CN114716547B - 一种包括抗原结合结构域的结合蛋白及其生产方法和应用 - Google Patents
一种包括抗原结合结构域的结合蛋白及其生产方法和应用 Download PDFInfo
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Abstract
本发明公开了一种包括抗原结合结构域的结合蛋白及其生产方法和应用,涉及抗体领域,该结合蛋白包括以下互补决定区:CDR‑VH1为G‑X1‑S‑I‑T‑S‑X2‑Y‑V;CDR‑VH2为I‑X1‑Y‑S‑X2‑S‑T;CDR‑VH3为A‑X1‑G‑R‑D‑D‑G‑V‑T‑W‑X2‑A‑Y;CDR‑VL1为Q‑S‑X1‑S‑T‑S‑S‑Y‑S‑Y;CDR‑VL2为Y‑X1‑S;CDR‑VL3为Q‑H‑S‑X1‑E‑I‑P‑X2‑T。具有上述互补决定区的结合蛋白具备较好的亲和力,能够有效识别并结合与β2‑糖蛋白I,为与β2‑糖蛋白I的检测和研发提供了新的途径。
Description
技术领域
本发明涉及抗体领域,具体而言,涉及一种包括抗原结合结构域的结合蛋白及其生产方法和应用。
背景技术
β2GPⅠ是分子量约45~50kD的糖蛋白,在血浆中浓度为200μg/ml左右,即3μmol/L,其结构由5个补体调控蛋白样结构区(I~V)组成,肝脏是主要合成部位。抗磷脂综合征(Antiphospholipid syndrome,APS)为一种非器官特异性自身免疫性疾病,主要临床表现为复发性动、静脉血栓及习惯性流产。APS患者血清中高滴度的抗磷脂抗体(Antiphospho-lipid antibody,APL)与其血栓形成密切相关。β2-糖蛋白Ⅰ(beta-2-glycoprotein I,β2GPⅠ)是APL的关键靶抗原,其与相应抗体(anti-β2GPⅠ)形成复合物,在APS病理过程中发挥重要作用。
自身免疫疾病引起的妊娠不良事件的发病率较高且对妊娠者造成了极大的危险。其中抗磷脂抗体在自身免疫性疾病中扮演着重要的角色。抗磷脂抗体是指一类针对与负电荷磷脂或蛋白质-磷脂复合物具有亲和力的蛋白质的自身抗体。抗磷脂抗体主要包括抗心磷脂抗体(ACA)、抗β2-糖蛋白I抗体(aβ2-GPIs)和狼疮抗凝物(LA)。相关研究表明,反复流产的妊娠者中约有2%~10%的人体内抗磷脂抗体为阳性,并且抗磷脂抗体阳性的妊娠者较正常妊娠发生不良反应高2-3倍。虽然现在的治疗使妊娠发生的不良事件率降低了,但仍是危险母亲和胎儿的主要危险因素之一。因此,临床亟待一种更准确的预测指标,进而预测妊娠不良事件的发生。既往研究表明,抗心磷脂抗体联合抗β2-糖蛋白Ⅰ抗体可以预测妊娠不良事件的发生。
但是,从人血液中分离天然抗β2-糖蛋白I抗体的量太少而且难度大,这为开发检测抗磷脂综合症的试剂盒带来困难。因此,开发出高亲和力的针对β2-糖蛋白I的重组单抗有着重要意义和价值。
鉴于此,特提出本发明。
发明内容
本发明的目的在于提供一种包括抗原结合结构域的结合蛋白及其生产方法和应用。
本发明是这样实现的:
第一方面,本发明实施例提供了一种包括抗原结合结构域的结合蛋白,所述抗原为β2-糖蛋白I,所述抗原结合结构域包括以下互补决定区:
CDR-VH1为G-X1-S-I-T-S-X2-Y-V,其中,X1是Y,X2是D或E;
CDR-VH2为I-X1-Y-S-X2-S-T,其中,X1是S,X2是G或A;
CDR-VH3为A-X1-G-R-D-D-G-V-T-W-X2-A-Y,其中,X1是R,X2是F或W;
CDR-VL1为Q-S-X1-S-T-S-S-Y-S-Y,其中,X1是V;
CDR-VL2为Y-X1-S,其中,X1是A;
CDR-VL3为Q-H-S-X1-E-I-P-X2-T,其中,X1是W,X2是Y或S。
第二方面,本发明实施例提供了一种分离的核酸分子,其编码如前述实施例所述的结合蛋白。
第三方面,本发明实施例提供了一种载体,其包括如前述实施例所述的核酸分子。
第四方面,本发明实施例提供了一种宿主细胞,其包括如前述实施例所述的载体。
第五方面,本发明实施例提供了如前述实施例所述的结合蛋白的生产方法,其包括培养如前述实施例所述的宿主细胞。
第六方面,本发明实施例提供了如前述实施例所述的结合蛋白在制备用于检测β2-糖蛋白I的试剂盒中的应用。
第七方面,本发明实施例提供了一种用于检测β2-糖蛋白I的试剂盒,其包括如前述实施例所述的结合蛋白。
第八方面,本发明实施例提供了一种质控品,其包括如前述实施例所述的结合蛋白。
本发明具有以下有益效果:
