CN113150153B - 一种抗人pdl1单克隆抗体及其用途 - Google Patents
一种抗人pdl1单克隆抗体及其用途 Download PDFInfo
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Abstract
本发明属于生物技术领域，涉及一种抗人PDL1单克隆抗体及其应用，同时提供了该抗体的编码核酸分子、表达载体、宿主细胞、以及用于表达该抗体的方法。本发明能特异识别人PDL1的单克隆抗体，该抗体与人PDL1结合的亲和力强于现有抗人PDL1单克隆抗体，序列新颖。
Description
技术领域
本发明属于生物技术领域，涉及了一种高亲和力且具有功能性的抗人PDL1的单克隆抗体或抗体片段。本发明同时提供了该抗体的编码核酸分子、表达载体、宿主细胞、以及用于表达该抗体的方法。还提供了包括本发明抗体的抗体免疫偶联缀合物、双特异性分子、嵌和抗原受体、药物组合物以及诊断和治疗方法。
背景技术
程序性死亡配体1(PD-L1)，也称为分化簇274(CD274)或B7同系物1(B7-H1)，是一种40kDa的I型跨膜蛋白。PDL1是PD-1的表面糖蛋白配体，PD-1是由活化的T细胞和B细胞表达的关键免疫检查点受体，并介导免疫抑制。PDL1与慢性感染、妊娠、同种异体移植、自身免疫性疾病和癌症期间的免疫系统反应的抑制有关。在抗原呈递细胞和人类癌细胞，例如头颈部鳞状细胞癌、黑色素瘤和脑瘤、甲状腺、胸腺、食道、肺、乳腺、胃肠道、结肠直肠、肝脏、胰腺、肾脏、肾上腺皮质、膀胱、尿路上皮、卵巢和皮肤上，都发现了PDL1(Katsuya Y.et al.(2015)."Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma".Lung Cancer.88(2):154–159；Nakanishi J.et al.(2007)."Overexpression of B7-H1(PD-L1)significantly associates with tumor grade and postoperative prognosisin human urothelial cancers".Cancer Immunol Immunother.56(8):1173–1182；NomiT.et al.(2007)."Clinical significance and therapeutic potential of theprogrammed death-1ligand/programmed death-1pathway in human pancreaticcancer".Clin Cancer Res.13(7):2151–2157；Fay AP et al.(2015)."Programmed deathligand-1expression in adrenocortical carcinoma:an exploratory biomarkerstudy".J Immunother Cancer.3:3；Strome SE et al.(2003)."B7-H1 blockadeaugments adoptive T-cell immunotherapy for squamous cell carcinoma".CancerRes.63(19):6501–6505；Jacobs JF.et al.(2009)."Regulatory T cells and the PD-L1/PD-1pathway mediate immune suppression in malignant human brain tumors".Neuro Oncol.11(4):394–402；Wilmotte R.et al.(2005)."B7-homolog 1 expressionby human glioma:a new mechanism of immune evasion".Neuroreport.16(10):1081–1085)。PDL1在正常组织中很少表达，但在肿瘤部位可诱导表达(Dong H.et al.(2002)."Tumor-associated B7-H1 promotes T-cell apoptosis:a potential mechanism ofimmune evasion".Nat Med.8(8):793–800；Wang.et al.(2016)."PD-L1 expression inhuman cancers and its association with clinical outcomes".Onco TargetsTher.9:5023–5039)。PDL1通过与PD-1结合而下调T细胞活化和细胞因子分泌(Freeman.etal.(2000)."Prolactin:structure,function,and regulation of secretion".PhysiolRev.80(4):1523-631；Latchman.et al.(2001)."PD-L2 is a second ligand for PD-1and inhibits T cell activation".Nat Immunol.2(3):261-268)。由PDL1激活的PD-1可能为肿瘤的发展和生长提供免疫耐受的环境。PDL1还通过与另一种受体B7.1(B7-1，CD80)相互作用来负调节T细胞功能。
PDL1/PD-1相互作用的抑制能够提供有效的抗肿瘤活性。已知多种抗PDL1的抗体(例如WO 2013/079174和WO 2017/118321)，并且许多破坏PD-1信号传导的抗体已进入临床开发阶段。这些抗体属于以下两个主要类别：靶向PD-1的抗体(nivolumab,Bristol-MyersSquibb；pembrolizumab,Merck,Whitehouse Station,NJ；pidilizumab,CureTech,Yavne,Israel)和靶向PDL1的抗体(MPDL3280A,Genentech,South San Francisco,CA；MEDI4736,MedImmune/AstraZeneca；BMS-936559,Bristol-Myers Squibb；MSB0010718C,EMD Serono,Rockland,MA)(Postow MA.et al.