CN116836279B - 抗四碘甲状腺素的抗体、检测四碘甲状腺素的试剂和试剂盒 - Google Patents
抗四碘甲状腺素的抗体、检测四碘甲状腺素的试剂和试剂盒 Download PDFInfo
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- CN116836279B CN116836279B CN202210290000.4A CN202210290000A CN116836279B CN 116836279 B CN116836279 B CN 116836279B CN 202210290000 A CN202210290000 A CN 202210290000A CN 116836279 B CN116836279 B CN 116836279B
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Abstract
本发明公开了一种抗四碘甲状腺素的抗体、检测四碘甲状腺素的试剂和试剂盒,涉及抗体技术领域。本发明公开的抗四碘甲状腺素抗体包括重链互补决定区和轻链互补决定区。该抗体为四碘甲状腺素的检测提供了重要的原料来源。
Description
技术领域
本发明涉及抗体技术领域,具体而言,涉及一种抗四碘甲状腺素的抗体、检测四碘甲状腺素的试剂和试剂盒。
背景技术
四碘甲状腺素(3,5,3’,5’-tetraiodo-L-thyronine,T4)是从甲状腺滤泡上皮分泌产生的激素,释放入血后,绝大部分T4与甲状腺结合球蛋白结合,诱导该蛋白产生活性构象从而激活DNA的转录过程,达到调节基因表达的生物功能,其中约0.03%的总血清T4呈游离状态,游离态T4与结合态T4呈动态平衡,维持正常的生理功能。大量的实验结果表明,甲状腺激素对细胞的正常发育分化、动物的体温调节和各种糖、脂肪和蛋白质代谢平衡的维持起重要的调节和控制作用。
血清中T4浓度受多种因素的影响,其中甲状腺机能亢进,妊娠,服用甲状腺素、雌激素类药物、避孕药等药物,先天遗传性甲状腺结合球蛋白增高症、急性传染性肝炎、间歇性血卟啉等疾病可使血清中T4浓度高于正常值。而原发性甲状腺功能下症、慢性淋巴性甲状腺炎等甲状腺疾病,严重肝肾功能衰竭、肾病综合症、活动性肢端肥大症、遗传性甲状腺素结合球蛋白减少症等可使血清中T4浓度低于正常值。因此,检测血清T4浓度对于甲状腺功能亢进、甲状腺功能减低及甲状腺肿瘤的诊断或鉴别诊断,对甲状腺功能相关疾病的发展过程、疗效及预后评估中具有十分重要的意义。
目前,T4的检测方法主要有化学发光竞争法,其是基于抗体和抗原的特异性反应,同时利用发光物质(如吖啶酯、异鲁米诺等)对被检测信号进行放大和显示的一种免疫学检测方法。类似的免疫学检测方法还有生化免疫比浊法、放射免疫法、荧光免疫层析法等。上述免疫学检测方法都需要针对于T4的抗体。因此,本领域对于有效且结合T4并对其进行检测的抗体存在着强烈需求。
鉴于此,特提出本发明。
发明内容
针对抗四碘甲状腺素的抗体来源少的问题,本申请提供一种亲和力、活性改善的抗四碘甲状腺素抗体,为四碘甲状腺素的检测提供重要的原料来源。
为了实现上述目的,根据本发明的一个方面,提供了一种抗体或其功能性片段,所述抗体或其功能性片段包括氨基酸序列如SEQ ID NO:1至SEQ ID NO:3所示的HCDR1、HCDR2、HCDR3,和氨基酸序列如SEQ ID NO:4至SEQ ID NO:6所示的LCDR1、LCDR2、LCDR3。
为了实现上述目的,根据本发明的第二个方面,提供了一种抗四碘甲状腺素抗体或其功能性片段,所述抗体或其功能性片段包含重链可变区和/或轻链可变区,所述重链可变区含有HFR1-HCDR1-HFR2-HCDR2-HFR3-HCDR3-HFR4的序列结构,所述轻链可变区区含有LFR1-LCDR1-LFR2-LCDR2-LFR3-LCDR3-LFR4的序列结构,所述HCDR1、HCDR2、HCDR3、LCDR 1、LCDR2、LCDR3的氨基酸序列为上述的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、LCDR3的氨基酸序列。
为了实现上述目的,根据本发明的第三个方面,提供了一种抗四碘甲状腺素抗体,包括重链和/或轻链,所述重链包括上述的重链可变区,所述轻链包括上述的轻链可变区。
为了实现上述目的,根据本发明的第四个方面,提供了一种抗体偶联物,所述抗体偶联物包括上述的抗体或其功能性片段。
