CN114316047B - 一组pd-1单克隆抗体及其医药用途 - Google Patents
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Abstract
本发明属于肿瘤治疗和分子免疫学领域;具体涉及一组抗PD‑1受体的单克隆抗体及其医药用途。本发明通过杂交瘤技术获得了一组在阻断PD‑1的抑制信号,从而活化人体T淋巴细胞方面有优异效果的抗PD‑1单克隆抗体,并成功地对其进行了人源化改造。所述抗体在制备应用于激活和调节PD‑1的作用、水平以及显著增强机体免疫力的相关药物,尤其是治疗癌症相关药物方面具有广阔的应用前景。
Description
技术领域
本发明属于肿瘤免疫治疗和分子免疫学领域,涉及PD-1抗体及其用途。具体地,本发明涉及到多种PD-1单克隆抗体。
技术背景
程序性死亡受体1(PD-1),也称为CD279,由位于2号染色体长臂37区3带(2q37.3)的PDCD1基因编码,是一个55KD的跨膜蛋白(Agata,et al.,(1996),Int.Immunol.8:765-772)。PD-1是免疫球蛋白B7-CD28家族成员之一,由胞外区、疏水性跨膜区、胞内区组成,其胞内段含有免疫受体酪氨酸抑制基序(immunoreceptor tyrosine-based inhibitorymotif,ITIM)以及免疫受体酪氨酸转换基序(immunoreceptor tyrosine-based switchmotif,ITSM)。其中,ITSM的激活与效应T细胞活性密切相关(Ishida,et al.,(1992)EMBO J11:3887-3895)。PD-1蛋白在B淋巴细胞、T淋巴细胞、自然杀伤细胞(natural killer cell,NK)、单核细胞和树突状细胞(dendritic cell,DC)均有表达(Duraiswamy,et al.,(2013)Cancer Res.73:6900-12)。
PD-1有两个配体,分别为PD-L1(也称为B7-H1、CD274)和PD-L2(也称为B7-DC、CD273)两者都是膜蛋白,其胞外区具有IgV样结构域和IgC样结构域。PD-L1广泛表达于造血细胞、非造血细胞及肿瘤细胞等表面(Lesterhuis,et al.,(2011)Mol Immunol 49:1-3)。PD-L1被认为是PD-1的主要配体,但PD-L2对PD-1的亲和力比PD-L1高2-6倍。PD-L2主要表达于抗原呈递细胞和Th2细胞,在其它细胞中通常处于低表达状态,因此对PD-L1与PD-1的结合一般没有影响(Rozali,et al.,(2012)Clin.Dev.Immunol.2012:656340)。
PD-1/PD-L1信号通路的激活可导致免疫抑制性肿瘤微环境形成,使肿瘤细胞逃避机体免疫监控和清除。而阻断PD-1/PD-L1信号通路可以逆转肿瘤免疫微环境,增强机体内源性抗肿瘤免疫效应(Pardoll,et al.,(2012)Nat.Rev.Cancer 12:252-264)。PD-1受体通过与其配体PD-L1结合可抑制T细胞的活化增殖和细胞因子的分泌,负性调控免疫应答,并诱导T细胞的凋亡。阻断PD-1/PD-L1信号通路可以重新激活肿瘤患者体内的T细胞,增强对肿瘤的抑制和杀伤(Wherry,et al.,(2015)Nat.Rev.Immunol.15:486-499)。研究表明,PD-1/PD-L1信号通路激活后,通过下调Akt通路活性,诱导调节性T细胞的产生并维持其功能,从而起到免疫抑制的作用(Francisco,et al.(2009)J.Exp.Med.206:3015-3029)。PD-1/PD-L1通路的信号传导,同时需要PD-1与其配体PD-L1的结合以及MHC-抗原肽复合物与T细胞表面的TCR相互作用(Maine,et al.,(2014)Cancer Immunol.Immunother.63(3):215-224;Dai,et al.(2014)Cell Immunol.290:72-79)。
