CN114195897B - Pd-l1单克隆抗体、重链、轻链可变区、单克隆细胞株及运用和试剂盒 - Google Patents
Pd-l1单克隆抗体、重链、轻链可变区、单克隆细胞株及运用和试剂盒 Download PDFInfo
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Abstract
本申请涉及单克隆抗体领域，更具体地说，它涉及PPD‑L1单克隆抗体、重链、轻链可变区、单克隆细胞株及运用和试剂盒，重链可变区包括如下互补决定区：CDRH1：DIYMH；CDRH2：RIGPANGDIKYDPKFQG；CDRH3：YGSYFAMDY；轻链可变区包括如下互补决定区：CDRL1：RASGNIHNYLA；CDRL2：NAKTLAD；CDRL3：QHFWSTPYT。本申请中的抗体对PD‑L1抗原具有良好的特异性和结合性，具有广阔的运用前景。
Description
技术领域
本申请涉及单克隆抗体领域，更具体地说，它涉及PD-L1单克隆抗体、重链、轻链可变区、单克隆细胞株及运用和试剂盒。
背景技术
程序性死亡受体1(PD-1)是一种重要的免疫抑制分子，其具有两个天然配体，分别为PD-L1和PD-L2，PD-L1可以在多种肿瘤细胞中检测表达，如非小细胞肺癌、恶性黑素肿瘤、胃癌、乳腺癌、食管癌、胶质瘤等。因此，对PD-L1可以作为肿瘤治疗和诊断的靶点，在临床上具有重要的意义。
目前，市面上常用的用于检测PD-L1的方法是免疫组化法，主要通过PD-L1抗体对PD-L1抗原及逆行免疫识别，并通过其他显色剂对抗原-抗体进行显色，进而对PD-L1进行表征。同时，通过特异性靶向PD-L1靶点，具有良好的靶向用药的潜力，因此，开发高亲和力、高特异性的PD-L1抗体，在精确诊断和合理用药方面具有重要的意义。
发明内容
为了，本申请提供PD-L1单克隆抗体，具有高亲和力、高特异性的优势，同时，本申请提供了该单克隆抗体的重链、轻链可变区、单克隆细胞株及运用和试剂盒。
首先，本申请提供了PD-L1单克隆抗体重链、轻链可变区，重链可变区包括如下互补决定区：
CDRH1：DIYMH；
CDRH2：RIGPANGDIKYDPKFQG；
CDRH3：YGSYFAMDY；
轻链可变区包括如下互补决定区：
CDRL1：RASGNIHNYLA；
CDRL2：NAKTLAD；
CDRL3：QHFWSTPYT。
可选的，重链序列如SEQ ID No.2所示，轻链序列如SEQ ID No.3所示。
具有如上互补决定区的重链、轻链可变区对抗原具有较好的结合性和选择性，在实际检测和诊断治疗领域中具有显著的优势。
同时，本申请还提供PD-L1单克隆抗体，包括上述重链、轻链可变区。
具有上述重链、轻链可变区的抗体具有高选择性，亲和力和特异性都较好，具有效价高、灵敏度高、线性良好等优点。
具有上述互补决定区的抗体可以为鼠源抗体，也可以将具有上述互补决定区的可变区运用于人鼠嵌合抗体，或将上述互补决定区运用于人源的改型抗体。
同时，对上述抗体可以进行表面重塑，或进行修饰或替换其中非互补决定区部分的氨基酸序列。
抗体的种类可以为IgM、IgD、IgG、IgA和IgE型，可以为
可选的，重链恒定区为鼠源IgG1恒定区。
重链的序列如SEQ ID No.4所示，轻链的序列如SEQ ID No.5所示。
该抗体具有高亲和力、高特异性，经实验正式，具有较好的线性和灵敏度。
可选的，抗体经过人源化改造。
经人源化改造后，可以激活人体免疫系统，避免诱导HAMA反应，适用于免疫治疗。
人源化改造包括恒定区替换为人源，或直接将互补决定区植入到人源抗体中替代人员抗体的互补决定区，或其他有助于减少HAMA反应且不影响抗体特异结合性能的改性方式。
另外，本申请还提供用于表达上述单克隆抗体的单克隆细胞株。
单克隆细胞株可以为啮齿类动物的抗原激活后的B细胞与骨髓瘤细胞融合细胞，也可以是其他具有表达上述抗体的能力细胞株。
另外，本申请还提供了上述PD-L1单克隆抗体的运用，运用于PD-L1抗原的表达检测或肿瘤细胞的免疫杀伤领域。
其中，抗原表达检测可以为酶联免疫吸附测定法、免疫组化测定法或其他应用抗原和抗体质检相互结合的测定方法，也包括上述单克隆抗体与其他单克隆抗体形成夹心配对并对抗原进行检测的测定方法。
