CN113121678B - 一种抗hiv-1 p24的重组抗体 - Google Patents
一种抗hiv-1 p24的重组抗体 Download PDFInfo
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- CN113121678B CN113121678B CN201911422902.3A CN201911422902A CN113121678B CN 113121678 B CN113121678 B CN 113121678B CN 201911422902 A CN201911422902 A CN 201911422902A CN 113121678 B CN113121678 B CN 113121678B
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Abstract
本发明涉及一种新颖的包含HIV‑1 P24抗原结合结构域的分离的结合蛋白,并对该结合蛋白的制备、应用等方面进行研究。所述结合蛋白包括至少一个互补决定区,其活性强,与HIV‑1 P24蛋白具有很高的亲和力,可广泛应用于HIV‑1 P24蛋白的检测领域。
Description
技术领域
本发明涉及免疫技术领域,具体而言,涉及一种抗HIV-1 P24的重组抗体。
背景技术
人类免疫缺陷病毒(Human Immunodeficiency Virus;abbr: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。目前,艾滋病不仅已成为严重威胁我国人民健康的公共卫生问题,且已影响到经济发展和社会稳定。
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。根据卫生部统计,中国自1985年发现第一例艾滋病病人以来,截至2009年10月底,累计报告艾滋病病毒感染者和病人319877例。2009年当年新发艾滋病病毒感染者4.8万人,我国艾滋病疫情形势依然严峻,性传播正成为主要传播途径。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,主要有双抗体夹心ELISA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,但是单纯利用物理吸附把单克隆抗体或者多克隆抗体吸附在酶标板上会存在单抗使用量大,活性损失大。传统的临床诊断使用的都是鼠源的单克隆抗体,现有的针对HIV-1P24抗原的抗体灵敏度、特异性上都还不够理想,可选择性的不多,因此市面上对于高活性高亲和力的HIV-1 P24单克隆抗体具有强烈的需求。
有鉴于此,特提出本发明。
发明内容
本发明涉及一种新颖的包含HIV-1 P24抗原结合结构域的分离的结合蛋白,并对该结合蛋白的制备、应用等方面进行研究。
其中所述抗原结合结构域包括选自下述氨基酸序列的至少一个互补决定区:或;与下述氨基酸序列的互补决定区具有至少80%的序列同一性且与HIV-1 P24具有KD≤1.74×10-9的亲和力;
互补决定区CDR-VH1为D-X1-S-F-T-X2-Y-T-X3-H,其中,
X1是S、Y或T,X2是P或A,X3是I或L;
互补决定区CDR-VH2为I-N-P-Y-N-X1-T-S-X2-N-Q-K-F-X3-G,其中,
X1是Q、N或GG,X2是S、Y或T,X3是Q或N;
互补决定区CDR-VH3为A-R-X1-G-Y-D-R-E-G-X2-Y-Y-X3-M-D-Y-X4-G,其中,
X1是R或K,X2是Q、H或N,X3是P、A或G,X4是W或F;
互补决定区CDR-VL1为X1-A-S-E-X2-I-Y-T-F-X3-A,其中,
X1是N、R或Q,X2是Q或N,X3是L或I;
互补决定区CDR-VL2为T-X1-K-T-X2-A-E,其中,
X1是T或S,X2是I、V或L;
互补决定区CDR-VL3为Q-H-H-Y-G-X1-P-X2-T-X3-G,其中,
X1是L或I,X2是I或L,X3是F或W。
一个重要优点在于,所述结合蛋白活性强,与HIV-1 P24具有很高的亲和力。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明一个实施例中抗HIV-1 P24的单克隆抗体电泳图。
具体实施方式
本发明可通过后续对于本发明一些实施方案描述以及其中所包括的实施例的详细内容而更容易被了解。