在小鼠模型中,利用抗PD-1抗体阻断PD-1/PD-L1信号通路可以减少促癌细胞因子的表达,增强效应T细胞的功能,改善肿瘤微环境,延长小鼠寿命(Balai,et al.,(2014)Carcinogenesis 35:424-431)。研究表明,PD-1基因敲除小鼠易发生自身免疫病,间接证明阻断PD-1/PD-L1信号通路可以增强机体免疫应答作用(Nishimura,et al.,(2001)Science291:319-322;Dong,et al.,(2004)Immunity 20:327-336)。临床实验显示,抗PD-1抗体可激活机体免疫效应,发挥有效的抗肿瘤作用,在黑色素瘤患者治疗过程中,展现了比其他抑制类药物更高的客观应答率(objective response rate,ORR)、持久的疗效和更长的生存期(Robert,et al.,(2015)N.Engl.J.Med.372:320-330;Weber,et al.,(2015)LancetOncol.16:375-384)。非小细胞癌(non-small cell lung cancer,NSCLC)患者对PD-1抗体药物也有较好的应答率;与传统药物相比,PD-1抗体治疗能够显著降低死亡风险,并且毒性反应较低(Brahmer,et al.(2015)N.Engl.J.Med.373:123-135)。抗PD-1抗体治疗可以与放射治疗、化学疗法、激酶抑制剂或表观遗传学药物等联合使用(Galluzzi,et al.,(2015)Cancer Cell 28:690)。有研究表明,对黑色素瘤患者,采用抗CTLA-4和抗PD-1联合治疗可以显著增加临床疗效,在提高对肿瘤的抑制和清除,延长患者的生存期方面效果显著(Larkin,et al.,(2015)N Engl.J.Med.373:23)。免疫检查点阻滞药物的联合治疗或者双功能抗体药物治疗目前已经变成一种趋势,也为创新型抗体研发提供了新的契机,为免疫治疗提供了新的思路。目前临床使用的PD-1抗体药物对PD-1的结合亲和力不高,一般在纳摩尔级,临床使用剂量较高。因此,开发疗效更好的新型PD-1抗体在肿瘤免疫治疗领域仍然具有重要的社会意义和经济价值。
发明内容
本发明采用杂交瘤技术获得了一组在阻断PD-1与PD-L1的相互作用方面具有优异效果的抗PD-1单克隆抗体,并成功对其进行了人源化改造。这些抗体在制备应用于阻断或调节PD-1水平、以及治疗癌症的相关药物方面有巨大的应用前景。
本发明提供的鼠源或人源化PD-1抗体或功能性片段,包括了重链序列和轻链序列。抗人PD-1鼠源抗体的重链可变区、轻链可变区的氨基酸序列信息如下:10A10重链可变区、轻链可变区的氨基酸序列分别为SEQ ID NO:1、2;4B5重链可变区、轻链可变区的氨基酸序列分别为SEQ ID NO:3、4;9H8重链可变区、轻链可变区的氨基酸序列分别为SEQ ID NO:5、6;8D4重链可变区、轻链可变区的氨基酸序列分别为SEQ ID NO:7、8;5F7重链可变区、轻链可变区的氨基酸序列分别为SEQ ID NO:9、10;5H10重链可变区、轻链可变区的氨基酸序列分别为SEQ ID NO:11、12。
抗人PD-1鼠源抗体重链及轻链的CDR1、CDR2、CDR3氨基酸序列信息如下:10A10重链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:13、14、15,其轻链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:16、17、18;4B5重链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:19、20、21,其轻链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:22、23、24;9H8重链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:25、26、27,其轻链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:28、29、30;8D4重链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:31、32、33,其轻链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:34、35、36;5F7重链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:37、38、39,其轻链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:40、41、42;5H10重链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:43、44、45,其轻链CDR1、CDR2、CDR3氨基酸序列分别为SEQ ID NO:46、47、48。
进一步,抗人PD-1抗体或片段经过改造后,成为人源化抗体。
分离的核酸分子,其编码上述的抗体或功能性片段。
抗人PD-1人源化抗体9H8重链和轻链可变区氨基酸序列为SEQ ID NO:49、50;人源化抗体8D4重链和轻链可变区氨基酸序列为SEQ ID NO:51、52。