免疫杀伤领域可以用于体内、体外不同区域，作用目标可以为人、除人外的动物、细胞、阻止、器官或其他生物活性成分，目的在于针对肿瘤体、肿瘤细胞、癌细胞的抑制、杀灭、诱导凋亡、限制扩散、减轻症状等作用。
另外，本申请还提供一种试剂盒，包含上述单克隆抗体或含有上述重链、轻链可变区的任意单克隆抗体。
该试剂盒可为酶联免疫吸附试剂盒、免疫荧光试剂盒或其他运用上述单克隆抗体或含有上述重链、轻链可变区的单克隆抗体与抗原发生特异性免疫反应后对产物进行检测的试剂盒，其具有特异性高、灵敏度高的优点，具有较好的运用前景。
附图说明
图1为PD-L1抗原SDS-PAGE电泳图，左边为纯化前，右边为纯化后；
图2为抗体1和抗体2的SDS-PAGE电泳图，其中，从左至右依次为抗体1纯化后和抗体2纯化后；
图3为抗体1和抗体2检测抗原效价线性分析图。
具体实施方式
以下结合附图和实施例对本申请作进一步详细说明。
实施例1，PD-L1单克隆抗体、重链、轻链可变区、单克隆细胞株及运用，其中PD-L1单克隆抗体的序列具体如表1所示。
表1、抗体PD-L1的序列表
该PD-L1单克隆抗体通过如下步骤制备得到。
一、构建PD-L1表达载体
从美国国家生物技术信息中心(NCBI)中人PD-L1的基因序列(NP_054862)选取N端(1-238aa)氨基酸片段，通过基因合成克隆至pcDNA3.1(+)表达载体，最终合成构建为pcDNA3.1(+)-PD-L1载体。同时基因合成时，在PD-L1氨基酸C端添加6个组氨酸(His)标签，上述载体所表达重组PD-L1分子量约32KD，氨基酸序列为SEQ ID NO:1。
二、免疫原细胞的表达
1、转化及抽提质粒
将上述pcDNA3.1(+)-PD-L1载体转化至大肠杆菌DH5α(天根公司)感受态细胞中，均匀涂布到含100ug/ml氨苄青霉素的LB琼脂糖平板上，37℃培养箱中培养过夜；挑取平板上的单克隆菌落，加入到5ml含100ug/ml氨苄青霉素的LB培养基中，恒温震荡培养摇床(250rpm，37℃)连续培养约6小时；取1ml培养后的菌液扩大培养至含200ml的LB培养基中，恒温震荡培养摇床(200rpm，37℃)连续培养18h；将培养后菌液离心(8000rpm，5min)，丢弃上清液，按照内毒素质粒抽提试剂盒(天根公司)指导说明书进行抽提质粒，装于-20℃保存备用。
2、细胞培养及转染
用FreeStyleTM293表达培养基(Thermo Fisher)培养293F细胞，，细细胞培养箱设置温度37℃，转速90rpm；在转染前24小时保证293F细胞密度在0.6×106-0.7×106个细胞/mL，转染当天细胞密度控制在1.0×106–1.5×106个/mL，细胞存活率大于90％，转染时每1ug的PD-L1质粒使用1ul的FreeStyleTM MAX转染试剂，每1ml细胞液加入约1ug的上述质粒，转染后培养细胞约5-7天可以达到最大表达量。转染后7天，离心(8000rpm，10min)细胞液并收集上清，进入下一步纯化步骤。
三、PD-L1抗原纯化。
通过Ni Sepharose 6Fast Flow(Cytiva)对上述上清液进行纯化，提纯其中的抗原。
先对亲和层析柱进行上样前预处理，调节流速3ml/min，流出层析填料中20％乙醇，用平衡液(具体配方见表5)平衡镍亲和层析柱至电导率基线稳定；将收集到的PD-L1细胞上清液上样纯化，调节纯化仪速度为1ml/min；上样结束后用洗涤液(具体配方见表5)清洗5倍柱体积以上去除非特异性结合的杂蛋白，调节纯化仪速度为3ml/min；洗涤结束后用洗脱液(具体配方见表5)洗脱PD-L1蛋白，调节纯化仪洗脱速度为1ml/min，根据UV(A280)的洗脱峰值收集洗脱液。
收集的洗脱液进行透析(50mM Tris-HCl,200mM NaCl,pH 8.0)处理，透析3次，每次透析时间≥4小时；透析后的样品利用SDS-PAGE电泳判定蛋白的纯化结果。如图1所示，透析后蛋白分子量约为32KDa，与PD-L1重组蛋白大小相符，没有杂蛋白，纯度＞95％。
四、通过上述抗原进行免疫小鼠实验
