CN115785274A - 一种抗胃蛋白酶原i的抗体及其应用 - Google Patents
一种抗胃蛋白酶原i的抗体及其应用 Download PDFInfo
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- CN115785274A CN115785274A CN202111059908.6A CN202111059908A CN115785274A CN 115785274 A CN115785274 A CN 115785274A CN 202111059908 A CN202111059908 A CN 202111059908A CN 115785274 A CN115785274 A CN 115785274A
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Abstract
本发明涉及一种抗胃蛋白酶原I的抗体及其应用。本发明制备的单克隆抗体与胃蛋白酶原I亲和力、反应活性、灵敏度及特异性上均表现出良好的性能，为胃蛋白酶原I的检测提供了重要的原料来源，具备非常大的市场潜力。
Description
技术领域
本发明属于抗体技术领域。更具体地，涉及一种抗胃蛋白酶原I的抗体及其应用。
背景技术
胃蛋白酶原是由细胞合成，并以不具有活性的酶原颗粒形式贮存在细胞内。当细胞内充满酶原颗粒时，它对新的酶原地产生有负反馈作用。分泌进入胃腔内的胃蛋白酶原在胃酸的作用下，从分子中解离出一个小分子多肽，转变为具有生物活性的胃蛋白酶。同时，已激活的胃蛋白酶对胃蛋白酶原也有激活作用。
根据胃蛋白酶原的生化性质和免疫原性可将其分成2个亚群，组分1-5的免疫原性相同，称为胃蛋白酶原I(PG I)，主要由胃底腺的主细胞和黏液颈细胞分泌；组分6和7被称为胃蛋白酶原II(PG II)，除由胃底腺的主细胞和黏液颈细胞分泌外，贲门腺和胃窦的幽门腺的黏液颈细胞以及十二指肠上段也能产生胃蛋白酶原II。
通常情况下，人体约有1％的PG透过胃黏膜毛细血管进入血液循环，进入血液循环的PG在血液中含量非常稳定。血清中PG I和PG II反映胃黏膜腺体和细胞的数量，也间接反映胃黏膜不同部位的分泌功能。当胃黏膜发生病理变化时，血清中PG的含量也随之改变。因此，监测血清中PG的浓度可以作为监测胃黏膜状态的手段。
血清中PG I是检测胃泌酸腺细胞功能的指标之一，胃酸分泌增多则PG I升高，分泌减少或胃粘膜腺体萎缩PG I降低；PG II与胃底粘膜病变的相关性较大，PG II升高与胃底腺管萎缩、胃上皮化生或假幽门腺化生、异型增值有关；PG I/II比值进行性降低与胃粘膜萎缩进展相关。因此，测定PG I、PG II及其比值有重要的作用，可作为胃炎、胃癌等多种胃部疾病的诊断标志物，相比胃钡餐造影、胃镜等传统检测手段，具有准确、无创、安全的优势。
临床上用于检测水平PGI的方法有酶联免疫吸附法(ELISA)，化学发光法，流式荧光发光法，时间分辨荧光免疫分析法，光激化学发光免疫分析法，胶体金等，不同方法都有各自的优缺点，但是都需要针对于PGI的特异性单克隆抗体。
目前国内用于检测PG I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PG I单克隆抗体原料特异性及灵敏度的缺陷问题，本发明制备的抗PG I的抗体亲和力、反应活性、特异性及灵敏度方面明显优于市场主流抗体。
本发明的目的是提供一种抗体或抗原结合片段，所述抗体含有以下CDRs：
重链CDR1，其包含SEQ ID NO.1所示的氨基酸序列D-H-P-M-H，或由其组成；
重链CDR2，其包含SEQ ID NO.2所示的氨基酸序列V-I-S-T-F-S-G-H-R-N-Y-N-Q-K-F-K-G，或由其组成；和
重链CDR3，其包含SEQ ID NO.3所示的氨基酸序列G-D-K-S-I-Y-Y-G，或由其组成；
并且所述抗体还包含：
轻链CDR1，其包含SEQ ID NO.4所示的氨基酸序列S-A-S-S-S-V-S-Y-M-Y，或由其组成；
轻链CDR2，其包含SEQ ID NO.5所示的氨基酸序列D-T-S-K-L-T-S，或由其组成；和
轻链CDR3，其包含SEQ ID NO.6所示的氨基酸序列Q-Q-W-S-S-S-P，或由其组成；。
本发明的另一目的是提供所述抗体或其抗原结合片段相关的核酸、载体或细胞。
本发明还提供了制备所述抗体或其抗原结合片段的方法。
本发明还提供了所述抗体或其抗原结合片段在制备试剂盒或诊断试剂中的应用。
本发明还提供了包含上述抗体或其抗原结合片段的试剂盒/诊断试剂。
附图说明
图1是Anti-HPG I 13A5抗体的还原性SDS-PAGE结果。
具体实施方式
以下结合具体实施例来进一步说明本发明，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。
本发明涉及一种抗体或抗原结合片段，所述抗体包含以下CDRs：
重链CDR1，其包含SEQ ID NO.1所示的氨基酸序列D-H-P-M-H，或由其组成；
重链CDR2，其包含SEQ ID NO.2所示的氨基酸序列V-I-S-T-F-S-G-H-R-N-Y-N-Q-K-F-K-G，或由其组成；和
重链CDR3，其包含SEQ ID NO.3所示的氨基酸序列G-D-K-S-I-Y-Y-G，或由其组成；
并且所述或抗原结合片段还包含：
轻链CDR1，其包含SEQ ID NO.4所示的氨基酸序列S-A-S-S-S-V-S-Y-M-Y，或由其组成；
轻链CDR2，其包含SEQ ID NO.5所示的氨基酸序列D-T-S-K-L-T-S，或由其组成；和
轻链CDR3，其包含SEQ ID NO.6所示的氨基酸序列Q-Q-W-S-S-S-P，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。术语“抗原结合片段”是包含抗体CDR的一部分或全部的物质，其缺乏至少一些存在于全长链中的氨基酸但仍能够特异性结合至抗原。此类片段具生物活性，因为其结合至抗原，且可与其他抗原结合分子(包括完整抗体)竞争结合至给定表位。此类片段选自Fab(由完整的轻链和Fd构成)，Fv(由VH和VL构成)，scFv(单链抗体，VH和VL之间由一连接肽连接而成)或单域抗体(仅由VH组成)。此类片段可通过重组核酸技术产生，或可通过抗原结合分子(包括完整抗体)的酶裂解或化学裂解产生。
