CN116836278B - 抗孕酮抗体、检测孕酮的试剂和试剂盒 - Google Patents
抗孕酮抗体、检测孕酮的试剂和试剂盒 Download PDFInfo
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- CN116836278B CN116836278B CN202210289987.8A CN202210289987A CN116836278B CN 116836278 B CN116836278 B CN 116836278B CN 202210289987 A CN202210289987 A CN 202210289987A CN 116836278 B CN116836278 B CN 116836278B
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Abstract
本发明公开了一种抗孕酮抗体、检测孕酮的试剂和试剂盒,涉及抗体技术领域。本发明公开的抗孕酮抗体包括重链互补决定区和轻链互补决定区。该抗体为孕酮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,涉及一种抗孕酮抗体、检测孕酮的试剂和试剂盒。
背景技术
孕酮(Progesterone,Prog)是一种21C类固醇激素,由胆固醇经孕烯醇酮通过异构酶转化而成。对于非妊娠妇女,孕酮由卵巢中的卵泡膜细胞产生;而妊娠期间,孕酮则主要由胎盘合体滋养细胞层分泌,故血中孕酮水平主要与胎盘重量及血液灌注量相关。在血中,孕酮主要与皮质类固醇结合蛋白(CBG)及白蛋白相结合,血液中绝大部分孕酮为结合型,极少数为游离型。孕酮对调节月经周期和维持妊娠具有重要的生理作用,可促进子宫内膜分泌期的转化,为受精卵着床做准备;松弛子宫肌,降低对前列腺素和催产素的反应性;抑制输卵管节律性收缩。孕酮还有促乳腺腺泡增生,增加能量代谢,升高基础体温,促进水钠排除的作用。孕酮对下丘脑-垂体系统具有正、负反馈作用,可调控垂体促性腺激素的合成和分泌。排卵前小剂量孕酮协同E3诱发排卵前LH高峰出现,排卵后大剂量P对下丘脑-垂体系统则呈现负反馈作用。
血中孕酮升高可见于:(a)在排卵的-1,0,+1天,孕酮含量成倍增加,提示为有排卵;(b)正常妊娠、双胎和多胎妊娠时孕酮合成量明显增加,血液中孕酮水平相对升高;(c)妊娠毒血症、先兆子痫、葡萄胎及原性高血压时,孕酮含量也会升高。血中孕酮含量降低见于:(a)先兆流产、宫外孕、早产、闭经、不孕症;(b)黄体功能不全,卵巢黄体发育不全时,孕酮含量相应降低;(c)肾上腺、甲状腺功能严重失调也可影响卵巢功能,使排卵发生障碍,孕酮含量也会相应降低。因此,对于血中孕酮的准确检测具有重要的意义。
免疫学检测方法是基于抗体和抗原的特异性反应进行检测的一种手段,由于其可以利用同位素、酶、化学发光物质等对被检测信号进行放大和显示,因此常被用于检测蛋白质,激素等微量生物活性物质。目前,孕酮的免疫学检测方法主要有化学发光竞争法,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孕酮的抗体。因此,本领域对于有效且结合孕酮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
针对现有抗孕酮抗体来源少的问题,本申请提供一种亲和力、活性改善的抗孕酮抗体,为孕酮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,提供了一种抗孕酮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,提供了一种抗孕酮抗体,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,提供了一种检测孕酮的试剂或试剂盒,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,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-Prog-5B3mut1与Anti-Prog-5B3mut2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亲和力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框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≤10-8M的亲和力结合孕酮。
在可选的实施方式中,所述抗体或其功能性片段以KD≤9.12×10-9M的亲和力结合孕酮。
在可选的实施方式中,所述抗体或其功能性片段以KD≤10-10M或KD≤10-11M的亲和力结合孕酮。
在可选的实施方式中,所述抗体或其功能性片段以KD≤3.30×10-10M的亲和力结合孕酮。
在可选的实施方式中,所述抗体或其功能性片段的LFR1如SEQ ID NO:15所示。
另一方面,本发明实施例提供一种抗孕酮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:16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:17或18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:19所示,所述轻链恒定区(CL)序列如SEQ ID NO:20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:19或20)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,本发明提供一种抗孕酮的抗体,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:21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:22或23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孕酮的试剂或试剂盒,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孕酮检测中的用途。
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-Prog-5B3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 SMARTTMRACE cDNA Amplification Kit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
从分泌抗孕酮的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-Prog-5B3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327bp,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360bp,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