准备实验动物Balb/c小鼠，个体体重要求在20g以上。PD-L1抗原与弗氏完全佐剂按1:1比例混合成乳状，进行皮下多点注射，注射量为500ul/只；以后每隔14天免疫一次，每只小鼠初次免疫反应投入的PD-L1抗原剂量为50ug，后续每次注射的量为25ug，抗原与弗氏不完全佐剂按1:1比例混合成乳状，共免疫4次；第4次免疫后第10天通过小鼠尾静脉采血，利用酶联免疫法(ELISA)检测血清中免疫抗体效价，测定其OD450，筛选其中效价较高的小鼠，结果如表2所示。
表2、PD-L1抗原免疫小鼠血清效价检测
| 血清稀释比例 | 免疫小鼠血清 | 未免疫鼠血清 |
| 1:500 | 3.939 | 0.014 |
| 1:2500 | 3.474 | 0.016 |
| 1:12500 | 2.232 | 0.019 |
| 1:62500 | 0.864 | 0.013 |
| 1:312500 | 0.227 | 0.014 |
| 1:1562500 | 0.115 | 0.012 |
| 空白 | 0.037 | 0.015 |
血清效价检测结果从表2中可以看出，包被2ug/ml PD-L1抗原，血清效价可达到1:1562500，符合要求，可进行细胞融合实验。
五、杂交瘤融合
1、骨髓瘤细胞制备
事先培养3瓶T175细胞培养瓶SP2/0细胞，在融合前，利用显微镜观察细胞生长状态，确保细胞没有细菌和真菌污染。
2、脾细胞制备
步骤四中的小鼠用CO2或者颈椎脱臼法安乐死，在75％酒精中浸泡消毒5min。在无菌操作获得小鼠脾脏用灭菌PBS洗涤，修剪脾脏上的多余脂肪组织，修剪后的脾脏组织置于40目不锈钢网膜上，轻柔研磨制备脾脏细胞悬液。
3、细胞融合及亚克隆筛选
将SP2/0骨髓瘤细胞和脾细胞计数，按照SP2/0与脾细胞1:5的数量混合，使用电融合仪BTX ECM2001系统SP2/0与脾细胞。融合后的细胞铺到96孔板中进行培养，将细胞培养板放到CO2培养箱连续培养，观察融合细胞生长状态。
细胞融合后10天左右更换为HAT选择性培养基，再培养10天后，取细胞上清，通过酶联免疫法检测识别PD-L1抗体分泌；在抗体分泌的情况下，利用有限稀释法经过5轮的亚克隆筛选，最终筛选出单克隆细胞株。
4、小鼠腹水制备
选取8-10周龄的Balb/c小鼠，提前一周用石蜡油进行致敏；将挑选出的单克隆细胞株培养至细胞生长在对数期，每种克隆株注射到3只小鼠的腹腔内，每只小鼠腹腔注射杂交瘤细胞数1×106。待杂交瘤细胞注射约7天后，观察小鼠的腹水及存活情况，触摸小鼠腹部有明显的肿胀，可以用注射器采集腹水，隔天再采集一次。将采集到的腹水至于-20℃保存，用于纯化单克隆抗体。
5、小鼠腹水单克隆抗体纯化
取收集到的小鼠腹水离心(12000rpm,4℃,20min)，去除腹水中不容的杂质及细胞碎片，离心结束后再用定性滤纸过滤，量筒量取腹水体积，加入等体积的1×PBS(10mM，pH7.4)混合均匀。上样前用5倍柱体积1×PBS预处理Protein A亲和层析柱，处理好的腹水加入到层析柱中，室温孵育30min，期间不定时重悬Protein A填料，使单克隆抗体与纯化介质充分结合；孵育结束后用10倍柱体积5×PBS洗杂处理，去除非特异吸附的杂质。
向离心管中加入100ul的1M Tris-HCl(pH＝9.0)，用100mM甘氨酸水溶液(pH3.0)洗脱柱体，每管收集1ml，收集的单克隆抗体洗脱液用1×PBS进行透析，每次透析≥4小时，共透析三次；透析后SDS-PAGE电泳测定抗体纯度，结果如图2所示。
另外，通过ELISA测定抗体效价，判断该抗体的亲和力，具体单克隆抗体效价见表3，其中PD-L1抗原包被2ug/ml，抗体稀释成1mg/ml后从1:1000稀释度开始测定。
表3、PD-L1单克隆抗体亲和力检测
| 抗体稀释比例 | 抗体效价 |
| 0.736111 | 2.398 |
| 2.125 | 2.269 |
| 6.291667 | 2.036 |
| 1:27000 | 1.678 |
| 1:81000 | 1.16 |
| 1:243000 | 0.743 |
| 1:729000 | 0.316 |
| 空白 | 0.023 |
通过上述实验数据可知，制备得到的PD-L1单克隆抗体具有较高的亲和性。
