CN114656565B - 一种抗pd-l1抗体及其应用 - Google Patents
一种抗pd-l1抗体及其应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域,具体而言,涉及一种抗PD‑L1抗体及其应用。本发明提供的抗PD‑L1抗体或其抗原结合片段与PD‑L1蛋白高亲和力和高特异性结合,能够有效阻断细胞表面表达的PD‑L1与PD‑1的相互作用,具有刺激细胞因子产生的生物学功能活性,应用前景广泛。
Description
本申请要求于2020年12月23日提交中国专利局的申请号为2020115411079、名称为“一种抗PD-L1抗体及其应用”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
技术领域
本发明涉及免疫学技术领域,具体而言,涉及一种抗PD-L1抗体及其应用。
背景技术
程序化细胞死亡蛋白1(PD-1,也称为CD279)是一种表达在抗原刺激T细胞表面的共刺激受体。PD-L1(CD274)和PD-L2(CD273)是PD-1的两种配体。PD-L1表达在包括T细胞、B细胞、巨噬细胞、树突细胞、巨大细胞等造血细胞,及血管内皮细胞、角质细胞、胰岛细胞、星形胶质细胞、胎盘合包体滋养层、角膜表皮和内皮细胞在内的非造血细胞。PD-L1和PD-L2在多种肿瘤细胞和肿瘤基质中表达。
PD-1和PD-L1均属于免疫超家族蛋白中的I形跨膜蛋白,由Ig-V和Ig-C样胞外结构域、跨膜结构域和短序列的胞内结构域组成。PD-L1和PD-1胞外区的相互作用能诱导PD-1蛋白构象变化,从而诱导胞内免疫受体酪氨酸抑制基序(ITIM)和免疫受体酪氨酸转化基序(ITSM)被Src家族激酶磷酸化。磷酸化的酪氨酸基序随后招募SHP-2和SHP-1蛋白酪氨酸磷酸酶下调T胞活化信号。除PD-1外,PD-L1与CD80相互作用,从而传递抑制T细胞活性的信号。PD-1和PD-L1相互作用在多方面下调T细胞活性,包括抑制T细胞增殖,细胞因子的释放和其他效应功能。
PD-1和PD-L1相互作用对于免疫系统的稳态至关重要。不同基因型的PD-1缺陷型小鼠倾向于发生狼疮样自体免疫病或致命性自体免疫心肌病。PD-1缺陷型小鼠改变了胸腺T细胞的驯化,PD-L1的阻断能够破坏胎儿和母体之间的耐受性。同时,抑制PD-1和PD-L1的相互作用增强了宿主对病原体的免疫作用。
PD-L1表达在多种不良预后的肿瘤(例如,肾癌、胃癌、尿道上皮癌、卵巢癌和黑色素瘤)上,使用PD-L1抗体能杀死肿瘤细胞或抑制杀伤性T细胞CTLs的活性。鉴于PD-1和PD-L1在下调免疫反应方面的重要性,开发阻断PD-L1蛋白与PD-1相互作用的抗PD-L1抗体,从而将其用于肿瘤免疫治疗具有重要意义。
发明内容
本发明要解决的技术问题是克服现有抗PD-L1抗体结合PD-L1的亲和力和特异性不高,不能够有效阻断PD-L1与PD-1结合的缺陷和不足,提供一种抗PD-L1抗体及其应用。
本发明的目的是提供抗PD-L1抗体或其抗原结合片段,所述抗体含有以下CDRs:
如SEQ ID NO.19、25、31或37任一项所示或与SEQ ID NO.19、25、31或37任一项所示具有至少95%同一性的氨基酸序列所示的HCDR1,如SEQ ID NO.20、26、32、38任一项所示或与SEQ ID NO.20、26、32、38任一项所示具有至少95%同一性的氨基酸序列所示的HCDR2,如SEQ ID NO.21、27、33、39任一项所示或与SEQ ID NO.21、27、33、39任一项所示具有至少95%同一性的氨基酸序列所示的HCDR3;
如SEQ ID NO.22、28、34、40任一项所示或与SEQ ID NO.22、28、34、40任一项所示具有至少95%同一性的氨基酸序列所示的LCDR1,如SEQ ID NO.23、29、35、41任一项所示或与SEQ ID NO.23、29、35、41任一项所示具有至少95%同一性的氨基酸序列所示的LCDR2,如SEQ ID NO.24、30、36、42任一项所示或与SEQ ID NO.24、30、36、42任一项所示具有至少95%同一性的氨基酸序列所示的LCDR3。
本发明另一目的是提供一种核酸,编码所述抗体或其抗原结合片段的重链可变区的第一核酸,和/或,编码所述抗体或其抗原结合片段的轻链可变区的第二核酸。
本发明还提供了一种载体,所述载体包含所述核酸。
本发明还提供了一种细胞,所述细胞包含所述核酸或所述载体。
本发明还提供了一种药物组合物,所述药物组合物含有所述抗PD-L1抗体或其抗原结合片段、所述核酸、所述载体或所述细胞。
本发明还涉及所述抗PD-L1抗体或其抗原结合片段、及其相关的核酸载体、载体、细胞或药物组合物在制备用于治疗PD-L1介导的疾病或病症的药物中的应用。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对范围的限定,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他相关的附图。
图1是抗人PD-L1抗体与CHO空细胞的结合活性检测结果;
图2是抗人PD-L1抗体与稳定表达人PD-L1的CHO-hPD-L1的结合活性检测结果;
图3是抗人PD-L1抗体与稳定表达猕猴PD-L1的CHO-cynoPD-L1的结合活性检测结果;
图4是抗人PD-L1抗体与IFNγ刺激的A375细胞的结合活性检测结果;
图5是抗人PD-L1抗体与CHO-hPD-L1竞争结合活性检测结果;
图6是实验方法1中的抗人PD-L1抗体阻断CHO-hPD-L1与hPD-L1 hFc重组蛋白结合活性检测结果;
图7是实验方法2中的抗人PD-L1抗体阻断CHO-hPD-L1与hPD-L1 hFc重组蛋白结合活性模式二检测结果;
图8是抗人PD-L1抗体阻断CHO-hPD-L1与hCD80 hFc重组蛋白结合活性检测结果;
图9是荧光素酶报告基因法分析抗人PD-L1抗体的体外活性板一、板二结果;其中,(a)图是板一结果;(b)图是板二结果;
图10是抗人PD-L1抗体介导的混合淋巴细胞反应中IL-2的分泌板一结果;
图11是抗人PD-L1抗体介导的混合淋巴细胞反应中IL-2的分泌板二结果;
图12是抗人PD-L1抗体介导的混合淋巴细胞反应中IFNγ的分泌板一结果;
图13是抗人PD-L1抗体介导的混合淋巴细胞反应中IFNγ的分泌板二结果;
图14是抗人PD-L1抗体与重组蛋白hPD-L1 hFc、hPD-L2 hFc、hICOSLG hFc、hB7-H3hFc的结合特异性结果;其中,(a)图是与重组蛋白hPD-L1 hFc的结合特异性结果;(b)图是与重组蛋白hPD-L2 hFc的结合特异性结果;(c)图是与重组蛋白hICOSLG hFc的结合特异性结果;(d)图是与重组蛋白hB7-H3 hFc的结合特异性结果;
图15是抗人PD-L1抗体与重组蛋白hCD28 hFc、hCD86 hFc、hCTLA-4hFc的结合特异性结果;其中,(a)图是与重组蛋白hCD28 hFc的结合特异性结果;(b)图是与重组蛋白hCD86hFc的结合特异性结果;(c)图是与重组蛋白hCTLA-4hFc的结合特异性结果;
图16是抗人PD-L1抗体的体内活性表征结果;其中,(a)图是mIgG1亚型的抗hPD-L1抗体对小鼠肿瘤体积的影响结果;(b)图是mIgG2a亚型的抗hPD-L1抗体对小鼠肿瘤体积的影响结果;(c)图是mIgG1亚型、mIgG2a亚型的抗hPD-L1抗体对小鼠体重的影响结果。
具体实施方式
以下结合具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
本发明涉及抗PD-L1抗体或其抗原结合片段,所述抗体含有以下CDRs:
如SEQ ID NO.19、25、31或37任一项所示或与SEQ ID NO.19、25、31或37任一项所示具有至少95%同一性的氨基酸序列所示的HCDR1,如SEQ ID NO.20、26、32、38任一项所示或与SEQ ID NO.20、26、32、38任一项所示具有至少95%同一性的氨基酸序列所示的HCDR2,如SEQ ID NO.21、27、33、39任一项所示或与SEQ ID NO.21、27、33、39任一项所示具有至少95%同一性的氨基酸序列所示的HCDR3;