(2015)."Immune Checkpoint Blockade in CancerTherapy".J Clin Oncol.33(17):1974-82)。靶向PDL1与靶向PD-1可能导致不同的生物学效应。PD-1抗体可防止PD-1与它的两个配体PDL1和PDL2相互作用。尽管PD-1与PDL2相互作用的影响仍然未知，但PDL1抗体不会阻止PD-1与PDL2相互作用。然而，PDL1抗体不仅会阻止PDL1与PD-1的相互作用，还会阻止与B7-1的相互作用(Butte MJ.et al.(2007)."Programmed death-1ligand 1interacts specifically with the B7-1 costimulatorymolecule to inhibit T cell responses".Immunity.27(1):111-122)，这被认为会对T细胞产生负信号。阻断PDL1已显示出令人鼓舞的早期数据，目前正在测试四种临床抗PDL1mAb：atezolizumab和MEDI4736(均为人IgG1的Fc空变体)、MSB001078C(IgG1)和BMS-936559(IgG4)(Chester C.et al.(2016)."4-1BB agonism:adding the accelerator to cancerimmunotherapy".Cancer Immunol Immunother.65(10):1243-8)。
迄今为止，还没有证明令人满意的方法能够在癌症患者中诱导有效的免疫反应。在该领域中需要创造改善的PDL1/PD-1相互作用的治疗调节剂和方法以克服癌症患者中观察到的免疫抑制机制。
发明内容
为了克服上述缺陷，本发明的目的是提供一种抗人PDL1单克隆抗体及其用途，该抗体具有高亲和力和功能性，其优于现有的抗人PDL1单克隆抗体。
为了达到上述目的，本发明提供一种抗人PDL1单克隆抗体，其特征在于，所述抗体包含：重链和轻链；
所述的重链和轻链均包括可变区，所述可变区包括互补决定区；
所述重链的互补决定区CDR1、CDR2和CDR3分别用CDR-H1、CDR-H2和CDR-H3表示；
所述轻链的互补决定区CDR1、CDR2和CDR3分别用CDR-L1、CDR-L2和CDR-L3表示；
所述的CDR-H1的氨基酸序列为SEQ ID NO：3所示；
所述的CDR-H2的氨基酸序列为SEQ ID NO：4所示；
所述的CDR-H3的氨基酸序列为SEQ ID NO：5所示；
所述的CDR-L1的氨基酸序列为SEQ ID NO：6所示；
所述的CDR-L2的氨基酸序列为SEQ ID NO：7所示；
所述的CDR-L3的氨基酸序列为SEQ ID NO：8所示。
重链可变区氨基酸序列为SEQ ID NO：1所示；轻链可变区氨基酸序列为SEQ IDNO：2所示。
一种核苷酸分子，该核苷酸分子编码所述的抗人PDL1单克隆抗体；
该核苷酸分子的序列选自SEQ ID NO：9和SEQ ID NO：10；
序列SEQ ID NO：9编码所述的抗体的重链可变区；
序列SEQ ID NO：10编码所述的抗体的轻链可变区。
一种表达载体，该表达载体含有所述的核苷酸分子。
一种宿主细胞，该宿主细胞含有所述的表达载体。
一种抗人PDL1单克隆抗体的制备方法，该制备方法包含如下步骤：
步骤1：制备含有表达所述的抗PDL1单克隆抗体的核苷酸分子的表达载体；
步骤2：用步骤1的表达载体转染真核宿主细胞；
步骤3：培养步骤2转染的真核宿主细胞；
步骤4：分离纯化，获得所述的抗体。
本发明还涉及包括前述的抗人PDL1单克隆抗体的抗体免疫偶联缀合物、双特异性分子、嵌和抗原受体或药物组合物。
所述的重链和轻链都还包括恒定区，该恒定区为鼠IgG的恒定区，优选地为IgG1的恒定区。
所述的重链和轻链都包括恒定区，重链恒定区如SEQ ID NO：11所示；轻链恒定区如SEQ ID NO：12所示。
相对于现有技术，本发明具有以下优点：
本发明能特异识别人PDL1的单克隆抗体，该抗体与人PDL1结合的亲和力强于现有抗人PDL1单克隆抗体，序列新颖。
附图说明
图1为捕获ELISA测定抗体对人PDL1蛋白的结合能力；
图2为间接ELISA测定抗体对食蟹猴PDL1蛋白的交叉反应；
图3为流式细胞术测评抗体与细胞膜表面PDL1蛋白的结合；
图4为配体受体结合阻断ELISA；
图5为参照抗体阻断ELISA；
图6为流式细胞术测评抗体阻断PD1蛋白与细胞膜表面PDL1蛋白的结合；
图7为PDL1单克隆抗体功能测评实验。
具体实施方式
下文将通过实施例的方式进行本发明进一步的说明，但是本发明的保护范围不限于这些实施例。
一、抗体的获得：
实施例1通过融合杂交瘤技术获得特异性抗PDL1的小鼠单克隆抗体
1.1动物免疫
根据文献中(E Harlow,D.Lane,Antibody:A Laboratory Manual,Cold SpringHarbor Laboratory Press,Cold Spring Harbor,N.Y.,1998)通用的方法免疫小鼠。免疫原为重组人PDL1-Fc蛋白(公司自产，插入氨基酸序列为FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK)。使用重组人PDL1带his标签的蛋白(ACRO,Cat#PD1-H5229)作为测定血清效价和杂交瘤筛选的检测抗原。简要地，取出适量的福氏佐剂到1.5ml EP管中，振荡器混匀。用PBS配制人PDL1-Fc抗原蛋白溶液。按照需要量混匀佐剂和蛋白抗原溶液，通过注射器互推充分乳化抗原形成稳定油包水的溶液，而后进行动物注射。根据血清效价测定结果，首次免疫后通常需要进行2到3次加强免疫后才能达到良好的免疫效果。选择血清效价高的免疫小鼠进行腹腔注射，终免后进行细胞融合。
1.2杂交瘤融合和筛选
