CN117088975A - 抗白蛋白抗体、检测白蛋白的试剂和试剂盒 - Google Patents
抗白蛋白抗体、检测白蛋白的试剂和试剂盒 Download PDFInfo
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- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
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- C12N5/0681—Cells of the genital tract; Non-germinal cells from gonads
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Abstract
本发明公开了一种抗白蛋白抗体、检测白蛋白的试剂和试剂盒,涉及抗体技术领域。本发明公开的抗白蛋白抗体包括重链互补决定区和轻链互补决定区。该抗体为白蛋白的检测提供了重要的原料来源,且具有改善的亲和力和活性。
Description
技术领域
本发明涉及抗体技术领域,具体而言,涉及一种抗白蛋白抗体、检测白蛋白的试剂和试剂盒。
背景技术
白蛋白(Albumin,ALB)又称清蛋白,是血浆中含量最多的蛋白质,由肝实质细胞合成,广泛存在于人体的血液、淋巴、肌肉组织中。白蛋白在机体中具有维持血浆渗透压稳定,作为重要的营养物质,运输小分子有机物和无机离子,保证细胞内液、细胞外液与组织液间的交流的作用,同时白蛋白具有黏性、胶质性,在人体内遇到重金属离子时,会自动与重金属离子结合,起到解毒的作用。
血清白蛋白是临床实验室的常规肝功能检测项目,其含量的测定对临床疾病的诊断、治疗、预后判断都具有非常重要的意义。不同年龄段血清白蛋白的正常值也不相同,新生儿正常值范围为28-44g/L,14岁后正常值范围为38-54g/L,成人正常值范围为35-50g/L,60岁后正常值范围为34-48g/L。一般情况下,血清白蛋白增高主要见于血液浓缩而致相对性增高,如严重脱水和休克、严重烧伤、烫伤等。血清白蛋白降低常见于肝脏疾病、营养不良、肾病综合征、严重出血等危重病人,故低白蛋白血症常作为营养评价指标、肝脏疾病指标、危重病人病情及预后指标等。因此,在常规肝功能检查中,可根据血清白蛋白的检查结果来判断疾病。
目前,白蛋白的检测方法主要有荧光免疫层析法,其是基于抗体和抗原的特异性反应,同时利用荧光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放射免疫法、酶联免疫分析法、化学发光法等。上述免疫学检测方法都需要针对于白蛋白的抗体。因此,本领域对于有效且结合白蛋白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
本申请提供一种亲和力和/或活性改善的抗白蛋白抗体,以改善白蛋白的检测,为白蛋白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所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3或15所示的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,提供了一种抗白蛋白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、LCDR1、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,提供了一种抗白蛋白抗体,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,提供了一种检测白蛋白的试剂或试剂盒,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-ALB-2G9mut1至Anti-ALB-2G9mut7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所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3或15所示的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/或活性。
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≤10-7M的亲和力结合白蛋白。
在可选的实施方式中,所述抗体或其功能性片段以KD≤3.24×10-8M的亲和力结合白蛋白。
在可选的实施方式中,所述抗体或其功能性片段以KD≤10-8M、KD≤10-9M、KD≤10-10M、KD≤10-11M的亲和力结合白蛋白。
在可选的实施方式中,所述抗体或其功能性片段以KD≤2.36×10-9M的亲和力结合白蛋白。
在可选的实施方式中,所述抗体或其功能性片段的HFR3如SEQ ID NO:16所示。
在可选的实施方式中,所述抗体或其功能性片段的LFR4如SEQ ID NO:17所示。
另一方面,本发明实施例提供一种抗白蛋白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、LCDR1、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:20至23任一所示。
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:24至25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鼠。
在可选的实施方式中,所述重链恒定区序列(CH)如SEQ ID NO:18所示,所述轻链恒定区(CL)序列如SEQ ID NO:19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:18或19)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,本发明提供一种抗白蛋白的抗体,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:26至29任一所示。
在可选的实施方式中,所述轻链的氨基酸序列如SEQ ID NO:30至31任一所示。
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白蛋白的试剂或试剂盒,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白蛋白检测中的用途。
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-ALB-2G9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Anti-ALB 2G9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-ALB-2G9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318bp,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354bp,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1.41kb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ALB蛋白(天然提取)至0.2ug/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;加入羊抗鼠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ALB蛋白有活性。
(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3μg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-ALB-2G9单克隆抗体虽然具备结合白蛋白的能力,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-ALB-2G9mut1至Anti-ALB-2G9mut7。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-ALB-2G9mut1 | SEQ ID NO:26 | SEQ ID NO:30 |
Anti-ALB-2G9mut2 | SEQ ID NO:27 | SEQ ID NO:30 |
Anti-ALB-2G9mut3 | SEQ ID NO:28 | SEQ ID NO:30 |
Anti-ALB-2G9mut4 | SEQ ID NO:26 | SEQ ID NO:31 |
Anti-ALB-2G9mut5 | SEQ ID NO:28 | SEQ ID NO:31 |
Anti-ALB-2G9mut6 | SEQ ID NO:29 | SEQ ID NO:30 |
Anti-ALB-2G9mut7 | SEQ ID NO:29 | SEQ ID NO:31 |
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,ALB蛋白(天然提取)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 | 3.24E-08 | 1.49E+04 | 4.83E-04 |
Anti-ALB-2G9mut1 | 2.54E-10 | 1.20E+07 | 3.05E-03 |
Anti-ALB-2G9mut2 | 1.85E-09 | 1.30E+06 | 2.41E-03 |
Anti-ALB-2G9mut3 | 1.44E-09 | 1.60E+06 | 2.31E-03 |
Anti-ALB-2G9mut4 | 1.52E-09 | 1.70E+06 | 2.58E-03 |
Anti-ALB-2G9mut5 | 1.47E-09 | 1.63E+06 | 2.39E-03 |
Anti-ALB-2G9mut6 | 2.36E-09 | 1.26E+06 | 2.97E-03 |
Anti-ALB-2G9mut7 | 1.48E-09 | 1.54E+06 | 2.28E-03 |
2活性鉴定
包被液(主要成分NaHCO3)稀释ALB蛋白(自研,天然提取)至0.2ug/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;加入羊抗鼠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。