如SEQ ID NO.22、28、34、40任一项所示或与SEQ ID NO.22、28、34、40任一项所示具有至少95%同一性的氨基酸序列所示的LCDR1,如SEQ ID NO.23、29、35、41任一项所示或与SEQ ID NO.23、29、35、41任一项所示具有至少95%同一性的氨基酸序列所示的LCDR2,如SEQ ID NO.24、30、36、42任一项所示或与SEQ ID NO.24、30、36、42任一项所示具有至少95%同一性的氨基酸序列所示的LCDR3。
该抗PD-L1抗体或其抗原结合片段的一个重要优点在于其与PD-L1具有高亲和力和高特异性结合能力。
该抗PD-L1抗体或其抗原结合片段的一个重要优点在于其具有阻断细胞表面表达的PD-L1与PD-1的相互作用。
该抗PD-L1抗体或其抗原结合片段的一个重要优点在于其能够刺激细胞因子的产生。
因此,该抗PD-L1抗体或其抗原结合片段可作为或用于制备抗体药物。
本发明采用Kabat编号系统标示CDR区,但其他方法标示的CDR区也属于本发明的保护范围。
在本发明中,术语“抗体或其抗原结合片段”是结合特定抗原的蛋白,其泛指包含互补决定区(CDR区)的一切蛋白及蛋白片段。“抗体”特别指全长抗体,“全长抗体”此用语包括多克隆抗体及单克隆抗体。“抗原结合片段”是包含抗体CDR的一部分或全部的物质,其缺乏至少一些存在于全长链中的氨基酸但仍能够特异性结合至抗原。此类片段具生物活性,因为其结合至靶抗原,且可与其他抗原结合分子(包括完整抗体)竞争结合至给定表位。
术语“CDR”是指免疫球蛋白的重链和轻链的高度可变区。有三种重链CDR和三种轻链CDR。此处,取决于情况,术语“CDR”和“CDRs”用于指包含一种或多种或者甚至全部的对抗体或其抗原结合片段与其识别的抗原或表位的结合亲和力起作用的主要氨基酸残基的区域。
术语“特异性结合”或其类似表述是指抗体或其抗原结合片段对预先确定的抗原上的表位的结合。通常,抗体或其抗原结合片段以大约小于10-6M,例如大约小于10-7M、10- 8M、10-9M或10-10M或更小的亲和力(KD)结合。KD是指解离速率与结合速率的比率(koff/kon),该量可通过本领域技术人员熟悉的方法测量。
在一些实施方式中,所述抗体含有重链可变区和轻链可变区,所述重链可变区的氨基酸序列如SEQ ID NO:5、9、13或17任一项所示或与SEQ ID NO:5、9、13或17任一项所示具有至少95%同一性的序列;
在一些实施方式中,所述轻链可变区的氨基酸序列如SEQ ID NO:6、10、14或18任一项所示或与SEQ ID NO:6、10、14或18任一项所示具有至少95%同一性的序列。
在本发明中,所述抗体具有恒定区,重链恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgD、IgE或IgM中的任一种;轻链恒定区为κ链或λ链。
在一些实施方式中,所述恒定区的种属来源为人或鼠。
在一些实施方式中,所述抗体为双特异性抗体、CDR移植抗体或多聚体抗体中的任一种或几种。
在一些实施方式中,所述抗原结合片段为scFv、Fab、Fab’、F(ab’)2、Fv及单域抗体中的任一种或几种。
在一些实施方式中,所述PD-L1为人、猴或鼠PD-L1。
本发明还涉及一种核酸,编码所述抗体或其抗原结合片段的重链可变区的第一核酸,和/或,编码所述抗体或其抗原结合片段的轻链可变区的第二核酸。
核酸通常是RNA或DNA,核酸分子可以是单链或双链的,但优选是双链DNA。当将核酸与另一个核酸序列置于功能关系中时,核酸是“有效连接的”。例如,如果启动子或增强子影响编码序列的转录,那么启动子或增强子有效地连接至所述编码序列。当其连入载体时优选采用DNA。此外,鉴于抗体为膜蛋白,所以核酸通常带有信号肽序列。
在一些实施方式中,所述第一核酸的碱基序列如SEQ ID NO:3、SEQ ID NO:7、SEQID NO:11或SEQ ID NO:15任一项所示或与SEQ ID NO:3、SEQ ID NO:7、SEQ ID NO:11或SEQID NO:15任一项所示具有至少95%同一性的序列。
在一些实施方式中,所述第二核酸的碱基序列如SEQ ID NO:4、SEQ ID NO:8、SEQID NO:12或SEQ ID NO:16任一项所示或与SEQ ID NO:4、SEQ ID NO:8、SEQ ID NO:12或SEQID NO:16任一项所示具有至少95%同一性的序列。
本发明还涉及一种载体,所述载体包含上述核酸。
术语“载体(vector)”是可将多聚核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。
本发明还涉及一种细胞,所述细胞包含所述核酸或所述载体。
在一些实施方式中,所述细胞为真核哺乳动物细胞。
在优选实施方式中,所述细胞为中国仓鼠CHO细胞。
本发明还涉及一种药物组合物,所述药物组合物含有所述抗PD-L1抗体或其抗原结合片段、所述核酸、所述载体或所述细胞。
在一些实施方式中,所述药物组合物还含有药学可接受的载体。
术语“药物组合物”是以允许活性成分的生物学活性有效的形式存在,并且不包含对将施用所述组合物的对象具有不可接受的毒性的另外的成分。
术语“药学可接受的载体”可以包括生理学上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和延迟吸收剂等,用来延长抗体的保存限期或效力。
另外,所述抗PD-L1抗体或其抗原结合片段、及其相关的核酸、载体、细胞或药物组合物在制备用于治疗PD-L1介导的疾病或病症的药物中的应用,也应在本发明的保护范围之内。
本发明具有以下有益效果:
本发明公开了抗PD-L1抗体或其抗原结合片段,以及与PD-L1蛋白高亲和力和高特异性结合的抗人PD-L1抗体,该抗体能阻断细胞表面表达的PD-L1与PD-1的相互作用,并且在体外细胞功能实验中,显示出刺激细胞因子产生的生物学功能活性;因此,本发明的抗PD-L1抗体或其抗原结合片段、核酸、载体、细胞或所述药物组合物在制备用于治疗PD-L1介导的疾病或病症的药物中具有广泛的应用前景。
实施例1
抗人PD-L1抗体的产生。
1、免疫原
采用重组人PD-L1融合蛋白作为免疫原,用于产生人PD-L1抗体。在免疫过程中,采用携带mFc标签的人PD-L1胞外结构域融合蛋白hPD-L1-mFc(Sino biological)作为免疫原。
2、免疫流程
采用常用的小鼠杂交瘤体系产生抗人PD-L1鼠单抗。过程如下:
将重组人PD-L1重组蛋白0.25mg/mL与弗氏完全佐剂(Sigma)等体积混合,得到的油状乳液,以0.2mL的剂量皮下施给6周龄雌性BALB/c小鼠(广东省医学实验动物中心雌性)背部位点。第一次免疫7天后,采用重组人PD-L1重组蛋白与弗氏不完全佐剂(Sigma)等体积混合后进行腹腔免疫,免疫至4-5针后,采集尾血进行效价检测,待效价达到既定滴度后,采用0.1mL用生理盐水稀释的免疫原进行免疫加强,3天后进行脾脏融合。
3、杂交瘤细胞的制备
将小鼠瘤细胞与免疫脾细胞以1:2的细胞数量比例混合,转移至50mL离心管中,用RPMI1640基础培养基洗涤一次。弃上清,用18mL电融合液(BTX)将细胞混匀,加入电融合槽,按照既定参数进行电融合。融合后,加入100mL RPMI1640基础培养基轻轻混悬,平分于96孔板中,共20块,50μL/孔,37℃、5%CO2细胞培养箱静置培养。培养至第6天,更换含HT的RPMI1640完全培养基一次。
4、抗人PD-L1克隆上清的检测
用0.05M碳酸缓冲液稀释携带人Fc标签的自制的人PD-L1重组蛋白至终浓度为1μg/mL,按100μL/孔加入96孔ELISA检测板中,2℃-8℃包被过夜。弃上清,按200μL/孔加入封闭液(1×PBS+1%BSA),37℃封闭1h。融合后第7天,按100μL/孔加入细胞上清,37℃静置孵育30min。用1×PBS洗涤3次。按100μL/孔加入HRP标记的羊抗鼠IgG(sigma),37℃静置孵育30min,用1×PBS洗涤3次后,进行显色反应。
5、亚克隆的筛选
挑选OD450≥0.5的融合子,采用有限稀释法进行克隆化,至少2次。采用以上步骤4的实验流程进行检测,所得的阳性亚克隆经体外培养进行保种和表达。
6、抗人PD-L1抗体的表达