细胞融合前，培养小鼠骨髓瘤细胞(SP2/0-Ag14,ATCC,Cat#CRL-1581)处于对数生长期。处死免疫小鼠于无菌环境取脾，根据文献中方法使用PEG化学融合脾B细胞和SP2/0骨髓瘤细胞(E Harlow,D.Lane,Antibody:A Laboratory Manual,(Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.,1998)；Kohler G,and Milstein C,"Continuous cultures of fused cell secreting antibody of predefinedspecificity,"Nature,256:495-497(1975))。融合后的细胞铺96孔细胞培养板，通常7到10天后显微镜下可观察到存活的杂交瘤细胞生长出来。细胞铺板两周后，收集各孔培养上清，以ELISA方法用人PDL1-Fc蛋白抗原进行杂交瘤筛选。简述如下，用60μl含有1μg/ml的山羊抗小鼠IgG F(ab’)2特异性片段(Jackson Immunoresearch Laboratories,Inc.,Cat#115-005-072)的PBS溶液包被酶标板，4℃过夜。而后用含0.05％的吐温20的PBS溶液(即1xPBST)洗板1次后，加入200μl/孔含有5％脱脂奶粉的PBST溶液，置于37℃封闭2h。再次洗板，加入60μl/孔的杂交瘤上清，37℃孵育40min，而后洗板4次。加入100μl/孔的生物素标记人PDL1 Fc蛋白溶液(1：1000稀释在含2.5％脱脂奶粉的1x PBST中)，37℃孵育40min后洗板4次，拍干。而后以100μl/孔加入1：5000稀释在含5％脱脂奶粉的PBST溶液中的辣根过氧化物酶标记的链霉亲和素(Jackson ImmunoResearch Laboratories,Inc.,Cat#016-030-084)，37℃孵育40min后洗板4次,拍干。添加100μl/孔的TMB(InnoReagents,Cat#TMB-S-002)显色底物，室温显色5-15min，而后用1M的硫酸溶液终止，测定450nm处各孔的吸光值。挑出ELISA结合阳性的杂交瘤孔细胞，转移到24孔板中，继续培养。并通过ELISA方法进行第二轮复筛，筛选出特异识别PDL1抗原的杂交瘤(结果见表1，其中D6A2C2B2是本发明得到的杂交瘤，该杂交瘤表达本发明所制得的抗人PDL1单克隆抗体)，通过有限稀释法亚克隆，获得目标单克隆细胞株。而后小量表达生产小鼠单克隆抗体，纯化后的抗体进行下一步的功能测评分析。
表1融合杂交瘤上清检测ELISA数据
二、体外分析方法：
实施例2用于测定PDL1单克隆抗体功能活性的体外分析方法
2.1基于捕获ELISA测定抗体的结合能力
用1xPBS配制山羊抗小鼠IgG F(ab')2特异的二抗(Jackson ImmunoResearchLaboratories,Inc.,Cat#115-005-072)，使其终浓度为2μg/ml，以100μl/孔加液于96孔酶标板，37℃包被2h。包被结束后，用含0.05％的吐温20的PBS溶液(即1x PBST)洗板1次后，加入200μl/孔的含有5％脱脂奶粉的1x PBST溶液置于37℃封闭2h。再次洗板，加入100μl/孔的稀释抗体溶液以及PDL1-Benchmark(即Tecentriq抗体，购自Roche)后，37℃孵育40min，而后洗板4次。以100μl/孔加入生物素标记人PDL1 Fc蛋白溶液(1:10000稀释在含2.5％脱脂奶粉的1x PBST中)，37℃孵育40min，而后洗板4次。以100μl/孔加入1:10000稀释的辣根过氧化物酶标记的链霉亲和素(Jackson ImmunoResearch Laboratories,Inc.,Cat#016-030-084)，37℃孵育40min，而后洗板4次，拍干。添加100μl/孔的ELISA显色底物TMB(InnoReagents,Cat#TMB-S-002)，室温显色3-10min，而后用1M的硫酸溶液终止显色，测定450nm处各孔的吸光值。使用GraphPad Prism软件进行数据处理，结果如图1。从图中可以看出，本发明的D6A2C2B2单克隆抗体能够识别人PDL1抗原，且结合活性优于PDL1-Benchmark。
2.2间接ELISA测定抗体与食蟹猴PDL1抗原的交叉反应能力
用1x carbonate/bicarbonate buffer配制食蟹猴PDL1抗原(Sino BiologicalInc,Cat#90251-C08H)，使其终浓度为2μg/ml，以100μl/孔加液于96孔酶标板，37℃包被2h。包被结束后，用含0.05％的吐温20的PBS溶液(即1x PBST)洗板4次后，加入200μl/孔的含有5％脱脂奶粉的1x PBST溶液置于37℃封闭2h。再次洗板，加入100μl/孔的梯度稀释抗体溶液后，37℃孵育40min，而后洗板4次。以100μl/孔加入1：5000稀释的辣根过氧化物酶标记的山羊抗小鼠Fcγ特定片段(Jackson ImmunoResearch Laboratories,Inc.,Cat#115-035-071)，37℃孵育40min，而后洗板4次，拍干。添加100μl/孔的ELISA显色底物TMB(InnoReagents,Cat#TMB-S-002)，室温显色3-10min，而后用1M的硫酸溶液终止显色，测定450nm处各孔的吸光值。使用GraphPad Prism软件进行数据处理，结果如图2。从图中可以看出，本发明的D6A2C2B2单克隆抗体与食蟹猴PDL1抗原发生交叉反应，且结合活性优于PDL1-Benchmark。
2.3流式细胞术测评抗体结合细胞膜表面PDL1抗原的结合能力
收集处于对数生长期的膜表面过表达人PDL1蛋白的GS-C2/PDL1细胞系(Genscript)，用PBS洗细胞2次后用FACS缓冲液(含2％胎牛血清的PBS溶液)重悬细胞。调节密度，以1x105个细胞/孔铺板于96孔U底板中，300g离心5min，倾去上清，添加以10％FBSDMEM梯度稀释的PDL1抗体溶液及对照抗体后，4℃孵育40min。300g离心5min，倾去上清。再用FACS缓冲液洗细胞2次，添加100μL/孔R-Phycoerythrin AffiniPure F(ab')2FragmentGoat Anti-Mouse IgG(H+L)(Jackson Immunoresearch,Cat#115-116-148，1：1000稀释)，4℃孵育40min后，300g离心5min，倾去上清。再用FACS缓冲液洗细胞2次。而后每孔加100μL的PBS重悬，吹匀细胞后上机检测。使用BD公司Canto II型号流式细胞仪测定每孔细胞的平均荧光强度MFI值。使用GraphPad Prism软件进行数据处理，得出抗体结合细胞的EC50浓度值(即达到该抗体最大荧光结合信号50％时对应的抗体浓度值)，结果如图3。从图中可以看出，本发明的D6A2C2B2单克隆抗体可特异性结合细胞膜表面的人PDL1蛋白，且结合活性优于PDL1-Benchmark。
2.4 PDL1抗体阻断活性检测
