CN116948024B - 抗Tau蛋白的捕获抗体 - Google Patents
抗Tau蛋白的捕获抗体 Download PDFInfo
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- CN116948024B CN116948024B CN202311186561.0A CN202311186561A CN116948024B CN 116948024 B CN116948024 B CN 116948024B CN 202311186561 A CN202311186561 A CN 202311186561A CN 116948024 B CN116948024 B CN 116948024B
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Abstract
本发明公开了抗Tau蛋白的捕获抗体，所述捕获蛋白命名为23H9E4，其具备如SEQ ID NO:1、2、3所示的重链可变区HCDR1、HCDR2、HCDR3，和如SEQ ID NO:9、10、11所示的轻链可变区LCDR1、LCDR2、LCDR3；同事本发明公开了编码23H9E4单克隆抗体的核苷酸序列，包含核苷酸序列的核苷酸分子、表达载体和宿主细胞。
Description
技术领域
本发明属于生物技术领域，涉及抗Tau蛋白的捕获抗体。
背景技术
微管系统是神经细胞骨架成分，可参与多种细胞功能。微管由微管蛋白及微管相关蛋白组成，Tau蛋白是含量最高的微管相关蛋白。正常脑中Tau蛋白的细胞功能是与微管蛋白结合促进其聚合形成微管；与形成的微管结合，维持微管稳定性，降低微管蛋白分子的解离，并诱导微管成束。Tau蛋白基因位于17染色体长臂。正常人中由于Tau蛋白mRNA剪辑方式不同，可表达出6种同分异构体。Tau蛋白为含磷酸基蛋白，正常成熟脑中Tau蛋白分子含2～3个磷酸基。而阿尔茨海默症（老年痴呆症）患者脑的Tau蛋白则异常过度磷酸化，每分子Tau蛋白可含5～9个磷酸基，并丧失正常生物功能。
Tau蛋白异常磷酸化 AD患者脑中Tau蛋白总量多于正常人，且正常Tau蛋白减少而异常过度磷酸化Tau蛋白大量增加。AD患者脑Tau蛋白异常过度磷酸化后与微管蛋白的结合力仅是正常Tau蛋白的1/10，也失去其促进微管装配形成的生物学功能并丧失维持微管稳定的作用，PHF-Tau与微管蛋白竞争结合正常Tau蛋白及其它大分子微管相关蛋白，并从微管上夺取这些蛋白导致微管解聚，破坏正常的微管系统，异常磷酸化的Tau蛋白则自身聚集成PHF/NFT结构。AD患者脑中受累神经元微管结构广泛破坏，正常轴突转运受损，引起突触丢失神经元功能损伤，发生脑神经退行性病变。AD患者脑中发现三种Tau蛋白，即胞浆正常Tau蛋白（C-Tau），可溶于水的异常磷酸化Tau蛋白（AD p-Tau）以及异常修饰聚集成PHF的Tau蛋白（PHF-Tau），它存在泛素蛋白修饰。
发明内容
为了解决现有技术中存在的技术问题，本发明提供了如下的实施方案：
本发明提供了一种抗Tau的单克隆抗体，所述单克隆抗体包括如SEQ ID NO:1、2、3所示的重链可变区HCDR1、HCDR2、HCDR3氨基酸序列、和如SEQ ID NO:9、10、11所示的轻链可变区LCDR1、LCDR2、LCDR3。
在某些具体的实施方案中，所述单克隆抗体的重链可变区HCDR1、HCDR2、HCDR3以及轻链可变区LCDR1、LCDR2、LCDR3是通过据Kabat、IMGT、Chothia、AbM或Contact编号系统定义的。在某个具体的实施方案中，所述单克隆抗体的重链可变区HCDR1、HCDR2、HCDR3以及轻链可变区LCDR1、LCDR2、LCDR3的分区是通过Kabat规则进行的，所述可变区的CDR1使用“CXXXXXXXX”，CDR3使用“CXX+···+WGXG”，其中X代表任何氨基酸。
