CN116143909B - 一种抗hiv-1 p24的抗体及其制备方法和用途 - Google Patents
一种抗hiv-1 p24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HIV‑1P24的抗体及其制备方法和用途。本发明制备的抗HIV‑1P24的单克隆抗体对HIV‑1P24具有高亲和性、高反应活性、高灵敏度和特异性,为HIV‑1P24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HIV-1 P24的抗体及其制备方法和用途。
背景技术
人类免疫缺陷病毒(Human Immunodeficiency Virus,HIV),即艾滋病(AIDS,获得性免疫缺陷综合征)病毒,是造成人类免疫系统缺陷的一种病毒。1981年,人类免疫缺陷病毒在美国首次发现。它是一种感染人类免疫系统细胞的慢病毒(Lentivirus),属逆转录病毒的一种。
HIV是艾滋病的病原体,主要通过性接触、血液和母婴传播。近年来,HIV 感染患者数量一直呈上升趋势。而目前测定血清HIV抗体是诊断HIV感染的常规实验方法,但是测定HIV抗体有局限性:有超过70%的HIV感染者在感染6个月后才能检测出抗体,在同性恋群体,这个数字超过80%,检测抗体方法增加了 HIV“窗口期”传播的危险;另外新生儿产生抗体需要出生1年后,来自母亲的 HIV抗体会致使假阳产生;由于HIV抗体在疾病过程中的持续存在,只有到艾滋病晚期时消失,无法作为治疗监测的稳定指标。
P24是HIV病毒颗粒的主要结构蛋白,是结构基因GAG的产物,在病毒的包装和成熟过程中起重要作用。P24蛋白的氨基酸序列在HIV各毒株之间高度保守,缺失P24会导致病毒无法正常组装。P24蛋白特异性很强,与多数其他逆转录病毒无交叉反应。HIV感染人体,感染者血液中首先出现的病毒标志物为病毒 P24蛋白,从病毒感染到检出HIV抗体之间存在较长的窗口期,因此检测HIV-P24 抗原已在HIV感染的早期诊断、患者的预后判断、筛选和评价抗HIV的药物,以及发现母婴传播等方面发挥了重要作用。
HIV-1 P24抗原的检测采用血清学诊断方法,主要有基于双抗体夹心的酶联免疫检测法和化学发光法、免疫复合物裂解检测法、超敏感EIA法、酶联免疫荧光法等。目前普遍使用双抗体夹心法检测人类免疫缺陷病毒P24抗原,具有很好的特异性,该方法需要针对人类免疫缺陷病毒P24抗原的特异性抗体,且单克隆抗体需求居多。然而目前市场上针对的人类免疫缺陷病毒P24抗原的单克隆抗体产品虽然多,但是灵敏度、亲和力以及特异性都存在缺陷。
发明内容
为了解决现有抗HIV-1 P24抗体灵敏度、亲和力以及特异性存在缺陷的问题,本发明提供了一种抗P24HIV-1 P24单克隆抗体,它的活性、亲和力、灵敏度、特异性都较现在主流抗体有明显优势。
为了实现上述目的,根据本发明的一个方面,提供了一种抗HIV-1 P24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、21任一所示的氨基酸序列,或由其组成;
LCDR1,其包含SEQ ID NO:4、22任一所示的氨基酸序列,或由其组成;
LCDR2,其包含SEQ ID NO:5、23任一所示的氨基酸序列,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、25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HIV-1 P24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HIV-1 P24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HIV-1 P24 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6F13RMb1至6F13RMb6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HIV-1 P24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、21任一所示的氨基酸序列,或由其组成;
LCDR1,其包含SEQ ID NO:4、22任一所示的氨基酸序列,或由其组成;
LCDR2,其包含SEQ ID NO:5、23任一所示的氨基酸序列,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、25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,LFR1的氨基酸序列还可以是SEQ ID NO:24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HIV-1 P24。
在可选的实施方式中,所述抗体或其功能性片段以KD≤3.23×10-9或 9.42×10-10的亲和力结合HIV-1 P24。
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HIV-1 P24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、26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、27、 28、29、30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人。
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 IDNO: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 IDNO: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HIV-1 P24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、31任一所示;所述轻链的氨基酸序列如SEQ ID NO:20、32、33、34、35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HIV-1 P24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 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。
实施例1 6F13RMb1抗体的制备
1、表达质粒构建
(1)6F13RMb1抗体基因制备
从分泌抗HIV-1 P24 6F13RMb1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)6F13RMb1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333bp,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381bp,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6F13RMb1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1.46kb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HIV-1 P24抗原(购自菲鹏)至3ug/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;加入羊抗人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HIV-1 P24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。取6.6μg纯化的抗体进行还原性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6F13RMb1,经测序及Kabat分析,重链CDR1-3分别如 SEQ IDNO: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SEQID NO:15、16所示,重链及轻链依次如SEQ ID NO:19、 20所示。
对6F13RMb1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),经活性鉴定,筛选得到5个突变抗体,命名为6F13MRb2至6。
6F13MRb1至6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、活性鉴定以及性能评估