在进一步叙述本发明之前,应明了本发明不会被局限于所述特定实施方案中,因为这些实施方案必然是多样的。亦应明了本说明书中所使用的用语仅是为了阐述特定实施方案,而非作为限制,因为本发明的范围将会被仅仅界定在所附的权利要求中。
名词定义
“包含抗原结合结构域的分离的结合蛋白”泛指包含CDR区的一切蛋白/蛋白片段。“抗体”此用语包括多克隆抗体及单克隆抗体以及这些抗体的抗原化合物结合片段,包括Fab、F(ab’)2、Fd、Fv、scFv、双特异抗体和抗体最小识别单位,以及这些抗体和片段的单链衍生物。抗体的类型可以选择IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD。此外,“抗体”此用语包括天然发生的抗体以及非天然发生的抗体,包括例如嵌合型(chimeric)、双功能型(bifunctional)和人源化(humanized)抗体,以及相关的合成异构形式(isoforms)。“抗体”此用语可和“免疫球蛋白”互换使用。
抗体的“可变区”或“可变结构域”是指抗体的重链或轻链的氨基端结构域。重链的可变结构域可以被称为“VH”。轻链的可变结构域可以被称为“VL”。这些结构域通常是抗体的最可变的部分,并含有抗原结合位点。轻链或重链可变区(VL或VH)由被三个称为“互补决定区”或“CDR”的高变区打断的构架区构成。构架区和CDR的范围已被精确定义,例如在Kabat(参见《免疫重要的蛋白质的序列》(Sequences of Proteins of ImmunologicalInterest),E.Kabat等,美国卫生与人类服务部(U.S.Department of Health and HumanServices),(1983))和Chothia中。抗体的构架区,即构成要件轻链和重链的组合的构架区,起到定位和对齐CDR的作用,所述CDR主要负责与抗原的结合。
当在本文中使用时,“构架”或“FR”区意味着抗体可变结构域的排除被定义为CDR的那些区域之外的区域。每个抗体可变结构域构架可以被进一步细分成被CDR分隔开的毗邻区域(FR1、FR2、FR3和FR4)。
通常情况下,重链和轻链的可变区VL/VH可由以下编号的CDR与FR按如下组合排列连接获得:FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。
当在本文中使用时,与多肽或核酸相关联的术语“纯化的”或“分离的”是指多肽或核酸不是处于其天然介质中或天然形式下。因此,术语“分离的”包括从其原始环境,例如如果它是天然存在的,从天然环境取出的多肽或核酸。例如,分离的多肽通常不含通常与其结合或通常与其混合或在溶液中的至少某些蛋白质或其他细胞组分。分离的多肽包括细胞裂解物中包含的天然生产的所述多肽,纯化或部分纯化形式的所述多肽,重组多肽,被细胞表达或分泌的所述多肽,以及在异源宿主细胞或培养物中的所述多肽。与核酸相关联,术语分离的或纯化的指示例如所述核酸不在其天然的基因组背景中(例如在载体中,作为表达盒,连接到启动子,或人工引入到异源宿主细胞中)。
本发明的示例性实施方案
本发明涉及一种包含抗原结合结构域的分离的结合蛋白,其中所述抗原结合结构域包括选自下述氨基酸序列的至少一个互补决定区:或;与下述氨基酸序列的互补决定区具有至少80%的序列同一性且与HIV-1 P24具有KD≤1.74×10-9的亲和力;
互补决定区CDR-VH1为D-X1-S-F-T-X2-Y-T-X3-H,其中,
X1是S、Y或T,X2是P或A,X3是I或L;
互补决定区CDR-VH2为I-N-P-Y-N-X1-T-S-X2-N-Q-K-F-X3-G,其中,
X1是Q、N或GG,X2是S、Y或T,X3是Q或N;
互补决定区CDR-VH3为A-R-X1-G-Y-D-R-E-G-X2-Y-Y-X3-M-D-Y-X4-G,其中,
X1是R或K,X2是Q、H或N,X3是P、A或G,X4是W或F;
互补决定区CDR-VL1为X1-A-S-E-X2-I-Y-T-F-X3-A,其中,
X1是N、R或Q,X2是Q或N,X3是L或I;
互补决定区CDR-VL2为T-X1-K-T-X2-A-E,其中,
X1是T或S,X2是I、V或L;
互补决定区CDR-VL3为Q-H-H-Y-G-X1-P-X2-T-X3-G,其中,
X1是L或I,X2是I或L,X3是F或W。
