CN110526973A - 高亲和力、高特异性、多抗原识别表位的具有更高功能性的抗人ctla4抗体 - Google Patents
高亲和力、高特异性、多抗原识别表位的具有更高功能性的抗人ctla4抗体 Download PDFInfo
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Abstract
本发明公开一种高亲和力、高特异性、多抗原识别表位的具有更高功能性的抗人CTLA4抗体。本发明的CTLA4单克隆抗体能够特异性的与CTLA4结合，并且能够有效的阻断CTLA4与B7蛋白的结合，特异地解除CTLA4的免疫负调节，激活T细胞分泌细胞因子。上述功能均达到或超过目前市场上的唯一CTLA4靶向药物Yervoy的水准,并且有部分抗体不同于Yervoy的抗原表位，具有更大的多样性。
Description
本申请是申请日为2016年12月21日，申请号为2016111933707，发明名称为《高亲和力、高特异性、多抗原识别表位的具有更高功能性的抗人CTLA4抗体》的分案申请。
技术领域
本发明属于肿瘤免疫疗法和分子免疫学领域，具体涉及一种高亲和力、高特异性、多抗原识别表位的具有更高功能性的抗人CTLA4抗体。
背景技术
脊椎动物的免疫系统是一个多层次，由多种器官、组织、细胞和分子组成的功能性系统，用来保护机体免受外来侵染和维护内平衡(Janeway et al.,Immunology:TheImmune System in Health and Disease.New York:Garland Science,2005)。它包括天然免疫系统和获得性免疫系统。其中，获得性免疫系统是由高度专业的T细胞和B细胞，以及多种效应分子组成，能够特异性识别包括细菌、真菌、病毒等在内的病原体并清除它们。获得性免疫系统由体液免疫(B细胞介导)和细胞免疫(T细胞介导)组成。其中，细胞免疫是通过T细胞受体(TCR)识别抗原呈递细胞(APC)上主要组织相容性复合体(MHC)呈递的抗原来引起的。
T细胞激活需要两级信号。第一级信号，也称为主要刺激信号，是通过TCR识别特异性MHC呈递的抗原来实现的。这种信号是抗原特异性的。激活T细胞的第二级刺激信号，也称为共刺激信号，是通过由表达在APC上的B7家族成员B7.1(也称为CD80)和B7.2(也称为CD86)，与表达在T细胞上的CD28结合时传递并导致T细胞激活的。CD28是免疫球蛋白(Ig)超家族的，由两条同源的具有胞外可变区的多肽组成，表达在T细胞表面，通过与B7蛋白结合传递T细胞激活的第二信号。如果没有CD28介导的第二信号，而只有TCR介导的第一信号，T细胞就会变得无能(anergic)。
细胞毒性T淋巴细胞相关抗原4(CTLA4)(又称为CD152)，是T细胞上的一种跨膜抗体，表达在激活的T细胞上，发现于1987年(Brunet et al.,Nature 328:267-270,1987)。CTLA4与CD28同是Ig超家族成员，有单个胞外Ig结构域，而且CTLA4与CD28一样，也结合表达在APC表面的B7蛋白。但CTLA4的作用主要是通过结合B7蛋白，从而抑制T细胞激活达到控制内平衡，对免疫系统进行负调节。并且，由于CTLA4与B7蛋白的结合比CD28与B7蛋白的结合有更高的亲和力，这种机制可以在T细胞激活后，诱导T细胞凋亡，从而维持体内T细胞稳态，发挥免疫负调控功能。
CTLA4单克隆抗体能够特异性阻断CTLA4与B7蛋白的结合，从而减弱或封闭CTLA4对T细胞负调节信号的传导，增强T细胞对各种抗原的免疫反应。体外和体内实验都表明，阻断CTLA4可以增强T细胞免疫应答(Walunas et al.,Immunity 1:405-413,1994,和Kearneyet al.,J.Immunology 155:1032-1036,1995)，也可以增加机体抗肿瘤免疫力(Leach etal.,Science 271:1734-1736,1996)。因此，用单克隆抗体阻断CTLA4传导的负调节信号可以提供受益于免疫刺激的人类疾病的新疗法，比如癌症和传染性疾病的免疫治疗。目前CTLA4单克隆抗体已在临床试验阶段用于治疗多种人类癌症，包括黑色素瘤，前列腺癌，膀胱癌，结肠直肠癌，恶性间皮瘤，胃肠道癌，肝癌，非小细胞肺癌(Grosso et al.,CancerImmunology 13:5,2013)。目前已经成功上市一种CTLA4单克隆抗体，Ipilimumab(商品名Yervoy)标志着肿瘤免疫疗法在临床阶段切实可行。而且，随着临床前实验验证针对不同免疫调节因子的单克隆抗体在协同治疗癌症方面的能力，CTLA4单克隆抗体已与不同免疫抑制分子的单克隆抗体或者小分子化合物形成组合疗法在进行针对不同癌症的临床实验。但目前上市的只有一种CTLA4单克隆抗体，而且CTLA4单克隆抗体也存在不同程度的副反应，包括可在某些患者中诱导免疫原性，过度抑制CTLA4信号可能引起自身免疫病，以及不同CTLA4单克隆抗体具有不同程度的可开发性。因此，尚需开发新的能够阻断CTLA4与B7蛋白结合的功能性抗体，具有更高的亲和力、特异性、功能性以及多样性。
发明内容
本发明的目的是提供一种人CTLA4单克隆抗体及其应用。
本发明的另一目的在于提供上述人CTLA4单克隆抗体的编码基因。
本发明的又一目的在于提供上述人CTLA4单克隆抗体的制备方法。
本发明的又一目的在于提供一种抗肿瘤制剂。
本发明的目的可以通过以下技术方案实现：
一种人CTLA4单克隆抗体，该单克隆抗体的蛋白序列含有重链可变区和轻链可变区，该单克隆抗体选自如下(1)～(5)中的任意一种：
(1)所述的重链可变区具有如SEQ ID NO：1所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：3所示的氨基酸序列；
(2)所述的重链可变区具有如SEQ ID NO：5所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：7所示的氨基酸序列；
(3)所述的重链可变区具有如SEQ ID NO：9所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：11所示的氨基酸序列；
(4)所述的重链可变区具有如SEQ ID NO：13所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：15所示的氨基酸序列；
(5)所述的重链可变区具有如SEQ ID NO：17所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：19所示的氨基酸序列。
上述单克隆抗体的编码基因。
上述的编码基因选自如下(6)～(10)中的任意一种：
(6)含有如SEQ ID NO：2所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ IDNO：4所示的编码所述单克隆抗体轻链可变区的核苷酸序列；