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40ug/ml,HIV-1 P24 抗原(购自菲鹏)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10 mM pH 1.69 GLY溶液及缓冲液3进行传感器再生,输出数据。
表2
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HIV-1 P24抗原(购自菲鹏)至1ug/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;加入羊抗人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
抗体浓度(ng/ml) | 250 | 125 | 62.5 | 31.25 | 15.625 | 0 |
对照抗体 | 1.568 | 1.278 | 0.756 | 0.537 | 0.337 | 0.038 |
6F13RMb1 | 1.517 | 1.419 | 1.034 | 0.673 | 0.455 | 0.043 |
6F13RMb2 | 1.592 | 1.421 | 1.017 | 0.627 | 0.461 | 0.047 |
6F13RMb3 | 1.594 | 1.431 | 1.191 | 0.737 | 0.511 | 0.031 |
6F13MRb4 | 1.547 | 1.423 | 1.045 | 0.687 | 0.466 | 0.044 |
6F13MAb5 | 1.572 | 1.404 | 0.992 | 0.615 | 0.453 | 0.036 |
6F13MRb6 | 1.593 | 1.412 | 1.011 | 0.628 | 0.459 | 0.041 |
3、性能评价
将上述制备的系列抗体作为包被抗体,分别与另一株HIV p24包被抗体(购自菲鹏)配套使用,在酶联免疫平台上检测性能差异,测试500份已定值标本,具体性能见下表::
表4
/ | 最低检出线 | 与标本定值相关性 |
对照抗体 | 5pg/ml | 0.9899 |
6F13RMb1 | 2.5pg/ml | 0.9921 |
6F13RMb2 | 2.5pg/ml | 0.9936 |
6F13RMb3 | 1pg/ml | 0.9997 |
6F13MRb4 | 2.5pg/ml | 0.9942 |
6F13MAb5 | 1pg/ml | 0.9984 |
6F13MRb6 | 1pg/ml | 0.9991 |
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) | 125 | 15.625 | 0 |
4℃,21天样品 | 1.385 | 0.375 | 0.012 |
-80℃,21天样品 | 1.342 | 0.367 | 0.021 |
37℃,21天样品 | 1.327 | 0.333 | 0.016 |
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 | SYAIS |
SEQ ID NO:2 | GSIPIFGTTHYAQKFQG |
SEQ ID NO:3 | AATAIFGVPRNNFYAM |
SEQ ID NO:4 | RSSQSILHSNGYNYLD |
SEQ ID NO:5 | IGSTRAS |
SEQ ID NO:6 | MQAVQT |
SEQ ID NO:7 | QVQLVQSGAEVKKPGSSVKVSCKASGGTFS |
SEQ ID NO:8 | WVRQAPGQGLEWMG |
SEQ ID NO:9 | RVAIIVDESTSTSYMELSSLRSDDTAAYYCAR |
SEQ ID NO:10 | EVWGQGTTVTVSS |
SEQ ID NO:11 | DIVMTQSPLSLSVTPGEPASISC |
SEQ ID NO:12 | WYLQRPGQSPKLLIY |
SEQ ID NO:13 | GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC |
SEQ ID NO:14 | FFGPGTKVDLK |
SEQ ID NO:21 | AATALFGVPRNNFYAM |
SEQ ID NO:22 | RSSQSLLHSNGYNYLD |
SEQ ID NO:23 | LGSTRAS |
SEQ ID NO:24 | DIVMTQSPLSLSVTPGEPASLSC |
SEQ ID NO:25 | GVPDRFSGSGSGTNFTLKISRVEAEDVGVYYC |
SEQUENCE LISTING
<110> 东莞市朋志生物科技有限公司
<120> 一种抗HIV-1 P24的抗体及其制备方法和用途
<130> 3
<160> 35
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 1
Ser Tyr Ala Ile Ser
1 5
<210> 2
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 2
Gly Ser Ile Pro Ile Phe Gly Thr Thr His Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 3
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 3
Ala Ala Thr Ala Ile Phe Gly Val Pro Arg Asn Asn Phe Tyr Ala Met
1 5 10 15
<210> 4
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 4
Arg Ser Ser Gln Ser Ile Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp
1 5 10 15
<210> 5
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 5
Ile Gly Ser Thr Arg Ala Ser
1 5
<210> 6
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 6
Met Gln Ala Val Gln Thr
1 5
<210> 7
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser
20 25 30
<210> 8
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 8
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 9
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 9
Arg Val Ala Ile Ile Val Asp Glu Ser Thr Ser Thr Ser Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Ala Tyr Tyr Cys Ala Arg
20 25 30
<210> 10
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 10
Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 11
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 11
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys
20
<210> 12
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 12
Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu 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 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 14
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 14
Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys
1 5 10
<210> 15
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 15