在一些实施方式中,所述抗原结合结构域与下述氨基酸序列的互补决定区具有至少85%,或90%,或91%,或92%,或93%,或94%,或95%,或96%,或97%,或98%,或99%的序列同一性且与HIV-1 P24具有KD≤1.74×10-9mol/L,KD值也可以选择1×10-9mol/L、8×10-11mol/L、7×10-11mol/L、6×10-11mol/L、5×10-11mol/L、4×10-11mol/L、3×10-11mol/L、2×10-11mol/L、1×10-11mol/L、8.45×10-11mol/L、1×10-10mol/L、2×10-10mol/L、3×10- 10mol/L、4×10-10mol/L、5×10-10mol/L、6×10-10mol/L、7×10-10mol/L、8×10-10mol/L、或9×10-10mol/L;或者8.45×10-11mol/L≤KD≤1.74×10-9mol/L;
其中,亲和力按照本发明说明书中的方法测定。
在一些实施方式中:
所述互补决定区CDR-VH1中,X2是A;
所述互补决定区CDR-VH2中,X3是N;
所述互补决定区CDR-VH3中,X4是W;
所述互补决定区CDR-VL1中,X3是L;
所述互补决定区CDR-VL2中,X1是T;
所述互补决定区CDR-VL3中,X3是F。
在一些实施方式中,所述互补决定区CDR-VH1中,X1是S。
在一些实施方式中,所述互补决定区CDR-VH1中,X1是Y。
在一些实施方式中,所述互补决定区CDR-VH1中,X1是T。
在一些实施方式中,所述互补决定区CDR-VH1中,X3是I。
在一些实施方式中,所述互补决定区CDR-VH1中,X3是L。
在一些实施方式中,所述互补决定区CDR-VH2中,X2是Q。
在一些实施方式中,所述互补决定区CDR-VH2中,X2是N。
在一些实施方式中,所述互补决定区CDR-VH2中,X2是GG。
在一些实施方式中,所述互补决定区CDR-VH2中,X2是S。
在一些实施方式中,所述互补决定区CDR-VH2中,X2是Y。
在一些实施方式中,所述互补决定区CDR-VH2中,X2是T。
在一些实施方式中,所述互补决定区CDR-VH3中,X1是R。
在一些实施方式中,所述互补决定区CDR-VH3中,X1是K。
在一些实施方式中,所述互补决定区CDR-VH3中,X2是Q。
在一些实施方式中,所述互补决定区CDR-VH3中,X2是H。
在一些实施方式中,所述互补决定区CDR-VH3中,X2是N。
在一些实施方式中,所述互补决定区CDR-VH3中,X3是P。
在一些实施方式中,所述互补决定区CDR-VH3中,X3是A。
在一些实施方式中,所述互补决定区CDR-VH3中,X3是G。
在一些实施方式中,所述互补决定区CDR-VL1中,X1是N。
在一些实施方式中,所述互补决定区CDR-VL1中,X1是R。
在一些实施方式中,所述互补决定区CDR-VL1中,X1是Q。
在一些实施方式中,所述互补决定区CDR-VL1中,X2是Q。
在一些实施方式中,所述互补决定区CDR-VL1中,X2是N。
在一些实施方式中,所述互补决定区CDR-VL2中,X2是I。
在一些实施方式中,所述互补决定区CDR-VL2中,X2是V。
在一些实施方式中,所述互补决定区CDR-VL2中,X2是L。
在一些实施方式中,所述互补决定区CDR-VL3中,X1是L。
在一些实施方式中,所述互补决定区CDR-VL3中,X1是I。
在一些实施方式中,所述互补决定区CDR-VL3中,X2是I。
在一些实施方式中,所述互补决定区CDR-VL3中,X2是L。
在一些实施方式中,各互补决定区的突变位点选自下述突变组合中的任一种:
在一些实施方式中,所述结合蛋白中包括至少3个CDRs(例如3个轻链CDR或3个重链CDR);或者,所述结合蛋白包括至少6个CDRs。
在一些实施方式中,所述结合蛋白为包含可变区和恒定区的完整抗体。
在一些实施方式中,所述结合蛋白为抗体的“功能片段”,例如纳米抗体、F(ab’)2、Fab’、Fab、Fv、scFv、双特异抗体和抗体最小识别单位中的一种。
scFv(sc=单链),双特异抗体(diabodies)。
本发明所述的“功能片段”特别地指对于HIV-1 P24具有与母体抗体相同特异性的抗体片段。除上述功能片段外,还包括半衰期已增加的任何片段。
这些功能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说明中记载的内容推断,本发明的抗体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上述的功能片段。
抗体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,通过肽合成获得。