本发明提供了一种用于结合β2-糖蛋白I的结合蛋白,其包括互补决定区:CDR-VH1为G-X1-S-I-T-S-X2-Y-V,其中,X1是Y,X2是D或E;CDR-VH2为I-X1-Y-S-X2-S-T,其中,X1是S,X2是G或A;CDR-VH3为A-X1-G-R-D-D-G-V-T-W-X2-A-Y,其中,X1是R,X2是F或W;CDR-VL1为Q-S-X1-S-T-S-S-Y-S-Y,其中,X1是V;CDR-VL2为Y-X1-S,其中,X1是A;CDR-VL3为Q-H-S-X1-E-I-P-X2-T,其中,X1是W,X2是Y或S。具有上述互补决定区的结合蛋白具备较好的亲和力,能够有效识别并结合与β2-糖蛋白I,为与β2-糖蛋白I的检测和研发提供了新的途径。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对范围的限定,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相关的附图。
图1为回收的鼠源抗体重链可变区基因片段和鼠源抗体轻链可变区基因片段的电泳图;
图2为人源化嵌合抗体的重链和轻链的电泳图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。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,均为可以通过市售购买获得的常规产品。
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或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。轻链可变区(VL)或重链可变区(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”、“骨架”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
本发明实施例提供了一种包括抗原结合结构域的结合蛋白,所述抗原为β2-糖蛋白I,所述抗原结合结构域包括以下互补决定区:
CDR-VH1为G-X1-S-I-T-S-X2-Y-V,其中,X1是Y,X2是D或E;
CDR-VH2为I-X1-Y-S-X2-S-T,其中,X1是S,X2是G或A;
CDR-VH3为A-X1-G-R-D-D-G-V-T-W-X2-A-Y,其中,X1是R,X2是F或W;
CDR-VL1为Q-S-X1-S-T-S-S-Y-S-Y,其中,X1是V;
CDR-VL2为Y-X1-S,其中,X1是A;
CDR-VL3为Q-H-S-X1-E-I-P-X2-T,其中,X1是W,X2是Y或S。
本发明所提供的结合蛋白活性强,且与现有的抗β2-糖蛋白I抗体相比,与β2-糖蛋白I具有更高的亲和力,能够实现对β2-糖蛋白I的高效检测,从而为β2-糖蛋白I相关疾病的检测和诊断提供依据。
在一些实施例中,所述抗原结合结构域与β2-糖蛋白I具有KD≤9.3×10-8mol/L的亲和力,例如KD值可以≤(9.3×10-8mol/L、7.4×10-8mol/L、7.3×10-8mol/L、7.2×10-8mol/L、6.4×10-8mol/L、5.3×10-8mol/L、4.3×10-8mol/L、3.5×10-8mol/L、3.4×10-8mol/L、3.1×10-8mol/L、2.6×10-8mol/L、2.3×10-8mol/L、1.7×10-8mol/L、3.1×10-9mol/L、1.3×10- 9mol/L)中任意一种。
可选地,所述互补决定区CDR-VH1中,X2是D;
可选地,所述互补决定区CDR-VH1中,X2是E;
可选地,所述互补决定区CDR-VH2中,X2是A;
可选地,所述互补决定区CDR-VH2中,X2是G;
可选地,所述互补决定区CDR-VH3中,X2是F;
可选地,所述互补决定区CDR-VH3中,X2是W;
可选地,所述互补决定区CDR-VL3中,X2是Y;
可选地,所述互补决定区CDR-VL3中,X2是S。
可选地,所述结合蛋白的互补决定区选自如下突变组合中的任意一种:
在一些实施例中,所述结合蛋白还包括轻链骨架区FR-L1、FRL2、FR-L3及FR-L4和重链骨架区FR-H1、FR-H2、FRH3及FR-H4。
在一些实施例中,所述重链骨架区、CDR-VH1、CDR-VH2和CDR-VH3共同组成结合蛋白的重链可变区,所述重链可变区的序列如SEQ ID No.1、3、5和7中任意一项所示。
所述轻链骨架区、CDR-VL1、CDR-VL2和CDR-VL3共同组成结合蛋白的轻链可变区,所述轻链可变区的序列如SEQ ID No.2、4、6和8中任意一项所示,序列信息如下表所示。
在一些实施例中,所述重链可变区的序列如SEQ ID No.1所示,所述轻链可变区的序列如SEQ ID No.2所示。
在一些实施例中,所述重链可变区的序列如SEQ ID No.3所示,所述轻链可变区的序列如SEQ ID No.4所示。
在一些实施例中,所述重链可变区的序列如SEQ ID No.5所示,所述轻链可变区的序列如SEQ ID No.6所示。
在一些实施例中,所述重链可变区的序列如SEQ ID No.7所示,所述轻链可变区的序列如SEQ ID No.8所示。
所述结合蛋白可以为完整的抗体或抗体的功能片段。
在一些实施例中,所述结合蛋白为抗体的功能片段,例如F(ab’)2、Fab’、Fab、Fv、scFv和双特异抗体中的任意一种。scFv(sc=单链),双特异抗体(diabodies)。