为了实现上述目的,根据本发明的第五个方面,提供了一种检测四碘甲状腺素的试剂或试剂盒,所述试剂或试剂盒包括上述的抗体或其功能性片段或上述的抗体偶联物。
为了实现上述目的,根据本发明的第六个方面,提供了上述的抗体或其功能性片段、上述的抗体偶联物或上述的试剂或试剂盒在四碘甲状腺素检测中的用途。
为了实现上述目的,本发明还提供了一种载体、一种细胞及一种制备上述抗体或其功能性片段的方法。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对范围的限定,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他相关的附图。
图1为Anti-T4-8C2mut1的还原性SDS-PAGE的结果。
具体实施方式
本发明提供了一种抗体或其功能性片段,所述抗体或其功能性片段包括氨基酸序列如SEQ ID NO:1至SEQ ID NO:3所示的HCDR1、HCDR2、HCDR3,和氨基酸序列如SEQ ID NO:4至SEQ ID NO:6所示的LCDR1、LCDR2、LCDR3。上述抗体具有改善的亲和力和活性。
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。
在本发明中,术语“互补性决定区”、“CDR”或“CDRs”是指免疫球蛋白的重链和轻链的高度可变区,指包含一种或多种或者甚至全部的对抗体或抗原结合片段与其识别的抗原或表位的结合起作用的主要氨基酸残基的区域。在本发明具体实施方式中,CDRs是指所述抗体的重链和轻链的高度可变区。
在本发明中,重链互补决定区用HCDR表示,其包括HCDR1、HCDR2和HCDR3;轻链互补决定区用LCDR表示,其包括LCDR1、LCDR2和LCDR3。本领域常用的CDR标示方法包括:Kabat编号方案、IMGT编号方案、Chothia和Lesk编号方案以及1997年Lefranc等人为免疫球蛋白超家族的所有蛋白质序列引入的新的标准化编号系统。Kabat等人是第一个为免疫球蛋白可变区提出标准化编号方案的人。在过去的几十年中,序列的积累导致了KABATMAN数据库的创建,Kabat编号方案通常被认为是编号抗体残基广泛采用的标准。本发明采用Kabat注释标准标示CDR区,但其他方法标示的CDR区也属于本发明的保护范围。
在本发明中,“框架区”或“FR”区包括重链框架区和轻链框架区,是指抗体重链可变区和轻链可变区中除CDR之外的区域;其中,重链框架区可以被进一步细分成被CDR分隔开的毗邻区域,包含HFR1、HFR2、HFR3和HFR4框架区;轻链框架区可以被进一步细分成被CDR分隔开的毗邻区域,包含LFR1、LFR2、LFR3和LFR4框架区。
在本发明中,重链可变区由以下编号的CDR与FR按如下组合排列连接获得:HFR1-HCDR1-HFR2-HCDR2-HFR3-HCDR3-HFR4;轻链可变区由以下编号的CDR与FR按如下组合排列连接获得:LFR1-LCDR1-LFR2-LCDR2-LFR3-LCDR3-LFR4。
在可选的实施方式中,所述抗体或其功能性片段还包括氨基酸序列如SEQ ID NO:7至SEQ ID NO:10所示的HFR1、HFR2、HFR3、HFR4和氨基酸序列如SEQ ID NO:11至SEQ IDNO:14所示的LFR1、LFR2、LFR3和LFR4。
需要说明的是,在其他的实施例中,本发明提供的抗体或其功能性片段的各骨架区氨基酸序列可以与上述对应框架区(SEQ ID NO:7、8、9、10、11、12、13或14)具有至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的同源性。
在可选的实施方式中,所述抗体或其功能性片段以KD≤10-7M、KD≤10-8M、KD≤10- 9M、KD≤10-10M、KD≤10-11M的亲和力结合四碘甲状腺素。
在可选的实施方式中,所述抗体或其功能性片段以KD≤6.93×10-8M的亲和力结合四碘甲状腺素。
在可选的实施方式中,所述抗体或其功能性片段以KD≤3.34×10-10M的亲和力结合四碘甲状腺素。
另一方面,本发明实施例提供一种抗四碘甲状腺素的抗体或其功能性片段,所述抗体或其功能性片段包含重链可变区和/或轻链可变区,所述重链可变区含有HFR1-HCDR1-HFR2-HCDR2-HFR3-HCDR3-HFR4的序列结构,所述轻链可变区区含有LFR1-LCDR1-LFR2-LCDR2-LFR3-LCDR3-LFR4的序列结构,所述HCDR1、HCDR2、HCDR3、LCDR 1、LCDR2、LCDR3的氨基酸序列为上述的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、LCDR3的氨基酸序列,所述HFR1、HFR2、HFR3、HFR4、LFR1、LFR2、LFR3、LFR4的氨基酸序列为上述的HFR1、HFR2、HFR3、HFR4、LFR1、LFR2、LFR3、LFR4的氨基酸序列。