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其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HFR1、HFR2、HFR3和HFR4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。
在一些实施方式中，所述抗体还包含重链可变区的框架区HFR1、HFR2、HFR3和HFR4，和轻链可变区的框架区LFR1、LFR2、LFR3和LFR4，其中：
HFR1包含选自SEQ ID NO:7或与SEQ ID NO:7具有90％以上同源性的氨基酸序列；
HFR2包含SEQ ID NO:8或与SEQ ID NO:8具有90％以上同源性的氨基酸序列；
HFR3包含SEQ ID NO:9或与SEQ ID NO:9具有90％以上同源性的氨基酸序列；
HFR4包含SEQ ID NO:10或与SEQ ID NO:10具有90％以上同源性的氨基酸序列；和
LFR1包含SEQ ID NO:11或与SEQ ID NO:11具有90％以上同源性的氨基酸序列；
LFR2包含SEQ ID NO:12或与SEQ ID NO:12具有90％以上同源性的氨基酸序列；
LFR3包含SEQ ID NO:13或与SEQ ID NO:13具有90％以上同源性的氨基酸序列；
LFR4包含SEQ ID NO:14或与SEQ ID NO:14具有90％以上同源性的氨基酸序列。
在一些实施方式中，所述HFR1由SEQ ID NO:7或与SEQ ID NO:7具有90％以上同源性的氨基酸序列组成；
HFR2由SEQ ID NO:8或与SEQ ID NO:8具有90％以上同源性的氨基酸序列组成；
HFR3由SEQ ID NO:9或与SEQ ID NO:9具有90％以上同源性的氨基酸序列组成；
HFR4由SEQ ID NO:10或与SEQ ID NO:10具有90％以上同源性的氨基酸序列组成；和
LFR1由SEQ ID NO:11或与SEQ ID NO:11具有90％以上同源性的氨基酸序列组成；
LFR2由SEQ ID NO:12或与SEQ ID NO:12具有90％以上同源性的氨基酸序列组成；
LFR3由SEQ ID NO:13或与SEQ ID NO:13具有90％以上同源性的氨基酸序列组成；
LFR4由SEQ ID NO:14或与SEQ ID NO:14具有90％以上同源性的氨基酸序列组成。
在一些实施方式中，所述抗体还包含重链可变区和轻链可变区：所述抗体的重链可变区的氨基酸序列如SEQ ID NO:15所示，或由其组成；所述抗体的轻链可变区的氨基酸序列如SEQ ID NO:16所示，或由其组成。
在一些实施方式中，所述抗体还包含重链恒定区和轻链恒定区；所述重链恒定区为IgG1、IgG2、IgG3、IgG4、IgA、IgD、IgE或IgM中的任一种或几种，所述轻链恒定区为κ链或λ链。
在一些实施方式中，所述重链恒定区和轻链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。
在一些实施方式中，所述抗体的重链的氨基酸序列如SEQ ID NO:17所示，或由其组成；所述抗体的轻链的氨基酸序列如SEQ ID NO:18所示，或由其组成。
在一些实施方式中，所述抗原结合片段选自Fab，Fab'，F(ab')2，scFv，Fv，Fd，单链抗体，双价抗体或结构域抗体。
本发明还涉及核酸，所述核酸编码所述抗体或其抗原结合片段。
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。
本发明还涉及载体，所述载体含有所述核酸。
本发明还涉及细胞，所述细胞含有所述核酸或所述载体。
所述抗体或其抗原结合片段在制备试剂盒或诊断试剂中的应用，同样在本发明的保护范围之内。
本发明还涉及一种试剂盒或诊断试剂，其包含所述抗体或其抗原结合片段。
下面将结合实施例对本发明的实施方案进行详细描述。
以下实施例中，限制性内切酶、Prime Star DNA聚合酶购自Takara公司。pMD-18T载体购自Takara公司。MagExtractor-RNA提取试剂盒购自TOYOBO公司。BD SMARTTMRACEcDNA Amplification Kit试剂盒购自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 Anti-HPG I抗体(13A5抗体)的制备
1、表达质粒构建
(1)13A5抗体基因制备
从分泌Anti-HPG I 13A5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DH5α感受态细胞，长出菌落后分别取重链(Heavy Chain)及轻链(Light Chain)基因克隆各4个克隆送基因测序公司进行测序。
(2)13A5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，轻链可变区(variable region of light chain，VL)基因序列为318bp，属于VkII基因家族，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，重链可变区(variable region of heavy chain，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
pcDNATM3.4