待产生抗人PD-L1抗体的克隆生长至汇合率至80%-90%时,将细胞吹落,1000rpm离心5min后,用30mL含5%FBS的SFM完全培养基重悬细胞,并转移至150mL SF摇瓶中,37℃,8%CO2,120rpm培养2-3天。当细胞密度达到5×10E5/mL时,1000rpm离心5min,用50mL无血清的SFM基础培养基重悬细胞,并转移至250mL SF摇瓶中,37℃,8%CO2,120rpm培养4-5天,9000rpm离心20min,收集上清进行克隆结合鉴定。
7、发酵上清的结合活性鉴定
为评价抗人PD-L1克隆发酵上清与人PD-L1和猕猴PD-L1的结合活性,筛选并构建稳定表达人PD-L1全长蛋白(Uniprot No.NP_0548621.1,SEQ ID NO.1)和猕猴PD-L1(Uniprot No.XP_005581836,SEQ ID NO.2)的中国仓鼠CHO稳定细胞株,抗人PD-L克隆发酵上清的结合活性评价。实验流程如下:
用1×FCM缓冲液(1×PBS+3%BSA)重悬CHO稳定细胞株至2×10E6/mL,按100μL/孔加入到96孔V底板中,250×g离心5min后,吸弃上清,按100μL/孔加入抗人PD-L1克隆发酵上清,冰上静置孵育30min后,250×g离心5min后,吸弃上清。用1×FCM洗涤2次后,按100μL/孔加入用1×FCM缓冲液稀释的iFluorTM633 GAM荧光二抗(稀释倍数为1:400)(ATTbioquest),冰上孵育30min。250×g离心5min后,吸弃上清,加入1×FCM洗涤2次后,按100μL/孔加入1×PBS重悬细胞,采用流式细胞仪(Beckman,CytoFLEX)进行检测。
8、纯化
选取阳性克隆上清进行纯化。纯化采用ProA亲和层析。过程如下:
使用AKTA avant 150层析设备,用至少5CV平衡缓冲液(10mM PBS)平衡层析柱(如MabSelectSuRe LX,GE),加载样品至层析柱,使目标蛋白吸附在层析柱上而其他杂质穿透分离。完成上样后使用至少5CV平衡缓冲液(10mM PBS)再次冲洗层析柱,随后使用洗脱缓冲液(20mM NaAc,pH=3.4)洗脱目标蛋白,收集管中预先加入中和缓冲液(1M Tris,pH8.0),中和缓冲液的加入体积根据洗脱样品的预估含量而定(一般加入10%洗脱体积量)。
9、抗人PD-L1抗体浓度的测定
样品使用Biotek-Epoch-Take-3进行浓度测定,利用A280方法检测抗体浓度,即以消光系数E.C.=1.37,光程=0.05mm(Take-3板不同孔光程由细微差异,会自动校正),通过设备检测样品吸光值,按照Lambert-Beer law计算待测抗体的浓度。样品浓度过低则需要进行超滤浓缩,使用超滤浓缩管( Ultra-15Centrifugal Filter Devices,30kD)按照说明书提供的通用操作方法,将样品浓度浓缩至>0.5mg/mL;收集浓缩端样品,0.22μm无菌枕头滤器除菌过滤(科百特,PES,0.22μm,直径13mm)。
10、抗人PD-L1抗体亚型的鉴定
用0.05M pH 9.5碳酸缓冲溶液稀释携带自产的携带人Fc标签的重组人PD-L1重组蛋白,使其终浓度为1μg/mL。按100μL/孔加入96孔ELISA检测板中,2℃-8℃包被过夜。吸弃上清,按200μL/孔加入封闭液(1×PBS+1%BSA),37℃封闭1h。用含1%BSA的1×PBS稀释抗体至1μg/mL,按100μL/孔加入抗人PD-L1抗体,37℃孵育30分钟。用1×PBS洗涤3次。按100μL/孔加入HRP标记的羊抗鼠IgG(sigma A0168-1ML)、HRP标记的羊抗鼠IgG2a(thermofisher M32207)、HRP标记的羊抗鼠IgG1(thermo fisher PA1-74421)、HRP标记的羊抗鼠IgG2b(thermo fisher M32407)、HRP标记的羊抗鼠IgG3(thermo fisher M32607)、HRP标记的羊抗鼠IgM(thermo fisher 31440),37℃静置孵育30min,用1×PBS洗涤3次后,进行显色反应。得到4株抗人PD-L1抗体(F016-21、F016-193、F016-568、F016-870)。
11、抗人PD-L1抗体序列的鉴定
以上4株抗人PD-L1抗体(F016-21、F016-193、F016-568和F016-870)的鼠杂交瘤克隆的序列调取与测序采用常规的方法,简述如下:
使用RNA提取试剂盒MagExtractor–RNA-(Toyobo),从5×106个鼠杂交瘤细胞中提取获得总RNA。通过5’RACE方法流程,采用SMARTer RACE 5’Kit试剂盒(Takara Bio),获得cDNA序列。使用5’RACE通用引物和3’鼠特异性保守区引物,扩展出抗体可变区序列,并将含可变区序列的PCR克隆序列连接到pMD18-T载体上(Takara,Cat.D101A),转染大肠杆菌E.coliDH5α感受态细胞(NEB)。采用SanPrep柱式质粒DNA小量抽提试剂盒(生工生物)抽提质粒,然后进行序列测序。
4株抗人PD-L1抗体可变区的核苷酸序列如表1所示,氨基酸序列如表2所示。
表1 4株抗人PD-L1抗体的核苷酸序列
抗人PD-L1抗体 | 重链可变区 | 轻链可变区 |
F016-21 | SEQ ID NO.3 | SEQ ID NO.4 |
F016-193 | SEQ ID NO.7 | SEQ ID NO.8 |
F016-568 | SEQ ID NO.11 | SEQ ID NO.12 |
F016-870 | SEQ ID NO.15 | SEQ ID NO.16 |
表2 4株抗人PD-L1抗体的氨基酸序列
抗人PD-L1抗体 | 重链可变区 | 轻链可变区 |
F016-21 | SEQ ID NO.5 | SEQ ID NO.6 |
F016-193 | SEQ ID NO.9 | SEQ ID NO.10 |
F016-568 | SEQ ID NO.13 | SEQ ID NO.14 |
F016-870 | SEQ ID NO.17 | SEQ ID NO.18 |
实施例2
抗人PD-L1抗体的结合活性。
1、抗人PD-L1抗体与CHO-FP1(CHO空细胞)的结合活性检测。
(1)实验方法
检测抗人PD-L1抗体与CHO空细胞的结合活性,流程如下:
用1×FCM缓冲液(1×PBS+3%BSA)重悬CHO空细胞至2×10E6/mL,按100μL/孔加入到96孔V底板中。用1×FCM缓冲液稀释抗人PD-L1抗体至浓度为20μg/mL。按100μL/孔加入到细胞中,冰上静置孵育30min后,250×g离心5min后,吸弃上清。用1×FCM洗涤2次后,按100μL/孔加入用1×FCM缓冲液稀释的iFluorTM633 GAM荧光二抗(稀释倍数为1:400)(ATTbioquest),冰上孵育30min。250×g离心5min后,吸弃上清,加入1×FCM洗涤2次后,按100μL/孔加入1×PBS重悬细胞,采用流式细胞仪(Beckman,CytoFLEX)进行检测。以avelumab-mIgG2a(mIgG2a亚型)、atezolizumab-mIgG1(mIgG1亚型)、mIgG1同型、mIgG2a同型以及APCanti-mIgG作为对照抗体。
(2)实验结果
抗人PD-L1抗体与CHO-FP1的结合活性检测结果如图1所示,结果显示4株抗人PD-L1抗体不与CHO空细胞结合。
2、抗人PD-L1抗体与稳定表达人PD-L1的CHO-hPD-L1的结合活性检测。
(1)实验方法
为表征抗人PD-L1抗体与膜蛋白PD-L1的结合亲和力,用1×FCM缓冲液(1×PBS+3%BSA)将抗人PD-L1抗体进行3倍倍比稀释,起始浓度为60μg/mL,然后与CHO-hPD-L1稳定细胞株共孵育。具体实验流程同上述步骤1。以avelumab-mIgG2a(mIgG2a亚型)、atezolizumab-mIgG1(mIgG1亚型)、mIgG1同型以及mIgG2a同型作为对照抗体。
(2)实验结果
抗人PD-L1抗体与稳定表达人PD-L1的CHO-hPD-L1的结合活性检测结果如图2所示。
结果显示,4株抗人PD-L1抗体与CHO-hPD-L1的结合活性EC50为0.5~1.3nM,对照抗体与CHO-hPD-L1的结合活性EC50为0.2-1.0nM。
3、抗人PD-L1抗体与稳定表达猕猴PD-L1的CHO-cynoPD-L1的结合活性检测