在可选的实施方式中,所述重链可变区氨基酸序列如SEQ ID NO:15所示。
在可选的实施方式中,所述轻链可变区氨基酸序列如SEQ ID NO:16所示。
在可选的实施方式中,所述抗体还包含恒定区。
在可选的实施方式中,所述恒定区包括重链恒定区和/或轻链恒定区。
在可选的实施方式中,所述重链恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE或IgD的重链恒定区,所述轻链恒定区选自κ型或λ型轻链恒定区。
在可选的实施方式中,所述恒定区的种属来源为牛、马、乳牛、猪、羊、大鼠、小鼠、狗、猫、兔、驴、鹿、貂、鸡、鸭、鹅、火鸡、斗鸡或人。
在可选的实施方式中,所述恒定区的种属来源为羊。
在可选的实施方式中,所述恒定区的种属来源为山羊。
在可选的实施方式中,所述重链恒定区序列(CH)如SEQ ID NO:17所示,所述轻链恒定区(CL)序列如SEQ ID NO:18所示。
需要说明的是,在其他的实施例中,所述恒定区序列可以与上述恒定区(SEQ IDNO:17或18)具有至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的同源性。
在可选的实施方式中,所述功能性片段选自所述抗体的F(ab’)2、Fab’、Fab、Fv和scFv中的任意一种。
上述抗体的功能性片段通常具有与其来源抗体相同的结合特异性。本领域技术人员根据本发明记载的内容容易理解到,上述抗体的功能性片段可以通过比如酶消化的方法(包括胃蛋白酶或木瓜蛋白酶)和/或通过化学还原分裂二硫键的方法获得。在本发明公开了完整抗体的结构基础上,本领域技术人员容易获得上述的功能性片段。
上述抗体的功能性片段还可以通过也是本领域技术人员所知的重组遗传学技术或通过例如自动肽合成仪,比如Applied BioSystems等销售的自动肽合成仪合成获得。
另一方面,本发明提供一种抗四碘甲状腺素的抗体,包括重链和/或轻链,所述重链包括上述的重链可变区和上述的重链恒定区;所述轻链包括上述的轻链可变区和上述的轻链恒定区。
在可选的实施方式中,所述重链的氨基酸序列如SEQ ID NO:19所示。
在可选的实施方式中,所述轻链的氨基酸序列如SEQ ID NO:20所示。
另一方面,本发明提供一种抗体偶联物,所述抗体偶联物包括上述的抗体或其功能性片段。
在可选的实施方式中,上述抗体偶联物中所述抗体或其功能性片段标记有标记物。
在可选的实施方式中,上述标记物是指具有能够被肉眼直接观察或被仪器检测或探测到的特性例如发光、显色、放射性等特性的一类物质,通过该特性可以实现对相应目标物的定性或定量检测。
在可选的实施方式中,所述标记物包括但不限于荧光染料、酶、放射性同位素、化学发光试剂和纳米颗粒类标记物。
在实际的使用过程中,本领域技术人员可以根据检测条件或实际需要选择合适的标记物,无论使用何种标记物,其均属于本发明的保护范围。
在可选的实施方式中,所述荧光染料包括但不限于荧光素类染料及其衍生物(例如包括但不限于异硫氰酸荧光素(FITC)羟基光素(FAM)、四氯光素(TET)等或其类似物)、罗丹明类染料及其衍生物(例如包括但不限于红色罗丹明(RBITC)、四甲基罗丹明(TAMRA)、罗丹明B(TRITC)等或其类似物)、Cy系列染料及其衍生物(例如包括但不限于Cy2、Cy3、Cy3B、Cy3.5、Cy5、Cy5.5、Cy3等或其类似物)、Alexa系列染料及其衍生物(例如包括但不限于AlexaFluor350、405、430、488、532、546、555、568、594、610、33、647、680、700、750等或其类似物)和蛋白类染料及其衍生物(例如包括但不限于藻红蛋白(PE)、藻蓝蛋白(PC)、别藻蓝蛋白(APC)、多甲藻黄素-叶绿素蛋白(preCP)等)。
在可选的实施方式中,所述酶包括但不限于辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶、葡萄糖氧化酶、碳酸酐酶、乙酰胆碱酯酶以及6-磷酸葡萄糖脱氧酶。