(7)含有如SEQ ID NO：6所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ IDNO：8所示的编码所述单克隆抗体轻链可变区的核苷酸序列；
(8)含有如SEQ ID NO：10所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ IDNO：12所示的编码所述单克隆抗体轻链可变区的核苷酸序列；
(9)含有如SEQ ID NO：14所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ IDNO：16所示的编码所述单克隆抗体轻链可变区的核苷酸序列；
(10)含有如SEQ ID NO：18所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ IDNO：20所示的编码所述单克隆抗体轻链可变区的核苷酸序列；
含有上述编码基因的重组载体、表达盒、转基因细胞系或重组菌。
上述的重组表达载体、表达盒、转基因细胞系或重组菌在制备人CTLA4单克隆抗体中的应用。
一种制备人CTLA4单克隆抗体的方法，将包含上述编码基因的重组表达载体转染感受态细胞，并进行培养得到人CTLA4单克隆抗体。
本发明技术人员通过以下方法获得了克隆26A12E8，24H2C4B4,42B11G12D3,41B6F9C8,42F8A6的独特V-区域核苷酸/蛋白序列：
1)用重组表达的人CTLA4胞外区免疫小鼠，获得针对人CTLA4的免疫反应；
2)取步骤1)中小鼠的脾脏细胞进行融合，并对获得的杂交瘤细胞进行筛选，获得特异性识别人CTLA4，并且能够阻断CTLA4与B7蛋白结合的阳性母克隆；
3)对步骤2)中获得的阳性母克隆进行亚克隆，获得稳定的杂交瘤细胞株；
4)用步骤3)中获得的杂交瘤细胞株进行测序，获得抗体轻链和重链的可变区编码序列。
用步骤4)中获得的可变区编码序列进行重组抗体生产功能性人CTLA4单克隆抗体。
本发明所述的单克隆抗体能够特异性结合人CTLA4，能够阻断CTLA4与B7蛋白结合，并且能够解除CTLA4的免疫负调节，激活T细胞分泌细胞因子。
上述的人CTLA4单克隆抗体在制备抗肿瘤药物中的应用。
一种抗肿瘤制剂，其包含上述的人CTLA4单克隆抗体。
本发明的有益效果
本发明的CTLA4单克隆抗体能够特异性的与CTLA4结合，并且能够有效的阻断CTLA4与B7蛋白的结合，特异地解除CTLA4的免疫负调节，激活T细胞分泌细胞因子。上述功能均达到或超过目前市场上的唯一CTLA4靶向药物Yervoy(Ipilimumab)的水准,并且有部分抗体不同于Yervoy的抗原表位，具有更大的多样性。
附图说明
图1：免疫之后的鼠血清效价检测
图2：纯化单克隆抗体能够特异性结合人CTLA4重组蛋白
图3：纯化单克隆抗体能够特异性结合表达人CTLA4的细胞系
图4：纯化单克隆抗体能够阻断CTLA4与B7蛋白的结合
图5：纯化单克隆抗体能够解除CTLA4的免疫负调节，刺激T细胞分泌白介素2
图6：纯化单克隆抗体的亲和力测定
具体实施方式
本发明涉及一种具有功能性的人CTLA4抗体，下面将结合实施例对本发明的实施方案进行详细描述。除非另有说明，本发明所用的技术和科学术语与本发明所属领域的普通技术员通常所理解的含义相同。除非另有说明，下文描述的实施例的方法和材料均为可以通过市场购买获得的常规产品。本发明所属领域技术员将会理解，下文描述的方法和材料，仅是示例性的，而不应视为限定本发明的范围。
实施例1：人CTLA4杂交瘤细胞株的获得
1)动物免疫
抗原采用融合至人IgG1Fc段的人CTLA4胞外结构域的重组蛋白CTLA4-Fc(GenScript，Z03373)。用含50μg CTLA4-Fc融合蛋白的200μl弗氏完全佐剂(Sigma-Aldrich)的1:1乳液皮下免疫雌性Balb/c和C57bl/6小鼠。随后，每二周腹腔/皮下交替注射含25μg CTLA4-Fc的弗氏不完全佐剂(Sigma-Aldrich)的1:1乳液最多达3次，从而对小鼠进行加强免疫。骨髓瘤融合前4天，表现出最高抗体滴度(图1)的一只小鼠接受了25ug CTLA4-Fc(不含佐剂)的腹腔加强免疫。
2)杂交瘤融合和筛选
提取脾脏并进行均质化以产生单细胞悬液，同时准备骨髓瘤细胞(SP2/0)单细胞悬液。使用电融合将8.9×107个脾细胞与4.1×107个SP2/0小鼠骨髓瘤细胞进行融合。将融合的细胞重悬于100ml含杂交瘤细胞选择剂胸腺核苷嘧啶，次黄嘌呤和氨基喋呤的DMEM/10％FBS培养基中，并用移液管以100μl的体积移至50×96孔板中。将板在37℃下在6％CO2中孵育。7天的孵育之后，开始使用下文所述的ELISA结合，ELISA竞争和FACS结合来测试针对CTLA4-Fc的抗体的存在情况。
ELISA结合检测方法：间接ELISA用于评估上清液中抗体对于CTLA4-Fc的结合能力。将ELISA板(Nunc)用100μl/孔的PBS中0.5μg/ml的重组CTLA4-Fc或人IgG1在4℃下包被过夜。用PBS-T(0.05％吐温)洗涤板，并将其用200μl/孔的含1％BSA的PBST在37℃封闭0.5小时。随后弃去封闭液，向每个板加入100μl杂交瘤细胞培养上清液，然后在室温下孵育1小时。将板用PBST洗涤三次，并用100μl/孔的缀合辣根过氧化物酶的山羊抗小鼠IgG(Fab-特异性)(GenScript)37℃孵育0.5小时。将板用PBST洗涤五次，然后加入TMB显色液(GenScript)并在室温下在黑暗中孵育15分钟。通过加入50μl的1MHCl终止液(Sigma)终止反应。使用酶标仪在450nm下读板。
ELISA竞争检测方法：竞争法ELISA被用于评估上清液种的抗体对于CTLA4和其配体B7蛋白的结合的阻断能力。将ELISA板(Nunc)用100μl/孔的PBS中0.5μg/ml的重组人B7蛋白在4℃下包被过夜。用PBS-T(0.05％吐温)洗涤板，并将其用200μl/孔的含1％BSA的PBST在37℃封闭0.5小时。随后弃去封闭液，每个测试孔加入50μl待测上清液，对照孔加入50μl无关上清液。然后每孔添加50μl生物素标记的CTLA4-Fc(浓度为0.15μg/ml)，在37℃孵育1小时。将板用PBST洗涤三次，并用100μl/孔的抗生物素蛋白链菌素HRP(SA-HRP，GenScript)37℃孵育10分钟。最后将板用PBST洗涤五次，然后加入TMB显色液(GenScript)并在室温下在黑暗中孵育15分钟。通过加入50μl的1MHCl终止液(Sigma)终止反应。使用酶标仪在450nm下读板。
FACS检测方法：FACS结合实验被用于评估上清液中的抗体对于CHO细胞膜表面表达的CTLA4的结合能力。收集用于检测的表达CTLA4的CHO细胞和阴性对照的母细胞，用PBS清洗3次。在96孔板中加入2.5X105个检测细胞和待测上清液100ul，4℃孵育1小时。随后用PBS清洗细胞3次，添加100μliFluor标记的山羊抗小鼠IgG，4℃孵育45分钟。最后用PBS清洗细胞3次，用FACS BD Calibur读取信号。
3)杂交瘤亚克隆