在一些实施方式中,所述结合蛋白包括序列依次如SEQ ID NO:1-4所示的轻链骨架区FR-L1、FR-L2、FR-L3及FR-L4,和/或,序列依次如SEQ ID NO:5-8所示的重链骨架区FR-H1、FR-H2、FR-H3及FR-H4。
需要说明的是,除本申请上述公开的氨基酸序列外,骨架区的种属来源可以为人,以构成人源化抗体。
在一些实施方式中,所述结合蛋白还包含抗体恒定区序列。
在一些实施方式中,所述恒定区序列选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任何其中之一恒定区的序列。
在一些实施方式中,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。
在一些实施方式中,所述恒定区来源于鼠;
轻链恒定区序列如SEQ ID NO:9所示;
重链恒定区序列如SEQ ID NO:10所示。
根据本发明的一方面,本发明还涉及一种分离的核酸分子,所述核酸分子为DNA或RNA,其编码如上所述的结合蛋白。
根据本发明的一方面,本发明还涉及一种载体,其包含如上所述的核酸分子。
本发明进一步包含至少一种编码如上所述的核酸分子的核构建体,例如质粒,进一步为表达质粒,在本申请的一个实施例中会介绍该载体的构建方法。
根据本发明的一方面,本发明还涉及一种宿主细胞,其被如上所述的载体转化。
所述宿主细胞可以为真核细胞,比如哺乳动物细胞。
在一些实施方式中,所述宿主细胞为CHO细胞。
根据本发明的一方面,本发明还涉及一种生产如上所述的结合蛋白的方法,所述方法包括如下步骤:
在培养基中和合适的培养条件下培养如上所述的宿主细胞,从培养基中或从所培养的宿主细胞中回收如此产生的结合蛋白。
根据本发明的一方面,本发明还涉及如上所述的结合蛋白在制备HIV检测剂中的应用。
在一些实施方式中,所述癌症包括急性淋巴母细胞性白血病、急性骨髓源性白血病、胆管癌、乳腺癌、子宫颈癌、慢性淋巴细胞性白血病、慢性骨髓源性白血病、结肠直肠癌、子宫内膜癌、食道癌、胃癌、头颈部癌、霍奇金氏淋巴瘤、肺癌、甲状腺髓样癌、非霍奇金氏淋巴瘤、多发性骨髓瘤、肾癌、卵巢癌、胰腺癌、神经胶质瘤、黑素瘤、肝癌、前列腺癌和尿路膀胱癌。
根据本发明的一方面,本发明还涉及一种检测测试样品中HIV-1 P24的方法,其包括:
a)在足以发生抗体/抗原结合反应的条件下,使所述测试样品中的HIV-1 P24抗原与如上所述的结合蛋白接触以形成免疫复合物;和
b)检测所述免疫复合物的存在,所述复合物的存在指示所述测试样品中所述HIV-1 P24的存在。
在此实施方式中,所述结合蛋白可以标记由显示信号强度的指示剂,以使得所述复合物容易被检测。
在一些实施方式中,在步骤a)中,所述免疫复合物中还包括第二抗体,所述第二抗体与所述结合蛋白结合。
在一些实施方式中,在步骤a)中,所述免疫复合物中还包括第二抗体,所述第二抗体与所述HIV-1 P24结合;
在此实施方式中,所述结合蛋白以第一抗体的形式与所述第二抗体形成配对抗体,用于结合HIV-1 P24的不同抗原表位;
所述的第二抗体可以标记由显示信号强度的指示剂,以使得所述复合物容易被检测。
在一些实施方式中,在步骤a)中,所述免疫复合物中还包括第二抗体,所述第二抗体与所述HIV-1 P24抗原结合;
在此实施方式中,所述结合蛋白作为所述第二抗体的抗原,所述的第二抗体可以标记由显示信号强度的指示剂,以使得所述复合物容易被检测。
在一些实施方式中,所述显示信号强度的指示剂包括荧光物质、量子点、地高辛标记探针、生物素、放射性同位素、放射性造影剂、顺磁离子荧光微球、电子致密物质、化学发光标记物、超声造影剂、光敏剂、胶体金或酶中的任一种。
在一些实施方式中,所述荧光物质包括Alexa 350、Alexa 405、Alexa 430、Alexa488、Alexa 555、Alexa 647、AMCA、氨基吖啶、BODIPY 630/650、BODIPY 650/665、BODIPY-FL、BODIPY-R6G、BODIPY-TMR、BODIPY-TRX、5-羧基-4′,5′-二氯-2′,7′-二甲氧基荧光素、5-羧基-2′,4′,5′,7′-四氯荧光素、5-羧基荧光素、5-羧基罗丹明、6-羧基罗丹明、6-羧基四甲基罗丹明、Cascade Blue、Cy2、Cy3、Cy5、Cy7、6-FAM、丹磺酰氯、荧光素、HEX、6-JOE、NBD(7-硝基苯并-2-氧杂-1,3-二唑)、Oregon Green 488、Oregon Green 500、Oregon Green514、Pacific Blue、邻苯二甲酸、对苯二甲酸、间苯二甲酸、甲酚固紫、甲酚蓝紫、亮甲酚蓝、对氨基苯甲酸、赤藓红、酞菁、偶氮甲碱、花青、黄嘌呤、琥珀酰荧光素、稀土金属穴状化合物、三双吡啶基二胺铕、铕穴状化合物或螯合物、二胺、双花青苷、La Jolla蓝染料、别藻蓝蛋白、allococyanin B、藻蓝蛋白C、藻蓝蛋白R、硫胺、藻红青蛋白、藻红蛋白R、REG、罗丹明绿、罗丹明异硫氰酸酯、罗丹明红、ROX、TAMRA、TET、TRIT(四甲基罗丹明异硫醇)、四甲基罗丹明和德克萨斯红中的任一种。