在可选的实施方式中,所述放射性同位素包括但不限于212Bi、131I、111In、90Y、186Re、211At、125I、188Re、153Sm、213Bi、32P、94mTc、99mTc、203Pb、67Ga、68Ga、43Sc、47Sc、110mIn、97Ru、62Cu、64Cu、67Cu、68Cu、86Y、88Y、121Sn、161Tb、166Ho、105Rh、177Lu、172Lu和18F。
在可选的实施方式中,所述化学发光试剂包括但不限于鲁米诺及其衍生物、光泽精、甲壳动物荧光素及其衍生物、联吡啶钌及其衍生物、吖啶酯及其衍生物、二氧环乙烷及其衍生物、洛粉碱及其衍生物和过氧草酸盐及其衍生物。
在可选的实施方式中,所述纳米颗粒类标记物包括但不限于纳米颗粒、胶体、有机纳米颗粒、磁性纳米颗粒、量子点纳米颗粒和稀土络合物纳米颗粒。
在可选的实施方式中,所述胶体包括但不限于胶体金属、分散型染料、染料标记的微球和乳胶。
在可选的实施方式中,所述胶体金属包括但不限于胶体金、胶体银和胶体硒。
在可选的实施方式中,上述抗体偶联物中所述抗体或其功能性片段包被至固相。
在可选的实施方式中,所述固相选自微球、板和膜。
在可选的实施方式中,所述固相包括但不限于磁性微球、塑料微球、塑胶微粒、微孔板、玻璃、毛细管、尼龙和硝酸纤维素膜。
在可选的实施方式中,所述固相为硝酸纤维素膜。
另一方面,本发明提供一种检测四碘甲状腺素的试剂或试剂盒,所述试剂或试剂盒包括上述的抗体或其功能性片段或上述的抗体偶联物。
另一方面,本发明提供上述抗体或其功能性片段、抗体偶联物或上述的试剂或试剂盒在四碘甲状腺素检测中的用途。
另一方面,本发明提供一种编码上述抗体或其功能性片段的核酸分子。
另一方面,本发明提供含有上述核酸分子的载体。
另一方面,本发明提供含有上述载体的细胞。
另一方面,本发明提供一种制备抗体或其功能性片段的方法,其包括:培养如上所述的细胞。
在本发明公开了抗体或其功能性片段的氨基酸序列的基础上,本领域技术人员容易想到采用基因工程技术或其他技术(化学合成、重组表达)制备得到该抗体或其功能性片段,例如从能够重组表达如上任一项所述的抗体或其功能性片段的重组细胞的培养产物中分离纯化得到该抗体或其功能性片段,这对本领域技术人员来说是容易实现的,基于此,无论采用何种技术制备本发明的抗体或其功能性片段,其均属于本发明的保护范围。
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
除非另有定义,否则本文使用的所有技术和科学术语具有与本公开内容所属领域的普通技术人员通常理解的含义相同的含义。尽管与本文描述的那些方法和材料类似或等同的任何方法和材料都可用于本文的制剂或单位剂量的实践或测试,但现在描述一些方法和材料。除非另有说明,否则本文采用或考虑的技术是标准方法。材料、方法和实例仅是说明性而非限制性的。
除非另外指明,否则实践本发明将采用细胞生物学、分子生物学(包含重组技术)、微生物学、生物化学和免疫学的常规技术,所述常规技术在本领域技术人员的能力范围内。文献中充分解释了这种技术,如《分子克隆:实验室手册(Molecular Cloning:ALaboratory Manual)》,第二版(Sambrook等人,1989);《寡核苷酸合成(OligonucleotideSynthesis)》(M.J.Gait编,1984);《动物细胞培养(Animal Cell Culture)》(R.I.Freshney编,1987);《酶学方法(Methods in Enzymology)》(学术出版社有限公司(Academic Press,Inc.);《实验免疫学手册(Handbook of Experimental Immunology)》(D.M.Weir和C.C.Blackwell编);《哺乳动物细胞用基因转移载体(Gene Transfer Vectors forMammalian Cells)》(J.M.Miller和M.P.Calos编,1987);《当代分子生物学方法(CurrentProtocols in Molecular Biology)》(F.M.Ausubel等人编,1987);《PCR:聚合酶链反应(PCR:The Polymerase Chain Reaction)》(Mullis等人编,1994);以及《当代免疫学方法(Current Protocols in Immunology)》(J.E.Coligan等人编,1991),所述文献中的每个文献均通过引用明确并入本文中。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1Anti-T4-8C2单克隆抗体的制备