2.4.1配体受体结合阻断ELISA
通过竞争ELISA方法测评PDL1抗体对PD1/PDL1结合的阻断能力。简述如下，用1xcarbonate/bicarbonate buffer配制人PDL1 Fc抗原，使其终浓度为2μg/ml，以100μl/孔加液于96孔酶标板，37℃包被2h。包被结束后，用含0.05％的吐温20的PBS溶液(即1x PBST)洗板1次后，加入200μl/孔的含有5％脱脂奶粉的1x PBST溶液置于37℃封闭2h。再次洗板，加入100μl/孔的梯度稀释抗体溶液后，37℃孵育40min，而后洗板4次。以100μl/孔加入1：4000稀释的生物素标记的人PDL1 Fc抗原，37℃孵育40min，洗板4次，拍干。而后以100μl/孔加入1：10000稀释在1x PBST溶液中的辣根过氧化物酶标记的链霉亲和素，37℃孵育40min后，洗板4次,拍干。添加TMB显色和1M硫酸终止反应，测定450nm处的吸收值。使用GraphPad Prism软件进行数据处理，得出抗体阻断PD1/PDL1结合的IC50浓度值，结果表明本发明的D6A2C2B2单克隆抗体能够特异性阻断PD1与PDL1的结合，且其阻断能力与PDL1-Benchmark相当。
2.4.2参照抗体阻断ELISA
通过竞争ELISA方法测评PDL1抗体阻断参照抗体/PDL1抗原结合的阻断能力。简述如下，用1x PBS配制参照抗体(PDL1-Benchmark)，使其终浓度为1μg/ml,以100μl/孔加液于96孔酶标板，4℃包被过夜。次日，用含0.05％的吐温20的PBS溶液(即1x PBST)洗板1次后，加入200μl/孔的含5％脱脂奶粉的PBST溶液，置于37℃封闭2h，再次洗板4次。把PDL1抗体或对照抗体梯度稀释在含有生物素标记的人PDL1 Fc蛋白溶液中，配好后室温预孵40min。而后把已孵育的抗体和PDL1 Fc biotin的溶液以100μl/孔加到包被好参照抗体的板上，37℃孵育40min后，再次洗板4次。而后以100μl/孔加入1：10000稀释在含5％脱脂奶粉的1x PBST溶液中的辣根过氧化物酶标记的链霉亲和素中，37℃孵育40min，洗板4次,拍干。添加TMB显色和1M硫酸终止反应，测定450nm处的吸收值。使用GraphPad Prism软件进行数据处理，得出抗体阻断参照抗体与PDL1结合的IC50浓度值，结果如图5。从图中可以看出，本发明的D6A2C2B2单克隆抗体能够特异性阻断PDL1蛋白结合其参照抗体PDL1-Benchmark，且其阻断能力与PDL1-Benchmark相当，提示本发明的D6A2C2B2单克隆抗体结合抗原的表位和PDL1-Benchmark相近。
2.4.3流式细胞术测评抗体阻断PD1蛋白与细胞膜表面PDL1蛋白的结合
收集处于对数生长期的膜表面过表达人PDL1蛋白的GS-C2/PDL1细胞系(Genscript)，用PBS洗细胞2次后，用FACS缓冲液(含2％胎牛血清的PBS溶液)重悬细胞。调节密度，以1x105个细胞/孔铺板于96孔U底板中，300g离心5min，倾去上清，把稀释在FACS缓冲液中的PDL1抗原及对照抗体以100μl/孔加入到膜表面过表达人PDL1蛋白的GS-C2/PDL1的细胞板上。4℃孵育40min，300g离心5min，倾去上清。再用FACS缓冲液洗细胞2次，加入100μL/孔生物素标记的人PD1 Fc(1:1500稀释在FACS缓冲液中)。4℃孵育40min后，300g离心5min，倾去上清。再用FACS缓冲液洗细胞2次，每孔加入100μL的SA-PE(JacksonImmunoresearch,Cat#016-110-084，1：500稀释)，4℃孵育40min，300g离心5min，倾去上清。再用FACS缓冲液洗细胞2次。而后每孔加100μL的PBS重悬，吹匀细胞后上机检测。使用BD公司Canto II型号流式细胞仪测定每孔细胞的平均荧光强度MFI值。使用GraphPad Prism软件进行数据处理，得出抗体阻断PD1/PDL1结合的IC50浓度值，结果如图6。从图中可以看出，本发明的D6A2C2B2单克隆抗体可特异性阻断人PD1蛋白结合细胞膜表面的人PDL1配体，其阻断能力与PDL1-Benchmark相当，提示本发明的D6A2C2B2是与参照抗体相当且具有PD1/PDL1阻断活性的功能抗体。
2.5 PDL1单克隆抗体功能测评实验
收集处于对数生长期的GS-C2/PDL1细胞系(Genscript，抗原呈递细胞)，用DPBS(Hyclone，Cat#SH30028.02)洗细胞后，完全生长培养基(购自Gibco，含10％胎牛血清的F-12K培养基)重悬细胞。调节密度，以20μl/孔(约1x104个细胞)铺板于384-well assayplates，37℃，5％CO2培养箱过夜培养。次日，准备处于对数生长期的GS-J2/PD1细胞系(Genscript，效应细胞)，200g离心5min，倾去上清。用assay buffer(购自Gibco，含1％胎牛血清的RPMI 1640培养基)重悬细胞。调节细胞密度为7.5x105细胞/ml。弃去PDL1细胞上清，加入20μl PDL1抗体或对照抗体(梯度稀释在2倍浓度的assay buffer)以及20μl PD1细胞(7.5x105细胞/ml)，37℃，5％CO2培养箱培养6h。培养结束后，移出384孔细胞培养板至室温。5-10min后，每孔加入30μl luciferase substrate reagent。室温静置5min，使用PHERAStarPlus仪器检测生物发光强度。使用GraphPad Prism软件进行数据处理，结果如图7。从图中可以看出，本发明的D6A2C2B2单克隆抗体能够逆转GS-J2/PD-1细胞中PD-1-PD-L1相互作用诱导的萤光素酶表达的降低，其效果与PDL1-Benchmark相当。
实施例3 DNA克隆和测序，抗PDL1小鼠单克隆抗体的可变区测序