(1)实验方法
为表征抗人PD-L1抗体与猕猴PD-L1的结合亲和力,用1×FCM缓冲液(1×PBS+3%BSA)将抗人PD-L1抗体进行3倍倍比稀释,起始浓度为30μg/mL,然后与CHO-cynoPD-L1稳定细胞株共孵育。具体实验流程同上述步骤1。以avelumab-mIgG2a(mIgG2a亚型)、atezolizumab-mIgG1(mIgG1亚型)、mIgG1同型以及mIgG2a同型作为对照抗体。
(2)实验结果
抗人PD-L1抗体与稳定表达猕猴PD-L1的CHO-cynoPD-L1的结合活性检测结果如图3所示,结果显示4株抗人PD-L1抗体与CHO-cynoPD-L1的结合活性EC50为0.9-1.3nM,对照抗体与CHO-cynoPD-L1的结合活性EC50为0.5-2.1nM。
4、抗人PD-L1抗体与IFNγ刺激的A375细胞的结合活性检测。
(1)实验方法
用人IFNγ刺激肿瘤细胞表面PD-L1的表达,检测抗人PD-L1抗体与PD-L1膜蛋白的结合活性。实验流程如下:
用50ng/mL人IFNγ(R&D)过夜刺激人黑色素瘤细胞A375(上海细胞库)上人PD-L1的表达,次日,用0.25%胰酶(Gibco)消化处理A375细胞,用DPBS洗涤一次后,调活细胞密度至2E6/mL,按100μL/孔加入到96孔V底板中。用1×FCM缓冲液稀释抗人PD-L1抗体至浓度为60μg/mL。按100μL/孔加入到细胞中,冰上静置孵育30min后,250×g离心5min后,吸弃上清。用1×FCM洗涤2次后,按100μL/孔加入用1×FCM缓冲液稀释的iFluorTM633 GAM荧光二抗(稀释倍数为1:400)(ATT bioquest),冰上孵育30min。250×g离心5min后,吸弃上清,加入1×FCM洗涤2次后,按100μL/孔加入1×PBS重悬细胞,采用流式细胞仪(Beckman,CytoFLEX)进行检测。以avelumab-mIgG2a(mIgG2a亚型)、atezolizumab-mIgG1(mIgG1亚型)、mIgG1同型以及mIgG2a同型作为对照抗体。
(2)实验结果
抗人PD-L1抗体与IFNγ刺激的A375细胞的结合活性检测结果如图4所示,结果显示抗人PD-L1抗体与IFNγ刺激的A375细胞的结合EC50为0.12-0.18nM,对照抗体与IFNγ刺激的A375细胞的结合EC50为0.12-0.19nM。
5、抗人PD-L1抗体与人PD-L1的结合动力学KD分析。
(1)实验方法
采用MD ForteBIO QKe平台进行抗人PD-L1抗体与人PD-L1的结合动力学常数分析。实验方法如下:
用平衡缓冲液(1×PBS+0.02%吐温20)稀释自产的携带his标签的人PD-L1胞外区重组蛋白hPD-L1-his至终浓度为5μg/mL。用平衡缓冲液(1×PBS+0.02%吐温20)2倍倍比稀释4株抗人PD-L1抗体,起始浓度为100nM,共7个浓度。待anti-Penta-HIS生物传感器(ForteBIO)充分水化后,先固化hPD-L1-his重组蛋白150秒,平衡90秒后,与抗人PD-L1抗体结合,其中结合时间为180秒,解离时间为600秒。整个反应在25℃,1000rpm条件下进行。最后用Octet分析软件进行曲线拟合,获得抗人PD-L1抗体的结合动力学常数KD。以avelumab-mIgG2a(mIgG2a亚型)和atezolizumab-mIgG1(mIgG1亚型)作为对照抗体。
(2)实验结果
抗人PD-L1抗体与人PD-L1的结合动力学KD分析结果如表3所示,结果显示与对照抗体一样,4株抗人PD-L1抗体与人PD-L1重组蛋白的结合动力学常数均在pM级别。
表3抗人PD-L1抗体与人PD-L1的结合动力学KD分析结果
抗体名称 | KD,×10E-10(M) |
F016-21 | 0.566 |
F016-193 | 0.098 |
F016-568 | 1.010 |
F016-870 | 0.742 |
avelumab-mIgG2a | 0.943 |
atezolizumab-mIgG1 | 0.565 |
实施例3
抗人PD-L1抗体的表位分析。
1、表位结合(epitope binning)
(1)实验方法
采用MD ForteBIO QKe平台进行抗人PD-L1抗体的表位竞争分析。实验方法如下:
用平衡缓冲液(1×PBS+0.02%吐温20)稀释自产的携带his标签的人PD-L1胞外区重组蛋白hPD-L1-his至终浓度为5μg/mL。用平衡缓冲液(1×PBS+0.02%吐温20)稀释抗人PD-L1抗体,其终浓度为20μg/mL。待anti-Penta-HIS生物传感器(ForteBIO,Cat.18-5122)充分水化后,先固化hPD-L1-his重组蛋白150秒,平衡90秒后,与第一种抗人PD-L1抗体结合120秒,平衡90秒后,再与第二种抗人PD-L1抗体结合其中结合时间120秒。整个反应在25℃,1000rpm条件下进行。最后用Octet分析软件进行表位结合分析。
(2)实验结果
表位结合分析结果显示F016-21和F016-193与avelumab不竞争。
2、细胞水平的抗体表位竞争分析
(1)实验方法
用1×FCM缓冲液(1×FBS+3%BSA)稀释抗PD-L1抗体,其中第一种抗体包括avelumab-hIgG1(hIgG1亚型)、hIgG1同型对照抗体,其浓度为40μg/mL,第二种抗体为抗人PD-L1抗体、avelumab-mIgG2a(mIgG2a亚型)和mIgG2a同型对照抗体,其浓度为2μg/mL。用1×FCM缓冲液重悬CHO-hPD-L1稳定细胞株,调整细胞密度为2×10E6/mL,按100μL/孔分于96孔板中,加入第一种抗体50μL,冰上孵育30min后,加入第二种抗体50μL,冰上孵育30min。250×g离心5min后,吸弃上清。用1×FCM洗涤2次后,按100μL/孔加入用1×FCM缓冲液稀释的iFluorTM633 GAM荧光二抗(稀释倍数为1:400)(ATT bioquest),冰上孵育30min。250×g离心5min后,吸弃上清,加入1×FCM洗涤2次后,按100μL/孔加入1×PBS重悬细胞,采用流式细胞仪(Beckman,CytoFLE×)进行检测。
(2)实验结果
抗人PD-L1抗体与CHO-hPD-L1竞争结合活性检测结果如图5所示,F016-21和F016-193与avelumab不竞争。
实施例4
抗人PD-L1抗体介导的配体阻断实验。
1、与PD-1结合阻断活性。
肿瘤细胞或抗原递呈细胞表达的PD-L1蛋白,通过与淋巴细胞表面表达的PD-1蛋白通结合,抑制淋巴细胞的刺激活性。对PD-1和PD-L1结合的阻断型抗人PD-L1抗体进行评价,可通过实验方法1和2进行,实验方法1和2分别如下:
1)实验方法1
(1)实验方法
用1×FCM缓冲液3倍倍比稀释抗人PD-L1抗体,起始浓度为200μg/mL。用1×FCM缓冲液稀释自产的携带hFc的重组人PD-1蛋白至浓度为4μg/mL。用1×FCM缓冲液重悬CHO-hPD-L1细胞至2×10E6/mL细胞密度,按100μL/孔均分于96孔V底板中。按50μL/孔将抗体加入到CHO-hPD-L1细胞中,冰上孵育30min后,按50μL/孔加入重组人PD-1-hFc蛋白,冰上孵育30min。250×g离心5min后,吸弃上清,用1×FCM洗涤1次后,按100μL孔加入用1×FCM缓冲液稀释的APC标记的羊抗鼠Fc荧光二抗(稀释倍数为1:500)(Biolegend),冰上孵育30min。250×g离心5min后,吸弃上清,加入1×FCM洗涤2次后,按100μL/孔加入1×PBS重悬细胞,采用流式细胞仪(Beckman,CytoFLEX)进行检测。以avelumab-mIgG2a(mIgG2a亚型)和atezolizumab-mIgG1(mIgG1亚型)作为对照抗体。
(2)实验结果
实验方法1中的抗人PD-L1抗体阻断CHO-hPD-L1与hPD-L1 hFc重组蛋白结合活性检测结果如图6所示,结果显示4株鼠单抗阻断PD-1与PD-L1的结合活性IC50为4.9-6.9nM,对照抗体阻断PD-1与PD-L1的结合活性IC50为5.0-6.4nM。
2)实验方法2
(1)实验方法