表达载体,包含上述抗体的核酸分子。
药物组合物,其包含上述的抗体或其功能片段,以及药用载体。一种单克隆抗体偶联物,包括单克隆抗体和偶联部分,其中,所述单克隆抗体为上述PD-1单克隆抗体或其抗原结合片段,所述偶联部分为选自放射性核素、药物、毒素、细胞因子、细胞因子受体片段、酶、荧光素、和生物素中的一种或多种。
上述的抗体或其功能性片段,抗体偶联物、核酸分子、表达载体、宿主细胞、药物组合物在制备PD-1免疫功能药物的用途。
本专利采用重组的PD-1胞外区片段作为抗原,免疫小鼠后,将小鼠脾脏细胞与骨髓瘤细胞融合获得杂交瘤细胞。通过对大量杂交瘤细胞进行多次克隆及筛选,得到多个单克隆杂交瘤细胞株。这些杂交瘤细胞株可以分泌产生与PD-1特异性结合的单克隆抗体(图1、图3),这些单克隆抗体能够有效阻断PD-1与PD-L1的结合(图2,图4),并能促进人CD4+T细胞分泌细胞因子IL-2和IFN-γ(图5a,5b)。进一步地,通过RT-PCR(ReverseTranscription-Polymerase Chain Reaction,逆转录聚合酶链式反应)克隆编码抗体轻链和重链可变区的基因,采用互补决定簇嫁接方法(complementarity-determining regionsgraft,CDR-graft)构建人源化抗体。体外功能实验表明,人源化PD-1抗体能特异性结合PD-1蛋白(图6、图8),并能阻断PD-1与PD-L1的结合(图7、图9)。与默克公司的阳性对照抗体pembrolizumab相比,本专利中的人源化抗体具有更高的PD-1结合亲和力以及更强的促进人CD4+T细胞分泌细胞因子IL-2和IFN-γ的活性(表7,图10)。阳性对照抗体pembrolizumab的序列来自默克的专利US8168757B2。
附图说明
图1:用ELSIA方法检测鼠源PD-1单克隆抗体与PD-1-hFc蛋白结合的EC50;
图2:用ELSIA方法检测鼠源PD-1单克隆抗体阻断配体PD-L 1结合PD-1-hFc的IC50;
图3:用FACS方法检测鼠源PD-1单克隆抗体结合293T-PD-1细胞的EC50;
图4:用FACS方法检测鼠源PD-1单克隆抗体阻断配体PD-L1结合293T-PD-1细胞的IC50;
图5a-5b:用混合淋巴细胞反应(MLR)方法检测鼠源PD-1单克隆抗体对CD4+T细胞分泌IL-2和IFN-γ的刺激作用;
图6:用ELSIA方法检测人源化PD-1抗体与PD-1-mFc蛋白结合的EC50;
图7:用ELSIA方法检测人源化PD-1抗体阻断配体PD-L1结合PD-1-mFc的IC50;
图8:用FACS方法检测人源化PD-1抗体结合293T-PD-1细胞的EC50;
图9:用FACS方法检测人源化PD-1抗体阻断配体PD-L1结合293T-PD-1细胞的IC50;
图10:用混合淋巴细胞反应(MLR)检测人源化PD-1单克隆抗体对CD4+T细胞分泌IL-2和IFN-γ的刺激作用。
具体实施方式
实施例1
鼠源杂交瘤抗体的构建
小鼠免疫和杂交瘤细胞融合。用人的PD-1胞外区与小鼠Fc融合蛋白(PD-1-ECD-mFc)作为抗原,与等体积完全弗氏佐剂(Sigma,Cat.No.:F5581)充分乳化后,经皮下免疫6-8周龄Balb/c小鼠(购自昭衍(苏州)新药研究中心有限公司),抗原免疫量为50μg/只。随后每隔2周,用相同剂量的抗原与不完全弗氏佐剂(Sigma,Cat.No.:F5506)充分乳化后,经皮下免疫小鼠三次。免疫三次后测定小鼠血清效价,融合前3天经腹腔进行加强免疫。以PEGHybri-Max(Sigma,Cat.No.:7181)作为融合剂,将小鼠脾脏细胞与SP2/0细胞按照4:1的比例混合。将融合后的细胞加入到96孔板中(1×105细胞/孔),每孔含有0.1mL1×HAT培养基(Invitrogen,Cat.No.:21060-017)。在第3天加入0.1mL HT(Invitrogen,Cat.No.:11067-030)培养基,在第7天吸掉96孔板中的培养液,补加0.2mL新鲜的HT培养基。在第9天,收取上清液进行ELISA和FACS检测。
与PD-1-ECD结合抗体的ELISA筛选。用人的PD-1胞外区与人Fc融合蛋白(PD-1-ECD-hFc)包被96孔板(Corning,Cat.No.:9018),置4度过夜,用洗涤缓冲液(PBS+0.05%Tween20)洗涤3次后,加入封闭缓冲液(PBS+1%BSA)孵育1小时;洗涤96孔板3次;加入杂交瘤上清孵育1小时,洗涤3次;每孔加入100μL 1:10000倍稀释的羊抗鼠IgG二抗(Thermo,Cat.No.:31432),室温孵育1小时后洗涤3次;每孔加入100μL TMB(北京百奥赛博,Cat.No.:ES-002)显色3分钟,再加入100μL/孔的终止液(2N H2SO4)终止反应,用酶标仪测定各样品的OD450信号。