使用FastPure Cell/Tissue Total RNA Isolation Kit(Vazyme，Cat#RC101)从培养的小鼠单克隆细胞株中提取总RNA。过程简述如下，离心收集1.5x106的细胞到1.5ml离心管中，吸干上清。向细胞沉淀中加入500μl Buffer RL1，并吹打混匀。将处理好的细胞转移到gDNA-Filter Columns中(gDNA-Filter Columns已放入收集管中)，13,000g室温离心2min，保留收集管内上清液。加入1.6倍体积Buffer RL2，轻柔混匀。混合液转移至RNAPureColumns中，13,000g室温离心1min，弃废液。向RNAPure Columns中加入500μl Buffer RW1，13,000g室温离心1min，弃废液。加入700μl Buffer RW2，13,000g室温离心1min，弃废液。再加入700μl Buffer RW2，13,000g室温离心1min，弃废液。13,000g离心2min，以彻底去RNAPure Columns中残留的Buffer RW2。将吸附柱转移至新的RNase-free CollectionTubes 1.5ml离心管中，向吸附柱中央部位悬空滴加50μl的RNase-free ddH2O。室温放置2min，13,000g室温离心1min，洗脱RNA。
紧接着，选用Takara的逆转录cDNA试剂盒(Cat#6210A)把总RNA变为CDNA。实验体系配制如下，5μl总RNA+0.5μl Oligo(dT)Primer+0.5μl Random 6mers+1.0μl dNTPMixture+3.0μl RNase-free ddH2O(共10μl)。先置于65℃5min预变性，而后放冰上2min。进一步加入4μl 5x PrimeScript II Buffer+0.5μl RNase Inhibitor+1.0μl PrimeScriptII RTase+4.5μl RNase-free ddH2O(共20μl体系)，配好后混匀，使用PCR仪运行40℃50min后，转70℃运行10min，完成cDNA合成。
cDNA进一步在3’端加Poly G，反应体系配制如下：5μl cDNA+33.5μl ddH2O+5μl10x TdT Buffer+5μl CoCl+1μl dGTP+0.5μl Terminal TransPerase(共50μl体系)，配好后混匀，使用PCR仪运行37℃30min后，转70℃10min，完成Poly G加尾。
进一步，以加尾的cDNA为模板进行抗体可变区的基因扩增。对于扩增抗体重链可变区序列，选用诺唯赞的试剂盒(Cat#P525-03)，配制PCR反应体系：25μl 2x Phanta MaxMaster Mix(Dye Plus)+2.0μl BSJ-Pri3 AntisenseP-mIgG1(核苷酸序列为GCATCCCAGGGTCACCATGGAGTTAGTT)+2.0μl BSJ-Pri1 Universal C1(核苷酸序列为AAGCAGTGGTATCAACGCAGAGTCATCCCCCCCCCCCCCCCC)+1.25μl加Poly G尾的cDNA+19.75μl ddH2O(共50μl体系)。对于扩增抗体轻链可变区序列，先用Takara的试剂盒(Cat#R010A)，配制PCR反应体系：10μl 5x PrimeSTAR Buffer+0.5μl PrimeSTAR+1.25μl BSJ-Pri1 Universal C1(核苷酸序列为AAGCAGTGGTATCAACGCAGAGTCATCCCCCCCCCCCCCCCC)+1.25μl BSJ-Pri19(核苷酸序列为GCACACGACTGAGGCACCTCCAGATGTT)+4μl aberrant-L-R2(核苷酸序列为TCTGGCTATAGTTATATGCACTGGAACCAACAGAAACCAGGACAGC)+4μl dNTP+1.25μl加Poly G尾的cDNA+27.75μl ddH2O(共50μl体系)。
抗体重链可变区PCR扩增的温度循环如下：
98℃*5min+(98℃*10s+62℃*10s+72℃*1min)*2Cycle+(98℃*10s+60℃*10s+72℃*1min)*4Cycles+(98℃*10s+58℃*10s+72℃*1min)*10Cycles+(98℃*10s+56℃*10s+72℃*1min)*20Cycles+72℃*10min+4℃*∞
抗体轻链可变区PCR扩增的温度循环如下：
98℃*5min+(98℃*10s+64℃*10s+72℃*1min)*2Cycle+(98℃*10s+62℃*10s+72℃*1min)*6Cycles+(98℃*10s+60℃*10s+72℃*1min)*12Cycles+(98℃*10s+58℃*10s+72℃*1min)*16Cycles+72℃*10min+4℃*∞
PCR产物经1％琼脂糖凝胶电泳分析，切出对应大小的DNA区段条带(VH的约500bp，Vkappa轻链约500bp)，用TIANGEN的凝胶DNA回收试剂盒(Cat#DP209-03)进行DNA的抽提。简述如下：凝胶称重，加入等倍体积溶液PN，而后50℃孵育10min直到凝胶完全溶解。将所得的溶液移至CA2吸附柱中(吸附柱放入收集管中)，室温放置至少2min，12,000rpm室温离心30sec，弃去废液。加入600μl的漂洗液PW到柱中，而后12,000rpm室温离心30sec，弃去废液。再次加入600μl的漂洗液PW到柱中，静置5min，12,000rpm室温离心30sec，弃去废液。并再次12,000rpm室温离心2min，去除柱中液体残留，并室温放置至少2min以彻底晾干残留液体。吸附柱放到一个干净的离心管，加入35μl的洗脱缓冲液EB，室温放置至少2min。12,000rpm离心2min，获得制备的DNA样品。纯化的PCR产物经测序获得抗体的可变区序列如表2所示，PDL1小鼠单克隆抗体的氨基酸全长序列如下文所示，PDL1小鼠单克隆抗体的核苷酸序列如下文所示。
表2 PDL1小鼠单克隆抗体的可变区氨基酸序列和CDR区
PDL1小鼠单克隆抗体的氨基酸全长序列如下：
D6A2C2B2小鼠PDL1单克隆抗体的氨基酸序列
VH(重链可变区)
EVQLQQSGPELLKPGASVKISCKASGYTFTDYTMHWVKQSHGKSLEWIGGFNPNYGDTSYNEKFKDKATLTVDKSSTTAYMELRSLTSEDSAVYYCGRGHGYYGYVMDSWGQGTSVTVSS(SEQ ID No:1)
CH(重链恒定区)
AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK(SEQ ID No:11)
VL(轻链可变区)
DIVMTQSPATLSVTPGDRVSFSCRASQSISLYLHWYQQKSHESPRLLIKYASQSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFPPTFGGGTKLEIK(SEQ ID No:2)