用1×FCM缓冲液3倍倍比稀释抗人PD-L1抗体,起始浓度为200μg/mL。用1×FCM缓冲液稀释自产的携带hFc的重组人PD-L1蛋白至浓度为2μg/ml。用1×FCM缓冲液重悬CHO-hPD-1细胞至2×10E6/ml细胞密度,按100μL/孔均分于96孔V底板中。按50μL/孔将抗体加入到CHO-hPD-1细胞中,冰上孵育30min后,按50μL/孔加入重组人PD-L1-hFc蛋白,冰上孵育30min。250×g离心5min后,吸弃上清,用1×FCM洗涤1次后,按100μL/孔加入用1×FCM缓冲液稀释的APC标记的羊抗鼠Fc荧光二抗(稀释倍数为1:500)(Biolegend),冰上孵育30min。250×g离心5min后,吸弃上清,加入1×FCM洗涤2次后,按100μL/孔加入1×PBS重悬细胞,采用流式细胞仪(Beckman,CytoFLEX)进行检测;
以avelumab-mIgG2a(mIgG2a亚型)、atezolizumab-mIgG1(mIgG1亚型)、作为对照抗体。
(2)实验结果
实验方法2中的抗人PD-L1抗体阻断CHO-hPD-L1与hPD-L1 hFc重组蛋白结合活性检测结果如图7所示,结果显示4株鼠单抗阻断PD-1与PD-L1的结合活性IC50为0.9-1.7nM,对照抗体阻断PD-1与PD-L1的结合活性IC50为1.1-1.6nM。
2、与CD80结合阻断活性
(1)实验方法
肿瘤细胞或抗原递呈细胞表达的PD-L1蛋白,通过与淋巴细胞表面表达的CD80蛋白通结合,抑制淋巴细胞的刺激活性。对CD80和PD-L1结合的阻断型抗人PD-L1抗体进行评价,实验方法如下:
用1×FCM缓冲液3倍倍比稀释抗人PD-L1抗体,起始浓度为200μg/mL。用1×FCM缓冲液稀释自产的携带hFc的重组人CD80蛋白至浓度为160μg/mL。用1×FCM缓冲液重悬CHO-hPD-L1细胞至2×10E6/ml细胞密度,按100μL/孔均分于96孔V底板中。
按50μL/孔将抗体加入到CHO-hPD-L1细胞中,冰上孵育30min后,按50μL/孔加入重组人CD80-hFc蛋白,冰上孵育30min。250×g离心5min后,吸弃上清,用1×FCM洗涤1次后,按100μL/孔加入用1×FCM缓冲液稀释的APC标记的羊抗鼠Fc荧光二抗(稀释倍数为1:500)(Biolegend),冰上孵育30min。250×g离心5min后,吸弃上清,加入1×FCM洗涤2次后,按100μl/孔加入1×PBS重悬细胞,采用流式细胞仪(Beckman,CytoFLEX)进行检测;
以avelumab-mIgG2a(mIgG2a亚型)、atezolizumab-mIgG1(mIgG1亚型)、作为对照抗体。
(2)实验结果
抗人PD-L1抗体阻断CHO-hPD-L1与hCD80 hFc重组蛋白结合活性检测结果如图8所示,结果显示4株鼠单抗阻断PD-L1与CD80的结合活性IC50为4.1-5.0nM,对照抗体阻断PD-L1与CD80的结合活性IC50为4.0-4.4nM。
实施例5
抗人PD-L1抗体的体外活性表征。
1、Jurkat-GL4.30-hPD-1和CHO-hPD-L1-OKT3共孵育下荧光素酶报告基因体系的检测
(1)实验方法
为利用荧光素酶报告基因体系检测抗人PD-L1鼠单抗的体外功能活性,通过慢病毒包装体系构建稳定表达hPD-1和荧光素酶基因的Jurkat-GL4.30-hPD-1效应细胞株。同时构建PD-L1递呈细胞CHO-hPD-L1-OKT3,即采用中国仓鼠CHO细胞稳定表达hPD-L1和抗原非依赖的TCR细胞表面驱动蛋白。实验当天,用含1%FBS的RPMI1640完全培养基重悬CHO-hPD-L1-OKT3细胞和Jurkat-GL4.30-hPD-1细胞,活细胞密度分别为1×10E6/mL和5×10E6/mL,按40μL/孔分于96孔荧光酶标板中。用含1%FBS的RPMI1640完全培养基稀释抗人PD-L1鼠单抗,起始浓度为50μg/ml,按20μL/孔吸取抗体至Jurkat-GL4.30-hPD-1和CHO-hPD-L1-OKT3混合细胞中,混匀后,37℃、5%CO2细胞培养箱中培养6h。按100μL/孔加入提前解冻的Bright-LumiTM溶液(碧云天),避光静止5min后,使用多功能酶标仪(Molecular Device,SpectraMax i3x多功能酶标仪)在Lumi模式下进行检测。以avelumab-mIgG2a(mIgG2a亚型)、atezolizumab-mIgG1(mIgG1亚型)、mIgG1同型以及mIgG2a同型作为对照抗体。
(2)实验结果
荧光素酶报告基因法分析抗人PD-L1抗体的体外活性板一、板二结果分别如图9所示,结果显示4株抗体能介导荧光素酶报告基因信号的回调,并呈抗体剂量依赖性。
2、T-DC异体混合淋巴反应体系中刺激IL-2和IFN gamma的产生
(1)实验方法
通过异体T-DC MLR实验,评价抗人PD-L1抗体刺激细胞因子IL-2和IFN gamma的活性。实验流程如下:
采用人淋巴细胞分离液LymphoprepTM(Axis-Shield)从健康人外周血中分离得到外周血淋巴细胞PBMC。其中,供体1的PBMC经人CD14 Microbeads(Miltenyi)正筛选获得CD14+单核细胞。将单核细胞按照5×10E5/mL接种于T75培养瓶中,补加细胞因子人GM-CSF和IL-4至终浓度为50ng/mL,连续刺激6天后,补加人TNF alpha至终浓度为50ng/mL,继续诱导分化3天获得成熟的DC细胞。供体2的PBMC经EasySepTM Human T Cell Enrichment Kit(Stemcell)负筛选获得CD3+T细胞。按照DC:T细胞比例为1:5,DC细胞量为2×10E4/孔,将DC和T细胞混合均匀后分于96孔U型板中,共150μL/孔体系。用X-VIVO 15完全培养基稀释抗人PD-L1抗体,起始浓度为20μg/mL,4倍倍比稀释,按50μL/孔加入到细胞中。混合淋巴实验反应3-5天后,检测细胞上清中IL-2和IFN gamma的表达。以avelumab-mIgG2a(mIgG2a亚型)、mIgG1同型以及mIgG2a同型作为对照抗体。
(2)实验结果
抗人PD-L1抗体介导的混合淋巴细胞反应中IL-2的分泌板一、板二结果分别如图10、图11所示,其EC50依次为0.07-0.1μg/mL、0.05-0.09μg/mL,对照抗体的EC50为依次为0.03μg/mL、0.04μg/mL;抗人PD-L1抗体介导的混合淋巴细胞反应中IFNγ的分泌板一、板二结果分别如图12、图13所示,其EC50依次为0.14-0.17μg/mL、0.1-0.14μg/mL,对照抗体的EC50为依次为0.089μg/mL、0.077μg/mL;结果显示在T-DC异体混合淋巴反应实验中,抗人PD-L1抗体能介导细胞因子IL-2、IFNγ的上调,并与抗体用量呈正相关。
实施例6
抗人PD-L1抗体的结合特异性分析。
PD-L1蛋白属于B7家族蛋白,其同家族蛋白包括PD-L2(B7-DC),ICOSL(B7-H2),B7-H3CD80(B7-1)、CD86(B7-2)等。为检测抗人PD-L1抗体结合特异性,实验流程如下:
用50mM CB缓冲液稀释携带hFc标签的重组人PD-L1蛋白、人PD-L2蛋白(Acrobiosystem)、人ICOSLG蛋白(Acrobiosystem),人B7-H3蛋白(Acrobiosystem),人CD28蛋白(Acrobiosystem),人CD86蛋白(Acrobiosystem)和人CTLA-4蛋白(Acrobiosystem)至1μg/ml,按100μl/孔加入96孔ELISA检测板中,2-4℃包被过夜。弃上清,按200μl/孔加入封闭液(1×PBS+1%BSA),37℃封闭1h。用含1%BSA的PBS稀释抗人PD-L1抗体至10μg/ml,按100μl/孔加入,37℃静置孵育30min。用1×PBS洗涤3次。按100μl/孔加入HRP标记的羊抗鼠IgG(sigma A0168-1ML),37℃静置孵育30min,用1×PBS洗涤3次后,进行显色反应。
2、实验结果