pcDNATM3.4vector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1.40kb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Prog-Albumin偶联物(购自益缪诺,货号PROGO2)至1ug/ml,每孔100μL,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Prog-Albumin偶联物有活性。
(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-Prog-5B3单克隆抗体虽然具备结合Prog-Albumin偶联物的能力,但亲和力和抗体活性均不够理想,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,得到亲和力和抗体活性显著提升的单克隆抗体,并命名为:Anti-Prog-5B3mut1及Anti-Prog-5B3mut2。各单克隆抗体的氨基酸序列如下表所示:
表1抗体序列
样品名称 | 重链序号 | 轻链序号 |
Anti-Prog-5B3mut1 | SEQ ID NO:21 | SEQ ID NO:22 |
Anti-Prog-5B3mut2 | SEQ ID NO:21 | SEQ ID NO:23 |
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,Prog-Albumin偶联物(购自益缪诺,货号PROGO2)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2亲和力数据
样品名称 | KD(M) | kon(1/Ms) | kdis(1/s) |
对照 | 9.12E-09 | 2.19E+04 | 2.00E-04 |
Anti-Prog-5B3mut1 | 1.68E-10 | 1.91E+06 | 3.20E-04 |
Anti-Prog-5B3mut2 | 3.30E-10 | 8.19E+05 | 2.70E-04 |
2活性鉴定
包被液(主要成分NaHCO3)稀释Prog-Albumin偶联物(购自益缪诺,货号PROGO2)至3ug/ml,每孔100μL,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Albumin,验证上述单克隆抗体与Albumin的反应OD值低于0.05,即上述抗体与Albumin无交叉反应性。
表3活性数据
样品浓度(ng/ml) | 250 | 125 | 62.5 | 31.25 | 15.625 | 0.000 |
对照 | 2.188 | 1.846 | 0.686 | 0.319 | 0.148 | 0.038 |
Anti-Prog-5B3mut1 | 2.220 | 1.924 | 0.940 | 0.566 | 0.320 | 0.040 |
Anti-Prog-5B3mut2 | 2.360 | 2.060 | 1.068 | 0.603 | 0.360 | 0.030 |
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4为抗体考核21天的酶免活性检测OD结果。
表4稳定性数据
样品浓度(ng/ml) | 250 | 62.5 | 0 |
4℃,21天样品 | 2.360 | 1.028 | 0.038 |
-80℃,21天样品 | 2.260 | 1.060 | 0.046 |
37℃,21天样品 | 2.330 | 1.090 | 0.034 |
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 | SKAVG |
SEQ ID NO:2 | SIVSGGATYYDPALKS |
SEQ ID NO:3 | ASYAAGIWYF |
SEQ ID NO:4 | SGSSTNIGGGSYVH |
SEQ ID NO:5 | GTSRRPS |
SEQ ID NO:6 | ATEDSGS |
SEQUENCE LISTING
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Thr Thr Thr Ser Gln Leu Asp Ala Asp Gly Ser Tyr Phe Leu Tyr Ser
275 280 285
Arg Leu Arg Val Asp Lys Ser Ser Trp Gln Arg Gly Asp Thr Tyr Ala
290 295 300
Cys Val Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Ile Ser Lys Pro Pro Gly Lys
325
<210> 20
<211> 106
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 20
Gly Gln Pro Lys Ser Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Thr
1 5 10 15
Glu Glu Leu Ser Thr Asn Lys Ala Thr Val Val Cys Leu Ile Asn Asp
20 25 30
Phe Tyr Pro Gly Ser Val Asn Val Val Trp Lys Ala Asp Gly Ser Thr
35 40 45
Ile Asn Gln Asn Val Lys Thr Thr Gln Ala Ser Lys Gln Ser Asn Ser
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Thr Leu Thr Gly Ser Glu Trp Lys
65 70 75 80
Ser Lys Ser Ser Tyr Thr Cys Glu Val Thr His Glu Gly Ser Thr Val
85 90 95
Thr Lys Thr Val Lys Pro Ser Glu Cys Ser
100 105
<210> 21
<211> 447
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 21
Gln Val Arg Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Glu Leu Thr Ser Lys
20 25 30
Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Val Pro Glu Trp Leu
35 40 45
Gly Ser Ile Val Ser Gly Gly Ala Thr Tyr Tyr Asp Pro Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Thr Arg Asp Thr Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Ser Ile Ser Ser Val Ser Ser Glu Asp Thr Ala Glu Tyr Trp Cys Val
85 90 95
