CN106046162A - 抗人程序性死亡因子1（pd‑1）单克隆抗体的制备及应用 - Google Patents
抗人程序性死亡因子1（pd‑1）单克隆抗体的制备及应用 Download PDFInfo
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- CN106046162A CN106046162A CN201610447042.9A CN201610447042A CN106046162A CN 106046162 A CN106046162 A CN 106046162A CN 201610447042 A CN201610447042 A CN 201610447042A CN 106046162 A CN106046162 A CN 106046162A
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Abstract
本发明公开了一种抗人程序性死亡因子1（PD‑1）单克隆抗体的制备，其可变区序列及应用。本发明提供了1种抗人PD‑1蛋白单克隆抗体，包括单克隆抗体轻链和重链可变区基因序列。所述的重链的氨基酸序列如SEQ ID NO.3的第20位至134位所示，所述的轻链的氨基酸序列如SEQ ID NO.4的第20位至131位所示。本发明新发现了一种能阻断人PD‑1功能的单克隆抗体189‑H‑1及其编码基因，该单克隆抗体189‑H‑1能够与人PD‑1抗原特异性结合，半数有效浓度EC50为1.0667nM，可以特异性阻断PD‑1/PD‑L抑制信号，因此可以将本发明的单克隆抗体189‑H‑1作为PD‑1通路的阻断剂，从而成为肿瘤免疫治疗、慢性病毒感染性疾病及自身免疫性疾病的治疗一种新药物。
Description
技术领域
本发明涉及生物医药技术领域，尤其涉及抗人PD-1单克隆抗体的制备及可变区序列及应用。
背景技术
PD-1基因最早是由Tasuku Honjo及其同事在1992年发现与克隆的，其胞外区有1个IgV样区，与CTLA-4有23%的同源性，由 288 个氨基酸组成的免疫球蛋白超家族Ⅰ型跨膜糖蛋白，最初被认为与细胞凋亡相关而命名为程序性死亡-1（programmed death-1，PD-1）。（Ishida,Y.等,Induced expression of PD-1,a novel member of theimmunoglobulingene superfamily,upon programmed cell death.EMBO J,1992，11:3887）。然而PD-1 蛋白因缺乏介导 CD28/CTLA-4与B7.1/B7.2 相结合的MYPPPY 序列，以及介导 ICOS 与 ICOS-L 相结合的 FDPPPF 序列，因而在结构上与 CD28、CTLA-4 及 ICOS存在明显差异。因此，PD-1与配体的结合非常特异，不与其他的 B7 家族分子产生交叉结合。
PD-1具有两个已知的配体，PD-L1(B7-H1,CD274)和PD-L2(B7-DC,CD273)，它们为B7家族的细胞表面表达的成员。PD-1主要表达于CD4+T细胞、CD8+T细胞、NKT细胞、B细胞和活化的单核细胞表面，主要受T细胞受体(TCR)或B细胞受体(BCR)信号的诱导表达，TNF可增强PD-1在这些细胞表面的表达(Francisco等,The PD-1pathway in tolerance andautoimmunity.Immunol Rev，2010，236：219-242)。该受体和其配体PD-L1和PD-L2相结合(Okazaki等,PD-1 and PD-1 ligands：from discovery to clinicalapplication.International Immunology，2007，19(7)：813-824)。给予PD-1或PD-L1抗体以阻断PD-1/PD-L1之间相互作用，则可打破或消除因肿瘤导致的免疫抑制或免疫耐受，恢复体内T淋巴细胞识别与攻击肿瘤靶细胞的能力，进而达到抗肿瘤生长与转移的良好效果（HiranoF.等 ,Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiatescancer therapeutic immunity[J]. Cancer Res, 2005, 65(3):1089-1096.）。