与PD-1-ECD结合抗体的FACS筛选。取50μL在上述ELISA检测中呈阳性的杂交瘤上清与50μL 293T-PD-1细胞混合(1×105细胞/孔),加入到U形底96孔板中孵育1小时,用FACS缓冲液(PBS+3%FCS)离心洗涤2次后加入1:400倍稀释的PE标记羊抗鼠二抗(Biolegend,Cat.No.:405307),孵育30分钟,经FACS缓冲液洗涤后,用BD C6流式细胞仪检测293T-PD-1细胞的PE信号。
阻断PD-1与PD-L1结合的抗体的ELISA筛选。采用竞争ELISA筛选能够阻断PD-1与PD-L1结合的杂交瘤抗体。用PD-1-ECD-hFc包被96孔ELISA板,孵育过夜,用洗涤缓冲液(PBS+0.05%Tween 20)洗涤3次后,加入200μL封闭缓冲液,孵育1小时;洗涤3次后加入100μL杂交瘤上清,室温孵育1小时;继续向样品孔中加入100μL PD-L1-Biotin,室温孵育1小时;洗涤3次,加入二抗Avidin HRP(Invitrogen,Cat.No.:18-4100-51),孵育30分钟,加入TMB显色3分钟,用100μL/孔的终止液(2N H2SO4)终止反应,用酶标仪测定各样品的OD450信号。
阻断PD-1与PD-L1结合的抗体的FACS筛选。采用竞争FACS筛选能够阻断PD-1与PD-L1结合的杂交瘤抗体。在U形底96孔板中,将杂交瘤上清或纯化的抗体与293T-PD-1细胞(1×105细胞/孔)孵育1小时,加入0.05μg/mL的PD-L1-biotin孵育1小时,离心后用FACS缓冲液洗涤2次,加入anti-biotin-PE(Biolegend,Cat.No.:409004)孵育30分钟,离心洗涤后,用BD C6流式细胞仪检测293T-PD-1细胞的PE信号。
杂交瘤的亚克隆。用有限稀释法,对能够阻断PD-1与PD-L1结合的杂交瘤进行亚克隆,随后再重复采用ELISA和FACS方法进行检测筛选,进而获得阳性杂交瘤单克隆。将阳性单克隆杂交瘤置50mL无血清培养基中(Invitrogen,Cat.No.:12045-076)培养9天,离心收取上清液。用Protein A亲和层析纯化单克隆抗体。纯化后的抗体样品经超滤离心管(Millipore,Cat.No.:ACS500024)换液浓缩后,用BCA方法测定蛋白浓度,用鳌试剂(厦门鲎试剂生物科技股份有限公司)检测抗体样品的内毒素含量。用ELISA和FACS检测纯化的抗体样品与PD-1的结合及其阻断PD-1与PD-L1结合的活性,具体结果见表1-4和图1-4。根据图表的信息可知抗体样品与PD-1具有良好的亲和力以及较强的阻断PD-1和PD-L1结合的活性。
表1.用ELSIA方法检测PD-1杂交瘤抗体与PD-1结合的EC50
抗体 | 10A10 | 4B5 | 9H8 | 8D4 | 5F7 | 5H10 |
EC50(ng/mL) | 1.140 | 1.753 | 0.5109 | 2.610 | 1.232 | 1.088 |
表2.用ELSIA方法检测PD-1杂交瘤抗体阻断PD-L1结合PD-1-hFc的IC50
抗体 | 10A10 | 4B5 | 9H8 | 8D4 | 5F7 | 5H10 |
IC50(ng/mL) | 361.0 | 343.3 | 319.1 | 369.7 | 323.9 | 339.1 |
表3.用FACS方法检测PD-1杂交瘤抗体结合293T-PD-1细胞的EC50
抗体 | 10A10 | 4B5 | 9H8 | 8D4 | 5F7 | 5H10 |
EC50(ng/mL) | 31.36 | 39.98 | 20.34 | 44.34 | 17.63 | 64.30 |
表4.用FACS方法检测PD-1杂交瘤抗体阻断PD-L1结合293T-PD-1细胞的IC50
抗体 | 10A10 | 4B5 | 9H8 | 8D4 | 5F7 | 5H10 |
EC50(ng/mL) | 27.59 | 35.50 | 8.540 | 29.63 | 18.15 | 41.22 |
实施例2
鼠源PD-1杂交瘤抗体在混合淋巴细胞反应中对CD4+T细胞分泌细胞因子的影响
用磁珠分选试剂盒,从人的外周血单核细胞(PBMC)中分选出CD4+T细胞(Miltenyi,Cat.No.:130-096-533)和CD14+单核细胞(Miltenyi,Cat.No.:130-050-201)。