本实施例中限制性内切酶、Prime Star DNA聚合酶购自Takara公司。MagExtractor-RNA提取试剂盒购自TOYOBO公司。BD SMARTTM RACE cDNA AmplificationKit试剂盒购自Takara公司。pMD-18T载体购自Takara公司。质粒提取试剂盒购自天根公司。引物合成和基因测序由Invitrogen公司完成。
1重组质粒的构建
(1)抗体基因制备
从分泌抗四碘甲状腺素单克隆抗体的杂交瘤细胞株中提取mRNA,通过RT-PCR方法获得DNA产物,该产物用rTaq DNA聚合酶进行加A反应后插入到pMD-18T载体中,转化到DH5α感受态细胞中,长出菌落后分别取Heavy Chain及Light Chain基因克隆,各4个克隆送基因测序公司进行测序。
(2)Anti-T4-8C2抗体可变区基因的序列分析
将上述测序得到的基因序列放在Kabat抗体数据库中进行分析,并利用VNTI11.5软件进行分析确定重链和轻链引物对扩增出的基因都是正确的,其中Light Chain扩增出的基因片段中,VL基因序列为339bp,其前方有57bp的前导肽序列;Heavy Chain引物对扩增出的基因片段中,VH基因序列为371bp,属于VH1基因家族,其前方有57bp的前导肽序列。
(3)重组抗体表达质粒的构建
pcDNATM 3.4vector为构建的重组抗体真核表达载体,该表达载体已经引入HindIII、BamHI、EcoRI等多克隆酶切位点,并命名为pcDNA3.4A表达载体,后续简称3.4A表达载体;根据上述pMD-18T中抗体可变区基因测序结果,设计该抗体的VL和VH基因特异性引物,两端分别带有HindIII、EcoRI酶切位点和保护碱基,通过PCR扩增方法扩出0.72kb的Light Chain基因片段和1.46kb的Heavy Chain基因片段。
Heavy Chain和Light Chain基因片段分别采用HindIII/EcoRI双酶切,3.4A载体采用HindIII/EcoRI双酶切,将片段和载体纯化回收后Heavy Chain基因和Light Chain基因分别连接3.4A表达载体中,分别得到Heavy Chain和Light Chain的重组表达质粒。
2稳定细胞株筛选
(1)重组抗体表达质粒瞬时转染CHO细胞,确定表达质粒活性
质粒用超纯水稀释至40ug/100ul,调节CHO细胞1.43×107cells/ml于离心管中,100μL质粒与700μL细胞混合,转入电转杯,电转,第3、5、7天取样计数,第7天收样检测。
包被液(主要成分NaHCO3)稀释T4-BSA(购自Biospacific,VI9100)至5ug/ml,每孔100uL,4℃过夜;次日,洗涤液清洗2次,拍干;加入封闭液(20%BSA+80%PBS),每孔120μL,37℃,1h,拍干;加入稀释后的细胞上清,100μL/孔,37℃,30min(部分上清1h);洗涤液清洗5次,拍干;加入鼠抗羊IgG-HRP,每孔100μL,37℃,30min;洗涤液清洗5次,拍干;加入显色液A液(50μL/孔,含柠檬酸+醋酸钠+乙酰苯胺+过氧化脲),加入显色液B液(50μL/孔,含柠檬酸+EDTA·2Na+TMB+浓HCL),10min;加入终止液(50μL/孔,含EDTA·2Na+浓H2SO4);酶标仪上450nm(参考630nm)处读OD值。结果显示细胞上清稀释1000倍后反应OD仍大于1.0,未加细胞上清孔反应OD小于0.1,表明质粒瞬转后产生的抗体对T4-BSA有活性。
(2)重组抗体表达质粒线性化
准备下述试剂:Buffer 50μL、DNA 100μg/管、PuvI酶10μL、无菌水补至500μL,37℃水浴酶切过夜;先用等体积酚/氯仿/异戊醇(下层)25:24:1,再用氯仿(水相)依次进行抽提;0.1倍体积(水相)3M醋酸钠和2倍体积乙醇冰上沉淀,70%乙醇漂洗沉淀,去除有机溶剂,待乙醇挥发完全用适量的灭菌水进行复融,最后进行浓度的测定。
(3)重组抗体表达质粒稳定转染,加压筛选稳定细胞株
质粒用超纯水稀释至40ug/100ul,调节CHO细胞1.43×107cells/ml于离心管中,100μL质粒与700μL细胞混合,转入电转杯,电转,次日计数;25umol/L MSX 96孔加压培养约25天。