Arg Ala Ser Tyr Ala Ala Gly Ile Trp Tyr Phe Asp Tyr Trp Gly Pro
100 105 110
Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Pro Pro Lys Val
115 120 125
Tyr Pro Leu Thr Ser Cys Cys Gly Asp Thr Ser Ser Ser Ile Val Thr
130 135 140
Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Ile
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ala Ser Thr Ser Gly Ala Gln Thr Phe Ile Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Arg Val Gly Leu Ser Ser Asp Tyr
210 215 220
Ser Lys Cys Ser Lys Pro Pro Cys Val Ser Arg Pro Ser Val Phe Ile
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Ser Leu Met Ile Thr Gly Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Gly Gln Gly Asp Pro Glu Val Gln
260 265 270
Phe Ser Trp Phe Val Asp Asn Val Glu Val Arg Thr Ala Arg Thr Lys
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Ala Leu
290 295 300
Pro Ile Gln His Asp His Trp Thr Gly Gly Lys Glu Phe Lys Cys Lys
305 310 315 320
Val His Ser Lys Gly Leu Pro Ala Pro Leu Val Arg Thr Ile Ser Arg
325 330 335
Ala Lys Gly Gln Ala Arg Glu Pro Gln Val Tyr Val Leu Ala Pro Pro
340 345 350
Gln Glu Glu Leu Ser Lys Ser Thr Leu Ser Val Thr Cys Leu Val Thr
355 360 365
Gly Phe Tyr Pro Asp Tyr Ile Ala Val Glu Trp Gln Arg Ala Arg Gln
370 375 380
Pro Glu Ser Glu Asp Lys Tyr Gly Thr Thr Thr Ser Gln Leu Asp Ala
385 390 395 400
Asp Gly Ser Tyr Phe Leu Tyr Ser Arg Leu Arg Val Asp Lys Ser Ser
405 410 415
Trp Gln Arg Gly Asp Thr Tyr Ala Cys Val Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Ile Ser Lys Pro Pro Gly Lys
435 440 445
<210> 22
<211> 215
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 22
Gln Ala Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ser Leu Gly Gln
1 5 10 15
Arg Val Ser Leu Thr Cys Ser Gly Ser Ser Thr Asn Ile Gly Gly Gly
20 25 30
Ser Tyr Val His Trp Tyr Gln Arg Leu Pro Ala Ser Gly Leu Lys Thr
35 40 45
Ile Ile Tyr Gly Thr Ser Arg Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Thr Ser Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Glu Asp Ser Gly
85 90 95
Ser Tyr Pro Phe Gly Ser Gly Thr Arg Leu Thr Val Leu Gly Gln Pro
100 105 110
Lys Ser Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu Leu
115 120 125
Ser Thr Asn Lys Ala Thr Val Val Cys Leu Ile Asn Asp Phe Tyr Pro
130 135 140
Gly Ser Val Asn Val Val Trp Lys Ala Asp Gly Ser Thr Ile Asn Gln
145 150 155 160
Asn Val Lys Thr Thr Gln Ala Ser Lys Gln Ser Asn Ser Lys Tyr Ala
165 170 175
Ala Ser Ser Tyr Leu Thr Leu Thr Gly Ser Glu Trp Lys Ser Lys Ser
180 185 190
Ser Tyr Thr Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys Thr
195 200 205
Val Lys Pro Ser Glu Cys Ser
210 215
<210> 23
<211> 215
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 23
Gln Ala Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ser Leu Gly Gln
1 5 10 15
Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Thr Asn Ile Gly Gly Gly
20 25 30
Ser Tyr Val His Trp Tyr Gln Arg Leu Pro Ala Ser Gly Leu Lys Thr
35 40 45
Ile Ile Tyr Gly Thr Ser Arg Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Thr Ser Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Glu Asp Ser Gly
85 90 95
Ser Tyr Pro Phe Gly Ser Gly Thr Arg Leu Thr Val Leu Gly Gln Pro
100 105 110
Lys Ser Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu Leu
115 120 125