表3活性数据
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4稳定性数据
样品浓度(ng/ml) | 6.25 | 1.56 | 0 |
4℃,21天样品 | 1.759 | 0.645 | 0.021 |
-80℃,21天样品 | 1.780 | 0.660 | 0.023 |
37℃,21天样品 | 1.732 | 0.631 | 0.035 |
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 | NYWMN |
SEQ ID NO:2 | QIYPGDGDTYYNGRFKG |
SEQ ID NO:3 | GVILGSF |
SEQ ID NO:4 | SASSSVSYMH |
SEQ ID NO:5 | DTSKLAS |
SEQ ID NO:6 | QQWGSNP |
SEQ ID NO:15 | GVLLGSF |
SEQUENCE LISTING
<110> 东莞市朋志生物科技有限公司
<120> 抗白蛋白抗体、检测白蛋白的试剂和试剂盒
<130> P2022049CN01
<160> 31
<170> PatentIn version 3.3
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<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 7
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser
20 25 30
<210> 8
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 8
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 9
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 9
Lys Ala Thr Leu Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr Met Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys Ala Arg
20 25 30
<210> 10
<211> 13
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 10
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
1 5 10
<210> 11
<211> 23
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 11
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys
20
<210> 12
<211> 15
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 12
Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
1 5 10 15
<210> 13
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 13
Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
1 5 10 15
Leu Thr Ile Arg Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
20 25 30
<210> 14
<211> 12
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 14
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 15
<211> 7
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 15
Gly Val Leu Leu Gly Ser Phe
1 5
<210> 16
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 16
Lys Ala Thr Ile Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr Met Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys Ala Arg
20 25 30
<210> 17
<211> 12
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 17
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 18
<211> 323
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 18
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
1 5 10 15
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
100 105 110
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
115 120 125
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
130 135 140
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
145 150 155 160
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
165 170 175
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
180 185 190
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
195 200 205
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
210 215 220
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
225 230 235 240
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
245 250 255
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
260 265 270
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
275 280 285
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
290 295 300
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
305 310 315 320
Ser Pro Gly
<210> 19
<211> 107
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 19
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
1 5 10 15
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
20 25 30
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
35 40 45
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
65 70 75 80
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
85 90 95
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
100 105
<210> 20
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 20
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Arg Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys
85 90 95
Ala Arg Gly Val Ile Leu Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 21
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 21
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Arg Phe
50 55 60
Lys Gly Lys Ala Thr Ile Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys
85 90 95
Ala Arg Gly Val Leu Leu Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 22
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 22
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Arg Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys
85 90 95
Ala Arg Gly Val Leu Leu Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 23
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 23
