CN116143917A - 一种抗d-二聚体的抗体及其制备方法和用途 - Google Patents
一种抗d-二聚体的抗体及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一种抗D‑二聚体的抗体及其制备方法和用途。本发明制备的抗D‑二聚体的单克隆抗体对D‑二聚体具有高亲和性、高反应活性、高灵敏度和特异性,为D‑二聚体的检测提供了重要的原料来源。
Description
技术领域
本发明属于抗体技术领域。更具体地,涉及一种抗D-二聚体的抗体及其制备方法和用途。
背景技术
D-二聚体(D-Dimer,DD)是血液中的纤维蛋白,经过活化和水解,产生的一种特异的,最简单的降解产物,是特异性的纤溶过程标记物。在病理状态下,交联纤维蛋白在溶解过程中,释放出X’、Y’、D’、E’等碎片,并形成DD、DD/E、YD/YD、YY/DD等复合物。这些碎片进一步降解为最小的片段DD和DD/E复合物,DD分子量约62000D,在体内半衰期>3h,主要经肾脏排泄。
D-二聚体水平的升高反映了体内存在着凝血及纤溶活性增强,是急性血栓形成的一个敏感的标记物。心肌梗死、脑梗死、肺栓塞、静脉血栓形成、手术、肿瘤、弥漫性血管内凝血、感染及组织坏死等均可导致D-二聚体升高。
近年来,应用单克隆抗体和蛋白质连接技术推出了血栓导向溶栓剂,基本原理是利用抗原〔D—二聚体〕和抗体〔抗D—二聚体单抗)之间的亲和力,将抗血栓特异性成分的单抗与溶栓药物相连接,形成抗体-溶栓剂复合体。其中的单抗如同导弹一样,可携带溶栓剂特异地与血栓结合,使得血栓部位的溶栓剂高度聚集,从而增强对血栓的溶解作用。后来又发现将抗D—二聚体单抗标记放射性核素,在抗体与抗原特异性结合过程中,可将放射性核素携带到血栓局部,再用放射性核素检测仪监测体内放射性核素的分布,从而达到利用导向示踪剂定位诊断血栓的目的。
D-二聚体的检测方法有三P试验、胶乳凝集法(LATEX)、ELISA法、免疫渗滤胶体金显色反应法等。目前用的这些检测方法都是建立在特异单抗的基础上的,也就是说针对D-二聚体的单抗制备成为提高检测灵敏度和特异性的关键。目前国内用于检测D-二聚体的单克隆抗体基本自外国采购,灵敏度、特异性上都存在缺陷。
发明内容
本发明要解决的技术问题是克服现有抗D-二聚体的单克隆抗体来源少、特异性及灵敏度的缺陷问题,本发明制备的抗D-二聚体的单克隆抗体具有较好的结合活性和亲和力,有利于提高检测的特异性和灵敏度,为D-二聚体水平的检测提供了重要原料来源。
为了实现上述目的,根据本发明的一个方面,提供了一种抗D-二聚体的抗体或其功能性片段,所述抗体或其功能性片段包含以下互补决定区:
HCDR1,其包含SEQ ID NO:1所示的氨基酸序列,或由其组成;
HCDR2,其包含SEQ ID NO:2所示的氨基酸序列,或由其组成;
HCDR3,其包含SEQ ID NO:3所示的氨基酸序列,或由其组成;
LCDR1,其包含SEQ ID NO:4所示的氨基酸序列,或由其组成;
LCDR2,其包含SEQ ID NO:5所示的氨基酸序列,或由其组成;
LCDR3,其包含SEQ ID NO:6所示的氨基酸序列,或由其组成。
进一步地,所述抗体或其功能性片段还具有以下的骨架区:
HFR1氨基酸序列如SEQ ID NO:7所示或与其具有至少80%同源性;
HFR2氨基酸序列如SEQ ID NO:8所示或与其具有至少80%同源性;
HFR3氨基酸序列如SEQ ID NO:9、21、22、23任一所示,或与其具有至少80%同源性;
HFR4氨基酸序列如SEQ ID NO:10所示或与其具有至少80%同源性;
LFR1氨基酸序列如SEQ ID NO:11、24、25、26任一所示,或与其具有至少80%同源性;
LFR2氨基酸序列如SEQ ID NO:12所示或与其具有至少80%同源性;
LFR3氨基酸序列如SEQ ID NO:13、27、28、29任一所示,或与其具有至少80%同源性;
LFR4氨基酸序列如SEQ ID NO:14所示或与其具有至少80%同源性。
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D-二聚体的抗体或其功能性片段,所述抗体或其功能性包含重链可变区和/或轻链可变区,所述重链可变区包含上述的HCDR1-3和上述的HFR1-4,所述轻链可变区包含上述的LCDR1-3和上述的LFR1-4。
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D-二聚体的抗体或其功能性片段,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。
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,提供了一种检测新D-二聚体的试剂或试剂盒,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核酸、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
图1是14D2RMb1至14D2RMb11抗体的还原性SDS-PAGE结果(从左至右)。
具体实施方式
本发明提供一种抗D-二聚体的抗体或其功能性片段,所述抗体或其功能性片段包含以下互补决定区:
HCDR1,其包含SEQ ID NO:1所示的氨基酸序列,或由其组成;
HCDR2,其包含SEQ ID NO:2所示的氨基酸序列,或由其组成;
HCDR3,其包含SEQ ID NO:3所示的氨基酸序列,或由其组成;
LCDR1,其包含SEQ ID NO:4所示的氨基酸序列,或由其组成;
LCDR2,其包含SEQ ID NO:5所示的氨基酸序列,或由其组成;
LCDR3,其包含SEQ ID NO:6所示的氨基酸序列,或由其组成。
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,“骨架区”或“FR”区包括重链骨架区和轻链骨架区,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,重链骨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骨架区;轻链骨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骨架区。
在可选的实施方式中,所述抗体还或其功能性片段还具有以下的骨架区:
HFR1氨基酸序列如SEQ ID NO:7所示或与其具有至少80%同源性;
HFR2氨基酸序列如SEQ ID NO:8所示或与其具有至少80%同源性;
HFR3氨基酸序列如SEQ ID NO:9、21、22、23任一所示,或与其具有至少80%同源性;
HFR4氨基酸序列如SEQ ID NO:10所示或与其具有至少80%同源性;
LFR1氨基酸序列如SEQ ID NO:11、24、25、26任一所示,或与其具有至少80%同源性;
LFR2氨基酸序列如SEQ ID NO:12所示或与其具有至少80%同源性;
LFR3氨基酸序列如SEQ ID NO:13、27、28、29任一所示,或与其具有至少80%同源性;
LFR4氨基酸序列如SEQ ID NO:14所示或与其具有至少80%同源性。
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骨架区(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。例如,HFR3的氨基酸序列还可以是SEQ ID NO:21、22、23任一所示。
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或KD≤10-11的亲和力结合D-二聚体。
在可选的实施方式中,所述抗体或其功能性片段以KD≤2.14×10-8或KD≤9.90×10-9或8.67×10-10的亲和力结合D-二聚体。
KD的检测参考本发明实施例中的方法进行。
另一方面,本发明实施例提供了一种抗D-二聚体的抗体或其功能性片段,所述抗体或其功能性包含重链可变区和/或轻链可变区,所述重链可变区包含上述的HCDR1-3和上述的HFR1-4,所述轻链可变区包含上述的LCDR1-3和上述的LFR1-4。