抗人PD-L1抗体与重组蛋白hPD-L1 hFc、hPD-L2 hFc、hICOSLG hFc、hB7-H3 hFc的结合特异性结果如图14所示,抗人PD-L1抗体与重组蛋白hCD28 hFc、hCD86 hFc、hCTLA-4hFc的结合特异性结果如图15所示,结果显示,4株抗人PD-L1抗体均不与除PD-L1外的其他B7家族蛋白及其他相关性蛋白(hPD-L1 hFc、hPD-L2 hFc、hICOSLG hFc、hB7-H3 hFc、hCD28hFc、hCD86 hFc、hCTLA-4hFc)结合;而对照抗体除了与PD-L1结合外,还与PD-L2、ICOSLG、B7-H3、CD28、CD86、CTLA-4具有相对很高的结合;表明与对照抗体相比,本发明抗人PD-L1抗体的结合特异性更强。
实施例7
抗人PD-L1抗体的体内活性表征。
本实施例研究了抗人PD-L1抗体针对小鼠肿瘤模型阻断的效力。由于本发明获得的抗人PD-L1鼠单抗与鼠源PD-L1不交叉,故采用C57BL/6背景的hPD-L1转基因鼠(百奥赛图)。实验方法如下:
在小鼠右侧皮下接种1×10E6 MC38 hPD-L1稳定表达结直肠癌细胞。接种当天定义为研究第0天。当平均肿瘤体积达到60~80mm3,对小鼠按肿瘤体积随机分组,研究第8天时,将小鼠按照肿瘤体积随机分为10组,每组8只小鼠,并开始进行腹腔给药。给药方案如表4所示。
表4
组别 | 剂量(mg/kg) | 给药体积(μL/g) | 给药频率 |
DPBS | \ | 10 | Q3D*6 |
mIgG2a同型对照 | 10 | 10 | Q3D*6 |
Avelumab-mIgG2a | 10 | 10 | Q3D*6 |
F016-21-mIgG2a | 10 | 10 | Q3D*6 |
F016-870-mIgG2a | 10 | 10 | Q3D*6 |
F016-568-mIgG2a | 10 | 10 | Q3D*6 |
Atezolizumab-mIgG1 | 10 | 10 | Q3D*6 |
F016-21-mIgG1 | 10 | 10 | Q3D*6 |
F016-870-mIgG1 | 10 | 10 | Q3D*6 |
F016-568-mIgG1 | 10 | 10 | Q3D*6 |
从第8天开始测量肿瘤体积并进行记录,在研究持续时间每周2次用游标卡尺测量肿瘤长径和短径。按照(1/2)×长径×(短径)2计算肿瘤体积。当小鼠体积下降20%或者肿瘤体积超过2000mm3时,达到仁慈肿瘤,用CO2窒息法处死小鼠。
表5
抗人PD-L1抗体的体内活性表征结果如表5和图16所示,结果显示:mIgG1亚型的抗hPD-L1抗体F016-21(TGI=69.19%,CR:3/8)和F016-870(TGI=53.22%,CR:0/8)的抗肿瘤作用优于Atezolizumab-mIgG1(TGI=36.29%,CR:0/8)(如图16a所示)。mIgG2a亚型的抗hPD-L1抗体F016-21、F016-870和F016-568的抗肿瘤作用显著,TGI分别为103.83%、106.73%和92.62%。8只小鼠中肿瘤全部消除(CR)分别为7只、7只和4只(即CR分别为7/8,7/8和4/8)(如图16b所示)。同时抗hPD-L1抗体各给药组对小鼠体重没有显著影响(如图16c所示)。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
SEQUENCE LISTING
<110> 广东菲鹏制药股份有限公司
<120> 一种抗PD-L1抗体及其应用
<160> 42
<170> PatentIn version 3.5
<210> 1
<211> 290
<212> PRT
<213> 人工序列
<400> 1
Met Arg Ile Phe Ala Val Phe Ile Phe Met Thr Tyr Trp His Leu Leu
1 5 10 15
Asn Ala Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr
20 25 30
Gly Ser Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu
35 40 45
Asp Leu Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile
50 55 60
Ile Gln Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser
65 70 75 80
Tyr Arg Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn
85 90 95
Ala Ala Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr
100 105 110
Arg Cys Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val
115 120 125
Lys Val Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val
130 135 140
Asp Pro Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr
145 150 155 160
Pro Lys Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser
165 170 175
Gly Lys Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn
180 185 190
Val Thr Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr
195 200 205
Cys Thr Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu
210 215 220
Val Ile Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His
225 230 235 240
Leu Val Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr
245 250 255
Phe Ile Phe Arg Leu Arg Lys Gly Arg Met Met Asp Val Lys Lys Cys
260 265 270
Gly Ile Gln Asp Thr Asn Ser Lys Lys Gln Ser Asp Thr His Leu Glu
275 280 285
Glu Thr
290
<210> 2
<211> 290
<212> PRT
<213> 人工序列
<400> 2
Met Arg Ile Phe Ala Val Phe Ile Phe Thr Ile Tyr Trp His Leu Leu
1 5 10 15
Asn Ala Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr
20 25 30
Gly Ser Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu
35 40 45
Asp Leu Thr Ser Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile
50 55 60
Ile Gln Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Asn
65 70 75 80
Tyr Arg Gln Arg Ala Gln Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn
85 90 95
Ala Ala Leu Arg Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr
100 105 110
Arg Cys Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val
115 120 125
Lys Val Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val