CL(轻链恒定区)
RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRGEC(SEQ ID No:12)
PDL1小鼠单克隆抗体的编码DNA序列如下：
重链可变区的DNA序列
5’-GAGGTCCAGCTGCAACAGTCTGGACCTGAACTGCTGAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGGCTTCTGGATACACATTCACTGACTACACCATGCACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAGGTTTTAATCCTAATTATGGTGATACTAGTTATAACGAGAAGTTCAAGGACAAGGCCACATTGACTGTAGACAAGTCCTCAACTACAGCCTACATGGAGCTCCGCAGCCTGACATCTGAGGATTCTGCAGTCTATTATTGTGGAAGAGGACATGGTTACTACGGCTATGTTATGGACTCCTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA-3’(SEQ IDNo:9)
重链恒定区的DNA序列
5’-GCCAAAACGACACCCCCATCTGTCTATCCACTGGCCCCTGGATCTGCTGCCCAAACTAACTCCATGGTGACCCTGGGATGCCTGGTCAAGGGCTATTTCCCTGAGCCAGTGACAGTGACCTGGAACTCTGGATCCCTGTCCAGCGGTGTGCACACCTTCCCAGCTGTCCTGCAGTCTGACCTCTACACTCTGAGCAGCTCAGTGACTGTCCCCTCCAGCACCTGGCCCAGCGAGACCGTCACCTGCAACGTTGCCCACCCGGCCAGCAGCACCAAGGTGGACAAGAAAATTGTGCCCAGGGATTGTGGTTGTAAGCCTTGCATATGTACAGTCCCAGAAGTATCATCTGTCTTCATCTTCCCCCCAAAGCCCAAGGATGTGCTCACCATTACTCTGACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGGATGATCCCGAGGTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACAGCTCAGACGCAACCCCGGGAGGAGCAGTTCAACAGCACTTTCCGCTCAGTCAGTGAACTTCCCATCATGCACCAGGACTGGCTCAATGGCAAGGAGTTCAAATGCAGGGTCAACAGTGCAGCTTTCCCTGCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGCAGACCGAAGGCTCCACAGGTGTACACCATTCCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGTCAGTCTGACCTGCATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAGTGGAATGGGCAGCCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGACACAGATGGCTCTTACTTCGTCTACAGCAAGCTCAATGTGCAGAAGAGCAACTGGGAGGCAGGAAATACTTTCACCTGCTCTGTGTTACATGAGGGCCTGCACAACCACCATACTGAGAAGAGCCTCTCCCACTCTCCTGGTAAATGA-3’(SEQ ID No:13)
轻链可变区的DNA序列
5’-GACATTGTGATGACTCAGTCTCCAGCCACCCTGTCTGTGACTCCAGGAGATAGAGTCTCTTTTTCCTGCAGGGCCAGCCAGAGTATTAGTCTCTACTTACACTGGTATCAACAAAAATCACATGAGTCTCCCAGGCTTCTCATCAAATATGCTTCCCAATCCATCTCTGGGATCCCCTCCAGGTTCAGTGGCAGTGGATCAGGGTCAGATTTCACTCTCAGTATTAACAGTGTGGAACCTGAAGATGTTGGAGTGTATTATTGTCAAAATGGTCACAGCTTTCCTCCGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA-3’(SEQ ID No:10)
轻链恒定区的DNA序列
5’-CGGGCTGATGCTGCACCAACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCTCACGTTGACTAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGGAGAGTGT-3’(SEQ ID No:14)
综上所述，本发明的能特异识别人PDL1的单克隆抗体D6A2C2B2，该抗体与人PDL1结合的亲和力更强，序列新颖，且能特异阻断人PD1和人PDL1结合，是新的抗人PDL1的单克隆功能抗体。
尽管本发明的内容已经通过上述优选实施例作了详细介绍，但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后，对于本发明的多种修改和替代都将是显而易见的。因此，本发明的保护范围应由所附的权利要求来限定。
序列表
<110> 博奥信生物技术（南京）有限公司
<120> 一种抗人PDL1单克隆抗体及其用途
<160> 14
<170> SIPOSequenceListing 1.0
<210> 1
