制备的同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体。
一种类风湿因子IgG、IgM、IgA复合质控品，由含有重组抗体的缓冲液配制而成。
同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体在抗类风湿因子抗体IgG检测试剂盒、抗类风湿因子抗体IgG检测试剂盒、抗类风湿因子抗体IgA检测试剂盒和抗类风湿因子抗体IgA/G/M检测试剂盒中的应用。
本发明与现有技术相比，具有如下的优点和有益效果：
1、本发明利用小鼠抗RF抗体可变区和人IgG、IgM、IgA Fc段融合蛋白作为RF检测试剂复合质控品的原料，极大提高原料的筛选效率，并较大降低原料批间差控制的难度。
2、本发明的质控品包括同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体，使质控品试剂配制的难度较大降低、提高调试及配制的效率，并能更好的控制质控品的批间差及稳定性。
3、本发明的质控品包括同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体，在用于检测试剂盒时，使用过程中可节约存储成本、减小工作量、提高工作效率，减少了试剂死体积，节约原料成本。
4、本发明制备的重组抗体同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区，可同时用于RF-IgG、RF-IgM、RF-IgA及RF-IgG/M/A四类检测试剂盒，其均一性、精密性和稳定性较好，既方便了临床操作，又极大的节约了成本，也极大的控制了质控品间的批间差。
附图说明
此处所说明的附图用来提供对本发明实施例的进一步理解，构成本申请的一部分，并不构成对本发明实施例的限定。在附图中：
图1为pFUSE-hIgG1-Fc2载体质粒图谱；
图2为Western-blot结果图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例和附图，对本发明作进一步的详细说明，本发明的示意性实施方式及其说明仅用于解释本发明，并不作为对本发明的限定。
实施例1：
类风湿因子IgG、IgM、IgA复合质控品的制备方法，包括以下步骤：
S1、分别获取小鼠RF抗体的可变区基因序列、人IgM恒定区基因序列和人IgA恒定区基因序列，小鼠RF抗体的可变区基因序列如SEQ ID No.2所示，其氨基酸序列如SEQ IDNo.4所示：
将类风湿因子抗原通过多次免疫小鼠获得可表达RF抗体的脾细胞；提取脾细胞与Sp2/0细胞融合、筛选、验证得到可高效表达抗RF抗原单克隆抗体的细胞株；通过细胞培养，表达纯化得到高纯度的单克隆抗体，对单克隆抗体进行氨基酸序列测序得到小鼠RF抗体的可变区氨基酸序列，根据哺乳动物密码子偏爱性，合成小鼠RF抗体的可变区基因序列；
通过GenBank查询获得人IgM、IgA重链恒定区基因序列；
RF抗体轻链V区(小鼠RF抗体的可变区)氨基酸序列(SEQ ID No.4)：
DIVLTQSPDSLSVSLGERVTVNCKLSQSVLHSSNKQNYLAWFQQNPGQPPKLLIYWASARQSGVPARFMGSGSGTEFSLTISSLQAEDVAVYYCQQYYDSTYTFGQGTKLEINR；
RF抗体轻链V区(小鼠RF抗体的可变区)核苷酸序列(SEQ ID No.2)：
人IgM恒定区的重链氨基酸序列：
GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGKYAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLGQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCY；
人IgM恒定区的重链核苷酸序列：
人IgA恒定区重链氨基酸序列：
ASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDASGDLYTTSSQLTLPATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY；
人IgA恒定区重链核苷酸序列：
S2、根据步骤S1获得的基因序列经过密码子优化后按以下排序顺序合成全基因序列：
真核KOZAK-信号肽-小鼠RF抗体的可变区基因序列-Linker-人IgA恒定区基因序列-Linker-人IgA恒定区基因序列；获得的全基因序列如SEQ ID No.1所示，其氨基酸序列如SEQ ID No.3所示；
将得到的针对抗RF的单克隆抗体的CDR的碱基序列和人IgA、IgM恒定区碱基序列合成，插入刚性linker(--EAAAKEAAAKEAAAK-)连接，N端加入蜂毒信号肽序列，在序列上游加入限制性核酸内切酶位点EcoRI，下游序列插入限制性核酸内切酶位点NcoI；
其中，
Linker碱基序列：GGAGGCGGCGGATCT；Linker氨基酸序列：GGGGS；
Linker碱基序列：GAAGCCGCTGCCAAG；Linker氨基酸序列：EAAAK；
真核KOZAK碱基序列：GCCACC；真核KOZAK氨基酸序列：AT；
蜂毒信号肽序列碱基序列：AAGTTCCTGGTCAACGTCGCTCTCGTGTTCATG；
蜂毒信号肽序氨基酸序列：KFLVNVALVFM；
全基因的氨基酸序列(SEQ ID No.3)：