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,所述重链可变区氨基酸序列如SEQ ID NO:15、30、31、32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:16、33、34、35、36任一所示。
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、绵羊、山羊、大鼠、小鼠、狗、猫、兔、骆驼、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小鼠。
在可选的实施方式中,所述重链恒定区序列(CH)如SEQ ID NO:17或与SEQ ID NO:17具有80%以上同源性的氨基酸序列;所述轻链恒定区为SEQ ID NO:18或与SEQ ID NO:18具有80%以上同源性的氨基酸序列。
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VHH、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D-二聚体的抗体或其功能性片段,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、37、38、39任一所示;所述轻链的氨基酸序列如SEQ ID NO:20、40、41、42、43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以及与其偶联的偶联部分。
在可选的实施方式中,所述偶联部分包括选自纯化标签(如His标签);可检测的标记,例如胶体金、放射性标记、发光物质、有色物质、酶,例如荧光标记、发色团标记、电子致密标记,例如放射性同位素、荧光团、罗丹明及其衍生物、荧光素酶、荧光素、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、糖类氧化酶、葡萄糖氧化酶、半乳糖氧化酶,和葡萄糖-6-磷酸脱氢酶,生物素/抗生物素蛋白,自旋标记、药物(如血栓导向溶栓剂)中的一种或多种。
在可选的实施方式中,所述偶联部分选自固相载体。
在可选的实施方式中,所述固相载体选自微球、板或膜。
在可选的实施方式中,所述固相载体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,所述固相载体为磁性微球。
另一方面,本发明提供一种检测D-二聚体的试剂或试剂盒,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,本发明提供一种编码上述抗体或其功能性片段的核酸分子。
核酸通常是RNA或DNA,核酸分子可以是单链或双链的。当将核酸与另一个核酸序列置于功能关系中时,核酸是“有效连接的”。例如,如果启动子或增强子影响编码序列的转录,那么启动子或增强子有效地连接至所述编码序列。当其连入载体时采用DNA核酸。
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重组细胞。
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,从培养产物中分离纯化得到所述抗体或其功能性片段。
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。
下面将结合实施例对本发明的实施方案进行详细描述。但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
以下实施例中,限制性内切酶、rTaq 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 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。
实施例1 14D2RMb-1抗体的制备
1、表达质粒构建
(1)14D2RMb-1抗体基因制备
从分泌抗D-二聚体14D2RMb-1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(重链)及Light Chain(轻链)基因克隆各4个克隆送基因测序公司进行测序。
(2)14D2RMb-1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363bp,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14D2RMb-1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0.74KB的Light Chain基因片段和1.43kb的Heavy Chain基因片段。Heavy Chain和LightChain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,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
将步骤1-(3)步骤制备得到的质粒用超纯水稀释至40μg/100μL,调节CHO细胞1.43×107cells/mL于离心管中,100μL上述质粒与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D-二聚体抗原(购自菲鹏)至2ug/ml,每孔100uL,4℃过夜;次日,洗涤液(主要成份Na2HPO4+Nacl)清洗2次,拍干;加入封闭液(20%BSA+80%PBS),每孔120uL,37℃,1h,拍干;加入稀释后的细胞上清,100uL/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100uL,37℃,30min;洗涤液清洗5次,拍干;加入显色液A液(50uL/孔,主要成份柠檬酸+醋酸钠+乙酰苯胺+过氧化脲),加入显色液B液(50uL/孔,主要成份柠檬酸+EDTA·2Na+TMB+浓HCL),10min;加入终止液(50uL/孔,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D-二聚体抗原有活性。
(2)重组抗体表达质粒线性化
准备下述试剂:Buffer 50μL、步骤1-(3)步骤制备得到的质粒100μg/管、PvuⅠ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
步骤2-(2)步骤制备得到的质粒用超纯水稀释至40μg/100μL,调节CHO细胞1.43×107cells/mL于离心管中,100μL上述质粒与700μL细胞混合,转入电转杯,电转,次日计数;25μmol/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。将抗体稀释到1mg/ml进行还原性SDS-PAGE,电泳图如图1所示。在还原性SDS-PAGE后显示两条带,1条Mr为50KD(重链),另一条Mr为28KD(轻链)。
经上述步骤获得的14D2RMb-1抗体,经测序及Kabat分析,重链CDR1-3分别如SEQID NO:1-3所示,轻链CDR1-3分别如SEQ ID NO:4-6所示,重链可变区及轻链可变区依次如SEQ ID NO:15、16所示,重链及轻链依次如SEQ ID NO:19、20所示。
对14D2RMb-1的结构进行分析,并进行突变引物设计,重复步骤1-(3)至3-(2),获得10个突变抗体,命名为14D2RMb-2至11。14D2RMb-1至11的重链和轻链氨基酸序列分别如下表所示:
表1
实施例2抗体亲和力分析及活性鉴定
1、亲和力分析
利用AMC传感器,将纯化出来的抗体用PBST稀释到20ug/ml,D-二聚体抗原用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进行传感器再生,输出数据。
表2