PD-1参与负向调控体内免疫功能的这一重要事实最早是由TasukuHonjo及其同事在研究PD-1基因敲除小鼠中观察到的。他们发现PD-1基因敲除的小鼠在C57BL/6基因背景下，发生狼疮样肾小球肾炎和关节炎（Nishimura H等，Developmentof lupus-likeautoimmune diseases by disruption of the PD-1gene encoding an ITIM motif-carrying immunoreceptor.Immunity,1999，11:141）；而在Balb/c基因背景下，则产生高滴度的抗心肌组织抗体并由此引发严重的自身免疫性心肌病。
PD-1和PD-L1相互作用以调节控制T细胞的活化在肿瘤和病毒感染中得到了大量验证。PD-L1表达于多种肿瘤细胞表面，这些肿瘤细胞包括：肺癌，肝癌，卵巢癌，宫颈癌，皮肤癌，膀胱癌，结肠癌，乳腺癌，神经胶质瘤，肾癌，胃癌，食道癌，口腔鳞状细胞癌，头颈癌。而且在这些癌症周边也发现了大量表达PD-L1的CD8+T细胞。临床统计显示，PD-L1在肿瘤细胞上的高表达水平与癌症患者不良预后相关。PD-1和PD-L1之间的相互作用导致渗入肿瘤的淋巴细胞减少、T细胞受体介导的增殖减少、及癌性细胞的免疫逃避（ Dong H. 等， B7-H1 pathway and its role in the evasion of tumor immunity . J Mol Med, 2003 ,81 : 281 – 7）。研究发现通过抑制PD-1与PD-L1的局部相互作可逆转免疫抑制，而且当PD-1与PD-L2的相互作用也被阻断时具有累加效果（Brown JA等, Blockade of programmeddeath-1 ligands on dendritic cells enhances T cell activation and cytokineproduction. J Immunol. 2003;170:1257–1266）。
综上所述，通过特异性阻断 PD-1/PD-L抑制信号可以使机体中失能的效应性细胞恢复生物学功能，促进肿瘤和病毒特异性 CD8+T 细胞的活化增殖与细胞因子的分泌，增强淋巴细胞对肿瘤抗原、外来入侵的病毒等的杀伤力，提高机体免疫力，及时清除肿瘤细胞和病毒。因此，PD-1/PD-L 有望成为肿瘤免疫治疗的有效靶分子，也为 HIV 等慢性病毒感染性疾病及自身免疫性疾病的治疗提供一个新的策略。
发明内容
本发明的目的在于提供对hPD-1(人PD-1)有很高亲和力的抗体，抗体名称为2-189-H-1。该抗体能阻断hPD-1受体与其配体B7-H1结合，可以应用于治疗抗肿瘤、抗感染及自身免疫性疾病等治疗药物中。
本发明提供1株稳定表达抗体蛋白的杂交瘤细胞株，并保藏在武汉大学中国典型培养物保藏中心。保藏单位地址为湖北省武汉市武昌区八一路299号武汉大学校内，武汉大学保藏中心。保藏日期为2015年9月28日，保藏编号为CCTCC C2015160。分类命名为杂交瘤细胞株2-189-H-1。
本发明提供一种分离的 DNA 分子，编码所述抗hPD-1人源抗体的重链和或轻链的可变区或全长氨基酸。
抗体重链可变区的核酸序列为 SEQ ID NO:1的第58位至402位所示的核苷酸序列；其抗体轻链可变区的核酸序列为 SEQ ID NO:2的第58位至393位所示的核苷酸序列。
抗体重链可变区的氨基酸序列为 SEQ ID NO:3 或其保守型变异序列；其抗体轻链可变区的氨基酸序列为 SEQID NO:4 或其保守型变异序列。
SEQ ID NO.1和2第1位至57位碱基序列是编码信号肽序列的核苷酸序列。
SEQ ID NO.3和4第1位至19位氨基酸序列是信号肽序列。
所述抗hPD-1 单克隆抗体可以是抗体的全长序列，也可以是抗 PD-1 抗体的片段，上述蛋白和抗体包括：重组蛋白，重组抗体、ScFv抗体、人源化抗体、嵌合抗体、双特异性抗体、单域抗体以及ADC偶联抗体和蛋白。
所述抗体也可以进一步提供所述抗 hPD-1抗体的衍生物，所述衍生物为hPD-1 抗体的片段、抗体 / 抗体片段 - 因子融合蛋白、抗体 / 抗体片段 - 化学偶联物 。
本发明新发现了1种对hPD-1有显著高亲和力的单克隆抗体2-189-H-1。这种单克隆抗体不仅能够与hPD-1抗原特异性结合，半数有效浓度与参照品相近，并且能阻断hPD-1与其配体结合的能力。
本发明从单克隆细胞株中获取目的抗体的基因序列，可用以构建真核表达载体，表达后即可重建抗体的活性，获得抗hPD-1单克隆抗体。
本发明所述的抗hPD-1单克隆抗体可用来制备抗肿瘤（包括高表达hPD-1的肺癌、肝癌、乳腺癌、鳞状细胞癌、卵巢癌、结直肠癌、胃癌、胃肠道间质瘤、膀胱癌、甲状腺癌、黑色素瘤、颈癌、前列腺癌）药物、抗感染（感染性疾病包括HIV、HBV、HCV等病毒感染引起的疾病）药物及用来制备自身免疫性疾病（包括系统性红斑狼疮、类风湿性关节炎、系统性脉管炎、银屑病、多发性硬化症、溃疡性结肠炎）治疗的药物，其制备方法是以抗PD-1单克隆抗体为主要成分，加上制药学上可接受的辅料和/或添加剂，经过冻干处理，制备成药学上可接受的药剂。