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Leu Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Thr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Gly Phe Asn Pro Asn Tyr Gly Asp Thr Ser Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Gly Arg Gly His Gly Tyr Tyr Gly Tyr Val Met Asp Ser Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 2
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Ser Leu Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 3
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Asp Tyr Thr Met His
1 5
<210> 4
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Gly Phe Asn Pro Asn Tyr Gly Asp Thr Ser Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asp
<210> 5
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gly His Gly Tyr Tyr Gly Tyr Val Met Asp Ser
1 5 10
<210> 6
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Arg Ala Ser Gln Ser Ile Ser Leu Tyr Leu His
1 5 10
<210> 7
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Tyr Ala Ser Gln Ser Ile Ser
1 5
<210> 8
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Gln Asn Gly His Ser Phe Pro Pro Thr
1 5
<210> 9
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
gaggtccagc tgcaacagtc tggacctgaa ctgctgaagc ctggggcttc agtgaagata 60
tcctgcaagg cttctggata cacattcact gactacacca tgcactgggt gaagcagagc 120
catggaaaga gccttgagtg gattggaggt tttaatccta attatggtga tactagttat 180
aacgagaagt tcaaggacaa ggccacattg actgtagaca agtcctcaac tacagcctac 240
atggagctcc gcagcctgac atctgaggat tctgcagtct attattgtgg aagaggacat 300
ggttactacg gctatgttat ggactcctgg ggtcaaggaa cctcagtcac cgtctcctca 360
<210> 10
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
gacattgtga tgactcagtc tccagccacc ctgtctgtga ctccaggaga tagagtctct 60
ttttcctgca gggccagcca gagtattagt ctctacttac actggtatca acaaaaatca 120
catgagtctc ccaggcttct catcaaatat gcttcccaat ccatctctgg gatcccctcc 180
aggttcagtg gcagtggatc agggtcagat ttcactctca gtattaacag tgtggaacct 240
gaagatgttg gagtgtatta ttgtcaaaat ggtcacagct ttcctccgac gttcggtgga 300
ggcaccaagc tggaaatcaa a 321
<210> 11
<211> 324
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
1 5 10 15
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
100 105 110
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
115 120 125
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
130 135 140
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
145 150 155 160
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
165 170 175
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
180 185 190
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
195 200 205
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
210 215 220
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
225 230 235 240
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
245 250 255
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
260 265 270
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
275 280 285