将分选出的CD14+单核细胞重悬于树突状细胞(DC)分化培养基(Miltenyi,Cat.No.:130-094-812)中,置37℃,5%CO2培养箱中培养7天后,加入树突状细胞成熟培养基(Miltenyi,Cat.No.:130-0940813),继续培养3天。用完全培养基(RPMI 1640+10%FBS+1%L-glutamine+1%Sodium pyruvate)配置不同浓度的抗体。在U形底96孔板中,每孔加入50μL CD4+T细胞,50μL已分化的树突状细胞以及100μL不同浓度的PD-1抗体(2000ng/mL,200ng/mL,20ng/mL),置37℃培养5天,收集上清液,用IL-2(R&D Systems,Cat.No.:DY202)以及IFN-γ(R&D Systems,Cat.No.:DY285)ELISA试剂盒检测上清液中细胞因子的浓度,测定结果见图5a和5b。混合淋巴细胞反应实验表明,鼠源PD-1杂交瘤抗体能够促进活化的T细胞分泌IL-2以及IFN-γ。
实施例3
PD-1抗体可变区基因的克隆
用TRIzon(Cwbiotech,Cat.No.:CW0580)裂解PD-1单克隆杂交瘤细胞株,提取杂交瘤细胞的总RNA。用HiFi Script cDNA合成试剂盒(Cwbiotech,Cat.No.:CW2569)将杂交瘤细胞的RNA反转录为cDNA。以cDNA为模板,用简并引物通过PCR方法(Kettleborough,etal.,(1993)Eur.J.Immunology 23:206-211;Strebe,et al.,(2010)AntibodyEngineering 1:3-14)扩增抗体的重链和轻链的可变区基因。将PCR扩增产物连接到T/A载体后,转化DH5a感受态细胞,涂板并置37℃过夜培养。从培养板上挑取单克隆,扩大培养后抽提质粒,测定抗体的基因序列。根据抗体的基因序列,分析其互补决定簇(CDR)和骨架区。一些抗体的重链和轻链的可变区氨基酸序列和CDR氨基酸序列见表5:
表5.PD-1杂交瘤抗体及CDR区的序列表
实施例4
鼠源PD-1抗体的人源化
采用互补决定簇嫁接法进行PD-1抗体的人源化改造。首先,在IMGT数据库中分别搜寻与鼠源9H8和8D4抗体的轻、重链可变区序列同源性最高的人胚系抗体(germlineantibody)序列。9H8抗体轻链可变区人源化选取的胚系为IGKV4-1*01,重链可变区人源化选取IGHV3-23*01。8D4抗体轻链可变区人源化选取的胚系为IGKV4-1*01,重链可变区人源化选取IGKV3-11*01。保留鼠源抗体的CDR区,将鼠源抗体的框架区序列用人胚系抗体的框架区序列置换。建立鼠源抗体的结构模型,逐个对比人源抗体与相应鼠源抗体框架区中每个位点的氨基酸,如果框架区的某个位点采用人的氨基酸序列没有导致CDR区域空间结构的破坏或改变,则该位点使用人的氨基酸序列,否则在该位点使用对应的鼠源序列(即回复突变为鼠源序列)。
根据结构模拟,将9H8抗体人源化重链的第93位Ala回复突变为Ser。将8D4抗体人源化重链的第48位Met回复突变为Ile,第67位Val回复突变为Ala,第69位Ile回复突变为Leu,第71位Arg回复突变为Ala,第93位Ala回复突变为Thr。将8D4抗体人源化轻链的第68位Gly回复突变为Glu。
9H8人源化抗体重链和轻链可变区的氨基酸序列号分别为SEQ ID NO:49和SEQ IDNO:50。8D4人源化抗体重链和轻链可变区的氨基酸序列号分别为SEQ ID NO:51和SEQ IDNO:52。将9H8和8D4人源化抗体构建为IgG4亚型。
表6.PD-1人源化抗体的序列
合成编码9H8和8D4人源化抗体轻链和重链的核酸片段,并插入到表达载体pcDNA3.1。用抗体轻链和重链表达质粒各0.1mg共转染200毫升293细胞(细胞密度为1×106),在37度振摇培养6天,离心收集上清液,用Protein A纯化人源化抗体,纯化后的人源化抗体用于活性检测。
实施例5
人源化PD-1抗体的亲和力检测。
用Biacore 3000测定人源化抗体样品与PD-1的结合。测定方法包括如下步骤:以氨基偶联的方式将Protein A固定于CM5芯片上,接着以10μL/min的流速捕获PD-1人源化抗体。切换流速到30μL/min,将不同浓度的带组氨酸标签的PD-1抗原(50nM,25nM,12.5nM,6.25nM,3.125nM,1.5625nM)依次流经样品通道和参比通道,结合时间为3min,解离时间为20min。最后用pH 2.0的甘氨酸缓冲液再生芯片。PD-1抗体与PD-1抗原的亲和力测定数据见表7。结果表明,本专利中的PD-1人源化抗体对PD-1的亲和力显著高于阳性对照抗体Pembrolizumab.