本发明的优点在于该抗体对hPD-1有很高的亲和力。在动物细胞中高效表达，可用于工业化生产。实验证明，本发明的抗hPD-1单克隆抗体能阻断hPD-1受体与其配体B7-H1结合。
所以，本发明所述抗体对肿瘤、感染性疾病及自身免疫性疾病的治疗具有广泛的应用前景。
附图说明
图 1 为抗 PD-1 抗体的亲和力能力实验。
图 2 为抗 PD-1 抗体的阻断试验。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式，本发明的保护范围不局限于下述特定的具体实施方案。
实施例 1 。
hPD-1的稳定膜表达。
为了得到细胞膜表面表达hPD-1蛋白的细胞株作为免疫原,购买编码人PD-1全长开放阅读框的cDNA克隆（北京义翘神州生物技术有限公司HG10377-CF，Genbank登录号NM-005018.2），将其定向插入到pCDNA3.1（+）（invitrogen公司）载体中，测序确定hPD-1基因编码框正确后。将质粒电转化到CHO-DG44细胞中，加压筛选，克隆得到稳定表达hPD-1的CHO-DG44细胞。命名为hPD-1/DG44。
实施例 2。
动物免疫。
挑选5只6-8周龄A/J小鼠，共进行5次免疫，每次免疫间隔14天。每次免疫107个hPD-1/DG44细胞，皮下和腹腔多点免疫。首次免疫采用等体积弗氏完全佐剂和细胞悬液混合，其余4次免疫为弗氏不完全佐剂和细胞悬液混合。
细胞培养基的配置。
培养sp2/0细胞时采用MD6无血清培养基。融合后细胞采用HAT培养基培养，具体成分如下：MD6无血清培养基中加入10%的胎牛血清和HAT。
细胞融合。
终免后3天，挑选效价高的3只老鼠进行细胞融合。无菌取出小鼠脾脏和预先准备好的sp2/0细胞，细胞计数后，按10:1的比例混匀，加入PEG3350进行细胞融合。融合后细胞采用HAT培养基培养于96孔细胞培养板中。
融合细胞的检测。
融合后第10天，96孔板中细胞培养板中各孔大部分变为黄色，细胞克隆群体约占整个孔底的20%-30%，进行ELISA筛选阳性克隆。具体如下：采用购买的人PD-1-Fc重组蛋白（RD）包被96孔ELISA板，加入融合后的细胞上清液作为一抗孵育，同时设定sp2/0细胞上清液为阴性对照，加入山羊抗鼠IgG-Fc-HRP作为二抗孵育，加入显色液，OD450读值。阳性克隆定义为：细胞融合后检测上清OD450值大于sp2/0上清OD450值的2倍。
阳性融合细胞的亚克隆筛选。
将检测后阳性的融合细胞培养于6孔细胞培养板中，待细胞状态良好，细胞计数，铺于96孔细胞培养板中，平均每孔1个细胞。培养10天后，挑选单个克隆群体的细胞进行ELISA检测，OD450值检测最高的细胞进行第二次亚克隆，经过3-5次亚克隆后，直至检测结果为100%阳性为止，确定细胞的稳定性。
抗体的制备。
将获得的单克隆细胞系在MD6培养基中进行摇瓶培养，表达时间通常为 7-14 天，当活细胞密度低于50％时收获细胞培养液上清。采用 Protein A 亲和层析柱从细胞培养上清中分离纯化目的抗体。
实例3。
抗hPD1单克隆抗体功能鉴定。
亲和力鉴定。
采用hPD-L1-Fc（RD）包被96孔ELISA板；阻断抗体作为一抗进行3倍稀释，共12个梯度，加入到hPD-L1-Fc包被96孔ELISA板中。加入山羊抗鼠IgG-Fc-HRP（SANT CruzBIotechnology）作为二抗，加入显色液，终止后读取OD450值。使用Graphpad软件生成EC50浓度。本抗体的EC50为1.0667nM，阳性对照的EC50是0.5344nM，从结果可以看出，筛选得到的抗体对 PD-1 具有明显的亲和力，并且与阳性对照品相近（见图1）。
抗体阻断hPD-1与hPD-L1结合的功能鉴定。
采用hPD-L1-Fc（RD）包被96孔ELISA板；将纯化的hPD-1抗体进行4倍稀释，共4个梯度，分别与hPD-1-Fc作用。将不同浓度的hPD-1抗体与hPD-1-Fc作用的混合液加入到hPD-L1-Fc包被的96孔ELISA板中。加入兔抗hPD-1抗体（北京义翘神州）作为一抗，在加入山羊抗兔IgG-Fc-HRP（SANT Cruz BIotechnology）作为二抗，加入显色液，读取OD450值。筛选出的抗体具有阻断hPD-1与HPDL1结合的功能。