抗体名称 | KD(M) | Kon(1/Ms) | Kdis(1/s) |
对照抗体 | 2.14E-08 | 6.17E+03 | 1.32E-04 |
14D2RMb-1 | 9.90E-09 | 5.50E+05 | 5.45E-03 |
14D2RMb-2 | 1.22E-09 | 6.75E+04 | 8.21E-05 |
14D2RMb-3 | 2.24E-09 | 5.71E+04 | 1.28E-04 |
14D2RMb-4 | 8.90E-09 | 5.10E+05 | 4.54E-03 |
14D2RMb-5 | 8.67E-10 | 6.02E+04 | 5.22E-05 |
14D2RMb-6 | 7.40E-09 | 5.00E+05 | 3.70E-03 |
14D2RMb-7 | 3.02E-09 | 5.93E+04 | 1.79E-04 |
14D2RMb-8 | 2.08E-09 | 6.12E+04 | 1.27E-04 |
14D2RMb-9 | 6.31E-09 | 6.10E+05 | 3.85E-03 |
14D2RMb-10 | 1.86E-09 | 5.61E+04 | 1.04E-04 |
14D2RMb-11 | 2.08E-09 | 6.16E+04 | 1.28E-04 |
注:KD表示平衡解离常数即亲和力;Kon表示结合速率常数;Kdis表示解离速率常数。
2、活性鉴定
包被液(主要成分NaHCO3)稀释D-二聚体抗原(购自菲鹏)至2ug/ml,每孔100uL,4℃过夜;次日,洗涤液(主要成份Na2HPO4+NaCl)清洗2次,拍干;加入封闭液(20%BSA+80%PBS),每孔120uL,37℃,1h,拍干;加入稀释后的纯化抗体和对照抗体,100uL/孔,37℃,30min;洗涤液清洗5次,拍干;加入羊抗鼠IgG-HRP,每孔100uL,37℃,30min;洗涤液清洗5次,拍干;加入显色液A液(50uL/孔),加入显色液B液(50uL/孔),10min;加入终止液,50uL/孔;酶标仪上450nm(参考630nm)处读OD值。
表3
实施例3稳定性考核
将自产最优抗体置于4℃(冰箱)、-80℃(冰箱)、37℃(恒温箱)放置21天,取7天、14天、21天抗体样品进行状态观察,并对21天抗体样品进行活性检测,结果显示三种考核条件下抗体样品放置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越势,说明自产抗体稳定。下表为考核21天的酶免活性检测OD结果。
表4
抗体浓度(ng/ml) | 62.5 | 15.625 | 0 |
4℃,21天样品 | 0.861 | 0.389 | 0.061 |
-80℃,21天样品 | 0.911 | 0.339 | 0.073 |
37℃,21天样品 | 0.991 | 0.339 | 0.077 |
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。
本申请涉及的部分氨基酸序列如下:
编号 | 序列 |
SEQ ID NO:1 | DYSIH |
SEQ ID NO:2 | VISTYSGNPDYNQKFKG |
SEQ ID NO:3 | MNDYYGDYFF |
SEQ ID NO:4 | RSSQSLVHTNGNTYLH |
SEQ ID NO:5 | KVSNRFS |
SEQ ID NO:6 | SQSRHVP |
SEQ ID NO:7 | QVQLQQSGPELVRPGVSVKISCKGSGYRFT |
SEQ ID NO:8 | WLKQSHAKSLEWIG |
SEQ ID NO:9 | KATMTVDQSSSTAYMELARLTSDDSAIYYCSR |
SEQ ID NO:10 | DHWGQGTTLIVSS |
SEQ ID NO:11 | DVVMTQTPLSLFVDLGDPASISC |
SEQ ID NO:12 | WYLQKPGQSPRLLIY |
SEQ ID NO:13 | GVPDRFSGSGSGTDFTFKISSVEAEDLGLYFC |
SEQ ID NO:14 | LTFGAGTKLELK |
SEQ ID NO:21 | KATMTVDQSSSTAYMELARLTSDDSALYYCSR |
SEQ ID NO:22 | KATMTVDQSSSTAYMELARITSDDSALYYCSR |
SEQ ID NO:23 | KATMTVDQSSSTAYMELARITSDDSAIYYCSR |
SEQ ID NO:24 | DVVMTQTPLSIFVDLGDPASISC |
SEQ ID NO:25 | DVVMTQTPISLFVDLGDPASISC |
SEQ ID NO:26 | DVVMTQTPISIFVDLGDPASISC |
SEQ ID NO:27 | GVPDRFSGSGSGTDFTFKISSVEAEDIGLYFC |
SEQ ID NO:28 | GVPDRFSGSGSGTDFTFKLSSVEAEDIGLYFC |
SEQ ID NO:29 | GVPDRFSGSGSGTDFTFKLSSVEAEDLGLYFC |
SEQUENCE LISTING
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<213> Artificial Sequence
<220>
<223> 人工序列
<400> 15
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Asp Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Ser Gly Asn Pro Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Asp Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ser Arg Met Asn Asp Tyr Tyr Gly Asp Tyr Phe Phe Asp His Trp Gly
100 105 110
Gln Gly Thr Thr Leu Ile Val Ser Ser
115 120
<210> 16
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 16
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 17
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 17
Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly
1 5 10 15
Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Leu 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 Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys
100 105 110
Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro
115 120 125
Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys
130 135 140
Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp
145 150 155 160
Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg
165 170 175
Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln
180 185 190
His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn
195 200 205
Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly
210 215 220
Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu
225 230 235 240
Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met
245 250 255
Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu
260 265 270
Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe
275 280 285
Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn
290 295 300
Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr
305 310 315 320
Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
325 330
<210> 18
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 18
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> 19
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 19
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Asp Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Ser Gly Asn Pro Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Asp Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ser Arg Met Asn Asp Tyr Tyr Gly Asp Tyr Phe Phe Asp His Trp Gly
100 105 110
Gln Gly Thr Thr Leu Ile Val Ser Ser Ala Lys Thr Thr Ala Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr
180 185 190
Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr
210 215 220
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
245 250 255
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu
260 265 270
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
275 280 285
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu
290 295 300
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
305 310 315 320
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
340 345 350
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
355 360 365
Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
370 375 380
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
405 410 415
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
420 425 430
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
435 440 445
Pro Gly Lys
450
<210> 20
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 20
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
115 120 125
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
130 135 140
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
145 150 155 160
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
180 185 190
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
195 200 205
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 21
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 21
Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ala Arg Leu Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys Ser Arg
20 25 30
<210> 22
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 22
Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ala Arg Ile Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys Ser Arg
20 25 30
<210> 23
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 23
Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ala Arg Ile Thr Ser Asp Asp Ser Ala Ile Tyr Tyr Cys Ser Arg
20 25 30
<210> 24
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 24
Asp Val Val Met Thr Gln Thr Pro Leu Ser Ile Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys
20
<210> 25
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 25
Asp Val Val Met Thr Gln Thr Pro Ile Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys
20
<210> 26
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 26
Asp Val Val Met Thr Gln Thr Pro Ile Ser Ile Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys
20
<210> 27