在一些实施方式中,所述放射性同位素包括110In、111In、177Lu、18F、52Fe、62Cu、64Cu、67Cu、67Ga、68Ga、86Y、90Y、89Zr、94mTc、94Tc、99mTc、120I、123I、124I、125I、131I、154-158Gd、32P、11C、13N、15O、186Re、188Re、51Mn、52mMn、55Co、72As、75Br、76Br、82mRb和83Sr中的任一种。
在一些实施方式中,所述酶包括辣根过氧化酶、碱性磷酸酶和葡萄糖氧化酶中的任一种。
在一些实施方式中,所述荧光微球为:聚苯乙烯荧光微球,内部包裹有稀土荧光离子铕。
根据本发明的一方面,本发明还涉及一种试剂盒,其包括如上所述的结合蛋白。
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限制本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1
本实施例提供了一种抗HIV-1 P24的重组抗体的示例性制备方法。
S1.构建表达质粒:
本实施例中限制性内切酶、Prime Star DNA聚合酶购自Takara公司;
MagExtractor-RNA提取试剂盒购自TOYOBO公司;BD SMARTTM RACE cDNAAmplification 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。
S11,引物的设计与合成:
扩增重链和轻链的5’RACE上游引物:
SMARTER II A Oligonucleotide:
5’>AAGCAGTGGTATCAACGCAGAGTACXXXXX<3’;
5'-RACE CDS Primer(5'-CDS):5’>(T)25VN<3’(N=A,C,G,orT;V=A,G,orC);
Universal Primer A Mix(UPM):
5’>CTAATACGACTCACTATAGGGCAAGCAGTGGTATCAACGCAGAGT<3’;
Nested Universal Primer A(NUP):
5’>AAGCAGTGGTATCAACGCAGAGT<3’;
mIg-kR:5’>ACACTCATTCCTGTTGAAGCTCTTGACAA<3’;
mIg-HR:5’>TTTACCCGGAGACCGGGAGATGGTCTTC<3’。
S12,抗体可变区基因克隆及测序:
从分泌Anti-HIV-1 P24单克隆抗体的杂交瘤细胞株中提取中RNA,用SMARTERTMRACE cDNA Amplification Kit试剂盒及试剂盒中的SMARTER II AOligonucleotide和5'-CDS引物进行第一链cDNA合成,获得的第一链cDNA产物作为PCR扩增模板。Light Chain基因以Universal Primer A Mix(UPM)、Nested Universal Primer A(NUP)和mIg-kR进行扩增,Heavy Chain基因以Universal Primer A Mix(UPM)、Nested Universal Primer A(NUP)和mIg-HR进行扩增。其中Light Chain的引物对扩增出0.7KB左右的目的条带,Heavy Chain的引物对扩增出1.4KB左右的目的条带。用琼脂糖凝胶电泳纯化回收,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HeavyChain及Light Chain基因克隆各4个克隆送Invitrogen公司进行测序。
S13,Anti-HIV-1 P24 4E2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IMGT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381bp,属于VkII基因家族,其前方有60bp的前导肽序列;HeavyChain引物对扩增出的基因片段中,VH基因序列为426bp,属于VH1基因家族,其前方有57bp的前导肽序列。