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
290 295 300
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
305 310 315 320
Ser Pro Gly Lys
<210> 12
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
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 Gly Glu Cys
100 105
<210> 13
<211> 975
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 60
tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 120
tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 180
ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 240
acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 300
gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 360
cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 420
gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 480
gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 540
agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 600
aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 660
aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 720
agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 780
aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 840
tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 900
acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 960
tctcctggta aatga 975
<210> 14
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
cgggctgatg ctgcaccaac tgtatccatc ttcccaccat ccagtgagca gttaacatct 60
ggaggtgcct cagtcgtgtg cttcttgaac aacttctacc ccaaagacat caatgtcaag 120
tggaagattg atggcagtga acgacaaaat ggcgtcctga acagttggac tgatcaggac 180
agcaaagaca gcacctacag catgagcagc accctcacgt tgactaagga cgagtatgaa 240
cgacataaca gctatacctg tgaggccact cacaagacat caacttcacc cattgtcaag 300
agcttcaaca ggggagagtg t 321
Claims (10)
1.一种抗人PDL1单克隆抗体，其特征在于，所述抗体包含重链和轻链；
所述重链和轻链均包括可变区，所述可变区包括互补决定区；
所述重链的互补决定区CDR1、CDR2和CDR3分别用CDR-H1、CDR-H2和CDR-H3表示；
所述轻链的互补决定区CDR1、CDR2和CDR3分别用CDR-L1、CDR-L2和CDR-L3表示；
所述的CDR-H1的氨基酸序列如SEQ ID NO：3所示；
所述的CDR-H2的氨基酸序列如SEQ ID NO：4所示；
所述的CDR-H3的氨基酸序列如SEQ ID NO：5所示；
所述的CDR-L1的氨基酸序列如SEQ ID NO：6所示；
所述的CDR-L2的氨基酸序列如SEQ ID NO：7所示；
所述的CDR-L3的氨基酸序列如SEQ ID NO：8所示。
2.根据权利要求1所述的抗人PDL1单克隆抗体，其特征在于，重链可变区氨基酸序列如SEQ ID NO：1所示；轻链可变区氨基酸序列如SEQ ID NO：2所示。
3.根据权利要求1所述的抗人PDL1单克隆抗体，其特征在于，所述的重链和轻链都包括恒定区，重链恒定区如SEQ ID NO：11所示；轻链恒定区如SEQ ID NO：12所示。
4.一种核苷酸分子，其特征在于，所述核苷酸分子编码如权利要求1~3任一项所述的抗人PDL1单克隆抗体。
5.根据权利要求4所述的核苷酸分子，其特征在于，所述核苷酸分子的序列选自SEQ IDNO：9和SEQ ID NO：10；
序列SEQ ID NO：9编码所述的抗体的重链可变区；
序列SEQ ID NO：10编码所述的抗体的轻链可变区。
6.一种表达载体，其特征在于，该表达载体含有如权利要求4或5所述的核苷酸分子。
7.一种宿主细胞，其特征在于，该宿主细胞含有如权利要求6所述的表达载体。
8.根据权利要求1~3任一项所述抗人PDL1单克隆抗体的制备方法，其特征在于，包含如下步骤：
制备含有表达如权利要求1~3任一项所述的抗人PDL1单克隆抗体的核苷酸分子的表达载体；
用得到的表达载体转染真核宿主细胞并培养；
分离纯化，获得抗人PDL1单克隆抗体。
9.包括权利要求1所述的抗人PDL1单克隆抗体的抗体免疫偶联缀合物、双特异性分子、嵌和抗原受体或药物组合物。
10.权利要求1所述的抗人PDL1单克隆抗体在制备抗实体瘤药物中的应用。
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