显微镜下观察标记长有细胞的克隆孔,并记录汇合度;取培养上清,送样检测;挑选抗体浓度、相对浓度高的细胞株转24孔,3天左右转6孔;3天后保种批培,调整细胞密度0.5×106cells/ml,2.2ml进行批培养,细胞密度0.3×106cells/ml,2ml进行保种;7天6孔批培上清送样检测,挑选抗体浓度及细胞直径较小的细胞株转TPP保种传代。
3重组抗体生产
(1)细胞扩培
细胞复苏之后先在125ml规格的摇瓶中培养,接种体积为30ml,培养基为100%Dynamis培养基,放置于转速120r/min,温度为37℃,二氧化碳为8%的摇床中。培养72h,以50万cells/ml接种密度接种扩培,扩培体积根据生产需求进行计算,培养基为100%Dynamis培养基。之后每72h扩培一次。当细胞量满足生产需求时,严格控制接种密度为50万cells/ml左右进行生产。
(2)摇瓶生产及纯化
摇瓶参数:转速120r/min,温度为37℃,二氧化碳为8%。流加补料:在摇瓶中培养至72h时开始每天补料,HyCloneTM Cell BoostTM Feed 7a每天流加初始培养体积的3%,Feed 7b每天流加量为初始培养体积的千分之一,一直补到第12天(第12天补料)。葡萄糖在第六天补加3g/L。第13天收样。用proteinA亲和层析柱进行亲和纯化。取6μg纯化的抗体进行还原性SDS-PAGE,电泳图如图所示,在还原性SDS-PAGE后显示两条带,1条Mr为50KD,另一条Mr为28KD。
实施例2亲和力及活性优化
实施例1得到的Anti-T4-8C2单克隆抗体虽然对T4-BSA有活性,但抗体亲和力和活性均不够理想,因而申请人通过对该抗体的轻链CDR及重链CDR进行定向突变。即利用计算机进行抗体可变区结构模拟、抗原与抗体可变区作用复合物结构模拟、抗体关键氨基酸分析及突变设计,根据突变方案设计合成覆盖突变位点的双向引物,合成目的DNA两端引物,进行高保真PCR反应,将PCR产物克隆至载体,再按照实施例1所述的方法进行突变抗体的制备。经筛选,得到亲和力和活性显著提升的单克隆抗体,并命名为:Anti-T4-8C2mut1。Anti-T4-8C2mut1的重链氨基酸序列如SEQ ID NO:19所示,轻链氨基酸序列如SEQ ID NO:20所示。
实施例3抗体的性能检测
1亲和力分析
利用AMC传感器,纯化出来的抗体用PBST稀释到10ug/ml,T4-BSA(购自Biospacific,VI9100)用PBST进行梯度稀释:
运行流程:缓冲液1(PBST)中平衡60s,抗体溶液中固化抗体300s,缓冲液2(PBST)中孵育180s,抗原溶液中结合420s,缓冲液2中解离1200s,用10mM pH 1.69GLY溶液及缓冲液3(PBST)进行传感器再生,输出数据。(KD表示平衡解离常数即亲和力;kon表示结合速率;kdis表示解离速率。PBST主要成分Na2HPO4+NaCl+TW-20)。
表1亲和力数据
样品名称 | KD(M) | kon(1/Ms) | kdis(1/s) |
对照 | 6.93E-08 | 4.23E+04 | 2.93E-03 |
Anti-T4-8C2mut1 | 3.34E-10 | 6.89E+05 | 2.30E-04 |
2活性鉴定
包被液(主要成分NaHCO3)稀释T4-BSA(购自Biospacific,VI9100)至5ug/ml,每孔100uL,4℃过夜;次日,洗涤液清洗2次,拍干;加入封闭液(20%BSA+80%PBS),每孔120μl,37℃,1h,拍干;加入稀释后的上述单克隆抗体,100μl/孔,37℃,30min-60min;洗涤液清洗5次,拍干;加入鼠抗羊IgG-HRP,每孔100μl,37℃,30min;洗涤液(PBS)清洗5次,拍干;加入显色液A液(50μl/孔,含2.1g/L柠檬酸、12.25g/L柠檬酸、0.07g/L乙酰苯胺和0.5g/L过氧化脲),加入显色液B液(50μl/孔,含1.05g/L柠檬酸、0.186g/LEDTA·2Na、0.45g/L TMB和0.2ml/L浓HCl),10min;加入终止液(50μl/孔,含0.75g/EDTA·2Na和10.2ml/L浓H2SO4);酶标仪上450nm(参考630nm)处读OD值。结果见下表。通过同样的方法,包被液稀释BSA,验证上述单克隆抗体与BSA的反应OD值低于0.05,与BSA无交叉反应性。
表2活性数据
样品浓度(ng/ml) | 1000 | 500 | 250 | 125 | 62.5 | 0.000 |
对照 | 1.582 | 1.043 | 0.654 | 0.389 | 0.199 | 0.024 |