130 135 140
Asp Pro Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr
145 150 155 160
Pro Lys Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser
165 170 175
Gly Lys Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Leu Asn
180 185 190
Val Thr Ser Thr Leu Arg Ile Asn Thr Thr Ala Asn Glu Ile Phe Tyr
195 200 205
Cys Ile Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu
210 215 220
Val Ile Pro Glu Leu Pro Leu Ala Leu Pro Pro Asn Glu Arg Thr His
225 230 235 240
Leu Val Ile Leu Gly Ala Ile Phe Leu Leu Leu Gly Val Ala Leu Thr
245 250 255
Phe Ile Phe Tyr Leu Arg Lys Gly Arg Met Met Asp Met Lys Lys Cys
260 265 270
Gly Ile Arg Val Thr Asn Ser Lys Lys Gln Arg Asp Thr Gln Leu Glu
275 280 285
Glu Thr
290
<210> 3
<211> 342
<212> DNA
<213> 人工序列
<400> 3
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaaaatg 60
tcctgcaagg cttctggata cacattcact gactatgtta tgcactgggt gaagcaaaaa 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatgg tactaagttc 180
aatgaaaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aaaacaaact 300
ctggactact ggggtcaagg aacctcagtc accgtctcct ca 342
<210> 4
<211> 336
<212> DNA
<213> 人工序列
<400> 4
gacattgtgc tcacccaatc tccagcttct ttggctgtgt ctctagggca gagagccacc 60
atctcctgca gagccagtga aagtgttgaa tattttggca caactttaat gcagtggtac 120
caacagagac caggacagcc acccaaactc ctcatctatg ctgcatccaa cgtagaatct 180
ggggtccctg ccaggtttag tggcagtggg tctgggacag acttcagcct caacatccat 240
cctgtggagg aggatgatat tgcaatgtat ttctgtcagc aaagtaggaa ggttccgtac 300
acgttcggag gggggaccaa gctggaaata aaacgg 336
<210> 5
<211> 114
<212> PRT
<213> 人工序列
<400> 5
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Phe Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gln Thr Leu Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 6
<211> 112
<212> PRT
<213> 人工序列
<400> 6
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Glu Tyr Phe
20 25 30
Gly Thr Thr Leu Met Gln Trp Tyr Gln Gln Arg Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Asp Asp Ile Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 7
<211> 342
<212> DNA
<213> 人工序列
<400> 7
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agttatgtta tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctc acaatgatgg taataagtac 180
aatgagaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag ctcagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aaaacagact 300
atggactact ggggtcaagg aacctcagtc accgtctcct ca 342
<210> 8
<211> 336
<212> DNA
<213> 人工序列
<400> 8
gacattgtgc tcacccaatc tccggcttct ttggctgtgt ctctagggca gagagccacc 60
ctctcctgca gagccagtga aagtgttgaa ttttatggca caactttaat gcagtggttc 120
caacagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa cgtagaatct 180
ggggtccctg ccaggtttag tggcagtggg tctgggacag acttcagcct caacatccat 240
cctgtggagg aggatgatat tgcaatgtat ttctgtcagc aaagtaggaa ggttccgtac 300
acgttcggag gggggaccaa gctggaaata aaacgg 336
<210> 9
<211> 114
<212> PRT
<213> 人工序列
<400> 9
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro His Asn Asp Gly Asn Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Ser Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gln Thr Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 10
<211> 112
<212> PRT
<213> 人工序列
<400> 10
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Glu Phe Tyr
20 25 30
Gly Thr Thr Leu Met Gln Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Asp Asp Ile Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 11
<211> 348
<212> DNA
<213> 人工序列
<400> 11
cagcttcagg agtcaggacc tagcctcgtg aaaccttctc aaactctgtc cctcacctgt 60
tctgtcactg gcgactccat caccagtgat tactggaact ggatccggaa attcccaggg 120