使用有限稀释法进行亚克隆。使用血球细胞计数器并在含杂交瘤细胞选择剂胸腺核苷嘧啶，次黄嘌呤和氨基喋呤的DMEM/10％FBS培养基中对细胞进行系列稀释来确定细胞数量，直至细胞密度达到5-15个细胞/ml。对于每个杂交瘤，将200μl的细胞溶液用移液管移至96孔中，密度为1-3个细胞/孔。将培养物在37℃下在5％CO2中培养1周后，对上清液进行上述ELISA结合，ELISA竞争和FACS结合测试，来评估针对CTLA4-Fc的抗体的存在情况。
实施例2：单克隆抗体的可变区测序及抗体重组生产
使用快速ELISA小鼠抗体亚型鉴定试剂盒(Clonotyping System-HRP，SouthernBiotech)对杂交瘤细胞培养上清中的抗体进行亚型鉴定后，使用TRIzol(Ambion)从3×106-5×106个杂交瘤细胞提取总RNA，并利用抗体亚型特异性引物和通用引物(PrimeScriptTM 1stStrand cDNA Synthesis Kit，Takara)将其逆转录为cDNA。随后通过RACE PCR(GenScript)扩增鼠免疫球蛋白重链和轻链V-区域片段，并将所得的PCR片段亚克隆至pMD18-T载体系统(Takara)中，并使用载体特异性引物对插入片段进行测序。最终获得了克隆26A12E8，24H2C4B4,42B11G12D3,41B6F9C8,42F8A6的独特V-区域核苷酸/蛋白序列。
26A12E8重链可变区氨基酸序列：SEQ ID NO:1
26A12E8重链可变区DNA序列：SEQ ID NO:2
26A12E8轻链可变区氨基酸序列：SEQ ID NO:3
26A12E8轻链可变区DNA序列：SEQ ID NO:4
24H2C4B4重链可变区氨基酸序列：SEQ ID NO:5
24H2C4B4重链可变区DNA序列：SEQ ID NO:6
24H2C4B4轻链可变区氨基酸序列：SEQ ID NO:7
24H2C4B4轻链可变区DNA序列：SEQ ID NO:8
42B11G12D3重链可变区氨基酸序列：SEQ ID NO:9
42B11G12D3重链可变区DNA序列：SEQ ID NO:10
42B11G12D3轻链可变区氨基酸序列：SEQ ID NO:11
42B11G12D3轻链可变区DNA序列：SEQ ID NO:12
41B6F9C8重链可变区氨基酸序列：SEQ ID NO:13
41B6F9C8重链可变区DNA序列：SEQ ID NO:14
41B6F9C8轻链可变区氨基酸序列：SEQ ID NO:15
41B6F9C8轻链可变区DNA序列：SEQ ID NO:16
42F8A6重链可变区氨基酸序列：SEQ ID NO:17
42F8A6重链可变区DNA序列：SEQ ID NO:18
42F8A6轻链可变区氨基酸序列：SEQ ID NO:19
42F8A6轻链可变区DNA序列：SEQ ID NO:20
分别合成包含轻链可变区+恒定区与重链可变区+恒定区的DNA片段，将其分别插入pTT5表达载体中，形成表达质粒。
将上述质粒共转染HEK293-6E细胞，并于37℃摇瓶中培养10天后，收取上清用于抗体纯化。纯化之前，将管道和蛋白A柱用0.2M NaOH去热原。将柱用含有0.05M Tris和1.5MNaCl(pH8.0)的缓冲液重新平衡。随后将收获的细胞培养物上清液，使用2×上述缓冲液1:1稀释并过滤除菌。将过滤的上清液和蛋白A柱室温孵育2小时，用并1×上述缓冲液洗涤柱后，使用无菌0.1M柠檬酸钠(pH3.5)洗脱IgG，收集了洗脱液并用九分之一体积的无菌1MTris-HCl(pH9)中和。在无菌条件下，将所述产品缓冲液交换为PBS(pH7.4)以除去任何的洗脱缓冲液并浓缩所述样品。浓缩之后，使用1.43的消光系数Ec(0.1％)通过OD280nm对抗体进行定量。
纯化的抗体通过BioRad电泳系统用10％预制胶(GenScript)通过SDS-PAGE来分析。将所述凝胶用Estain2.0(GenScript)染色并通过比较染色带与Protein Ladder(GenScript)来估计分子大小和纯度。
实施例3：单克隆抗体对人CTLA4重组蛋白的结合
间接ELISA用于评估纯化抗体对于CTLA4-Fc的结合能力。将ELISA板(Nunc)用100μl/孔的PBS中0.5μg/ml的重组CTLA4-Fc或人IgG1在4℃下包被过夜。用PBS-T(0.05％吐温)洗涤板，并将其用200μl/孔的含1％BSA的PBST在37℃封闭0.5小时。随后弃去封闭液，向首孔加入10μg/ml的纯化抗体100μl，并按照3倍梯度稀释，共计11个测试浓度梯度。然后在室温下孵育1小时。将板用PBST洗涤三次，并用100μl/孔的缀合辣根过氧化物酶的山羊抗小鼠IgG(Fab-特异性)(GenScript)37℃孵育0.5小时。将板用PBST洗涤五次，然后加入TMB显色液(GenScript)并在室温下在黑暗中孵育15分钟。通过加入50μl的1MHCl终止液(Sigma)终止反应。使用酶标仪在450nm下读板。克隆26A12E8，24H2C4B4,42B11G12D3,41B6F9C8,42F8A6对于重组蛋白CTLA4-Fc的结合能力如图2。与Yervoy相比，24H2C4B4，41B6F9C8和42F8A6达到或超过其抗原结合能力。
实施例4：单克隆抗体对表达人CTLA4的细胞系的结合
收集用于检测的表达CTLA4的CHO细胞和阴性对照的母细胞，用PBS清洗3次。在96孔板中加入2.5X105个检测细胞和5μg/ml纯化抗体100ul，4℃孵育1小时。随后用PBS清洗细胞3次，添加100μliFluor标记的山羊抗小鼠IgG，4℃孵育45分钟。最后用PBS清洗细胞3次，用FACS BD Calibur读取信号。克隆26A12E8，24H2C4B4,42B11G12D3,41B6F9C8,42F8A6对于表达CTLA4的CHO细胞系的结合如图3。与Yervoy相比，以上5个克隆都达到或超过其结合细胞膜表达的抗原的结合能力。
实施例5：单克隆抗体阻断CTLA4与B7蛋白的结合
将ELISA板(Nunc)用100μl/孔的PBS中0.5μg/ml的重组人B7蛋白在4℃下包被过夜。用PBS-T(0.05％吐温)洗涤板，并将其用200μl/孔的含1％BSA的PBST在37℃封闭0.5小时。随后弃去封闭液，首个测试孔加入50μg/ml待测纯化抗体50μl，并按照3倍梯度稀释，共计11个测试浓度梯度。然后每孔添加50μl生物素标记的CTLA4-Fc(浓度为0.15μg/ml)，在37℃孵育1小时。将板用PBST洗涤三次，并用100μl/孔的抗生物素蛋白链菌素HRP(SA-HRP，GenScript)37℃孵育10分钟。最后将板用PBST洗涤五次，然后加入TMB显色液(GenScript)并在室温下在黑暗中孵育15分钟。通过加入50μl的1MHCl终止液(Sigma)终止反应。使用酶标仪在450nm下读板。克隆26A12E8，24H2C4B4,42B11G12D3,41B6F9C8,42F8A6对于阻断CTLA4与B7重组蛋白的结合如图4。与Yervoy相比，以上5个克隆对于CTLA4与B7重组蛋白的结合的阻断能力均优于前者。
