CN106220733A - 一种单链抗体及其应用 - Google Patents

一种单链抗体及其应用 Download PDF

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CN106220733A
CN106220733A CN201610680168.0A CN201610680168A CN106220733A CN 106220733 A CN106220733 A CN 106220733A CN 201610680168 A CN201610680168 A CN 201610680168A CN 106220733 A CN106220733 A CN 106220733A
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antibody
seqidno
chain antibody
base sequence
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林志国
殷博
殷一博
黄建萍
葛海涛
慕璐岩
暴洪博
杨昌霖
龙宇
金林春
胡力
王佳斌
夏松松
唐重阳
陶海鹏
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Abstract

本发明公开了一种单链抗体及其应用，所述由IFNγ分泌信号肽、抗体可变区、IgG1铰链片段和IgG1CH2CH3区依次连接而成，其中：IFNγ分泌信号肽的氨基酸序列如SEQIDNo.1所示，碱基序列如SEQIDNo.2所示；IgG1铰链片段的氨基酸序列如SEQIDNo.3所示，碱基序列如SEQIDNo.4所示。上述单链抗体主要用于医疗和生物技术领域，主要用途如下：1、可作为偶联示踪剂用于术中肿瘤成像；2、作为靶向药物用于靶向治疗；3、作为所结合靶点的中和性抗体，实现抑制所结合靶点的功能；4、用于检测可变区所识别抗原的表达。本发明不仅保持了抗体的功能和稳定性，同时，简化了制备程序和抗体结构，提高了抗体的效能。