表7.人源化PD-1抗体与PD-1抗原的亲和力
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实施例6
人源化PD-1抗体的活性检测
采用ELISA和FACS检测纯化的人源化抗体样品与PD-1的结合,及其阻断PD-1与PD-L1结合的活性,具体方法参考实施例1。人源化抗体的活性测定结果见表8-11和图6-9。
表8.用ELSIA方法检测PD-1人源化抗体与PD-1结合的EC50
抗体 | hu9H8-hIgG4 | hu8D4-hIgG4 | Pembrolizumab |
EC50(ng/mL) | 5.317 | 48.87 | 45.08 |
表9.用ELSIA方法检测PD-1人源化抗体阻断PD-L1结合PD-1-hFc的IC50
抗体 | hu9H8-hIgG4 | hu8D4-hIgG4 | Pembrolizumab |
IC50(ng/mL) | 332.1 | 851.4 | 967.5 |
表10.用FACS方法检测PD-1人源化抗体结合293T-PD-1细胞的EC50
抗体 | hu9H8-hIgG4 | hu8D4-hIgG4 | Pembrolizumab |
EC50(ng/mL) | 285.3 | 310.6 | 291.6 |
表11.用FACS方法检测PD-1人源化抗体阻断PD-L1结合293T-PD-1细胞的IC50
实施例7
人源化PD-1抗体在混合淋巴细胞反应中对T细胞分泌细胞因子的影响
测定了人源化PD-1单克隆抗体对CD4+T细胞分泌IL-2和IFN-γ的促进作用,具体实验方法参考实施例2,测定结果见图10。混合淋巴细胞反应实验数据表明,本专利中的人源化PD-1抗体具有比对照抗体Pembrolizumab更强的促进T细胞分泌细胞因子IL-2和IFN-γ的活性。
以上实施例的结果表明,本发明所述的单克隆抗体或者抗原结合片段,以及包含本发明所述单克隆抗体或其抗原结合片段的偶联物在制备阻断PD-1与PD-L1结合的药物、调节PD-1活性或PD-1表达水平的药物、解除PD-1对机体免疫抑制的药物、激活T淋巴细胞的药物、提高T淋巴细胞表达IL-2和INF-γ的药物、以及在预防和治疗或者辅助治疗肿瘤的药物方面具有良好的应用前景。
SEQUENCE LISTING
<110> 东大生物技术(苏州)有限公司
<120> 一组PD-1单克隆抗体及其医药用途
<130> 2020
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Glu Asp Phe Val Ser Tyr Tyr Cys Gln Gln Leu Tyr Ile Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 11
<211> 122
<212> PRT
<213> 人工
<223> 5H10重链可变区
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Gly Asp Ser Asn Thr Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Thr Lys Arg Gly Pro Tyr Tyr Gly Tyr Thr His Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 12
<211> 107
<212> PRT
<213> 人工
<223> 5H10轻链可变区
<400> 12
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Lys Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Asn Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 13
<211> 5
<212> PRT
<213> 人工
<223> 10A10重链CDR1
<400> 13
Tyr Tyr Asp Ile Ser
1 5
<210> 14
<211> 17
<212> PRT
<213> 人工
<223> 10A10重链CDR2
<400> 14
Thr Ile Ser Gly Gly Gly Arg Tyr Thr Tyr Tyr Leu Asp Asn Val Gln
1 5 10 15
Gly
<210> 15
<211> 8
<212> PRT
<213> 人工
<223> 10A10重链CDR3
<400> 15
Pro Tyr Glu Gly Ala Met Asp Tyr
1 5
<210> 16
<211> 11
<212> PRT
<213> 人工
<223> 10A10轻链CDR1
<400> 16
Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala
1 5 10
<210> 17
<211> 7
<212> PRT
<213> 人工
<223> 10A10轻链CDR2
<400> 17
Trp Ala Ser Thr Arg His Thr
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工
<223> 10A10轻链CDR3
<400> 18
Gln Gln Tyr Ser Thr Phe Pro Tyr Thr
1 5
<210> 19
<211> 5
<212> PRT
<213> 人工
<223> 4B5重链CDR1
<400> 19
Ser Tyr Met Met Ser
1 5
<210> 20
<211> 17
<212> PRT
<213> 人工
<223> 4B5重链CDR2
<400> 20
Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Leu Asp Ser Met Lys
1 5 10 15