进一步，所述单克隆抗体还包括重链可变区框架区HFR1、HFR2、HFR3、HFR4；轻链可变区还包括轻链可变区框架区LFR1、LFR2、LFR3、LFR4，其中，重链可变区框架区HFR1、HFR2、HFR3、HFR4的氨基酸序列如SEQ ID NO:4、5、6、7所示，轻链可变区框架区LFR1、LFR2、LFR3、LFR4的氨基酸序列如SEQ ID NO:12、13、14、15所示。
进一步，所述单克隆抗体还包括与单克隆抗体重链可操作地连接的第一信号肽，和/或与单克隆抗体可操作地连接的第二信号肽。
进一步，所述第一信号肽的氨基酸序列如SEQ ID NO：33所示；所述第二信号肽的氨基酸序列如SEQ ID NO：34所示。
进一步，所述单克隆抗体的重链可变区具有与SEQ ID NO:8所示的氨基酸序列95%以上同一性；所述单克隆抗体的轻链可变区具有与SEQ ID NO:16所示的氨基酸序列95%以上同一性。
在一些实施方案中，所述单克隆抗体或其片段是人源化的。在一些实施方案中，还提供了一种单克隆抗体或其片段，所述单克隆抗体或其片段进一步包含与所述单克隆抗体或其片段缀合的细胞毒性药物。
在一些实施例中，本发明提供的单克隆抗体和其功能片段包含重链可变结构域的全部或一部分和/或轻链可变结构域的全部或一部分。在一个实施例中，本发明提供的抗体和其功能片段是由本发明提供的重链可变结构域的全部或一部分组成的单结构域抗体。
在某些实施例中，本发明提供的单克隆抗体和其功能片段进一步包含免疫球蛋白（Ig）恒定区，其任选地进一步包含重链和/或轻链恒定区。在某些实施例中，重链恒定区包含 CH1、铰链和/或CH2 CH3区（或任选地CH2 CH3 CH4区）。本发明提供的抗体和其功能片段的恒定区可与野生型恒定区序列一致或相差一或多个突变。
进一步，所述单克隆抗体还包括其功能片段。
进一步，所述功能片段包括核苷酸功能片段或氨基酸功能片段。
在某些具体的实施方案中，本发明提供的抗体涵盖其任何功能片段。如本发明所用，术语“功能片段”或“片段”是指由抗体的一部分形成的抗体片段，其包含一或多个CDR或与抗原结合但不包含完整天然抗体结构的任何其它抗体片段。功能片段的实例包括但不限于双功能抗体、Fab、Fab'、F（ab'）2、Fv片段、二硫键稳定的Fv片段（dsFv）、（dsFv）2、双特异性dsFv（dsFv dsFv'）、二硫键稳定的双功能抗体（ds双功能抗体）、单链抗体分子（scFv）、scFv二聚体（二价双功能抗体）、双特异性抗体、多特异性抗体、骆驼化单结构域抗体、纳米抗体、结构域抗体和二价结构域抗体。功能片段能够结合至与亲本抗体所结合相同的抗原。功能片段还包括抗体能够发挥功能的氨基酸片段的相对应核酸片段，包括RNA与DNA片段，包括但不限于mRNA、tRNA、rRNA、snRNA、hRNA、反义RNA、tCRNA、dsRNA、SCRNA、具有催化活性的RNA、各种病毒RNA、单链DNA、闭环DNA、连接DNA等。
本发明提供了如前面所述的单克隆抗体在制备诊断、预防、治疗Tau蛋白相关疾病的产品或药物组合物中的应用。
进一步，所述产品包括试剂、试剂盒、层析试纸。
进一步，所述药物组合物包括预防/治疗有效量的前面所述的单克隆抗体。
进一步，所述药物组合物还包括药学上可接受的辅料。
进一步，所述辅料包括佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、pH调节和/或缓冲剂、溶剂、表面活性剂或乳化剂。
进一步，所述药物组合物通过口服施用、栓剂施用、局部接触施用、静脉施用、肠胃外施用、腹腔施用、肌肉施用、病灶内施用、鞘内施用、鼻内施用或皮下施用。