S14,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中抗体基因测序结果,设计Anti-HIV-1 P24抗体的轻链和重链基因特异性引物,两端分别带有HindIII、EcoRI酶切位点和保护碱基,引物如下:
HIV-1 P24 4E2-HF:
5’>CCCAAGCTTGCCACCATGGGATGGAGCTGGATCTTTCTCTTCCTC<3’;
HIV-1 P24 4E2-HR:
5’>CCCGAATTCTCATTATTTACCCGGAGACCGGGAGATGGTCTTCTTC<3’;
HIV-1 P24 4E2-LF:
5’>CCCAAGCTTGCCACCATGAGTGTGCCCACTCAGGTCCTG<3’;
HIV-1 P24 4E2-LR:
5’>CCCGAATTCTCATTAACACTCATTCCTGTTGAAGCTCTTGACAATG<3’;
通过PCR扩增方法扩出0.7KB的Light Chain基因片段和1.4KB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。
S2.稳定细胞株筛选
S21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400ng/ml,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。
包被液稀释PET28A-P24(170706)到1ug/ml,每孔100μl,4℃过夜;次日,洗涤液清洗2次,拍干;加入封闭液(20%BSA+80%PBS),每孔120μl,37℃,1h,拍干;加入稀释后的细胞上清,100μl/孔,37℃,30min(部分上清1h);洗涤液清洗5次,拍干;加入羊抗鼠IgG-HRP,每孔100μl,37℃,30min;洗涤液清洗5次,拍干;加入显色液A液(50μl/孔),加入显色液B液(50μl/孔),10min;加入终止液,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P24蛋白有活性。
S22重组抗体表达质粒线性化
准备下述试剂:Buffer 50μl、DNA100ug/管、PuvⅠ酶10μl、无菌水补至500μl,37℃水浴酶切过夜;先用等体积酚/氯仿/异戊醇(下层)25:24:1,再用氯仿(水相)依次进行抽提;0.1倍体积(水相)3M醋酸钠和2倍体积乙醇冰上沉淀,70%乙醇漂洗沉淀,去除有机溶剂,待乙醇挥发完全用适量的灭菌水进行复融,最后进行浓度的测定。
S23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400ng/ml,调节CHO细胞1.43×107cells/ml于离心管中,100μl质粒与700μl细胞混合,转入电转杯,电转,次日计数;25umol/L MSX 96孔加压培养约25天。
显微镜下观察标记长有细胞的克隆孔,并记录汇合度;取培养上清,送样检测;挑选抗体浓度、相对浓度高的细胞株转24孔,3天左右转6孔;3天后保种批培,调整细胞密度0.5×106cells/ml,2.2ml进行批培养,细胞密度0.3×106cells/ml,2ml进行保种;7天6孔批培上清送样检测,挑选抗体浓度及细胞直径较小的细胞株转TPP保种传代。
S3.重组抗体生产
S31细胞扩培
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。
S32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,1条Mr为50KD(重链),另一条Mr为28KD(轻链)。
实施例2
抗体亲和力分析及活性鉴定
实施例1中得到的抗体(WT)经分析具有序列如SEQ ID NO:11所示的轻链以及12所示的重链。
经分析,重链的互补决定区:
CDR-VH1为D-S(X1)-S-F-T-P(X2)-Y-T-I(X3)-H;
CDR-VH2为I-N-P-Y-N-Q(X1)-T-S-S(X2)-N-Q-K-F-Q(X3)-G;
CDR-VH3为A-R-R(X1)-G-Y-D-R-E-G-Q(X2)-Y-Y-P(X3)-M-D-Y-F(X4)-G;
轻链的互补决定区:
CDR-VL1为N(X1)-A-S-E-Q(X2)-I-Y-T-F-I(X3)-A;
CDR-VL2为T-S(X1)-K-T-I(X2)-A-E;