本文所述的“功能片段”是指对β2-糖蛋白I具有与来源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。
抗体片段还可以通过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。
在一些实施例中,所述结合蛋白还包括抗体恒定区。
在一些实施例中,所述抗体恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE和IgD中任意一种的恒定区。具体地,所述抗体恒定区包括重链恒定区和轻链恒定区,重链恒定区可以选自μ链、δ链、γ链、α链或ε链恒定区,轻链恒定区可以选自κ轻链恒定区或λ轻链恒定区。
在一些实施例中,所述抗体的种属来源选自牛、马、猪、羊、鼠、狗、猫、兔、驴、鹿、貂、鸡、鸭、鹅和人中的任意一种。
在一些实施例中,所述牛包括乳牛。
在一些实施例中,所述鸡包括火鸡或斗鸡。
在一些实施例中,所述羊包括绵羊或山羊。
在一些实施例中,所述鼠包括大鼠或小鼠。
在一些实施例中,所述重链恒定区的序列如SEQ ID No.9所示,所述轻链恒定区的核苷酸序列如SEQ ID No.10所示,序列信息如下表所示。
本发明实施例提供了一种分离的核酸分子,其编码如前述任意实施例所述的结合蛋白。
本发明提供了一种载体,其包括如前述实施例所述的核酸分子。
在一些实施例中,所述载体可以是表达载体,也可以是克隆载体。
本发明提供了一种宿主细胞,其包括如前述实施例所述的载体。所述宿主细胞可以为真核细胞,比如哺乳动物细胞。
在一些实施例中,所述宿主细胞为293细胞。
本发明实施例提供了如前述任意实施例所述的结合蛋白的生产方法,其包括培养如前述任意实施例所述的宿主细胞。
本发明实施例还提供了如前述任意实施例所述的结合蛋白在制备用于检测β2-糖蛋白I的试剂盒中的应用。
本发明实施例还提供了一种用于检测β2-糖蛋白I的试剂盒,其包括如前述任意实施例所述的结合蛋白。
在一些实施例中,所述试剂盒还包括载体、缓冲液、稀释剂、稳定剂中的至少一种。
此外,本发明实施例提供了一种质控品,其包括如前述实施例所述的结合蛋白。
可以理解的是,所述质控品是包含抗原结合结构域的分离的结合蛋白的质控品。
在一些实施例中,所述质控品中还可以包括抗体的基质液,如血清。抗体在血清中的浓度可以基于实际需求设置。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
一种抗原结合结构域的结合蛋白的制备方法,其包括以下步骤:
(1)杂交瘤细胞的复苏与培养:
应用杂交瘤技术制备分泌鼠源抗β2糖蛋白I抗体的杂交瘤细胞,并使用液氮冷冻保存细胞,37℃水浴复苏杂交瘤细胞后,使用含10%胎牛血清和1%双抗的1640培养基,在37℃、含5%CO2的培养箱中,对其进行扩大培养。
(2)抗体亚型鉴定:
将杂交瘤细胞上清用小鼠单克隆抗体分型试剂(sigma)检测出抗体的亚型为IgG2a,轻链为Kappa。
表1抗体亚类鉴定
IgG1 | IgG2a | IgG2b | IgG3 | IgA | IgM | |
鼠抗体 | 0 | 1.318 | 0.015 | 0.01 | 0.01 | 0 |
阴性对照 | 0 | 0.02 | 0.023 | 0.01 | 0.01 | 0.01 |
阳性对照 | 2.672 | 2.049 | 2.675 | 2.495 | 2.55 | 2.519 |
(3)重链可变区和轻链可变区的扩增:
RNA提取:使用Mini Kit(QIAGEN)提取杂交瘤细胞的总RNA。
反转录:使用SMARTTM RACE cDNA Amplification Kit(Clontech)对提取的总RNA进行反转录,合成cDNA;
PCR扩增:以合成的cDNA为模板,以合成的cDNA为模板,使用设计的引物分别PCR扩增鼠源抗体重链可变区基因片段和鼠源抗体轻链可变区基因片段;
扩增重链和轻链的上游引物如下。
SMARTER II A Oligonucleotide:
5’>AAGCAGTGGTATCAACGCAGAGTACXXXX<3’;
5'-RACE CDS Primer(5'-CDS):5’>(T)25VN<3’(N=A,C,G,or T;V=A,G,or C);
Universal Primer A Mix(UPM):
5’>CTAATACGACTCACTATAGGGCAAGCAGTGGTATCAACGCAGAGT<3’;
Nested Universal Primer A(NUP):
5’>AAGCAGTGGTATCAACGCAGAGT<3’;
扩增重链的下游引物:
3’>GGACTGGCTGGGCCAGGTGCTCGAGGTT<5’;
扩增轻链的下游引物:
3’>CGTCCTTGGTCAACGTGAGGGTGCTGCT<5’。