DIVLTQSPDSLSVSLGERVTVNCKLSQSVLHSSNKQNYLAWFQQNPGQPPKLLIYWASARQSGVPARFMGSGSGTEFSLTISSLQAEDVAVYYCQQYYDSTYTFGQGTKLEINREAAAKGSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGKYAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLGQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCYGGGGSASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDASGDLYTTSSQLTLPATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCYGGGGS；
全基因的核苷酸序列(SEQ ID No.1)：
S3、将步骤S2获得的全基因序列与经过限制性内切酶酶切位点：EcoRI：(-GAATTC-)NcoI：(-CCATGG-)双酶切的载体pFUSE-hIgG1-Fc2进行连接，pFUSE-hIgG1-Fc2载体质粒图谱如图1所示，转化大肠杆菌细胞，挑选阳性克隆鉴定，制备同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组质粒；
S4、将步骤S3获得的重组质粒转染哺乳细胞，获取同时含有人IgG、人IgM、人IgAFc段和小鼠RF抗体可变区的重组抗体：
将得到的含有目的基因的重组质粒转染HEK293哺乳细胞进行表达，大量培养细胞，收集细胞培养物，离心取细胞上清，将含有目的基因的pFUSE-hIgG/M/A-RF质粒，通过Lipofectamine 2000试剂将转染至CHO(GS缺陷型)细胞中，通过GS筛选体系获得单克隆细胞株；大量培养细胞，收集细胞培养物，10000rpm、15min条件下离心取细胞上清。
对本实施例制备的重组抗体进行纯化和鉴定：
1)、将实施例1中获取的细胞上清用Protein A亲和柱纯化。利用Gly-HCl进行梯度洗脱，去除杂蛋白，结果如图2所示，得到由小鼠抗RF抗体可变区融合的同时具有人IgG、IgM、IgA Fc段的人源化IgG；
2)、用紫外可见分光光度计测定蛋白在波长280nm处的吸光值，用吸光值除以1.35得到抗体浓度为295.86mg/L；
3)、用自产RF抗体IgG试剂盒、RF抗体IgM检测试剂盒、RF抗体IgA检测试剂盒和RF抗体IgG/M/A检测试剂盒(磁微粒化学发光法)测试重组抗体的效价：
将重组抗体按1/25、1/50、1/100稀释梯度小样，分别使用自产RF抗体IgG试剂盒、RF抗体IgM检测试剂盒、RF抗体IgA检测试剂盒和RF抗体IgG/M/A检测试剂盒测试，根据计算软件反算出重组抗体原液浓度，结果如表1所示：
表1
| 稀释比例 | IgG(RU/mL) | IgM(RU/mL) | IgA(RU/mL) | IgG/M/A(RU/mL) |
| 1/25 | 326.80 | 413.36 | 304.16 | 412.12 |
| 1/50 | 132.42 | 198.60 | 174.46 | 192.30 |
| 1/100 | 77.70 | 91.16 | 64.32 | 60.70 |
| 反算原浓度 | 7520.33 | 9793.33 | 7586.33 | 8662.67 |
实施例2：
一种类风湿因子(RF)IgG、IgM、IgA复合质控品：
复合质控品的主要成分如表2所示：
表2：类风湿因子(RF)IgG、IgM、IgA复合质控品主要成分
使用该重组抗体可以通用于RF抗体IgG试剂盒、RF抗体IgM检测试剂盒、RF抗体IgA检测试剂盒和RF抗体IgG/M/A检测试剂盒(磁微粒化学发光法)，使质控品试剂配制的难度较大降低、提高调试及配制的效率，并能更好的控制质控品的批间差及稳定性。
类风湿因子(RF)IgG、IgM、IgA复合质控品的性能评估：
稳定性：将检测质控品于37℃分放置7天，用公司自产试剂盒测定质控品原料的信号保留率。结果如表3所示：
表3
表3的测试结果均＞90％，表明质控品稳定性好，符合临床要求。
结论：经验证该重组抗体可作为RF抗体IgG试剂盒、RF抗体IgM检测试剂盒、RF抗体IgA检测试剂盒和RF抗体IgG/M/A检测试剂盒(磁微粒化学发光法)的质控品使用。可作为RF抗体检测试剂盒的试剂研发及优化的备选原料。
以上所述的具体实施方式，对本发明的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施方式而已，并不用于限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
序列表
<110> 四川携光生物技术有限公司
<120> 类风湿因子IgG、IgM、IgA复合质控品及其制备方法、应用
<160> 4
<170> SIPOSequenceListing 1.0
<210> 1
<211> 2778
<212> DNA
<213> 人工序列1(人工序列)
<400> 1
gaattcgata ttgtgctgac ccagtccccc gattcactca gcgtttcatt gggcgaacgg 60
gtgactgtca actgtaagct gagccagagc gttttgcact cctccaacaa gcagaattat 120
ctcgcctggt ttcagcagaa tcctgggcag cccccaaaac tgttgatcta ctgggccagc 180
gcaagacagt caggagttcc tgcaaggttt atgggtagcg gatctggcac ggaattctcc 240