在一些实施方案中，药物组合物可特定地配制成以固体或液体形式施用，包括适于以下方式施用者：口服施用，例如药水(水性或非水性溶液或悬浮液)、片剂(例如旨在经颊、舌下和全身吸收者)、大丸剂、散剂、颗粒剂、供施用于舌部的糊剂；肠胃外施用，例如通过皮下、肌肉内、静脉内或硬膜外注射，如例如无菌溶液或悬浮液，或持续释放配制物；表面施用，例如施用于皮肤、肺或口腔的乳霜、软膏剂或控制释放贴片或喷雾剂；阴道内或直肠内施用，例如子宫托、乳霜或泡沫剂；舌下施用；经眼施用；经皮施用；或经鼻、肺施用和施用至其它粘膜表面。
本发明提供了如前面所述的单克隆抗体在检测体外神经细胞或组织是否神经原纤维缠结、神经毡线和营养不良性神经炎中的应用。
本发明提供了一种生产如前面所述的单克隆抗体的方法，所述方法包括：
将编码如前面所述的单克隆抗体的核苷酸序列用于构建表达所述的单克隆抗体的表达载体；导入宿主细胞；在表达条件下培养宿主细胞，分离纯化，获得前面所述的单克隆抗体。
进一步，所述表达载体包括质粒表达载体、慢病毒表达载体、腺病毒表达载体、腺相关病毒表达载体、piggyBac表达载体或Sleeping Beauty转座表达载体。
进一步，所述宿主细胞包括真核细胞或原核细胞。
进一步，所述真核细胞包括哺乳动物细胞、植物细胞、鸟类细胞、昆虫细胞。
进一步，所述真核细胞为杂交瘤细胞。
本发明提供了一种核苷酸分子，所述核苷酸分子编码如前面所述的单克隆抗体。
进一步，编码单克隆抗体的重链可变区HCDR1、HCDR2、HCDR3蛋白的核苷酸序列如SEQ ID NO:17、18、19所示；编码单克隆抗体的轻链可变区LCDR1、LCDR2、LCDR3蛋白的核苷酸序列如SEQ ID NO:25、26、27所示。
进一步，编码单克隆抗体的重链可变区框架区HFR1、HFR2、HFR3、HFR4蛋白的核苷酸序列如SEQ ID NO:20、21、22、23所示；编码单克隆抗体的轻链可变区框架区LFR1、LFR2、LFR3、LFR4蛋白的核苷酸序列如SEQ ID NO:28、29、30、31所示。
进一步，编码单克隆抗体的重链可变区蛋白的核苷酸序列如SEQ ID NO:24所示；编码单克隆抗体的轻链可变区蛋白的核苷酸序列如SEQ ID NO:32所示。
进一步，编码单克隆抗体的第一信号肽的核苷酸序列如SEQ ID NO:34所示；编码单克隆抗体的第二信号肽的核苷酸序列如SEQ ID NO:36所示。
本发明提供了一种表达载体，所述表达载体包含所述的单克隆抗体、和/或前面所述的核苷酸分子。
进一步，所述表达载体还可包括编码蛋白标签的多核苷酸。
本发明提供了一种宿主细胞，其特征在于，所述宿主细胞包括前面所述的单克隆抗体、前面所述的核苷酸分子、前面所述的表达载体中的任意一种或多种。
本发明提供了一种药物组合物，所述药物组合物包括治疗/预防有效量的前面所述的单克隆抗体。
本发明提供了一种产品，所述产品包括前面所述的单克隆抗体。
本发明提供了一种体外非治疗目的的抑制细胞或组织中过表达的Tau蛋白、磷酸化Tau蛋白或高磷酸化Tau蛋白的水平的方法，所述方法包括施用有效量的前面所述的药物组合物以降低体外细胞或组织的Tau蛋白、磷酸化Tau蛋白或高磷酸化Tau蛋白的水平。
进一步，所述导致Tau蛋白过表达、磷酸化Tau蛋白或高磷酸化Tau蛋白的疾病包括阿尔兹海默症、Pick病、进行性核上性麻痹、皮质基底节变性、嗜银颗粒病、胶质细胞球形包涵体tau蛋白病、进行性皮质下胶质细胞增生症、仅有神经原纤维缠结痴呆、星形胶质细胞斑。
定义：
术语“治疗有效量”是指适用于任何医学治疗的合理益处/风险比对被治疗的受试者赋予治疗效果的治疗性分子的量。治疗效果可以是客观的或主观的。特别地，“治疗有效量”是指如通过改善与疾病相关的症状、预防或延迟疾病的发作和/或还减轻疾病症状的严重程度或频率而有效治疗、改善或预防特定疾病或疾患或表现出可检测的治疗或预防效果的治疗性分子或组合物的量。用于任何特定受试者的具体治疗有效量(和/或单位剂量)可取决于多种因素，包括所治疗的病症和病症的严重程度；使用的具体药剂的活性；使用的具体组合物；受试者的年龄、体重、一般健康状况、性别和饮食；使用的具体治疗性分子的施用时间、施用途径和/或排泄或代谢速率；治疗的持续时间；以及医学领域中熟知的类似因素。