Anti-T4-8C2mut1 | 2.325 | 2.076 | 0.998 | 0.567 | 0.309 | 0.022 |
3稳定性考核
将上述抗体置于4℃(冰箱)、-80℃(冰箱)、37℃(恒温箱)放置21天,取7天、14天、21天样品进行状态观察,并对21天样品进行活性检测,结果显示三种考核条件下抗体放置21天均未见明显蛋白状态变化,活性也未随考核温度的升高呈下降趋势,说明上述抗体稳定。下表为抗体考核21天的酶免活性检测OD结果。
表3稳定性数据
样品浓度(ng/ml) | 1000 | 250 | 0 |
4℃,21天样品 | 2.323 | 0.988 | 0.044 |
-80℃,21天样品 | 2.258 | 0.978 | 0.052 |
37℃,21天样品 | 2.350 | 0.985 | 0.053 |
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
本申请涉及的部分氨基酸序列如下所示:
序列编号 | 序列片段 |
SEQ ID NO:1 | SANVG |
SEQ ID NO:2 | GITSGGSTVYNPVLKA |
SEQ ID NO:3 | ANYYGGYGYAADSGPYI |
SEQ ID NO:4 | SGSSSNVGSRGVG |
SEQ ID NO:5 | GTTNRPS |
SEQ ID NO:6 | GTIDDSS |
SEQUENCE LISTING
<110> 东莞市朋志生物科技有限公司
<120> 抗四碘甲状腺素的抗体、检测四碘甲状腺素的试剂和试剂盒
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Claims (33)
1.一种抗四碘甲状腺素的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包括重链可变区和轻链可变区,所述重链可变区包括:氨基酸序列依次如SEQ IDNO:1至SEQ ID NO:3所示的HCDR1、HCDR2、HCDR3,所述轻链可变区包括;氨基酸序列依次如SEQ ID NO:4至SEQ ID NO:6所示的LCDR1、LCDR2、LCDR3。
2.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段还包括氨基酸序列依次如SEQ ID NO:7至SEQ ID NO:10所示的HFR1、HFR2、HFR3、HFR4和氨基酸序列依次如SEQ ID NO:11至SEQ ID NO:14所示的LFR1、LFR2、LFR3和LFR4;或与上述各序列具有至少80%同源性的氨基酸序列。
3.根据权利要求2所述的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段以KD≤10-7M的亲和力结合四碘甲状腺素。
4.一种抗四碘甲状腺素的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包含重链可变区和轻链可变区,所述重链可变区含有HFR1-HCDR1-HFR2-HCDR2-HFR3-HCDR3-HFR4的序列结构,所述轻链可变区区含有LFR1-LCDR1-LFR2-LCDR2-LFR3-LCDR3-LFR4的序列结构,所述HCDR1、HCDR2、HCDR3、LCDR 1、LCDR2、LCDR3的氨基酸序列为权利要求1中所述的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、LCDR3的氨基酸序列,所述HFR1、HFR2、HFR3、HFR4、LFR1、LFR2、LFR3、LFR4的氨基酸序列为权利要求2中所述的HFR1、HFR2、HFR3、HFR4、LFR1、LFR2、LFR3、LFR4的氨基酸序列。
5.一种抗四碘甲状腺素的抗体或其抗原结合片段,其特征在于,所述抗体包括重链可变区和轻链可变区,所述重链可变区氨基酸序列如SEQ ID NO:15所示,所述轻链可变区氨基酸序列如SEQ ID NO:16所示。
6.根据权利要求1至5任一项所述的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段还包含恒定区。
7.根据权利要求6所述的抗体或其抗原结合片段,其特征在于,所述恒定区包括重链恒定区和轻链恒定区。
8.根据权利要求7所述的抗体或其抗原结合片段,其特征在于,所述重链恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE或IgD的重链恒定区;所述轻链恒定区选自κ型或λ型轻链恒定区。