ctcacaatca gcagcctgca ggctgaggac gttgcagtct actattgtca gcagtactac 300
gatagcacct atacgtttgg gcaggggacg aagctggaaa ttaatagaga agccgctgcc 360
aagggatcag cctcagcacc tacactcttt ccactcgtct cttgcgaaaa cagccccagc 420
gacacaagca gtgtagccgt gggatgcctg gctcaggatt tcctgccaga ctctatcacc 480
ttttcttgga agtataagaa taacagcgac atctcaagta ctcgagggtt tccaagcgtc 540
ctgagggggg gaaagtacgc agcgacatca caggtgctgc tcccctcaaa ggatgtcatg 600
cagggaacag atgagcacgt cgtgtgtaag gtgcaacacc caaacgggaa caaggagaag 660
aatgtgccat tgcctgtgat cgccgaactc ccccctaaag tgtcagtctt tgtgccaccc 720
cgggacggct tctttggaaa tccccggaaa tctaaactga tctgtcaggc taccggcttt 780
agtcctcggc agatacaggt gagctggctg agggaaggga aacaggttgg ttctggagtc 840
accactgatc aggttcaagc ggaagccaaa gagagtggac caactaccta caaagtgact 900
agtaccctta ccatcaaaga aagtgattgg ctgtcacaga gtatgttcac ctgtcgcgta 960
gaccatagag gtctgacatt tcagcagaac gcaagctcaa tgtgcgttcc tgatcaggac 1020
accgccatca gagtctttgc cattcccccc agttttgcct ctatctttct cacaaagagc 1080
acaaagctga cttgtctcgt taccgatctc acaacctacg actctgtcac catttcctgg 1140
acaagacaga acggggaggc cgtcaagaca cacacaaata tttccgaatc tcaccctaac 1200
gccacattct cagcagtagg cgaagcttct atttgcgagg acgattggaa cagcggtgag 1260
agatttacct gcacagtcac acataccgat ctgccaagcc ccctgaagca aacaataagc 1320
aggcctaaag gcgtcgcgtt gcatcggcct gacgtgtatt tgttgccacc tgcccgcgaa 1380
caactgaact tgcgggaatc cgccacaatt acttgtctgg tgaccgggtt ttcccccgct 1440
gatgtattcg ttcagtggat gcagagaggg cagccactta gcccagagaa atatgtcaca 1500
tctgccccta tgcccgagcc acaagctcct ggaagatatt ttgctcattc aatcttgact 1560
gtctctgagg aggagtggaa tacgggggag acatatactt gtgtggtcgc tcacgaggcc 1620
ctccccaata gagtaacaga gcggaccgtt gacaagtcca ctgggaagcc aaccctgtac 1680
aatgtgtctc tcgtgatgag tgacactgcc gggacatgtt acggaggcgg cggatctgct 1740
tctcccacgt ccccaaaagt gtttccactt tctctggact ctacccccca agatgggaat 1800
gtggtcgtgg cctgtcttgt gcagggcttc ttccctcagg agccattgag cgtcacttgg 1860
agcgagtccg gtcagaatgt gacagctcgc aacttccctc cttcacaaga cgcgtcaggt 1920
gacctctaca cgacctcttc acagctgact ctccctgcca ctcagtgccc tgatggaaaa 1980
agcgtgacat gtcatgtgaa acactataca aacccttcac aggatgtgac agtaccatgt 2040
cctgttcccc cacctcctcc atgctgtcac cctagactgt ccttgcaccg ccctgcactg 2100
gaggacctcc tcttgggatc cgaggctaac ctgacctgta ccttgactgg gctgagagat 2160
gcctcaggag ctacattcac ttggactcct agcagcggca aatccgctgt tcagggacct 2220
ccagaacgag atctttgcgg ctgctactca gttagttctg tactccctgg atgtgctcag 2280
ccctggaacc atggagaaac atttacctgc acggcggccc atcctgagct gaaaacaccc 2340