Ser Thr Asn Lys Ala Thr Val Val Cys Leu Ile Asn Asp Phe Tyr Pro
130 135 140
Gly Ser Val Asn Val Val Trp Lys Ala Asp Gly Ser Thr Ile Asn Gln
145 150 155 160
Asn Val Lys Thr Thr Gln Ala Ser Lys Gln Ser Asn Ser Lys Tyr Ala
165 170 175
Ala Ser Ser Tyr Leu Thr Leu Thr Gly Ser Glu Trp Lys Ser Lys Ser
180 185 190
Ser Tyr Thr Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys Thr
195 200 205
Val Lys Pro Ser Glu Cys Ser
210 215
Claims (33)
1.一种抗孕酮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氨基酸序列如SEQIDNO:1所示的HCDR1,SEQIDNO:2所示的HCDR2,SEQIDNO:3所示的HCDR3,和氨基酸序列如SEQID NO:4所示的LCDR1,SEQID NO:5所示的LCDR2,SEQID NO:6所示的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SEQIDNO:7至SEQIDNO:10所示的HFR1、HFR2、HFR3、HFR4和氨基酸序列依次如SEQIDNO:11至SEQIDNO:14所示的LFR1、LFR2、LFR3和LFR4,或与所述各序列具有至少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以KD≤10-8M的亲和力结合孕酮。
4.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的LFR1的氨基酸序列如SEQIDNO:15所示。
5.一种抗孕酮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,所述轻链可变区含有LFR1-LCDR1-LFR2-LCDR2-LFR3-LCDR3-LFR4的序列结构,所述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、LCDR3的氨基酸序列依次为权利要求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的氨基酸序列依次为权利要求2中所述的HFR1、HFR2、HFR3、HFR4、LFR1、LFR2、LFR3、LFR4的氨基酸序列。
6.一种抗孕酮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,所述重链可变区氨基酸序列如SEQIDNO:16所示,所述轻链可变区氨基酸序列如SEQIDNO:17或18所示。
7.根据权利要求1至6任一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。
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,所述恒定区包括重链恒定区和轻链恒定区。
9.根据权利要求8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。
10.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。
11.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绵羊。
12.根据权利要求8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SEQIDNO:19所示或与其具有至少80%同源性,所述轻链恒定区序列如SEQIDNO:20所示或与其具有至少80%同源性。
13.根据权利要求1至6任一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。
14.一种抗孕酮抗体,包括重链和轻链,其特征在于,所述重链包括权利要求5或6中所述的重链可变区和权利要求8、9、12任一项中所述的重链恒定区;所述轻链包括权利要求5或6中所述的轻链可变区和权利要求8、9、12任一项中所述的轻链恒定区。
15.一种抗孕酮抗体,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SEQIDNO:21所示,所述轻链的氨基酸序列如SEQIDNO:22或23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。
17.根据权利要求16所述的抗体偶联物,其特征在于,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。
18.根据权利要求17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。
19.根据权利要求17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。
20.根据权利要求17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。
21.根据权利要求17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。
22.根据权利要求17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。
23.根据权利要求22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。
24.根据权利要求22所述的抗体偶联物,其特征在于,所述胶体选自胶体金属、分散型染料、染料标记的微球、胶体硒和乳胶。
25.根据权利要求24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。
26.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。
27.根据权利要求26所述的抗体偶联物,其特征在于,所述固相选自微球、板和膜。
28.根据权利要求27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。
29.一种检测孕酮的试剂或试剂盒,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至28任一项所述的抗体偶联物。
30.一种核酸,其特征在于,其编码权利要求1至13任一项所述的抗体或其抗原结合片段或权利要求14至15任一项所述抗体。
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13任一项所述的抗体或其抗原结合片段或权利要求14至15任一项所述抗体的方法,其特征在于,其包括:培养权利要求32所述的细胞。
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