如本文所使用，“药学上可接受的辅料”是指在受试者体内无毒且无发炎性的任何无活性成分(例如能够将活性化合物悬浮或溶解的媒剂)。典型辅料包括例如：抗粘附剂、抗氧化剂、粘合剂、包衣剂、压缩助剂、崩解剂、染料(色素)、软化剂、乳化剂、填充剂(稀释剂)、成膜剂或包衣剂、调味剂、芳香剂、助流剂(流动增强剂)、润滑剂、防腐剂、印刷油墨、吸附剂、悬浮剂或分散剂、甜味剂或水合用水。辅料包括但不限于：任选被取代的丁基化羟基甲苯(BHT)、碳酸钙、磷酸氢钙、硬脂酸钙、交联羧甲基纤维素、交联聚乙烯基吡咯烷酮、柠檬酸、交联聚维酮、半胱氨酸、乙基纤维素、明胶、任选被取代的羟丙基纤维素、任选被取代的羟丙基甲基纤维素、乳糖、硬脂酸镁、麦芽糖醇、甘露糖醇、甲硫氨酸、甲基纤维素、对羟基苯甲酸甲酯、微晶纤维素、聚乙二醇、聚乙烯基吡咯烷酮、聚维酮、预胶化淀粉、对羟基苯甲酸丙酯、棕榈酸视黄酯、虫胶、二氧化硅、羧甲基纤维素钠、柠檬酸钠、羟基乙酸淀粉钠、山梨糖醇、淀粉(玉米淀粉)、硬脂酸、硬脂酸、蔗糖、滑石、二氧化钛、维生素A、维生素E、维生素C及木糖醇。本领域一般技术人员了解可用作辅料的多种试剂和材料。
术语“抗体”包括有相同结构特征的约150000道尔顿的异四聚糖蛋白，其由两个相同的轻链(L)和两个相同的重链(H)组成。每条轻链通过一个共价二硫键与重链相连，而不同免疫球蛋白同种型的重链间的二硫键数目不同。每条重链和轻链也有规则间隔的链内二硫键。每条重链的一端有可变区(VH)。其后是多个恒定区。每条轻链的一端有可变区(VL)，另一端有恒定区；轻链的恒定区与重链的第一个恒定区相对，轻链的可变区与重链的可变区相对。特殊的氨基酸残基在轻链和重链的可变区之间形成界面。
本文所用的术语“可变”表示抗体中可变区的某些部分在序列上有所不同，它形成了各种特定抗体对其特定抗原的结合和特异性。然而，可变性并不均匀地分布在整个抗体可变区中。它集中于轻链和重链可变区中成为互补决定区(CDR)或超变区中的三个片段中。
可变区中较保守的部分称为构架区(Framework regions，FR)。抗体重链和轻链的可变区中各自包含四个FR区，它们大致上呈β-折叠构型，由形成连接环的三个CDR相连，在某些情况下可形成部分β折叠结构。每条链中的CDR通过FR区紧密地靠在一起并与另一链的CDR一起形成了抗体的抗原结合部位(参见Ka ba t等，NIH Pu bl .No .91-3242，卷1，647-669页(1991))。抗体恒定区不直接参与抗体与抗原的结合，但是它们表现出不同的效应功能，例如参与抗体的依赖于抗体的细胞毒性(antibody-dependent cellularcytotoxicity，ADCC)或补体介导毒性(complement-dependent cytotoxicity，CDC)。
附图说明
图1是western检测单克隆抗体培养上清对重组抗原识别能力图；
图2是纯化抗体23H9E4和不同检测抗体联合检测与抗原结合的特异性图。
具体实施方式
实施例1 抗Tau蛋白抗体的制备
1、实验方法
1）动物免疫：选取BALB/c小鼠，常规方法免疫。经三次免疫后，用间接ELISA方法测试抗血清效价，选取效价高的小鼠进行后续实验，使用western测试抗血清对重组抗原的识别。
2）脾细胞制备：引颈处死小鼠，无菌条件下取出脾脏，置于已消毒的90~100目不锈钢网中。用注射器向脾脏内注入3 ml无血清培养液，反复抽吸数次获取细胞，再制成细胞悬液。把细胞悬液注入50 ml离心管中，加10~20 ml培养液，轻轻吹打数次，室温中静置5分钟。离心（800~1000转/分）计数，备用。