实施例6：单克隆抗体表位鉴定
竞争ELISA用于评估纯化抗体的抗原表位。将ELISA板(Nunc)用100μl/孔的PBS中0.5μg/ml的重组CTLA4-Fc在4℃下包被过夜。用PBS-T(0.05％吐温)洗涤板，并将其用200μl/孔的含1％BSA的PBST在37℃封闭0.5小时。随后弃去封闭液，每孔分别加入一对(其中一个已标记生物素)用于竞争实验的待测抗体，每个纯化抗体100μl(10μg/ml)。然后在37℃下孵育1小时。将板用PBST洗涤三次，并用100μl/孔的抗生物素蛋白链菌素HRP(SA-HRP，GenScript)37℃孵育10分钟。将板用PBST洗涤五次，然后加入TMB显色液(GenScript)并在室温下在黑暗中孵育15分钟。通过加入50μl的1MHCl终止液(Sigma)终止反应。使用酶标仪在450nm下读板。克隆26A12E8，42B11G12D3,41B6F9C8识别同一表位(表位#1)，克隆24H2C4B4识别表位#2，克隆42F8A6识别表位#3。以上表位均不同于Yervoy的识别表位，其中表位#2与Yervoy表位部分重叠。因此，本发明筛选到的抗体具有更大的多样性。
实施例7：单克隆抗体的功能性检测
从PBMC中分离CD4+T细胞(MiltenylBiotec)，与人源CD80过表达的CHO-K1细胞(在CHO-K上过表达人源CD80的稳定细胞系)共培养，抗人CTLA4的单克隆抗体按浓度梯度加入CD4+T细胞与人源CD80过表达的CHO-K1细胞共培养系统中，人源IgG1作为阴性对照，Ipilimumab(Yervoy，Bristol-Myers Squibb Company)作为实验的阳性对照，无抗体的PBS作为背景对照，在培养体系中加入CTLA4-Fc(GenScript,Z03373-50)蛋白，在37℃/5％CO2的培养箱孵育24小时后，取出100ul的上清，检测IL-2的含量(Cisbio)。克隆26A12E8，24H2C4B4,42B11G12D3,41B6F9C8,42F8A6对于T细胞的激活能力如图5。与Yervoy相比，以上克隆的细胞功能水平均达到或超过前者。
实施例8：单克隆抗体的亲和力测定
以10μl/min流速的HBS-EP缓冲液平衡芯片表面5min，随后以10μl/min的流速注射“NHS+EDC”的1：1混合液7mim来活化芯片，将稀释在10mM醋酸钠缓冲液中的捕获抗体(Goatanti-mouse IgG)以10μl/min流速注射约7min进行耦联，最后以10μl/min的流速注射乙醇胺7min进行表面封闭。
以HBS-EP缓冲液作为样品进行三个预循环来平衡芯片使基线稳定，10μl/min流速注射稀释在HBS-EP缓冲液中的抗体0～5min(通过调整捕获时间来控制抗体和抗原结合信号在～100RU)，缓冲液平衡1min。以30μl/min流速注射低浓度抗原0.33nMPD-L1-Fc 5min，抗原与抗体发生结合，之后30μl/min流速注射缓冲液15min进行解离，100μl/min流速注射50mMHCl共四次，每次10s进行再生，一次循环结束。改变抗原浓度(如1nMPD-L1-Fc)进行下一个梯度浓度的循环测定直到所有梯度浓度(0.33nM、1nM、3nM、9nM、27nMPD-L1-Fc)及重复浓度(如9nMPD-L1-Fc)测定结束。
实验数据经过双扣减(对照通道及零浓度)后，在Biacore T200evaluationsoftware中进行“1:1Binding”模型的拟合。克隆26A12E8，24H2C4B4,42B11G12D3,41B6F9C8,42F8A6的亲和力如图6。与Yervoy(KD(M)＝2.5E-10)相比，以上5个克隆的亲和力均达到或高于前者的水平。
序列表
<110> 南京金斯瑞生物科技有限公司
<120> 高亲和力、高特异性、多抗原识别表位的具有更高功能性的抗人CTLA4抗体
<130> 2019
<160> 20
<170> SIPOSequenceListing 1.0
<210> 1
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Met Asp Trp Ser Trp Val Phe Leu Phe Leu Leu Ser Val Asn Glu Gly
1 5 10 15
Val Tyr Cys Gln Val His Leu Gln Gln Ser Gly Asp Val Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Ile Asn Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Ala Pro Gly Ser Gly Thr Thr Tyr Tyr Asn
65 70 75 80
Glu Met Phe Thr Gly Lys Ala Thr Leu Thr Val Val Thr Ser Ser Thr
85 90 95
Thr Ala Tyr Ile His Leu Ser Ser Leu Ser Phe Glu Asp Ser Ala Val
100 105 110
Tyr Phe Cys Ala Arg Gly Asp Tyr Phe Asp Tyr Trp Asp Gln Gly Thr
115 120 125
Thr Leu Thr Val Ser Ser
130
<210> 2
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
atggactgga gttgggtctt tctcttcctc ctgtcagtaa atgaaggtgt ctactgtcag 60
gtccacctgc agcagtctgg agatgttttg gtaaagcctg gggcctcagt gaacttgtcc 120
tgcaaggctt ctggctacac cttcaccagc tactggatta actggataaa acagaggcct 180
ggacagggcc ttgagtggat aggacgtatt gctcctggaa gtggtaccac ttactacaat 240
gaaatgttca cgggcaaggc aacactgact gtggtcacat cctccaccac agcctacatt 300
cacctcagca gcctgtcatt tgaggactct gctgtctatt tctgtgcacg gggggactac 360
tttgactact gggaccaagg caccactctc acagtctcct ca 402
<210> 3
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Ser Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
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Met Ser Ala Ser Pro Gly Gly Lys Val Thr Ile Thr Cys Ser Ala Ser