CDR-VL3为Q-H-H-Y-G-L(X1)-P-I(X2)-T-W(X3)-G;
其中,X1、X2、X3、X4均为待突变位点。
经分析,上述CDR中与抗体活性有关的突变位点如下表:
表1与抗体活性有关的突变位点
发明人将WT中的CDR位点进行上述表1所示突变,以获得活性更好的抗体。
包被液(CB)稀释PET28A-P24(170706)到0.3ug/ml进行微孔板包被,每孔100μl,4℃过夜;次日,洗涤液(PBST)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P24单克隆抗体,100μl/孔,37℃,30min(部分上清1h);洗涤液清洗5次,拍干;加入羊抗鼠IgG-HRP,每孔100μl,37℃,30min;洗涤液清洗5次,拍干;加入显色液A液(50μl/孔,含2.1g/L柠檬酸、12.25g/L柠檬酸、0.07g/L乙酰苯胺和0.5g/L过氧化脲),加入显色液B液(50μl/孔,含1.05g/L柠檬酸、0.186g/LEDTA·2Na、0.45g/L TMB和0.2ml/L浓HCl),10min;加入终止液(50μl/孔,含0.75g/LEDTA·2Na和10.2ml/L浓H2SO4);酶标仪上450nm(参考630nm)处读OD值。
表2抗体活性分析数据
样品浓度ng/ml | WT | 突变1 | 突变2 | 突变3 | 突变4 |
111.11 | 1.820 | 2.246 | 2.132 | 2.179 | 2.087 |
37.04 | 1.438 | 1.737 | 1.695 | 1.718 | 1.616 |
12.35 | 0.638 | 0.867 | 0.735 | 0.806 | 0.701 |
4.12 | 0.228 | 0.371 | 0.351 | 0.331 | 0.298 |
1.37 | 0.127 | 0.146 | 0.132 | 0.147 | 0.118 |
0 | 0.098 | 0.077 | 0.068 | 0.098 | 0.046 |
从上表可知,突变1的活性效果最佳,因而以突变1作为骨架序列筛选效价较好的突变位点(保证筛选得到的抗体活性与突变1相近,抗体活性±10%),部分结果如下。
表3与抗体亲和力有关的突变位点
亲和力分析
以活性鉴定相同方式酶免间接法做数据,包被做四个梯度0.3ug/ml、0.15ug/ml、0.075ug/ml、0.03125ug/ml;抗体从1000ng/ml开始2倍梯度稀释至0.977ng/ml上样。得出不用包被浓度下不同抗体浓度对应的OD值。在同一包被浓度下,以抗体浓度为横坐标,OD值为纵坐标,对数作图,根据拟合方程计算出50%最大OD值时的抗体浓度;带入公式:K=(n-1)/(2×(n×Ab`-Ab))计算出亲和力常数的倒数,其中Ab和Ab`分别表示对应包被浓度(Ag、Ag`)下50%最大OD值时的抗体浓度,n=Ag/Ag`;每两个包被浓度可以组合计算出一个K值,最后可得六个K值,取其平均数值,再求其倒数则为亲和力常数KD。
表4亲和力分析数据
从表4可以看出,表3中列出的突变位点都有较好的亲和力。
为验证上述结果,以WT作为骨架序列重复上述实验,进行突变位点的亲和力验证,部分结果如下。
表5以WT为骨架进行的突变
表6亲和力分析数据
K<sub>D</sub>(M) | K<sub>D</sub>(M) | ||
WT | 1.35E-09 | WT 1-5 | 7.10E-10 |
WT 1-1 | 4.55E-10 | WT 1-6 | 9.00E-10 |
WT 1-2 | 6.78E-10 | WT 1-7 | 6.49E-10 |
WT 1-3 | 5.70E-10 | WT 1-8 | 1.74E-09 |
WT 1-4 | 6.14E-10 | WT 1-9 | 4.16E-10 |
从表5和表6分析,在保证具有抗体活性的前提下,上述突变位点也都有不错的亲和力。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,但本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
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Claims (20)
1.一种包含抗原结合结构域的分离的结合蛋白,其特征在于,其中所述抗原结合结构域包括选自下述氨基酸序列的6个互补决定区,所述抗原为HIV-1 P24;