Gly
<210> 21
<211> 8
<212> PRT
<213> 人工
<223> 4B5重链CDR3
<400> 21
Gln Ser Asp Arg Gly Phe Pro Tyr
1 5
<210> 22
<211> 11
<212> PRT
<213> 人工
<223> 4B5轻链CDR1
<400> 22
Leu Ala Ser Gln Pro Ile Gly Thr Trp Leu Ala
1 5 10
<210> 23
<211> 7
<212> PRT
<213> 人工
<223> 4B5轻链CDR2
<400> 23
Ala Ala Thr Thr Leu Thr Asp
1 5
<210> 24
<211> 9
<212> PRT
<213> 人工
<223> 4B5轻链CDR3
<400> 24
Gln Gln Phe Ser Ser Ile Pro Tyr Thr
1 5
<210> 25
<211> 5
<212> PRT
<213> 人工
<223> 9H8重链CDR1
<400> 25
Asp Tyr Tyr Met Tyr
1 5
<210> 26
<211> 17
<212> PRT
<213> 人工
<223> 9H8重链CDR2
<400> 26
Gln Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 27
<211> 12
<212> PRT
<213> 人工
<223> 9H8重链CDR3
<400> 27
Ser Tyr Tyr Lys Tyr Asp Gly Trp Tyr Phe Asp Val
1 5 10
<210> 28
<211> 15
<212> PRT
<213> 人工
<223> 9H8轻链CDR1
<400> 28
Arg Ala Ser Glu Ser Val Glu Tyr Ser Arg Thr Ser Leu Ile Gln
1 5 10 15
<210> 29
<211> 7
<212> PRT
<213> 人工
<223> 9H8轻链CDR2
<400> 29
Ala Ala Ser Tyr Val Glu Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工
<223> 9H8轻链CDR3
<400> 30
Gln Gln Ala Arg Lys Val Pro Trp Thr
1 5
<210> 31
<211> 5
<212> PRT
<213> 人工
<223> 8D4重链CDR1
<400> 31
Asn Phe Trp Met His
1 5
<210> 32
<211> 17
<212> PRT
<213> 人工
<223> 8D4重链CDR2
<400> 32
Ala Ile Phe Pro Gly Asn Thr Asp Thr Thr Tyr Asn Arg Lys Phe Lys
1 5 10 15
Asp
<210> 33
<211> 7
<212> PRT
<213> 人工
<223> 8D4重链CDR3
<400> 33
Asn His Tyr Gly Leu Asp Tyr
1 5
<210> 34
<211> 15
<212> PRT
<213> 人工
<223> 8D4轻链CDR1
<400> 34
Arg Ala Ser Glu Ser Val Ser Ile His Gly Thr His Leu Met His
1 5 10 15
<210> 35
<211> 7
<212> PRT
<213> 人工
<223> 8D4轻链CDR2
<400> 35
Ile Ala Ser Asn Leu Gly Ser
1 5
<210> 36
<211> 9
<212> PRT
<213> 人工
<223> 8D4轻链CDR3
<400> 36
Gln Gln Ser Ile Glu Asp Pro Trp Thr
1 5
<210> 37
<211> 5
<212> PRT
<213> 人工
<223> 5F7重链CDR1
<400> 37
Ser Tyr Met Met Ser
1 5
<210> 38
<211> 17
<212> PRT
<213> 人工
<223> 5F7重链CDR2
<400> 38
Ala Ile Ser Gly Gly Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 39
<211> 8
<212> PRT
<213> 人工
<223> 5F7重链CDR3
<400> 39
Arg Val Val Tyr Ala Met Asp Cys
1 5
<210> 40
<211> 11
<212> PRT
<213> 人工
<223> 5F7轻链CDR1
<400> 40
Leu Ala Ser Gln Ser Ile Gly Thr Trp Leu Val
1 5 10
<210> 41
<211> 7
<212> PRT
<213> 人工
<223> 5F7轻链CDR2
<400> 41
Ala Ala Thr Ser Leu Ala Asp
1 5
<210> 42
<211> 9
<212> PRT
<213> 人工
<223> 5F7轻链CDR3
<400> 42
Gln Gln Leu Tyr Ile Ile Pro Trp Thr
1 5
<210> 43
<211> 5
<212> PRT
<213> 人工
<223> 5H10重链CDR1
<400> 43
Asp Tyr Gly Met His
1 5
<210> 44
<211> 17
<212> PRT
<213> 人工
<223> 5H10重链CDR2
<400> 44
Tyr Ile Ser Gly Asp Ser Asn Thr Ile Tyr Tyr Ala Asp Thr Val Lys
1 5 10 15
Gly
<210> 45
<211> 13
<212> PRT
<213> 人工
<223> 5H10重链CDR3