ttgaccgcca acatcaccaa gagtggcaac accttcagac cagaggtgca tctgctcccc 2400
ccacctagtg aagagctggc tctgaatgaa ctggtgactc ttacctgtct ggctagggga 2460
tttagcccca aagacgtcct cgtcagatgg ctccagggtt ctcaggaact gccacgggag 2520
aagtacctga cctgggcctc tagacaggag ccttcacagg ggactaccac attcgcagtg 2580
accagtatat tgagagtggc tgccgaggat tggaaaaagg gggatacctt ctcttgcatg 2640
gttggccatg aagcactgcc tcttgcattc acccaaaaga ctattgaccg actggccggc 2700
aaacccaccc acgtaaacgt tagcgttgtt atggctgaag tcgatggaac gtgttacgga 2760
ggcggcggat ctccatgg 2778
<210> 2
<211> 342
<212> DNA
<213> 人工序列2(人工序列)
<400> 2
gatattgtgc tgacccagtc ccccgattca ctcagcgttt cattgggcga acgggtgact 60
gtcaactgta agctgagcca gagcgttttg cactcctcca acaagcagaa ttatctcgcc 120
tggtttcagc agaatcctgg gcagccccca aaactgttga tctactgggc cagcgcaaga 180
cagtcaggag ttcctgcaag gtttatgggt agcggatctg gcacggaatt ctccctcaca 240
atcagcagcc tgcaggctga ggacgttgca gtctactatt gtcagcagta ctacgatagc 300
acctatacgt ttgggcaggg gacgaagctg gaaattaata ga 342
<210> 3
<211> 935
<212> PRT
<213> 人工序列3(人工序列)
<400> 3
Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ser Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Val Asn Cys Lys Leu Ser Gln Ser Val Leu His Ser
20 25 30
Ser Asn Lys Gln Asn Tyr Leu Ala Trp Phe Gln Gln Asn Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ala Arg Gln Ser Gly Val
50 55 60
Pro Ala Arg Phe Met Gly Ser Gly Ser Gly Thr Glu Phe Ser Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asp Ser Thr Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Asn Arg Glu Ala Ala Ala Lys Gly Ser Ala Ser Ala Pro Thr Leu Phe
115 120 125
Pro Leu Val Ser Cys Glu Asn Ser Pro Ser Asp Thr Ser Ser Val Ala
130 135 140
Val Gly Cys Leu Ala Gln Asp Phe Leu Pro Asp Ser Ile Thr Phe Ser
145 150 155 160
Trp Lys Tyr Lys Asn Asn Ser Asp Ile Ser Ser Thr Arg Gly Phe Pro
165 170 175
Ser Val Leu Arg Gly Gly Lys Tyr Ala Ala Thr Ser Gln Val Leu Leu
180 185 190
Pro Ser Lys Asp Val Met Gln Gly Thr Asp Glu His Val Val Cys Lys
195 200 205
Val Gln His Pro Asn Gly Asn Lys Glu Lys Asn Val Pro Leu Pro Val
210 215 220
Ile Ala Glu Leu Pro Pro Lys Val Ser Val Phe Val Pro Pro Arg Asp
225 230 235 240
Gly Phe Phe Gly Asn Pro Arg Lys Ser Lys Leu Ile Cys Gln Ala Thr
245 250 255
Gly Phe Ser Pro Arg Gln Ile Gln Val Ser Trp Leu Arg Glu Gly Lys
260 265 270
Gln Val Gly Ser Gly Val Thr Thr Asp Gln Val Gln Ala Glu Ala Lys
275 280 285
Glu Ser Gly Pro Thr Thr Tyr Lys Val Thr Ser Thr Leu Thr Ile Lys
290 295 300
Glu Ser Asp Trp Leu Gly Gln Ser Met Phe Thr Cys Arg Val Asp His