vector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载体中抗体可变区基因测序结果，设计Anti-HPG I 13A5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40μg/100μL，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(主要成分为NaHCO3)稀释PG I蛋白(fitzgerald，30R-AP038)至3μg/mL，每孔100μL，4℃过夜；次日，洗涤液(主要成分为Na2HPO4+NaCl)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50μL/孔显色液A液(主要成分为柠檬酸、醋酸钠、乙酰苯胺和过氧化脲)，加入50μL/孔显色液B液(主要成分为柠檬酸、EDTA·2Na、TMB和浓HCl)，10min；加入终止液(主要成分为EDTA·2Na和浓H2SO4)，50μL/孔；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PG I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、DNA100μg/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
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质粒与700μL细胞混合，转入电转杯，电转，次日计数；25μmol/LMSX 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4μg纯化的抗体进行还原性SDS-PAGE，4μg外来对照抗体作为对照，电泳图如图1所示。在还原性SDS-PAGE后显示两条带，一条Mr为50KD(重链)，另一条Mr为28KD(轻链)。
13A5抗体的HCDR1-HCDR3的氨基酸序列分别如SEQ ID NO.1-3所示；LCDR1-3的氨基酸序列如SEQ ID NO.4-6所示；13A5抗体的重链可变区、轻链可变区、重链及轻链的氨基酸序列分别如SEQ ID NO.15-18所示。
实施例2 亲和力分析及活性鉴定
1、亲和力分析
利用AMC传感器，纯化后的抗体用PBST稀释到10μg/mL，PG I蛋白同样以PBST进行梯度稀释；
运行流程：缓冲液1(PBST；主要成分为Na2HPO4、NaCl和吐温20)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 pH1.69的GLY溶液及缓冲液3进行传感器再生，输出数据。
表1
| 样品名称 | KD(M) | kon(1/Ms) | kdis(1/s) |
| 对照 | 2.71E-10 | 1.95E+06 | 5.29E-04 |
| 13A5 | 2.75E-11 | 1.95E+07 | 5.36E-04 |
注：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。
2、活性鉴定
包被液(主要成分为NaHCO3)稀释PG I蛋白至3μg/mL，每孔100μL，4℃过夜；次日，洗涤液(主要成分为Na2HPO4+NaCl)清洗2次，拍干；加入封闭液(20％BSA+80％PBS)，每孔120μL，37℃，1h，拍干；加入稀释后的纯化抗体和对照抗体，100μL/孔，37℃，30min；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50μL/孔显色液A液(主要成分为柠檬酸、醋酸钠、乙酰苯胺和过氧化脲)，加入50μL/孔显色液B液(主要成分为柠檬酸、EDTA·2Na、TMB和浓HCl)，10min；加入终止液(主要成分为EDTA·2Na和浓H2SO4)，50μL/孔；酶标仪上450nm(参考630nm)处读OD值。
表2
表2中的OD值表示Anti-HPG I 13A5单克隆抗体活性良好。
实施例3 稳定性考核
将实施例1制备得到的Anti-HPG I 13A5单克隆抗体置于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，并对放置21天的样品进行活性检测(利用酶免检测OD结果考核样品的活性)。
13A5抗体的稳定性测试结果如表3所示，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，说明本发明制备得到的Anti-HPG I抗体的稳定性好。
表3
| 样品浓度(ng/mL) | 3.13 | 1.56 | 0 |
| 4℃，21天样品 | 1.835 | 0.908 | 0.094 |
| -80℃，21天样品 | 1.829 | 0.915 | 0.083 |
| 37℃，21天样品 | 1.887 | 0.908 | 0.067 |
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。
SEQUENCE LISTING
<110> 东莞市朋志生物科技有限公司
<120> 一种抗胃蛋白酶原I的抗体及其应用
<130> P2021037CN01
<160> 18
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 1
Asp His Pro Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 2
Val Ile Ser Thr Phe Ser Gly His Arg Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 3
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 3
Gly Asp Lys Ser Ile Tyr Tyr Gly
1 5
<210> 4
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 4
Ser Ala Ser Ser Ser Val Ser Tyr Met Tyr
1 5 10
<210> 5