<400> 45
Arg Gly Pro Tyr Tyr Gly Tyr Thr His Tyr Phe Asp Tyr
1 5 10
<210> 46
<211> 11
<212> PRT
<213> 人工
<223> 5H10轻链CDR1
<400> 46
Lys Ala Ser Gln Ser Val Ser Asn Asp Val Val
1 5 10
<210> 47
<211> 7
<212> PRT
<213> 人工
<223> 5H10轻链CDR2
<400> 47
Tyr Ala Ser Lys Arg Tyr Thr
1 5
<210> 48
<211> 9
<212> PRT
<213> 人工
<223> 5H10轻链CDR3
<400> 48
Gln Gln Asp Tyr Ser Ser Pro Trp Thr
1 5
<210> 49
<211> 121
<212> PRT
<213> 人工
<223> 9H8人源化重链可变区
<400> 49
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gln Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Lys Ser Tyr Tyr Lys Tyr Asp Gly Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 50
<211> 111
<212> PRT
<213> 人工
<223> 9H8人源化轻链可变区
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Ser
20 25 30
Arg Thr Ser Leu Ile Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Tyr Val Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ala Arg
85 90 95
Lys Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 51
<211> 116
<212> PRT
<213> 人工
<223> 8D4人源化重链可变区
<400> 51
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Ala Ile Phe Pro Gly Asn Thr Asp Thr Thr Tyr Asn Arg Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asn His Tyr Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 52
<211> 111
<212> PRT
<213> 人工
<223> 8D4人源化轻链可变区
<400> 52
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ile His
20 25 30
Gly Thr His Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ile Ala Ser Asn Leu Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ile
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Claims (6)
1.一组PD-1单克隆抗体,包括重链和轻链,其特征在于,
所述重链的CDR1的氨基酸序列如SEQ ID NO:25所示;所述重链的CDR2的氨基酸序列如SEQ ID NO:26所示;所述重链的CDR3的氨基酸序列如SEQ ID NO:27所示;所述轻链的CDR1的氨基酸序列如SEQ ID NO:28所示;所述轻链的CDR2的氨基酸序列如SEQ ID NO:29所示;所述轻链的CDR3的氨基酸序列如SEQ ID NO:30所示;
或者:
所述重链的CDR1的氨基酸序列如SEQ ID NO:31所示;所述重链的CDR2的氨基酸序列如SEQ ID NO:32所示;所述重链的CDR3的氨基酸序列如SEQ ID NO:33所示;所述轻链的CDR1的氨基酸序列如SEQ ID NO:34所示;所述轻链的CDR2的氨基酸序列如SEQ ID NO:35所示;所述轻链的CDR3的氨基酸序列如SEQ ID NO:36所示。
2.根据权利要求1所述的一组PD-1单克隆抗体,其特征在于,所述重链可变区的氨基酸序列如SEQ ID NO:5所示;所述轻链可变区的氨基酸序列如SEQ ID NO: 6所示;
或者:
所述重链可变区的氨基酸序列如SEQ ID NO:7所示;所述轻链可变区的氨基酸序列如SEQ ID NO:8所示。
3.根据权利要求1所述的一组PD-1单克隆抗体,其特征在于,所述重链和轻链经过人源化改造;
所述人源化后的重链可变区的氨基酸序列如SEQ ID NO:49所示;所述人源化后的轻链可变区的氨基酸序列如SEQ ID NO:50所示;
或者:
所述人源化后的重链可变区的氨基酸序列如SEQ ID NO:51所示;所述人源化后的轻链可变区的氨基酸序列如SEQ ID NO:52所示。
4.一组核酸分子,其特征在于,所述核酸分子编码如权利要求1-3任一项所述的PD-1单克隆抗体。
5.一组表达载体,其特征在于,所述载体包含如权利要求4所述的核酸分子的序列以及与该序列相关的表达调控序列。
6.一种单克隆抗体偶联物,包括单克隆抗体和偶联部分,其特征在于,所述单克隆抗体为权利要求1-3任一项所述的一组PD-1单克隆抗体,所述偶联部分选自放射性核素、毒素、细胞因子、细胞因子受体片段、酶、荧光素和生物素中的一种或多种。
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