305 310 315 320
Arg Gly Leu Thr Phe Gln Gln Asn Ala Ser Ser Met Cys Val Pro Asp
325 330 335
Gln Asp Thr Ala Ile Arg Val Phe Ala Ile Pro Pro Ser Phe Ala Ser
340 345 350
Ile Phe Leu Thr Lys Ser Thr Lys Leu Thr Cys Leu Val Thr Asp Leu
355 360 365
Thr Thr Tyr Asp Ser Val Thr Ile Ser Trp Thr Arg Gln Asn Gly Glu
370 375 380
Ala Val Lys Thr His Thr Asn Ile Ser Glu Ser His Pro Asn Ala Thr
385 390 395 400
Phe Ser Ala Val Gly Glu Ala Ser Ile Cys Glu Asp Asp Trp Asn Ser
405 410 415
Gly Glu Arg Phe Thr Cys Thr Val Thr His Thr Asp Leu Pro Ser Pro
420 425 430
Leu Lys Gln Thr Ile Ser Arg Pro Lys Gly Val Ala Leu His Arg Pro
435 440 445
Asp Val Tyr Leu Leu Pro Pro Ala Arg Glu Gln Leu Asn Leu Arg Glu
450 455 460
Ser Ala Thr Ile Thr Cys Leu Val Thr Gly Phe Ser Pro Ala Asp Val
465 470 475 480
Phe Val Gln Trp Met Gln Arg Gly Gln Pro Leu Ser Pro Glu Lys Tyr
485 490 495
Val Thr Ser Ala Pro Met Pro Glu Pro Gln Ala Pro Gly Arg Tyr Phe
500 505 510
Ala His Ser Ile Leu Thr Val Ser Glu Glu Glu Trp Asn Thr Gly Glu
515 520 525
Thr Tyr Thr Cys Val Val Ala His Glu Ala Leu Pro Asn Arg Val Thr
530 535 540
Glu Arg Thr Val Asp Lys Ser Thr Gly Lys Pro Thr Leu Tyr Asn Val
545 550 555 560
Ser Leu Val Met Ser Asp Thr Ala Gly Thr Cys Tyr Gly Gly Gly Gly
565 570 575
Ser Ala Ser Pro Thr Ser Pro Lys Val Phe Pro Leu Ser Leu Cys Ser
580 585 590
Thr Gln Pro Asp Gly Asn Val Val Ile Ala Cys Leu Val Gln Gly Phe
595 600 605
Phe Pro Gln Glu Pro Leu Ser Val Thr Trp Ser Glu Ser Gly Gln Gly
610 615 620
Val Thr Ala Arg Asn Phe Pro Pro Ser Gln Asp Ala Ser Gly Asp Leu
625 630 635 640
Tyr Thr Thr Ser Ser Gln Leu Thr Leu Pro Ala Thr Gln Cys Leu Ala
645 650 655
Gly Lys Ser Val Thr Cys His Val Lys His Tyr Thr Asn Pro Ser Gln
660 665 670
Asp Val Thr Val Pro Cys Pro Val Pro Ser Thr Pro Pro Thr Pro Ser
675 680 685
Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Cys Cys His Pro Arg Leu
690 695 700
Ser Leu His Arg Pro Ala Leu Glu Asp Leu Leu Leu Gly Ser Glu Ala
705 710 715 720
Asn Leu Thr Cys Thr Leu Thr Gly Leu Arg Asp Ala Ser Gly Val Thr
725 730 735
Phe Thr Trp Thr Pro Ser Ser Gly Lys Ser Ala Val Gln Gly Pro Pro
740 745 750
Glu Arg Asp Leu Cys Gly Cys Tyr Ser Val Ser Ser Val Leu Pro Gly
755 760 765
Cys Ala Glu Pro Trp Asn His Gly Lys Thr Phe Thr Cys Thr Ala Ala
770 775 780
Tyr Pro Glu Ser Lys Thr Pro Leu Thr Ala Thr Leu Ser Lys Ser Gly
785 790 795 800
Asn Thr Phe Arg Pro Glu Val His Leu Leu Pro Pro Pro Ser Glu Glu
805 810 815