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 5
Asp Thr Ser Lys Leu Thr Ser
1 5
<210> 6
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 6
Gln Gln Trp Ser Ser Ser Pro
1 5
<210> 7
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 7
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 Thr Phe Thr
20 25 30
<210> 8
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 8
Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile Gly
1 5 10
<210> 9
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 9
Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr Met Glu
1 5 10 15
Leu Asp Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys Ala Arg
20 25 30
<210> 10
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 10
Ser Tyr Leu Ser Trp Gly Gln Gly Thr Leu Ile Thr Val Ser Ala
1 5 10 15
<210> 11
<211> 23
<212> PRT
<213> Artificial Sequence
<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 Sequence
<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 Sequence
<220>
<223> 人工序列
<400> 13
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
1 5 10 15
Leu Thr Ile Ser Ser Met Glu Thr Glu Asp Ala Ala Thr Tyr Phe Cys
20 25 30
<210> 14
<211> 12
<212> PRT
<213> Artificial Sequence
<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> 121
<212> PRT
<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 Thr Phe Thr Asp His
20 25 30
Pro Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Phe Ser Gly His Arg Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Asp Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Lys Ser Ile Tyr Tyr Gly Ser Tyr Leu Ser Trp Gly
100 105 110
Gln Gly Thr Leu Ile Thr Val Ser Ala
115 120
<210> 16
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 16
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
Tyr Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Thr Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Thr Glu
65 70 75 80
Asp Ala Ala Thr Tyr Phe Cys Gln Gln Trp Ser Ser Ser Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 17
<211> 445
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 17
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 Thr Phe Thr Asp His
20 25 30
Pro Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Phe Ser Gly His Arg Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Asp Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Lys Ser Ile Tyr Tyr Gly Ser Tyr Leu Ser Trp Gly
100 105 110
Gln Gly Thr Leu Ile Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
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 Pro
180 185 190
Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
210 215 220
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