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Arg Phe
50 55 60
Lys Gly Lys Ala Thr Ile Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys
85 90 95
Ala Arg Gly Val Ile Leu Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 24
<211> 106
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 24
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Arg Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Gly Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 25
<211> 106
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 25
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Arg Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Gly Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 26
<211> 441
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 26
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Arg Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys
85 90 95
Ala Arg Gly Val Ile Leu Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
115 120 125
Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn
145 150 155 160
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr
180 185 190
Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser
195 200 205
Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro
210 215 220
Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro
225 230 235 240
Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys
245 250 255
Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp
260 265 270
Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu
275 280 285
Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met
290 295 300
His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser
305 310 315 320
Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
325 330 335
Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln
340 345 350
Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe
355 360 365
Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu
370 375 380
Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
385 390 395 400
Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn
405 410 415
Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr
420 425 430
Glu Lys Ser Leu Ser His Ser Pro Gly
435 440
<210> 27
<211> 441
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 27
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Arg Phe
50 55 60
Lys Gly Lys Ala Thr Ile Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys
85 90 95
Ala Arg Gly Val Leu Leu Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
115 120 125
Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn
145 150 155 160
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr
180 185 190
Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser
195 200 205
Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro
210 215 220
Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro
225 230 235 240
Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys
245 250 255
Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp
260 265 270
Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu
275 280 285
Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met
290 295 300
His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser
305 310 315 320
Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
325 330 335
Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln
340 345 350
Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe
355 360 365
Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu
370 375 380
Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
385 390 395 400
Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn
405 410 415
Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr
420 425 430
Glu Lys Ser Leu Ser His Ser Pro Gly
435 440
<210> 28
<211> 441
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 28
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Arg Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys
85 90 95
Ala Arg Gly Val Leu Leu Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
115 120 125
Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn
145 150 155 160
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr
180 185 190
Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser
195 200 205
Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro
210 215 220
Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro
225 230 235 240
Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys
245 250 255
Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp
260 265 270
Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu
275 280 285
Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met
290 295 300
His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser
305 310 315 320
Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