实施例2，如实施例1所示的PD-L1单克隆抗体的运用，其运用于抗原检测，采用双抗夹心检测方式，以实施例1中的PD-L1单克隆抗体标记抗体。
为方便描述，将实施例1中的PD-L1单克隆抗体记录为抗体1，将用于制备包被抗体的抗体记录为抗体2。
具体检测步骤如下：
1、抗体包被：用1×PBS将抗体2稀释浓度至4ug/ml，用移液器吸取加入到96空酶标板中，每孔加入100ul，至于4℃冰箱过夜。
2、酶标板封闭：弃去包被液，用PBST洗涤，每孔加入250ul，共清洗4次，拍干；酶标板每孔加入250ul封闭液(1×PBS,2％ BSA)，37℃孵育2小时。
3、封闭结束后用，用PBST洗涤，每孔加入250ul，共清洗4次，拍干；将PD-L1抗原从50ng/ml开始稀释，共稀释7个梯度：50ng/ml、10ng/ml、2ng/ml、400pg/ml、80pg/ml、16pg/ml、3.2pg/ml，每个酶标板孔中加入100ul稀释后的PD-L1抗原，置于37℃培养箱中孵育1小时。
4、孵育结束后用PBST洗涤，每孔加入250ul，共清洗4次，拍干；抗体1标记HRP，稀释5000倍，每个酶标板孔中加入100ul，置于37℃培养箱中孵育1小时。
5、孵育结束后用PBST洗涤，每孔加入250ul，共清洗4次，拍干；每孔加入100ul显示液(TMB)，避光显色10-15min；显色结束后加50ul的2M H2SO4终止，并测定最终样本的OD450，实验结果如表4和图3所示。
表4、PD-L1抗体配对效价检测
经计算机拟合，抗体1作为标记抗体、抗体2作为包被抗体，检出限低于16pg/mL，经计算机程序拟合，抗原线性关系R2＝0.99988，线性较好。
综上所述，采用上述抗体，可以以血浆为样品，肿瘤患者的预后PD-L1表达进行监测，也可以对单克隆抗体进行改造，增强用于肿瘤细胞的免疫杀伤，具有良好的推广前景和运用价值。
附表5，为实施例中部分实验物料的配比。
表5、部分实验物料配方一览
| 实验物料 | 成分 |
| 平衡液 | 50mM Tris-HCl,200mM NaCl,5mM咪唑，pH 8.0 |
| 洗涤液 | 50mM Tris-HCl,200mM NaCl,50mM咪唑，pH 8.0 |
| 洗脱液 | 50mM Tris-HCl,200mM NaCl,300mM咪唑，pH 8.0 |
本具体实施例仅仅是对本申请的解释，其并不是对本申请的限制，本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本申请的权利要求范围内都受到专利法的保护。
序列表
<110> 广州兆瑞医学生物科技有限公司
<120> PD-L1单克隆抗体、重链、轻链可变区、单克隆细胞株及运用和试剂盒
<130> WZF000PTPA01F2103787
<140> 202111485981X
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Claims (6)
1.一种PDL1单克隆抗体，包括重链、轻链可变区，其特征在于，重链可变区包括如下互补决定区：
CDRH1：DIYMH；
CDRH2：RIGPANGDIKYDPKFQG；
CDRH3：YGSYFAMDY；轻链可变区包括如下互补决定区：
CDRL1：RASGNIHNYLA；
CDRL2：NAKTLAD；
CDRL3：QHFWSTPYT。
2.根据权利要求1所述的PD-L1单克隆抗体，包括重链、轻链可变区，其特征在于，重链可变区的序列如SEQ ID No.2所示，轻链可变区的序列如SEQ ID No.3所示。
3.根据权利要求1-2任一项所述的PD-L1单克隆抗体，包括重链、轻链可变区，其特征在于，重链恒定区为鼠源IgG1恒定区。
4.根据权利要求1-3任一项所述的PD-L1单克隆抗体，包括重链、轻链可变区，其特征在于，重链的序列如SEQ ID No.4所示，轻链的序列如SEQ ID No.5所示。
5.根据权利要求1-4任一项所述的PD-L1单克隆抗体，包括重链、轻链可变区，其特征在于，抗体经过人源化改造。
6.试剂盒，其特征在于，包含有如权利要求1-5中任意一项所述的PD-L1单克隆抗体。
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