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Lys Ser Val Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Thr Ser
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Ala Arg Phe Ser Gly Ser Gly Ser Gly Pro Ser Tyr Ser Leu Thr Ile
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<210> 4
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<212> DNA
<213> 人工序列(Artificial Sequence)
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atgcattttc aagtgcagat tttcagcttc ctgctaatca gtgcctccgt cataatgtcc 60
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gtcaccatca cctgcagtgc cagcaaaagt gtaagttaca ttcactggtt ccagcagaag 180
ccaggcactt ctcccaaact cttgatttat gacacatcca ccctggcttc tggggtccct 240
gctcgcttca gtggcagtgg atctgggccc tcttactctc tcacaatcag ccgagtggag 300
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ggtgggacca aactggaggt gaga 384
<210> 5
<211> 142
<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Asn Phe Gly Phe Ser Leu Ile Phe Leu Val Leu Val Leu Lys Gly
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Val Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Ser Val Lys
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Ser Asn Phe Asp Met Ser Trp Ile Arg Gln Thr Pro Glu Lys Arg Leu
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Glu Trp Val Ser Ser Phe Thr Pro Asp Gly Asn Thr Tyr Phe Pro Asp
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Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile
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Leu Tyr Leu Gln Met Asn Ser Val Arg Ser Glu Asp Thr Ala Met Tyr
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Phe Cys Ala Arg Lys Gly Pro Tyr Tyr Tyr Gly Pro Arg Gly Trp Phe
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Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
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<210> 6
<211> 426
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
atgaacttcg ggttcagctt gattttcctt gtccttgttt taaaaggtgt ccagtgtgaa 60
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tgtgcagcct ctggattcac tctcagtaat tttgacatgt cttggattcg ccagactcca 180
gagaagaggc tggagtgggt ctcatccttt actcctgatg gtaacaccta ctttccagac 240
agtgtgaagg gccgattcac catctccaga gataacgcca ggaacatctt gtacctgcaa 300
atgaacagtg tgaggtctga ggacacggcc atgtatttct gtgcaagaaa ggggccttat 360
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tcctca 426
<210> 7
<211> 131
<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
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Gly Ser Thr Gly Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
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Val Glu Gly Tyr Gly Thr Ser Phe Ile Tyr Trp Tyr Gln Gln Lys Ser
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Gly Gln Pro Pro Asn Leu Leu Ile Tyr Leu Thr Ser His Leu Lys Pro
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Gly Val Pro Ala Arg Phe Thr Gly Ser Gly Ser Arg Thr Asp Phe Thr
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Leu Thr Ile Asp Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys
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Gln Gln Asn Asn Glu Asp Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
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Glu Leu Lys
130
<210> 8
<211> 393
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atggagacag acacactcct gctatgggtg ctgctgctct gggttccagg ttccacaggt 60
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atgtcctgca gagccagtga aagtgttgaa ggttatggca ctagttttat atactggtac 180
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<210> 9
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Asp Trp Ser Trp Val Phe Leu Phe Leu Leu Ser Val Asn Glu Gly
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Val Tyr Cys Gln Val His Leu Gln Gln Ser Gly Asp Val Leu Val Lys
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Thr Ser Tyr Trp Ile Asn Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu
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Glu Trp Ile Gly Arg Ile Ala Pro Gly Ser Gly Thr Thr Tyr Tyr Asn
65 70 75 80
Glu Met Phe Thr Gly Lys Ala Thr Leu Thr Val Val Thr Ser Ser Thr
85 90 95
Thr Ala Tyr Ile Gln Leu Ser Ser Leu Ser Phe Glu Asp Ser Ala Val
100 105 110
Tyr Phe Cys Ala Arg Gly Asp Tyr Phe Asp Tyr Trp Asp Gln Gly Thr
115 120 125
Thr Leu Thr Val Ser Ser
130
<210> 10
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atggactgga gttgggtctt tctcttcctc ctgtcagtaa atgaaggtgt ctactgtcag 60
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tgcaaggctt ctggctacac cttcaccagc tactggatta actggataaa acagaggcct 180
ggacagggcc ttgagtggat aggacgtatt gctcctggaa gtggtaccac ttactacaat 240
gaaatgttca cgggcaaggc aacactgact gtggtcacat cctccaccac agcctacatt 300
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<210> 11
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
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Val Ile Met Ser Ser Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
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Met Ser Ala Ser Pro Gly Gly Lys Val Thr Ile Thr Cys Ser Ala Ser
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100 105 110
Thr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Arg
115 120 125
<210> 12
<211> 384
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgcattttc aagtgcagat tttcagcttc ctgctaatca gtgcctccgt cataatgtcc 60
agcggacaaa ttgttctcac ccagtctcca gcaatcatgt ctgcatctcc cggggggaag 120
gtcaccatca cctgcagtgc cagcaaaagt gtaagttaca ttcactggtt ccagcagaag 180
ccaggcactt ctcccaaact cttgatttat gacacatcca ccctggcttc tggagtccct 240
cctcgcttca gtggcagtgg atctgggccc tcttactctc tcacaatcag ccgaatggag 300
gctgaagatg ctgccactta ttactgtcag caaaggacta cttacccgct cacgttcggt 360
ggtgggacca aactggaggt gaga 384
<210> 13
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Met Asp Trp Ser Trp Val Phe Leu Phe Leu Leu Ser Val Asn Glu Gly
1 5 10 15
Val Tyr Cys Gln Val His Leu Gln Gln Ser Gly Asp Val Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Ile Asn Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Ala Pro Gly Ser Gly Thr Thr Tyr Tyr Asn