245 250 255
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln
260 265 270
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
290 295 300
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
305 310 315 320
Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
340 345 350
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
355 360 365
Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
370 375 380
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly
385 390 395 400
Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
405 410 415
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
420 425 430
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 18
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 18
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
Tyr Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Thr Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Thr Glu
65 70 75 80
Asp Ala Ala Thr Tyr Phe Cys Gln Gln Trp Ser Ser Ser 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 Arg 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 (10)
1.一种抗体或抗原结合片段，其特征在于，所述抗体或抗原结合片段包含以下CDRs：
重链CDR1，其包含SEQ ID NO.1所示的氨基酸序列D-H-P-M-H，或由其组成；
重链CDR2，其包含SEQ ID NO.2所示的氨基酸序列V-I-S-T-F-S-G-H-R-N-Y-N-Q-K-F-K-G，或由其组成；和
重链CDR3，其包含SEQ ID NO.3所示的氨基酸序列G-D-K-S-I-Y-Y-G，或由其组成；
并且所述抗体或抗原结合片段还包含：
轻链CDR1，其包含SEQ ID NO.4所示的氨基酸序列S-A-S-S-S-V-S-Y-M-Y，或由其组成；
轻链CDR2，其包含SEQ ID NO.5所示的氨基酸序列D-T-S-K-L-T-S，或由其组成；和
轻链CDR3，其包含SEQ ID NO.6所示的氨基酸序列Q-Q-W-S-S-S-P，或由其组成。
2.根据权利要求1所述的抗体或抗原结合片段，所述抗体或抗原结合片段还包含重链可变区的框架区HFR1、HFR2、HFR3和HFR4，和轻链可变区的框架区LFR1、LFR2、LFR3和LFR4，其中：
HFR1包含选自SEQ ID NO:7或与SEQ ID NO:7具有90％以上同源性的氨基酸序列；
HFR2包含SEQ ID NO:8或与SEQ ID NO:8具有90％以上同源性的氨基酸序列；
HFR3包含SEQ ID NO:9或与SEQ ID NO:9具有90％以上同源性的氨基酸序列；
HFR4包含SEQ ID NO:10或与SEQ ID NO:10具有90％以上同源性的氨基酸序列；和
LFR1包含SEQ ID NO:11或与SEQ ID NO:11具有90％以上同源性的氨基酸序列；
LFR2包含SEQ ID NO:12或与SEQ ID NO:12具有90％以上同源性的氨基酸序列；
LFR3包含SEQ ID NO:13或与SEQ ID NO:13具有90％以上同源性的氨基酸序列；
LFR4包含SEQ ID NO:14或与SEQ ID NO:14具有90％以上同源性的氨基酸序列。
3.一种抗体或抗原结合片段，其特征在于，所述抗体或抗原结合片段包含重链可变区和轻链可变区，所述重链可变区包含如SEQ ID NO:15所示的氨基酸序列，或由其组成；所述轻链可变区包含如SEQ ID NO:16所示的氨基酸序列，或由其组成。
4.根据权利要求1或3所述的抗体或抗原结合片段，还包含重链恒定区和轻链恒定区，所述重链恒定区为IgG1、IgG2、IgG3、IgG4、IgA、IgD、IgE或IgM中的任一种或几种的重链恒定区；所述轻链恒定区为κ链或λ链；
可选地，所述重链恒定区和轻链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。
5.一种核酸，其特征在于，所述核酸编码权利要求1～4任一所述的抗体或抗原结合片段。
6.一种载体，其特征在于，所述载体包含权利要求5所述的核酸。
7.一种细胞，其特征在于，所述细胞包含权利要求5所述的核酸或权利要求6所述的载体。
8.一种制备权利要求1～4任一所述的抗体或抗原结合片段的方法，所述方法包括培养权利要求7所述的细胞。
9.权利要求1～4任一所述的抗体或抗原结合片段在制备用于诊断十二指肠溃疡、胃炎、胃溃疡、胃癌的试剂盒或诊断试剂中的应用。
10.一种试剂盒或诊断试剂，其特征在于，所述试剂盒或诊断试剂包含权利要求1～4任一所述的抗体或抗原结合片段。
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