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ser Ile Pro Ile Phe Gly Thr Thr His Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Ala Ile Ile Val Asp Glu Ser Thr Ser Thr Ser Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Ala Tyr Tyr Cys
85 90 95
Ala Arg Ala Ala Thr Ala Ile Phe Gly Val Pro Arg Asn Asn Phe Tyr
100 105 110
Ala Met Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 16
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 16
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Ile Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys
100 105 110
<210> 17
<211> 329
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 17
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 18
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 18
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 19
<211> 456
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ser Ile Pro Ile Phe Gly Thr Thr His Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Ala Ile Ile Val Asp Glu Ser Thr Ser Thr Ser Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Ala Tyr Tyr Cys
85 90 95
Ala Arg Ala Ala Thr Ala Ile Phe Gly Val Pro Arg Asn Asn Phe Tyr
100 105 110
Ala Met Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly
450 455
<210> 20
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 20
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Ile Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 21
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 21
Ala Ala Thr Ala Leu Phe Gly Val Pro Arg Asn Asn Phe Tyr Ala Met
1 5 10 15
<210> 22
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 22
Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp
1 5 10 15
<210> 23
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 23
Leu Gly Ser Thr Arg Ala Ser
1 5
<210> 24
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 24
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Leu Ser Cys
20
<210> 25
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 25
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 26
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 26
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ser Ile Pro Ile Phe Gly Thr Thr His Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Ala Ile Ile Val Asp Glu Ser Thr Ser Thr Ser Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Ala Tyr Tyr Cys
85 90 95
Ala Arg Ala Ala Thr Ala Leu Phe Gly Val Pro Arg Asn Asn Phe Tyr
100 105 110
Ala Met Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 27
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 27
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Ile Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys
100 105 110
<210> 28
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 28
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Ile Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys
100 105 110
<210> 29
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 29
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Leu Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys
100 105 110
<210> 30
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 30
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Leu Ser Cys Arg Ser Ser Gln Ser Ile Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Leu Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys
100 105 110
<210> 31
<211> 456
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 31
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ser Ile Pro Ile Phe Gly Thr Thr His Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Ala Ile Ile Val Asp Glu Ser Thr Ser Thr Ser Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Ala Tyr Tyr Cys
85 90 95
Ala Arg Ala Ala Thr Ala Leu Phe Gly Val Pro Arg Asn Asn Phe Tyr
100 105 110
Ala Met Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly
450 455
<210> 32
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 32