3）细胞融合：将小鼠骨髓瘤细胞和小鼠脾细胞按1：5比例混合，离心弃去上清，并以消毒滤纸吸净多余上清。将1 ml 40%的PEG溶液60秒内逐滴加入到细胞团中，同时并不断轻微转动离心管。在不断转动的离心管中，60秒内逐滴加入1 ml无血清培养液。而后于5分钟内缓慢加完20 ml无血清培养基。离心（800 转/分，8分钟），去上清，用完全培养液10 ml悬浮，轻轻混匀。将细胞悬液加入96孔板内，每孔50微升。37℃ CO2培养箱中培养24小时后更换成HAT选择性培养液。
4）融合后细胞培养：以重组蛋白作为抗原包被酶标板，包被抗原浓度为1 μg/ml，100 μl/孔。包被缓冲液为PBS（PH=7.4）。4℃放置过夜。次日PBS洗涤3次，每次5分钟。以1%BSA封闭，每孔加入200 μl。37℃恒温箱孵育2小时。弃去BSA，加入含有单克隆抗体的细胞培养上清，每孔100 μl。以小鼠的阳性抗血清作为阳性对照，以空白培养上清作为阴性对照。37℃恒温箱孵育2小时。弃去一抗，洗涤液洗5次，加Peroxidase-AffiniPure Goat Anti-Mouse IgG，37℃恒温箱孵育1小时。加入底物显色后，以酶标仪测定吸光值。
将检测的阳性细胞进行再一轮的克隆化培养，经验证后确定阳性细胞株，增殖后进行冻存和体外培养。
2、实验结果
在1:10的稀释条件下，抗体的吸光值>2.9，远远大于阴性对照值0.069，说明抗体对重组蛋白抗原有很好的亲和力，检测结果如表1所示。
表1抗体识别Tau重组蛋白
实施例2单克隆抗体的纯化及测序
1、实验方法
首先将产生单克隆抗体的培养液，应用半饱和、饱和硫酸铵进行沉淀，进行初步浓缩和纯化；再用亲和层析法进一步纯化。
1）用饱和硫酸铵溶液进行盐析。临用前取所需的量，用2 mol/L NaOH调PH至7.8；将产生抗体的培养液移入烧杯中，边搅拌边滴加饱和硫酸铵溶液5 ml，继续缓慢搅拌30分钟；10000 rpm/min离心15分钟；弃去上清液，沉淀物用1/3饱和度硫酸铵悬浮，搅拌作用30分钟，同法离心；重复前一步1-2次；沉淀物溶于PBS（0.01 mol/L pH=7.2）缓冲液中。
用透析法对盐析样本进行脱盐。将透析袋于2% NaHCO3，1 mmol/L EDTA溶液中煮10分钟，用蒸馏水清洗透析袋内外表面，再用蒸馏水煮透析袋10分钟，冷至室温即可使用。将盐析样品装入透析袋中，对50-100倍体积的PBS缓冲液透析（4℃）12-24小时，其间更换5次透析液，用萘氏试剂（碘化汞11.5 g，碘化钾8 g，加蒸馏水50 ml，待溶解后，再加20%NaOH 50 ml）检测，直至透析外液无黄色物形成为止。
2）亲和层析法进行抗体纯化：将初步纯化的抗体溶液经过protein A/G亲和层析柱过滤，经过结合、洗脱、收集，得到高纯度的抗体。利用分光光度计测定抗体浓度。将纯化的抗体分装后在-80℃保存。
3）单克隆抗体序列的测定：取对数生长期的杂交瘤细胞23H9E4，采用Invitrogen公司的Trizol抽提总RNA，逆转录生成cDNA。然后利用特异性引物PCR分别扩增其重、轻链可变区基因。PCR产物经电泳纯化后，通过TA克隆插入载体，测序、进行序列分析。
2、实验结果
序列检测结果如表2所示。
表2 单克隆抗体23H9E4的序列
实施例3 单克隆抗体的鉴定
1、实验方法
1）以临床样本中的Tau蛋白作为抗原，以小鼠杂交瘤细胞23H9E4的单克隆培养上清进行检测，使用间接ELISA方法检测抗体识别抗原的能力。
2）以临床样本中的Tau蛋白作为抗原，以含有单克隆抗体的小鼠杂交瘤细胞23H9E4培养上清进行检测，使用western blot检测抗体抗原的结合能力。
3）应用双抗体夹心ELISA方法，以23H9E4为包被抗体，以6G10D7-biotin、18G1G8-biotin、24F1H2-biotin抗体作为检测抗体，检测抗体对抗原的识别和捕获作用。