65 70 75 80
Glu Met Phe Thr Gly Lys Ala Thr Leu Thr Val Val Thr Ser Ser Thr
85 90 95
Thr Ala Tyr Ile His Leu Asn Ser Leu Ser Phe Glu Asp Ser Ala Val
100 105 110
Tyr Phe Cys Ala Arg Gly Asp Tyr Phe Asp Tyr Trp Asp Gln Gly Thr
115 120 125
Thr Leu Thr Val Ser Ser
130
<210> 14
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
atggactgga gttgggtctt tctcttcctc ctgtcagtaa atgaaggtgt ctactgtcag 60
gtccacctgc agcagtctgg agatgttttg gtaaagcctg gggcctcagt gaacttgtcc 120
tgcaaggctt ctggctacac cttcaccagc tactggatta actggataaa acagaggcct 180
ggacagggcc ttgagtggat aggacgtatt gctcctggaa gtggtaccac ttactacaat 240
gaaatgttca cgggcaaggc aacactgact gtggtcacat cctccaccac agcctacatt 300
cacctcaaca gcctgtcatt tgaggactct gctgtctatt tctgtgcacg gggggactac 360
tttgattact gggaccaagg caccactctc acagtctcct ca 402
<210> 15
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Met Met Ser Ser Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Gly Lys Val Thr Ile Thr Cys Ser Ala Ser
35 40 45
Lys Ser Val Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Thr Ser
50 55 60
Pro Lys Leu Leu Ile Tyr Asp Thr Ser Thr Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Pro Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg
100 105 110
Thr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Arg
115 120 125
<210> 16
<211> 384
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
atgcattttc aagtgcagat tttcagcttc ctgctaatca gtgcctccgt catgatgtcc 60
agcggacaaa ttgttctcac ccagtctcca gcaatcatgt ctgcatctcc cggggggaag 120
gtcaccatca cctgcagtgc cagcaaaagt gtaagttaca ttcactggtt ccagcagaag 180
ccaggcactt ctcccaaact cttgatttat gacacatcca ccctggcttc tggagtccct 240
gctcgcttca gtggcagtgg atctgggccc tcttactctc tcacaatcag ccgagtggag 300
gctgaagatg ctgccactta ttactgccag caaaggacta cttacccgct cacgttcggt 360
ggtgggacca aactggaggt gaga 384
<210> 17
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Asp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Trp Ile His Pro Arg Asp Gly Ser Thr Glu Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Lys Ala Thr Phe Thr Val Asp Thr Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Phe Cys Ala Arg Arg Gly Leu Leu Gly Pro Leu Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Thr Leu Thr Val Ser Ser
130 135
<210> 18
<211> 411
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
atgggatgga gctggatctt tctcttcctc ctgtcaggaa ctgcaggtgt ccactcccag 60
gttcagctgc agcagtctgg acctgagctg gtgaagcctg gggcttcagt gaagttgtcc 120
tgcaaggctt ctggctacac cttcacaagc tacgatataa actgggtgaa gcagaggcct 180
ggacagggac ttgagtggat tggatggatt catcctagag atggtagtac tgagtacaat 240
gagaagttca agggcaaggc cacatttact gtagacacat cctccagcac agcgtacatg 300
gagctccaca gcctgacatc tgaggactct gcggtctatt tctgtgcaag aaggggtctc 360
ctgggacctc ttgactactg gggccaaggc accactctca cagtctcctc a 411
<210> 19
<211> 130
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Met Gly Ile Lys Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu
1 5 10 15
Leu Trp Leu Ser Gly Val Glu Gly Asp Ile Val Met Thr Gln Ser His
20 25 30
Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys
35 40 45
Ala Ser Gln Asp Val Gly Thr Leu Val Ala Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr
65 70 75 80
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr Phe Cys
100 105 110
Gln Gln Tyr Ser Ser Tyr Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu
115 120 125
Leu Lys
130
<210> 20
<211> 390
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
atgggcatca agatggagac acattctcag gtctttgtat acatgttgct gtggttgtct 60
ggtgttgaag gagacattgt gatgacccag tctcacaaat tcatgtccac atcagtagga 120
gacagggtca gcatcacctg caaggccagt caggatgtgg gtactcttgt agcctggtat 180
caacagaaac cagggcaatc tcctaaatta ttgatttact gggcatccac ccggcacact 240
ggagtccctg atcgcttcac aggcagtgga tctgggacag atttcactct caccattagc 300
aatgtgcagt ctgaagactt ggcagattat ttctgtcagc aatatagcag ctatcccacg 360
ttcggtgctg ggaccaagct ggagctgaaa 390
Claims (8)
1.一种人CTLA4单克隆抗体，其特征在于：该单克隆抗体的蛋白序列含有重链可变区和轻链可变区，该单克隆抗体选自如下(1)～(5)中的任意一种：
(1)所述的重链可变区具有如SEQ ID NO：1所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：3所示的氨基酸序列；
(2)所述的重链可变区具有如SEQ ID NO：5所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：7所示的氨基酸序列；
(4)所述的重链可变区具有如SEQ ID NO：13所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：15所示的氨基酸序列；
(5)所述的重链可变区具有如SEQ ID NO：17所示的氨基酸序列，所述的轻链可变区具有如SEQ ID NO：19所示的氨基酸序列。
2.权利要求1所述单克隆抗体的编码基因。
3.根据权利要求2所述的编码基因，其特征在于该编码基因选自如下(6)～(10)中的任意一种：
(6)含有如SEQ ID NO：2所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ ID NO：4所示的编码所述单克隆抗体轻链可变区的核苷酸序列；
(7)含有如SEQ ID NO：6所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ ID NO：8所示的编码所述单克隆抗体轻链可变区的核苷酸序列；
(9)含有如SEQ ID NO：14所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ ID NO：16所示的编码所述单克隆抗体轻链可变区的核苷酸序列；
(10)含有如SEQ ID NO：18所示的编码所述单克隆抗体重链可变区的核苷酸序列，以及如SEQ ID NO：20所示的编码所述单克隆抗体轻链可变区的核苷酸序列。
4.含有权利要求3所述编码基因的重组载体、表达盒、转基因细胞系或重组菌。
5.权利要求4所述的重组表达载体、表达盒、转基因细胞系或重组菌在制备人CTLA4单克隆抗体中的应用。
6.一种制备人CTLA4单克隆抗体的方法，其特征在于将包含权利要求2或3所述编码基因的重组表达载体转染感受态细胞，并进行培养得到人CTLA4单克隆抗体。
7.权利要求1所述的人CTLA4单克隆抗体在制备抗肿瘤药物中的应用。
8.一种抗肿瘤制剂，其特征在于：其包含权利要求1所述的人CTLA4单克隆抗体。
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| CN201611193370.7A CN108218987B (zh) | 2016-12-21 | 2016-12-21 | 高亲和力、高特异性、多抗原识别表位的具有更高功能性的抗人ctla4抗体 |
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| CN110760002A (zh) | 2018-07-25 | 2020-02-07 | 南京金斯瑞生物科技有限公司 | 人源化抗人ctla4单克隆抗体及其制备方法和用途 |
| CN118340882A (zh) * | 2024-04-17 | 2024-07-16 | 天津力华源生物科技有限公司 | 一种能有效治疗癌症的靶向药及其制备方法和应用 |
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| CN101248089A (zh) * | 2005-07-01 | 2008-08-20 | 米德列斯公司 | 抗程序性死亡配体1（pd-l1）的人单克隆抗体 |
| CN101578296A (zh) * | 2006-11-15 | 2009-11-11 | 梅达雷克斯公司 | 结合btla的人类单克隆抗体及使用方法 |
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| CN101578296A (zh) * | 2006-11-15 | 2009-11-11 | 梅达雷克斯公司 | 结合btla的人类单克隆抗体及使用方法 |
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| CN115443291A (zh) * | 2020-04-13 | 2022-12-06 | 博奥信生物技术（南京）有限公司 | 结合ctla4的抗体及其用途 |
| EP4136120A4 (en) * | 2020-04-13 | 2024-07-03 | Biosion, Inc. | CTLA4 BINDING ANTIBODIES AND THEIR USES |
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