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Ile Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 33
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 33
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Ile Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 34
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 34
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Leu Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 35
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 35
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Leu Ser Cys Arg Ser Ser Gln Ser Ile Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Leu Gly Ser Thr Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Val Gln Thr Phe Phe Gly Pro Gly Thr Lys Val Asp Leu Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (27)
1.一种抗HIV-1P24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、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的氨基酸序列依次如SEQ ID NO:1~6所示;或
HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的氨基酸序列依次如SEQ ID NO:1、2、3、22、5、6所示;或
HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的氨基酸序列依次如SEQ ID NO:1、2、3、4、23、6所示;或
HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的氨基酸序列依次如SEQ ID NO:1、2、3、22、23、6所示;或
HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的氨基酸序列依次如SEQ ID NO:1、2、21、4、5、6所示。
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、25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HIV-1P24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重链可变区和轻链可变区,所述重链可变区和所述轻链可变区包含权利要求1中所述的HCDR1-3和LCDR1-3,所述重链可变区和所述轻链可变区还包含权利要求2中所述的HFR1-4和LFR1-4。
4.一种抗HIV-1P24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括重链可变区和轻链可变区;
所述重链可变区和所述轻链可变区的氨基酸序列依次如SEQ ID NO:15、16所示;或所述重链可变区和所述轻链可变区的氨基酸序列依次如SEQ ID NO:15、27所示;或所述重链可变区和所述轻链可变区的氨基酸序列依次如SEQ ID NO:15、28所示;或所述重链可变区和所述轻链可变区的氨基酸序列依次如SEQ ID NO:15、29所示;或所述重链可变区和所述轻链可变区的氨基酸序列依次如SEQ ID NO:15、30所示;或所述重链可变区和所述轻链可变区的氨基酸序列依次如SEQ ID NO:26、16所示。
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,所述抗体或其功能性片段还包含恒定区。
6.根据权利要求5所述的抗体或其功能性片段,其特征在于,所述恒定区包括重链恒定区和轻链恒定区。
7.根据权利要求6所述的抗体或其功能性片段,其特征在于,所述重链恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE或IgD的重链恒定区;所述轻链恒定区选自κ型或λ型轻链恒定区。
8.根据权利要求6所述的抗体或其功能性片段,其特征在于,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。
9.根据权利要求8所述的抗体或其功能性片段,其特征在于,所述牛为乳牛。
10.根据权利要求8所述的抗体或其功能性片段,其特征在于,所述鸡为火鸡或斗鸡。
11.根据权利要求8所述的抗体或其功能性片段,其特征在于,所述恒定区的种属来源为人。
12. 根据权利要求6所述的抗体或其功能性片段,其特征在于,所述重链恒定区的氨基酸序列为SEQ ID NO:17或与SEQ ID NO:17具有80%以上同源性的氨基酸序列;所述轻链恒定区的氨基酸序列为SEQ ID NO:18或与SEQ ID NO:18具有80%以上同源性的氨基酸序列。
13.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。
14.一种抗HIV-1P24的抗体或其功能性片段,包括重链和轻链,其特征在于,所述重链包括权利要求3或4中所述的重链可变区和权利要求5~12任一项中所述的重链恒定区;
所述轻链包括权利要求3或4中所述的轻链可变区和权利要求5~12任一项中所述的轻链恒定区。
15.一种抗HIV-1P24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括重链和轻链;
所述重链和所述轻链的氨基酸序列依次如SEQ ID NO:19、20所示;或所述重链和所述轻链的氨基酸序列依次如SEQ ID NO:19、32所示;或所述重链和所述轻链的氨基酸序列依次如SEQ ID NO:19、33所示;或所述重链和所述轻链的氨基酸序列依次如SEQ ID NO:19、34所示;或所述重链和所述轻链的氨基酸序列依次如SEQ ID NO:19、35所示;或所述重链和所述轻链的氨基酸序列依次如SEQ ID NO:31、20所示。
16.一种抗体偶联物,其特征在于,所述抗体偶联物包含权利要求1-15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。
17.根据权利要求16所述的抗体偶联物,其特征在于,所述偶联部分选自纯化标签或可检测的标记。
18.根据权利要求17所述的抗体偶联物,其特征在于,所述偶联部分选自胶体金、放射性标记、发光物质、有色物质和酶中的一种或多种。
19.根据权利要求17所述的抗体偶联物,其特征在于,所述偶联部分选自荧光标记、发色团标记和电子致密标记中的一种或多种。
20.根据权利要求17所述的抗体偶联物,其特征在于,所述偶联部分选自放射性同位素、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、生物素、抗生物素蛋白和自旋标记中的一种或多种。
21.根据权利要求20所述的抗体偶联物,其特征在于,所述偶联部分选自葡萄糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸脱氢酶中的一种或多种。
22.根据权利要求16所述的抗体偶联物,其特征在于,所述偶联部分选自固相载体。
23.根据权利要求22所述的抗体偶联物,其特征在于,所述偶联部分选自磁性微球、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。
24.一种检测HIV-1P24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1-15任一项所述的抗体或其功能性片段或权利要求16~23任一项所述的抗体偶联物。
25.一种核酸,其特征在于,所述核酸编码权利要求1-15任一所述的抗体或其功能性片段。
26.一种细胞,其特征在于,所述细胞包含权利要求25所述的核酸。
27.一种制备权利要求1-15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26所述的细胞。
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