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 27
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Phe Lys Ile Ser Ser Val Glu Ala Glu Asp Ile Gly Leu Tyr Phe Cys
20 25 30
<210> 28
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 28
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Phe Lys Leu Ser Ser Val Glu Ala Glu Asp Ile Gly Leu Tyr Phe Cys
20 25 30
<210> 29
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 29
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Phe Lys Leu Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys
20 25 30
<210> 30
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 30
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Asp Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Ser Gly Asn Pro Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys
85 90 95
Ser Arg Met Asn Asp Tyr Tyr Gly Asp Tyr Phe Phe Asp His Trp Gly
100 105 110
Gln Gly Thr Thr Leu Ile Val Ser Ser
115 120
<210> 31
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 31
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Asp Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Ser Gly Asn Pro Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Ile Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys
85 90 95
Ser Arg Met Asn Asp Tyr Tyr Gly Asp Tyr Phe Phe Asp His Trp Gly
100 105 110
Gln Gly Thr Thr Leu Ile Val Ser Ser
115 120
<210> 32
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 32
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Asp Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Ser Gly Asn Pro Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Ile Thr Ser Asp Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ser Arg Met Asn Asp Tyr Tyr Gly Asp Tyr Phe Phe Asp His Trp Gly
100 105 110
Gln Gly Thr Thr Leu Ile Val Ser Ser
115 120
<210> 33
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 33
Asp Val Val Met Thr Gln Thr Pro Ile Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 34
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 34
Asp Val Val Met Thr Gln Thr Pro Leu Ser Ile Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 35
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 35
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Leu
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 36
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 36
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Ile Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 37
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 37
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Asp Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Ser Gly Asn Pro Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys
85 90 95
Ser Arg Met Asn Asp Tyr Tyr Gly Asp Tyr Phe Phe Asp His Trp Gly
100 105 110
Gln Gly Thr Thr Leu Ile Val Ser Ser Ala Lys Thr Thr Ala Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr
180 185 190
Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr
210 215 220
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
245 250 255
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu
260 265 270
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
275 280 285
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu
290 295 300
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
305 310 315 320
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
340 345 350
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
355 360 365
Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
370 375 380
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