互补决定区CDR-VH1为D-X1-S-F-T-X2-Y-T-X3-H,其中,X2是A;
互补决定区CDR-VH2为I-N-P-Y-N-X1-T-S-X2-N-Q-K-F-X3-G,其中,X3是N;
互补决定区CDR-VH3为A-R-X1-G-Y-D-R-E-G-X2-Y-Y-X3-M-D-Y-X4-G,其中,X4是W;
互补决定区CDR-VL1为X1-A-S-E-X2-I-Y-T-F-X3-A,其中,X3是L;
互补决定区CDR-VL2为T-X1-K-T-X2-A-E,其中,X1是T;
互补决定区CDR-VL3为Q-H-H-Y-G-X1-P-X2-T-X3-G,其中,X3是F;
各互补决定区的突变位点选自下述突变组合中的任一种:
。
2.一种包含抗原结合结构域的分离的结合蛋白,其特征在于,其中所述抗原结合结构域包括选自下述氨基酸序列的6个互补决定区,所述抗原为HIV-1 P24;
互补决定区CDR-VH1为D-X1-S-F-T-X2-Y-T-X3-H,其中,X2是P;
互补决定区CDR-VH2为I-N-P-Y-N-X1-T-S-X2-N-Q-K-F-X3-G,其中,X3是Q;
互补决定区CDR-VH3为A-R-X1-G-Y-D-R-E-G-X2-Y-Y-X3-M-D-Y-X4-G,其中,X4是F;
互补决定区CDR-VL1为X1-A-S-E-X2-I-Y-T-F-X3-A,其中,X3是I;
互补决定区CDR-VL2为T-X1-K-T-X2-A-E,其中,X1是S;
互补决定区CDR-VL3为Q-H-H-Y-G-X1-P-X2-T-X3-G,其中,X3是W;
各互补决定区的突变位点选自下述突变组合中的任一种:
。
3.如权利要求1-2任一项所述的结合蛋白,其特征在于,所述结合蛋白为F(ab’)2、Fab’、Fab、Fv、scFv和双特异抗体中的任意一种。
4.根据权利要求1-2任一项所述的结合蛋白,其特征在于,所述结合蛋白包括序列依次如SEQ ID NO:1-4所示的轻链骨架区FR-L1、FR-L2、FR-L3及FR-L4,和/或,序列依次如SEQID NO:5-8所示的重链骨架区FR-H1、FR-H2、FR-H3及FR-H4。
5.根据权利要求4所述的结合蛋白,其特征在于,其特征在于,所述结合蛋白还包含抗体恒定区序列。
6.根据权利要求5所述的结合蛋白,其特征在于,所述恒定区序列选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任何其中之一恒定区的序列。
7.根据权利要求5所述的结合蛋白,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。
8.根据权利要求7所述的结合蛋白,其特征在于,所述牛选自乳牛;或,所述鸡选自火鸡或斗鸡。
9.根据权利要求7所述的结合蛋白,其特征在于,所述恒定区来源于小鼠。
10.根据权利要求9所述的结合蛋白,其特征在于,轻链恒定区序列如SEQ ID NO:9所示;
重链恒定区序列如SEQ ID NO:10所示。
11.一种分离的核酸分子,其特征在于,所述核酸分子为DNA或RNA,其编码权利要求1~10任一项所述的结合蛋白。
12.一种载体,其包含权利要求11所述的核酸分子。
13.一种宿主细胞,其被权利要求12所述的载体转化。
14.一种生产权利要求1~10任一项所述的结合蛋白的方法,其特征在于,包括如下步骤:
在培养基中和合适的培养条件下培养权利要求13所述的宿主细胞,从培养基中或从所培养的宿主细胞中回收如此产生的结合蛋白。
15.权利要求1~10任一项所述的结合蛋白在制备用于HIV-1 P24抗原检测试剂中的应用。
16.如权利要求1-10任一项所述的结合蛋白在制备检测测试样品中的HIV-1 P24的试剂盒中的应用。
17.根据权利要求16所述的应用,其特征在于,所述试剂盒用于:
a)在足以发生抗体/抗原结合反应的条件下,使测试样品中的HIV-1 P24抗原与权利要求1-10任一项所述的结合蛋白接触以形成免疫复合物;和
b)检测所述免疫复合物的存在,所述复合物的存在指示所述测试样品中所述HIV-1P24的存在。
18.根据权利要求17所述的应用,其特征在于,在步骤a)中,所述免疫复合物中还包括第二抗体,所述第二抗体与所述结合蛋白结合。
19.根据权利要求17所述的应用,其特征在于,在步骤a)中,所述免疫复合物中还包括第二抗体,所述第二抗体与所述HIV-1 P24结合。
20.一种试剂盒,其包括权利要求1~10任一项所述的结合蛋白。
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