9.根据权利要求7所述的抗体或其抗原结合片段,其特征在于,所述恒定区的种属来源为牛、马、猪、羊、大鼠、小鼠、狗、猫、兔、驴、鹿、貂、鸡、鸭、鹅或人。
10.根据权利要求9所述的抗体或其抗原结合片段,其特征在于,所述恒定区的种属来源为羊。
11.根据权利要求9所述的抗体或其抗原结合片段,其特征在于,所述恒定区的种属来源为绵羊。
12.根据权利要求7所述的抗体或其抗原结合片段,其特征在于,所述重链恒定区序列如SEQ ID NO:17所示或与其具有至少80%同源性,所述轻链恒定区序列如SEQ ID NO:18所示或与其具有至少80%同源性。
13.根据权利要求1至5任一项所述的抗体或其抗原结合片段,其特征在于,所述抗原结合片段选自所述抗体的F(ab’)2、Fab’、Fab、Fv和scFv中的任意一种。
14.一种抗四碘甲状腺素抗体,包括重链和轻链,其特征在于,所述重链包括权利要求1~5任一项中所述的重链可变区和权利要求6~12任一项中所述的重链恒定区;所述轻链包括权利要求1~5任一项中所述的轻链可变区和权利要求6~12任一项中所述的轻链恒定区。
15.一种抗四碘甲状腺素抗体,其特征在于,所述抗体包括重链和轻链,所述重链的氨基酸序列如SEQ ID NO:19所示,所述轻链的氨基酸序列如SEQ ID NO:20所示。
16.一种抗体偶联物,其特征在于,所述抗体偶联物包括权利要求1至15任一项所述的抗体或其抗原结合片段,所述抗体或其抗原结合片段标记有标记物;
所述标记物选自荧光染料、酶、放射性同位素、化学发光试剂和纳米颗粒类标记物。
17.根据权利要求16所述的抗体偶联物,其特征在于,所述荧光染料选自荧光素类染料、罗丹明类染料、Cy系列染料、Alexa系列染料和蛋白类染料。
18.根据权利要求16所述的抗体偶联物,其特征在于,所述酶选自辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶、葡萄糖氧化酶、碳酸酐酶、乙酰胆碱酯酶以及6-磷酸葡萄糖脱氧酶。
19.根据权利要求16所述的抗体偶联物,其特征在于,所述放射性同位素选自212Bi、131I、111In、90Y、186Re、211At、125I、188Re、153Sm、213Bi、32P、94mTc、99mTc、203Pb、67Ga、68Ga、43Sc、47Sc、110mIn、97Ru、62Cu、64Cu、67Cu、68Cu、86Y、88Y、121Sn、161Tb、166Ho、105Rh、177Lu、172Lu和18F。
20.根据权利要求16所述的抗体偶联物,其特征在于,所述化学发光试剂选自鲁米诺、光泽精、甲壳动物荧光素、联吡啶钌、吖啶酯、二氧环乙烷、洛粉碱和过氧草酸盐。
21.根据权利要求16所述的抗体偶联物,其特征在于,所述纳米颗粒类标记物选自纳米颗粒和胶体。
22.根据权利要求21所述的抗体偶联物,其特征在于,所述纳米颗粒选自有机纳米颗粒、磁性纳米颗粒、量子点纳米颗粒和稀土络合物纳米颗粒。
23.根据权利要求21所述的抗体偶联物,其特征在于,所述胶体选自胶体硒、乳胶、胶体金属、分散型染料和染料标记的微球。
24.根据权利要求23所述的抗体偶联物,其特征在于,所述胶体金属选自胶体金和胶体银。
25.根据权利要求16所述的抗体偶联物,其特征在于,所述抗体或其抗原结合片段包被至固相。
26.根据权利要求25所述的抗体偶联物,其特征在于,所述固相选自微球、板和膜。
27.根据权利要求26所述的抗体偶联物,其特征在于,所述固相选自磁性微球、塑料微球、塑胶微粒、微孔板、玻璃、毛细管、尼龙和硝酸纤维素膜。
28.一种检测四碘甲状腺素的试剂或试剂盒,其特征在于,所述试剂或试剂盒包括权利要求1至15任一项所述的抗体或其抗原结合片段或权利要求16~27任一项所述的抗体偶联物。
29.权利要求1至15任一项所述的抗体或其抗原结合片段、权利要求16~27任一项所述的抗体偶联物在制备检测四碘甲状腺素的试剂或试剂盒中的用途。
30.一种核酸,其特征在于,其编码权利要求1至15任一项所述的抗体或其抗原结合片段。
31.一种载体,其特征在于,其含有权利要求30所述的核酸。
32.一种细胞,其特征在于,其含有权利要求30所述的核酸或权利要求31所述的载体。
33.一种制备权利要求1至15任一项所述的抗体或其抗原结合片段的方法,其特征在于,其包括:培养权利要求32所述的细胞。
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