325 330 335
Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln
340 345 350
Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe
355 360 365
Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu
370 375 380
Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
385 390 395 400
Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn
405 410 415
Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr
420 425 430
Glu Lys Ser Leu Ser His Ser Pro Gly
435 440
<210> 29
<211> 441
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 29
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Arg Phe
50 55 60
Lys Gly Lys Ala Thr Ile Thr Ala Asp Lys Ser Pro Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Val Cys
85 90 95
Ala Arg Gly Val Ile Leu Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
115 120 125
Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn
145 150 155 160
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr
180 185 190
Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser
195 200 205
Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro
210 215 220
Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro
225 230 235 240
Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys
245 250 255
Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp
260 265 270
Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu
275 280 285
Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met
290 295 300
His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser
305 310 315 320
Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
325 330 335
Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln
340 345 350
Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe
355 360 365
Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu
370 375 380
Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
385 390 395 400
Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn
405 410 415
Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr
420 425 430
Glu Lys Ser Leu Ser His Ser Pro Gly
435 440
<210> 30
<211> 213
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 30
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Arg Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Gly Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 31
<211> 213
<212> PRT
<213> Artificial
<220>
<223> 人工序列
<400> 31
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Arg Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Gly Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
Claims (12)
1.一种抗白蛋白抗体或其功能性片段,其特征在于,所述抗体或其功能性片段包括氨基酸序列如SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3或15所示的HCDR3,和氨基酸序列如SEQ ID NO:4至SEQ ID NO:6所示的LCDR1、LCDR2、LCDR3。
2.根据权利要求1所述的抗体或其功能性片段,其特征在于,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 ID NO: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;
可选地,所述抗体或其功能性片段以KD≤10-7M的亲和力结合白蛋白;
可选地,所述抗体或其功能性片段的HFR3的氨基酸序列如SEQ ID NO:16所示;
可选地,所述抗体或其功能性片段的LFR4的氨基酸序列如SEQ ID NO:17所示。
3.一种抗白蛋白抗体或其功能性片段,其特征在于,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、LCDR1、LCDR2、LCDR3的氨基酸序列为权利要求1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所述的HFR1、HFR2、HFR3、HFR4、LFR1、LFR2、LFR3、LFR4的氨基酸序列;
可选地,所述重链可变区氨基酸序列如SEQ ID NO:20至23任一所示;
可选地,所述轻链可变区氨基酸序列如SEQ ID NO:24至25任一所示。
4.根据权利要求1至3任一所述的抗体或其功能性片段,其特征在于,所述抗体或其功能性片段还包含恒定区;
可选地,所述恒定区包括重链恒定区和/或轻链恒定区;
可选地,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;
可选地,所述恒定区的种属来源为牛、马、猪、绵羊、山羊、大鼠、小鼠、狗、猫、兔、驴、鹿、貂、鸡、鸭、鹅或人;
可选地,所述恒定区的种属来源为鼠;
可选地,所述重链恒定区序列如SEQ ID NO:18所示或与其具有至少80%同源性;
可选地,所述轻链恒定区序列如SEQ ID NO:19所示或与其具有至少80%同源性。
5.根据权利要求1至4任一所述的抗体或其功能性片段,其特征在于,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。
6.一种抗白蛋白抗体,包括重链和/或轻链,其特征在于,所述重链包括权利要求3所述的重链可变区和权利要求4所述的重链恒定区;所述轻链包括权利要求3所述的轻链可变区和权利要求4所述的轻链恒定区;
可选地,所述重链的氨基酸序列如SEQ ID NO:26至29任一所示;
可选地,所述轻链的氨基酸序列如SEQ ID NO:30至31任一所示。
7.一种抗体偶联物,其特征在于,所述抗体偶联物包括权利要求1至6任一项所述的抗体或其功能性片段;
可选地,所述抗体或其功能性片段标记有标记物;
可选地,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;
可选地,所述荧光染料选自荧光素类染料及其衍生物、罗丹明类染料及其衍生物、Cy系列染料及其衍生物、Alexa系列染料及其衍生物和蛋白类染料及其衍生物;
可选地,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;
可选地,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;
可选地,所述化学发光试剂选自鲁米诺及其衍生物、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;
可选地,所述纳米颗粒类标记物选自纳米颗粒、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;
可选地,所述胶体选自胶体金属、分散型染料、染料标记的微球和乳胶;
可选地,所述胶体金属选自胶体金、胶体银和胶体硒;
可选地,所述抗体或其功能性片段包被至固相;
可选地,所述固相选自微球、板和膜;
可选地,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。
8.一种检测白蛋白的试剂或试剂盒,其特征在于,所述试剂或试剂盒包括权利要求1至6任一项所述的抗体或其功能性片段或权利要求7所述的抗体偶联物。
9.一种核酸,其特征在于,其编码权利要求1至6任一项所述的抗体或其功能性片段。
10.一种载体,其特征在于,其含有权利要求10所述的核酸。
11.一种细胞,其特征在于,其含有权利要求10所述的核酸或权利要求11所述的载体。
12.一种制备权利要求1至6任一项所述的抗体或其功能性片段的方法,其特征在于,其包括:培养权利要求12所述的细胞。
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