50μL反应体系:1μL cDNA,1μLPrime F,1μLPrime R,2×PrimeSTAR GC Buffer,dNTP Mixture;反应体系:98℃10sec,60℃5sec,72℃1min,30个循环。反应液经1%琼脂糖凝胶电泳后,使用Gel Extrection Kit(Qiagen)分别回收鼠源抗体重链可变区基因片段和鼠源抗体轻链可变区基因片段,电泳图如图1所示。
(4)鼠源抗体重链可变区基因片段和鼠源抗体轻链可变区基因片段表达载体的构建:
回收的鼠源抗体重链可变区基因片段连接到pUcm-T表达载体上,转化鉴定,连接产物转化DH5α感受态细菌,在含有氨苄的LB平板上过夜培养。挑取单个菌落,接种于含有氨苄的LB培养基中,37℃过夜培养。使用Plasmid Mini Kit(Omega)提取质粒后,进行基因测序。
(5)测序:
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,其中轻链扩增出的基因片段中,VL基因序列为393bp,其前方有60bp的前导肽序列;重链引物对扩增出的基因片段中,VH基因序列为588bp,其前方有54bp的前导肽序列。
(6)嵌合抗体序列的合成:
测序完成后分别合成重链和轻链的可变区序列,并在序列后面接着合成人恒定区的序列,形成FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4(鼠可变区)-CH1-Hinge-CH2-CH3(人恒定区)人鼠嵌合抗体。
(7)嵌合抗体重链和轻链基因片段表达载体的构建:
使用2×Phanta Max Master Mix(诺唯赞)扩增抗体轻链和人源化的重链。在载体pcDNA3.1(+)的多克隆酶切位点处设计与抗体轻链和重链两端同源15bp的引物,扩增载体pcDNA3.1(+),使用Gel Extraction Kit(Omega)试剂盒纯化回收相应的PCR产物,再使用ClonExpress II One Step Cloning Kit(诺唯赞)将片段化的载体和抗体轻重链同源重组,转化TOP10(通用生物)后,涂布含氨苄的LB培养基平板,次日挑取数个单菌落进行菌落PCR鉴定,将鉴定正确的单菌落送测序公司测序正确后进行摇菌培养。
(8)人源化嵌合抗体的表达与纯化:
使用Plasmid Maxi Kit(Omega)试剂盒提取质粒,和PEI混合后转染处于对数生长期的293F悬浮细胞,在37℃震荡培养箱中培养,转速90rpm。7天后,将细胞培养基离心,保留上清,用rProtein A(常州天地人和)纯化IgG,0.1M Glycine(pH2.7)洗脱,再经30KD超滤管(Millipore)置换成PBS缓冲液后测定抗体浓度,聚丙烯酰胺凝胶电泳确定目的条带大小,电泳图如图2所示在还原性SDS-PAGE后显示两条带,1条为55KD(重链),另一条为25KD(轻链)。
实施例2
鉴定实施例1制备获得的抗体(结合蛋白)及其亲和力和活性。
实施例1中得到的抗体,经分析结合蛋白(WT)具有序列如SEQ ID NO.11、12所示的重链以及13、14所示的轻链,序列信息如下表所示。
经分析,重链的互补决定区为:
CDR-VH1为G-X1-S-I-T-S-X2-Y-V;
CDR-VH2为I-X1-Y-S-X2-S-T;
CDR-VH3为A-X1-G-R-D-D-G-V-T-W-X2-A-Y;
轻链的互补决定区为:
CDR-VL1为Q-S-X1-S-T-S-S-Y-S-Y;
CDR-VL2为Y-X1-S;
CDR-VL3为Q-H-S-X1-E-I-P-X2-T;
以上述互补决定区为骨架,以X1和X2为突变位点,进行突变,突变组合如表2所示。
表2突变组合
β糖蛋白1(Ag,外购)与抗β糖蛋白1抗体(Ab,突变)的结合是一个可逆反应: 当反应达到平衡时,解离常数KD=C(Ab)×C(Ag)/C(Ab×Ag)。其中,C(Ab)为反应平衡时游离抗β糖蛋白1抗体浓度;C(Ab)为反应平衡时游离β糖蛋白1抗原浓度;C(Ab×Ag)为反应平衡时抗原抗体复合物浓度。β糖蛋白1抗原初始浓度为a0,抗β糖蛋白1抗体初始浓度为i0,抗体结合律为B=A0-Ai/A0(A为吸光值),因此:KD×(a0-i0×B)=1-B。
竞争ELISA测定抗体亲和力:将0.1μg/ml的β糖蛋白1包被酶标板,每孔100μL,4℃过夜;用5%的脱脂奶粉室温封闭2h,PBST洗涤;将β糖蛋白1浓度从20μg/ml倍比10个梯度,抗β糖蛋白1抗体浓度为50ng/ml,两者混合使体积为100μL,37℃下反应1.5h;将上述反应的混合液加入到上述包被的酶标板中,37℃反应0.5h,PBST洗板;加入酶标二抗,孵育1h,PBST洗涤;加入显色底物显色,显色15min后加入终止液停止反应,进行OD值读数。以1-B为横坐标,a0-i0×B为纵坐标作图,斜率为解离常数KD。
不同突变组合的亲和力检测结果如表3所示。
表3各种突变组合亲和力分析数据
位点 | KD(M) | 位点 | KD(M) |
突变组合1 | 3.1E-9 | 突变组合17 | 7.3E-5 |