通过Biocore进一步检测抗体的阻断作用。将hPD-1-Fc偶联到芯片上，将纯化的hPD-1抗体进行2倍稀释，共7个梯度，分别与hPD-1-Fc作用。上机检测。使用Graphpad软件生成EC50浓度，本抗体的EC50为64.42nM，阳性对照的EC50是26.59nM，。从结果可以看出，筛选得到的抗体能阻断 PD-1 与其配体 B7-H1 的结合，与阳性对照品在同一个数量级（见图2）。
实例4。
抗体的亚类鉴定及稳定性试验。
参照鼠抗体亚型鉴定试剂盒（Pierce，37503）说明书对抗体进行亚类鉴定，结果重链为IgG1，轻链为Kappa。
将杂交瘤细胞株体外培养连续传代 3 个月后，测定上清液抗体效价，并将细胞株冻存 4个月后复苏，检测上清液抗体效价。均未发生变化。表明得到分泌抗体稳定的杂交瘤细胞株。
实例5。
抗体基因序列的获得。
参照SMARTer RACE试剂盒（clonetech，634859）使用说明书，根据鼠重链IgG1和轻链Kappa的Fc片段保守区设计下游引物，利用RACE PCR技术，对具有阻断作用的抗体重链和轻链可变区基因进行扩增和测序。
综上所述，本发明有效克服了现有技术中的种种缺点而具高度产业利用价值。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。
[0001]
序列表
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[0002]
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ctgcagaaac caggccagtc tccaaaggcc ctgatctcca aagtttccaa ccgattgtct 240
ggggtcccag acaggttcag tggcagtgga tcagggacag atttcacact caagatcagc 300
agagtggagg ctgaggatct gggagtttat tactgctttc aaggttcaca tattccgtac 360
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Gly Gln Ser Pro Lys Ala Leu Ile Ser Lys Val Ser Asn Arg Leu Ser
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Claims (11)
1.分离的抗人PD-1单克隆抗体或其抗原结合部分，其包含：
a)包含选自SEQ ID NO:5氨基酸序列的重链可变区CDR1；
b)包含选自SEQ ID NO:7氨基酸序列的重链可变区CDR2；
c)包含选自SEQ ID NO:9氨基酸序列的重链可变区CDR3；
d)包含选自SEQ ID NO:6氨基酸序列的轻链可变区CDR1；
e)包含选自SEQ ID NO:8氨基酸序列的轻链可变区CDR2；
f)包含选自SEQ ID NO:10氨基酸序列的轻链可变区CDR3。
2.分离的抗人PD-1单克隆抗体或其抗原结合部分，其包含：
a)包含选自SEQ ID NO:3的第20位至134位的氨基酸序列的重链可变区；
b)包含选自SEQ ID NO:4的第20位至131位的氨基酸序列的轻链可变区。
3.编码权利要求2所述的抗人PD-1单克隆抗体基因，其特征在于：
a)编码重链的核苷酸序列如SEQ ID NO.1的第58位至402位所示；
b)编码轻链的核苷酸序列如SEQ ID NO.2的第58位至393位所示。
4.根据权利要求2所述的抗人PD-1单克隆抗体可变区序列，改变至少一个可变区抗体序列中的至少一个氨基酸残基，所述序列选自重链可变区抗体序列和轻链可变区抗体序列，以创造至少一个经改变的抗体序列和将经改变的抗体
序列表达成蛋白质。
5.根据权利要求3所述的抗人PD-1单克隆抗体可变区序列，经过一个或者几个碱基替换、缺失或添加后仍具有与所述核苷酸序列产生的氨基酸序列具有相同活性的核苷酸序列。
6.一种表达载体，包含权利要求1至5任意一项所述的核苷酸序列。
7.一种表达宿主，包含权利要求6所述的表达载体。
8.根据权利要求1至5所述的核苷酸序列在制备蛋白和抗体上的应用，上述蛋白和抗体包括：重组蛋白，重组抗体、ScFv抗体、人源化抗体、嵌合抗体、双特异性抗体、单域抗体以及ADC偶联抗体和蛋白。
9.权利要求1-8中任一项的抗体或抗体片段在制备用于以下方面的药物中的用途：
a).提高免疫细胞活化；
b).治疗癌症；
c).治疗感染或感染性疾病。
10.权利要求1-11中任一项的抗体或抗体片段用于诊断应用的用途。
11.一种药物组合物，包括治疗有效量的所述抗 PD-1 抗体。
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