405 410 415
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
420 425 430
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
435 440 445
Pro Gly Lys
450
<210> 38
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 38
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Asp Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Ser Gly Asn Pro Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Ile Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys
85 90 95
Ser Arg Met Asn Asp Tyr Tyr Gly Asp Tyr Phe Phe Asp His Trp Gly
100 105 110
Gln Gly Thr Thr Leu Ile Val Ser Ser Ala Lys Thr Thr Ala Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr
180 185 190
Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr
210 215 220
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
245 250 255
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu
260 265 270
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
275 280 285
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu
290 295 300
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
305 310 315 320
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
340 345 350
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
355 360 365
Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
370 375 380
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
405 410 415
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
420 425 430
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
435 440 445
Pro Gly Lys
450
<210> 39
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 39
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Asp Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Ser Gly Asn Pro Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Ile Thr Ser Asp Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ser Arg Met Asn Asp Tyr Tyr Gly Asp Tyr Phe Phe Asp His Trp Gly
100 105 110
Gln Gly Thr Thr Leu Ile Val Ser Ser Ala Lys Thr Thr Ala Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr
180 185 190
Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr
210 215 220
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
245 250 255
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu
260 265 270
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
275 280 285
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu
290 295 300
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
305 310 315 320
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
340 345 350
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
355 360 365
Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
370 375 380
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
405 410 415
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
420 425 430
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
435 440 445
Pro Gly Lys
450
<210> 40
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 40
Asp Val Val Met Thr Gln Thr Pro Ile Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
115 120 125
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
130 135 140
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
145 150 155 160
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
180 185 190
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
195 200 205
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 41
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 41
Asp Val Val Met Thr Gln Thr Pro Leu Ser Ile Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
115 120 125
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