以2.5 μg/ml的纯化抗体包被酶标板，包被液为PBS（pH=7.4），4℃放置过夜。洗涤液洗涤3次，加入重组蛋白作为抗原，抗原浓度分别为0、1、10、100 ng/ml。37℃孵育1小时。洗涤3次，加入生物素标记的检测抗体，浓度为1 μg/ml。37℃孵育1小时。洗涤3次，加入HRP标记的链酶亲和素，与检测抗体结合，浓度为1 mg/ml，1:10000稀释，每孔加入100 μl。37℃孵育30分钟。加底物显色，酶标仪测定吸光值。
4）将单克隆抗体23H9E4与抗体6G10D7-biotin、18G1G8-biotin、24F1H2-biotin配对组合，检测纯化抗体与抗原结合的特异性，将抗原进行倍比稀释，根据抗原浓度与吸光值进行绘图。
2、实验结果
以临床样本中的人Tau蛋白作为抗原，以含有单克隆抗体的小鼠杂交瘤细胞培养上清进行检测。在目标位置，出现强阳性条带，说明抗体对临床样本中的抗原有很强的结合力，结合结果如图1所示。
双抗夹心ELISA检测结果如表3所示，单克隆抗体23H9E4与抗体6G10D7-biotin、18G1G8-biotin、24F1H2-biotin配对成功，随着抗体含量的增加，吸光值随之上升。抗原浓度为100 ng/ml 时，吸光值>1.7，明显高于阴性对照。说明该抗体对抗原有很强的识别和捕获作用。
表3纯化抗体对Tau抗原的识别
单克隆抗体23H9E4与抗体6G10D7-biotin、18G1G8-biotin、24F1H2-biotin配对组合检测抗原抗体的特异性结合如图2所示，随着抗原浓度升高，吸光值也随之升高，说明抗体与抗原结合具有特异性。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (8)
1.一种抗Tau的单克隆抗体，其特征在于，所述单克隆抗体包括如SEQ ID NO:1、2、3所示的重链可变区HCDR1、HCDR2、HCDR3氨基酸序列、和如SEQ ID NO:9、10、11所示的轻链可变区LCDR1、LCDR2、LCDR3。
2.如权利要求1所述的单克隆抗体，其特征在于，所述单克隆抗体还包括重链可变区框架区HFR1、HFR2、HFR3、HFR4；轻链可变区还包括轻链可变区框架区LFR1、LFR2、LFR3、LFR4，其中，重链可变区框架区HFR1、HFR2、HFR3、HFR4的氨基酸序列如SEQ ID NO:4、5、6、7所示，轻链可变区框架区LFR1、LFR2、LFR3、LFR4的氨基酸序列如SEQ ID NO:12、13、14、15所示。
3.权利要求1或2所述的单克隆抗体在制备检测Tau蛋白的产品中的应用。
4.一种生产如权利要求1或2所述的单克隆抗体的方法，其特征在于，所述方法包括：
将编码如权利要求1或2所述的单克隆抗体的核苷酸序列用于构建表达所述的单克隆抗体的表达载体；导入宿主细胞；在表达条件下培养宿主细胞，分离纯化，获得权利要求1或2所述的单克隆抗体。
5.一种核苷酸分子，其特征在于，所述核苷酸分子编码如权利要求1或2所述的单克隆抗体。
6.一种表达载体，其特征在于，所述表达载体包含权利要求5所述的核苷酸分子。
7.一种宿主细胞，其特征在于，所述宿主细胞包括权利要求1或2所述的单克隆抗体、权利要求5所述的核苷酸分子、权利要求6所述的表达载体中的任意一种或多种。
8.一种产品，其特征在于，所述产品包括权利要求1或2所述的单克隆抗体。
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| 刘恋 ; 陈嘉 ; 胡超 ; 夏影 ; 杨微 ; 王琳 ; 石琦 ; 董小平 ; 陈志宝 ; 陈操 ; .Tau蛋白外显子特异性单抗制备及初步应用.病毒学报.(第02期),全文. * |
| 马云峰 ; 王湘庆 ; 郎森阳 ; .微管相关蛋白Tau蛋白及Tau病的研究进展.解放军医学院学报.(第06期),全文. * |
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