Description

一种单链抗体及其应用
技术领域
本发明属于基因工程技术领域，涉及一种单链抗体及其应用。
背景技术
当今，抗体的应用越来越广泛，包括检测相关抗原表达、阻断相应抗原、术中成像、生产靶向药物等。工业上抗体的生产主要依靠纯化分泌相应抗体的杂交瘤细胞的上清液，但由于相应抗体的杂交瘤细胞并不容易获取，所以这种方法很难推广。利用基因工程手段，使细胞表达相应抗体的重链和轻链，经细胞自行组装分泌后，纯化上清液的提取方法，相对容易推广，但因涉及重链和轻链两条氨基酸链的表达和组装，效率较低，程序繁琐。另一方面，随着抗体在体内应用的增多，如何在保持其功能和稳定性的前提下，使其作用更加高效，成为目前的研究热点。
发明内容
本发明的目的是提供一种单链抗体及其应用，不仅保持了抗体的功能和稳定性，同时，简化了制备程序和抗体结构，提高了抗体的效能。
本发明的目的是通过以下技术方案实现的：
一种单链抗体，由IFNγ分泌信号肽、抗体可变区、IgG1铰链片段和IgG1CH2CH3区依次连接而成，其中：IFNγ分泌信号肽的氨基酸序列如SEQIDNo.1所示，碱基序列如SEQIDNo.2所示；IgG1铰链片段的氨基酸序列如SEQIDNo.3所示，碱基序列如SEQIDNo.4所示。
上述单链抗体主要用于医疗和生物技术领域，主要用途如下：1、可作为偶联示踪剂用于术中肿瘤成像；2、作为靶向药物用于靶向治疗；3、作为所结合靶点的中和性抗体，实现抑制所结合靶点的功能；4、用于检测可变区所识别抗原的表达。
本发明研发过程的资金来源为：国家国际科技合作专项No.2014DFA31630、黑龙江省应用技术研究与开发No.GA15C108、哈尔滨医科大学研究生创新科研项目No.YJSCX2015-20HYD。
本发明具有如下优点：
1、提高了抗体生产效率，使单链的简化结构发挥双链抗体功能；
2、减小了抗体体积，使其易于在体内扩散和渗透；
3、保留了抗体的ADCC和CDC功能及抗体的亲和性和稳定性；
4、保留了抗体通过结合蛋白A、G、L的纯化方式；
5、本发明以连接EGFR的可变区序列做成的EGFR抗体为例，使用短肽将抗体重链和轻链的可变区直接相连，前端连接IFNγ分泌信号肽，后端通过IgG1铰链片段与IgG1CH2CH3区域相连，该结构首次通过IFNγ分泌信号肽引导抗体的分泌，首次提出这种抗体的连接方式。除EGFR的抗体以外，其他的抗体的可变区序列也都可以连到本发明的抗体结构中。
附图说明
图1为单链抗体的连接形式。
具体实施方式
下面结合附图对本发明的技术方案作进一步的说明，但并不局限于此，凡是对本发明技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，均应涵盖在本发明的保护范围中。
具体实施方式一：如图1所示，本实施方式提供的单链抗体由IFNγ分泌信号肽、抗体可变区、IgG1铰链片段和IgG1CH2CH3区依次连接而成，其中：IFNγ分泌信号肽部分用于引导合成的抗体分泌到细胞结构外，其氨基酸序列如SEQIDNo.1所示，碱基序列如SEQIDNo.2所示；抗原结合区可以使这种单链抗体发挥相应完整抗体的作用；IgG1铰链片段用于保证单链抗体的功能和稳定性，其氨基酸序列如SEQIDNo.3所示，碱基序列如SEQIDNo.4所示；CH2区和CH3区用于稳定抗体结构，同时便于抗体的纯化，CH2区的氨基酸序列如SEQIDNo.5所示，碱基序列如SEQIDNo.6所示；CH3区的氨基酸序列如SEQIDNo.7所示，碱基序列如SEQIDNo.8所示。
具体实施方式二：本实施方式提供了一种单链抗体的应用，其可以作为偶联示踪剂用于术中肿瘤成像，具体方法如下：
1、将洗脱的抗体浓缩到10mg/ml的50mM磷酸钾溶液，pH＝8.5；
2、将IRDye 800CW NHS ester(LI-COR)与单链抗体以分子比例2.3：1，于20℃暗室偶联2小时；
3、洗脱未偶联的染料；
4、调节溶质为pH＝7的PBS，抗体终浓度为2mg/ml；
5、静脉注射，荧光显微镜观察肿瘤显影情况。
具体实施方式三：本实施方式提供了一种单链抗体的应用，其可以用于偶联药物做药物的靶向治疗，也可以作为所结合靶点的中和性抗体，实现抑制所结合靶点的功能。
具体实施方式四：本实施方式提供了一种单链抗体的应用，其可以用于检测可变区所识别抗原的表达，该单链抗体可用于免疫组化，Western blot等蛋白的定性定量方法，做为一抗检测可变区所识别抗原的表达，该单链抗体可偶联荧光分子，生物素或被已标记的靶向人IgG1Fc片段的二抗结合而用于鉴定可变区所识别抗原的表达。
具体实施方式五：本实施方式以连接EGFR的可变区序列做成的EGFR抗体为例，使用短肽将抗体重链和轻链的可变区直接相连，前端连接IFNγ分泌信号肽，后端通过IgG1铰链片段与IgG1CH2CH3区域相连(图1)，氨基酸序列如SEQIDNo.9所示，碱基序列如SEQIDNo.10所示，其制备方法如下：
(1)将SEQIDNo.10所示碱基序列连接到表达载体(可以是慢病毒载体、逆转录病毒载体、睡美人载体或者瞬时表达载体)；
(2)将哺乳动物细胞转染或转化上述载体(可用到的细胞包括骨髓瘤细胞，CHO细胞，猴COS细胞，人胚胎肾HEK293细胞等)；
(3)收集细胞培养液上清；
(4)使用蛋白A、G或L对上清液中的抗体进行亲和纯化；
(5)洗脱单链抗体。
<110>林志国
<120>一种单链抗体及其应用
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GGG CAG CCC CGG GAG CCC CAG GTC TAT ACA CTG CCG CCG TCT CGG GAG GAG ATGACA AAA AAC CAA GTA AGT CTC ACC TGC TTG GTT AAA GGG TTC TAT CCT TCA GAT ATAGCA GTT GAG TGG GAA TCT AAT GGT CAA CCT GAA AAT AAC TAC AAG ACA ACA CCT CCGGTC CTG GAC AGC GAT GGA AGT TTT TTT TTG TAC TCC AAA TTG ACC GTT GAT AAA TCAAGG TGG CAG CAA GGT AAT GTA TTT TCC TGC TCT GTG ATG CAC GAA GCT CTT CAT AATCAT TAT ACC CAA AAG TCC TTG AGT CTG AGC CCC GGG AAA
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Claims (9)

1.一种单链抗体，其特征在于所述单链抗体由IFNγ分泌信号肽、抗体可变区、IgG1铰链片段和IgG1CH2CH3区依次连接而成。
2.根据权利要求1所述的单链抗体，其特征在于所述IFNγ分泌信号肽的氨基酸序列如SEQIDNo.1所示，碱基序列如SEQIDNo.2所示。
3.根据权利要求1所述的单链抗体，其特征在于所述IgG1铰链片段的氨基酸序列如SEQIDNo.3所示，碱基序列如SEQIDNo.4所示。
4.根据权利要求1所述的单链抗体，其特征在于所述CH2区的碱基序列如SEQIDNo.6所示。
5.根据权利要求1所述的单链抗体，其特征在于所述CH3区的碱基序列如SEQIDNo.8所示。
6.权利要求1-5任一权利要求所述的单链抗体可作为偶联示踪剂用于术中肿瘤成像或。
7.权利要求1-5任一权利要求所述的单链抗体可作为靶向药物用于靶向治疗。
8.权利要求1-5任一权利要求所述的单链抗体可以作为所结合靶点的中和性抗体，实现抑制所结合靶点的功能。
9.权利要求1-5任一权利要求所述的单链抗体可以用于检测可变区所识别抗原的表达。
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