130 135 140
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
145 150 155 160
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
180 185 190
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
195 200 205
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 42
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 42
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Leu
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
115 120 125
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
130 135 140
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
145 150 155 160
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
180 185 190
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
195 200 205
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 43
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 43
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Phe Val Asp Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile
65 70 75 80
Ser Ser Val Glu Ala Glu Asp Ile Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Arg His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
115 120 125
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
130 135 140
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
145 150 155 160
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
180 185 190
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
195 200 205
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
Claims (11)
1.一种抗D-二聚体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包含以下互补决定区:
HCDR1,其包含SEQ ID NO:1所示的氨基酸序列,或由其组成;
HCDR2,其包含SEQ ID NO:2所示的氨基酸序列,或由其组成;
HCDR3,其包含SEQ ID NO:3所示的氨基酸序列,或由其组成;
LCDR1,其包含SEQ ID NO:4所示的氨基酸序列,或由其组成;
LCDR2,其包含SEQ ID NO:5所示的氨基酸序列,或由其组成;
LCDR3,其包含SEQ ID NO:6所示的氨基酸序列,或由其组成。
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具有以下的骨架区:
HFR1氨基酸序列如SEQ ID NO:7所示或与其具有至少80%同源性;
HFR2氨基酸序列如SEQ ID NO:8所示或与其具有至少80%同源性;
HFR3氨基酸序列如SEQ ID NO:9、21、22、23任一所示,或与其具有至少80%同源性;
HFR4氨基酸序列如SEQ ID NO:10所示或与其具有至少80%同源性;
LFR1氨基酸序列如SEQ ID NO:11、24、25、26任一所示,或与其具有至少80%同源性;
LFR2氨基酸序列如SEQ ID NO:12所示或与其具有至少80%同源性;
LFR3氨基酸序列如SEQ ID NO:13、27、28、29任一所示,或与其具有至少80%同源性;
LFR4氨基酸序列如SEQ ID NO:14所示或与其具有至少80%同源性。
3.一种抗D-二聚体的抗体或其功能性片段,其特征在于,所述抗体或其功能性包含重链可变区和/或轻链可变区,所述重链可变区包含权利要求1或2所述的HCDR1-3和权利要求2所述的HFR1-4,所述轻链可变区包含权利要求1或2所述的LCDR1-3和权利要求2所述的LFR1-4;
优选地,所述重链可变区氨基酸序列如SEQ ID NO:15、30、31、32任一所示;所述轻链可变区氨基酸序列如SEQ ID NO:16、33、34、35、36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,还包含恒定区;
优选地,所述恒定区包括重链恒定区和/或轻链恒定区;
优选地,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;
优选地,所述恒定区的种属来源为牛、马、乳牛、猪、绵羊、山羊、大鼠、小鼠、狗、猫、兔、骆驼、驴、鹿、貂、鸡、鸭、鹅、火鸡、斗鸡或人;
优选地,所述恒定区的种属来源为小鼠;
优选地,所述重链恒定区为SEQ ID NO:17或与SEQ ID NO:17具有80%以上同源性的氨基酸序列;所述轻链恒定区为SEQ ID NO:18或与SEQ ID NO:18具有80%以上同源性的氨基酸序列。
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D-二聚体的抗体或其功能性片段,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;
优选地,所述重链的氨基酸序列如SEQ ID NO:19、37、38、39任一所示;
所述轻链的氨基酸序列如SEQ ID NO:20、40、41、42、43任一所示。
7.一种抗体偶联物,其特征在于,所述抗体偶联物包含权利要求1-6任一所述的抗体或其功能性片段以及与其偶联的偶联部分;
优选地,所述偶联部分选自纯化标签或可检测的标记,例如胶体金、放射性标记、发光物质、有色物质、酶,例如荧光标记、发色团标记、电子致密标记,例如放射性同位素、荧光团、罗丹明及其衍生物、荧光素酶、荧光素、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、糖类氧化酶、葡萄糖氧化酶、半乳糖氧化酶,和葡萄糖-6-磷酸脱氢酶,生物素/抗生物素蛋白,自旋标记、药物中的一种或多种;
优选地,所述偶联部分选自固相载体,例如磁性微球、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D-二聚体的试剂或试剂盒,其特征在于,所述试剂或试剂盒包括权利要求1-6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,所述核酸编码权利要求1-6任一所述的抗体或其功能性片段。
10.一种细胞,其特征在于,所述细胞包含权利要求9所述的核酸。
11.一种制备权利要求1-6任一所述的抗体或其功能性片段的方法,其特征在于,所述方法包括培养权利要求10所述的细胞。
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