突变组合2 | 2.3E-8 | 突变组合18 | 6.5E-4 |
突变组合3 | 9.3E-8 | 突变组合19 | 5.6E-6 |
突变组合4 | 4.3E-8 | 突变组合20 | 7.5E-5 |
突变组合5 | 6.4E-8 | 突变组合21 | 3.5E-6 |
突变组合6 | 7.4E-8 | 突变组合22 | 4.2E-5 |
突变组合7 | 5.3E-8 | 突变组合23 | 6.4E-4 |
突变组合8 | 7.2E-8 | 突变组合24 | 6.2E-6 |
突变组合9 | 3.5E-8 | 突变组合25 | 6.8E-5 |
突变组合10 | 7.3E-8 | 突变组合26 | 7.5E-4 |
突变组合11 | 3.4E-8 | 突变组合27 | 6.5E-5 |
突变组合12 | 1.7E-8 | 突变组合28 | 7.3E-6 |
突变组合13 | 2.3E-8 | 突变组合29 | 5.6E-5 |
突变组合14 | 2.6E-8 | 突变组合30 | 2.2E-4 |
突变组合15 | 2.3E-8 | 突变组合31 | 1.2E-6 |
突变组合16 | 1.3E-9 | 突变组合31 | 1.4E-5 |
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
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35 40 45
Met Gly Tyr Ile Ser Tyr Ser Ala Ser Thr Trp Asn Trp Ile Arg Gln
50 55 60
Phe Pro Gly Asn Lys Leu Glu Trp Met Gly Tyr Ala Arg Gly Arg Asp
65 70 75 80
Asp Gly Val Thr Trp Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
85 90 95
Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro
100 105 110
Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val
115 120 125
Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser
130 135 140
Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu
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Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser
165 170 175
Gln Ser
<210> 8
<211> 111
<212> PRT
<213> 人工序列
<400> 8
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Ser Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 9
<211> 251
<212> PRT
<213> 人工序列
<400> 9
Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys
1 5 10 15
Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys
20 25 30
Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro
35 40 45
Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr
50 55 60
Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser
65 70 75 80
Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His
85 90 95
Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile
100 105 110
Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn
115 120 125
Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys
130 135 140
Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu
145 150 155 160
Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe
165 170 175
Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu
180 185 190
Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr
195 200 205
Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg
210 215 220
Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His
225 230 235 240
Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
245 250
<210> 10
<211> 107
<212> PRT
<213> 人工序列
<400> 10
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> 11
<211> 469
<212> PRT
<213> 人工序列
<400> 11
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly
1 5 10 15
Val Gln Cys Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile
35 40 45
Thr Ser Asp Tyr Val Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys
50 55 60
Leu Glu Trp Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn
65 70 75 80
Pro Ser Leu Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn
85 90 95
Gln Phe Phe Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr
100 105 110
Tyr Tyr Cys Ala Arg Gly Arg Asp Asp Gly Val Thr Trp Phe Ala Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 12
<211> 469
<212> PRT
<213> 人工序列
<400> 12
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly
1 5 10 15
Val Gln Cys Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile
35 40 45
Thr Ser Glu Tyr Val Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys
50 55 60
Leu Glu Trp Met Gly Tyr Ile Ser Tyr Ser Ala Ser Thr Tyr Tyr Asn
65 70 75 80
Pro Ser Leu Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn
85 90 95
Gln Phe Phe Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr
100 105 110
Tyr Tyr Cys Ala Arg Gly Arg Asp Asp Gly Val Thr Trp Trp Ala Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 13
<211> 238
<212> PRT
<213> 人工序列
<400> 13
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Thr Ser Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Asn Ile His Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys
100 105 110
Gln His Ser Trp Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 14
<211> 238
<212> PRT
<213> 人工序列
<400> 14
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser
35 40 45
Leu Ser Thr Ser Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Asn Ile His Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys
100 105 110
Gln His Ser Trp Glu Ile Pro Ser Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
Claims (28)
1.一种包括抗原结合结构域的结合蛋白,其特征在于,所述抗原为β2-糖蛋白I,所述抗原结合结构域包括以下互补决定区:
CDR-VH1为G-X1-S-I-T-S-X2-Y-V,其中,X1是Y,X2是D或E;
CDR-VH2为I-X1-Y-S-X2-S-T,其中,X1是S,X2是G或A;
CDR-VH3为A-X1-G-R-D-D-G-V-T-W-X2-A-Y,其中,X1是R,X2是F或W;
CDR-VL1为Q-S-X1-S-T-S-S-Y-S-Y,其中,X1是V;
CDR-VL2为Y-X1-S,其中,X1是A;
CDR-VL3为Q-H-S-X1-E-I-P-X2-T,其中,X1是W,X2是Y或S。
2.根据权利要求1所述的结合蛋白,其特征在于,所述抗原结合结构域与β2-糖蛋白I具有KD≤9.3×10-8mol/L的亲和力。
3.根据权利要求1所述的结合蛋白,其特征在于,
所述互补决定区CDR-VH1中,X2是D。
4.根据权利要求1所述的结合蛋白,其特征在于,所述互补决定区CDR-VH1中,X2是E。
5.根据权利要求1所述的结合蛋白,其特征在于,所述互补决定区CDR-VH2中,X2是A。
6.根据权利要求1所述的结合蛋白,其特征在于,所述互补决定区CDR-VH2中,X2是G。
7.根据权利要求1所述的结合蛋白,其特征在于,所述互补决定区CDR-VH3中,X2是F。
8.根据权利要求1所述的结合蛋白,其特征在于,所述互补决定区CDR-VH3中,X2是W。
9.根据权利要求1所述的结合蛋白,其特征在于,所述互补决定区CDR-VL3中,X2是Y。
10.根据权利要求1所述的结合蛋白,其特征在于,所述互补决定区CDR-VL3中,X2是S。
11.根据权利要求1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和双特异抗体中的一种。
12.根据权利要求1所述的结合蛋白,其特征在于,所述结合蛋白还包括轻链骨架区FR-L1、FRL2、FR-L3及FR-L4和重链骨架区FR-H1、FR-H2、FRH3及FR-H4。
13.根据权利要求1所述的结合蛋白,其特征在于,重链骨架区、CDR-VH1、CDR-VH2和CDR-VH3共同组成结合蛋白的重链可变区,所述重链可变区的序列如SEQ ID No.1、3、5中任意一项所示;
轻链骨架区、CDR-VL1、CDR-VL2和CDR-VL3共同组成结合蛋白的轻链可变区,所述轻链可变区的序列如SEQ ID No.2和4中任意一项所示。
14.根据权利要求1~13任一项所述的结合蛋白,其特征在于,所述结合蛋白还包括抗体恒定区。
15.根据权利要求14所述的结合蛋白,其特征在于,所述抗体恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE和IgD中任意一种的恒定区。
16.根据权利要求14所述的结合蛋白,其特征在于,所述抗体的种属来源选自牛、马、猪、羊、鼠、狗、猫、兔、驴、鹿、貂、鸡、鸭、鹅和人中的任意一种。
17.根据权利要求16所述的结合蛋白,其特征在于,所述牛包括乳牛。
18.根据权利要求16所述的结合蛋白,其特征在于,所述鸡包括火鸡或斗鸡。
19.根据权利要求16所述的结合蛋白,其特征在于,所述羊包括绵羊或山羊。
20.根据权利要求16所述的结合蛋白,其特征在于,所述鼠包括大鼠或小鼠。
21.根据权利要求14所述的结合蛋白,其特征在于,所述抗体恒定区包括重链恒定区和轻链恒定区,所述重链恒定区的序列如SEQ ID No.9所示,所述轻链恒定区的核苷酸序列如SEQ ID No.10所示。
22.一种分离的核酸分子,其特征在于,其编码如权利要求1~21任一项所述的结合蛋白。
23.一种载体,其特征在于,其包括如权利要求22所述的核酸分子。
24.一种宿主细胞,其特征在于,其包括如权利要求23所述的载体。
25.如权利要求1~21任一项所述的结合蛋白的生产方法,其特征在于,其包括培养如权利要求24所述的宿主细胞。
26.如权利要求1~21任一项所述的结合蛋白在制备用于检测β2-糖蛋白I的试剂盒中的应用。
27.一种用于检测β2-糖蛋白I的试剂盒,其特征在于,其包括如权利要求1~21任一项所述的结合蛋白。
28.一种质控品,其特征在于,其包括如权利要求1~21任一项所述的结合蛋白。
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