Leu Ala Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Ala Arg Gly Phe
820 825 830
Ser Pro Lys Asp Val Leu Val Arg Trp Leu Gln Gly Ser Gln Glu Leu
835 840 845
Pro Arg Glu Lys Tyr Leu Thr Trp Ala Ser Arg Gln Glu Pro Ser Gln
850 855 860
Gly Thr Thr Thr Phe Ala Val Thr Ser Ile Leu Arg Val Ala Ala Glu
865 870 875 880
Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys Met Val Gly His Glu Ala
885 890 895
Leu Pro Leu Ala Phe Thr Gln Lys Thr Ile Asp Arg Leu Ala Gly Lys
900 905 910
Pro Thr His Val Asn Val Ser Val Val Met Ala Glu Val Asp Gly Thr
915 920 925
Cys Tyr Gly Gly Gly Gly Ser
930 935
<210> 4
<211> 114
<212> PRT
<213> 人工序列4(人工序列)
<400> 4
Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ser Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Val Asn Cys Lys Leu Ser Gln Ser Val Leu His Ser
20 25 30
Ser Asn Lys Gln Asn Tyr Leu Ala Trp Phe Gln Gln Asn Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ala Arg Gln Ser Gly Val
50 55 60
Pro Ala Arg Phe Met Gly Ser Gly Ser Gly Thr Glu Phe Ser Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asp Ser Thr Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Asn Arg
Claims (9)
1.类风湿因子IgG、IgM、IgA复合质控品的制备方法，其特征在于，包括以下步骤：
S1、分别获取小鼠RF抗体的可变区基因序列、人IgM恒定区基因序列和人IgA恒定区基因序列，小鼠RF抗体的可变区基因序列如SEQ ID No.2所示，其氨基酸序列如SEQ ID No.4所示；
S2、根据步骤S1获得的基因序列按以下排序顺序合成全基因序列：
小鼠RF抗体的可变区基因序列-Linker-人IgA恒定区基因序列-Linker-人IgM-恒定区基因序列；获得的全基因序列如SEQ ID No.1所示，其氨基酸序列如SEQ ID No.3所示；
S3、将步骤S2获得的全基因序列引入含有人IgG Fc片段基因表达序列的pFUSE-hIgG1-Fc2载体中，制备同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组质粒；
S4、将步骤S3获得的重组质粒转染哺乳细胞，获取同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体。
2.根据权利要求1所述的类风湿因子IgG、IgM、IgA复合质控品的制备方法，其特征在于，步骤S2中，全基因序列的合成过程如下：
针对小鼠RF抗体的可变区基因序列、人IgM恒定区基因序列和人IgA恒定区基因序列，插入刚性linker连接，在小鼠RF抗体的可变区基因序列的N端加入蜂毒信号肽序列，在序列上游加入限制性核酸内切酶位点EcoRI，下游序列插入限制性核酸内切酶位点NcoI。
3.根据权利要求1所述的类风湿因子IgG、IgM、IgA复合质控品的制备方法，其特征在于，步骤S4中采用的哺乳细胞为HEK293哺乳细胞。
4.根据权利要求1所述的类风湿因子IgG、IgM、IgA复合质控品的制备方法，其特征在于，还包括以下步骤：
将获得的同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体制备成缓冲溶液。
5.如权利要求1-4任一项所述的制备方法制备的同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体。
6.一种类风湿因子IgG、IgM、IgA复合质控品，其特征在于，包括如权利要求1-4任一项所述的制备方法制备的同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体。
7.根据权利要求6所述的一种类风湿因子IgG、IgM、IgA复合质控品，其特征在于，由含有重组抗体的缓冲液配制而成。
8.如权利要求1-4任一项所述的制备方法在制备同时含有人IgG、人IgM、人IgA Fc段和小鼠RF抗体可变区的重组抗体中的应用。
9.如权利要求1-4任一项所述的制备方法在制备抗类风湿因子抗体IgG检测试剂盒、抗类风湿因子抗体IgG检测试剂盒、抗类风湿因子抗体IgA检测试剂盒和抗类风湿因子抗体IgA/G/M 检测试剂盒中的应用。
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