aataaacttg agtacatggg atacataagc tacactggta gcacttacta caatccatct 180
ctcaaaagtc gaatctccat cactcgagac acatccaaga accagtacta cctgcagttg 240
aattctgtga ctactgagga cacagccaca tattactgtg caaagcaggg gggatggtta 300
aatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcctca 348
<210> 12
<211> 342
<212> DNA
<213> 人工序列
<400> 12
gacattgtga tgtcacagtc tccatcctcc ctagctgtgt cagttggaga gaaggttact 60
gtgagctgca agtccagtca gagcctttta tatagtagca atcaaaagaa ctccttggcc 120
tggtaccagc agaaaccagg acagtctcct aaactgctga tttactgggc atccactagg 180
gaatctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 240
atcagcagtg tgaaggctga agacctggca gtttattact gtcagcaata ttatggctat 300
ccgtacacgt tcggaggggg gaccaagctg gaaataaaac gg 342
<210> 13
<211> 116
<212> PRT
<213> 人工序列
<400> 13
Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln Thr Leu
1 5 10 15
Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Ile Thr Ser Asp Tyr Trp
20 25 30
Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met Gly Tyr
35 40 45
Ile Ser Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg
50 55 60
Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu Gln Leu
65 70 75 80
Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Lys Gln
85 90 95
Gly Gly Trp Leu Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser
115
<210> 14
<211> 114
<212> PRT
<213> 人工序列
<400> 14
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Val Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Gly Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg
<210> 15
<211> 357
<212> DNA
<213> 人工序列
<400> 15
gaggtgcagc ttcaggagtc aggacctagc ctcgtgaaac cttctcagac tctgtccctc 60
acctgttctg tcactggcga ctccatcacc agtggttact ggaactggat ccggaaattc 120
ccagggaata aacttgagta catggggtac ataagctaca ctggtagcac ttaccagaat 180
ccatctctca aaagtcgaat ctccttcact cgagacacat ccaagaacca gtactacctg 240
cagttgagtt ctgtgactac tgaggacaca gccacatatt actgtgcaag atcccgggca 300
tggatacgga cctactttga ctactggggc cagggcacca ctctcacagt ctcctca 357
<210> 16
<211> 327
<212> DNA
<213> 人工序列
<400> 16
gaaattgtgc tcacccagtc tccagcactc atggctgcat ctccagggga gaaggtcacc 60
atcacctgca gtgtcagctc aagtataagt tccagcaact tgcactggta ccagcagaag 120
tcagaaacct cccccaaacc ctggatttat ggcacatcca acctggcttc tggagtccct 180
gttcgcttca gtggcagtgg atctgggacc tcttattctc tcacaatcag cagcatggag 240
gctgaagatg ctgccactta ttactgtcaa cagtggagta gttacccact cacgttcggt 300
gctgggacca agctggagct gaaacgg 327
<210> 17
<211> 119
<212> PRT
<213> 人工序列
<400> 17
Glu Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met
35 40 45
Gly Tyr Ile Ser Tyr Thr Gly Ser Thr Tyr Gln Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ile Ser Phe Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu
65 70 75 80
Gln Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Ser Arg Ala Trp Ile Arg Thr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 18
<211> 109
<212> PRT
<213> 人工序列
<400> 18
Glu Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ala Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Val Ser Ser Ser Ile Ser Ser Ser
20 25 30
Asn Leu His Trp Tyr Gln Gln Lys Ser Glu Thr Ser Pro Lys Pro Trp
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro
85 90 95
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
100 105
<210> 19
<211> 10
<212> PRT
<213> 人工序列
<400> 19
Gly Tyr Thr Phe Thr Asp Tyr Val Met His
1 5 10
<210> 20
<211> 17
<212> PRT
<213> 人工序列
<400> 20
Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Phe Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 21
<211> 5
<212> PRT
<213> 人工序列
<400> 21
Gln Thr Leu Asp Tyr
1 5
<210> 22
<211> 15
<212> PRT
<213> 人工序列
<400> 22
Arg Ala Ser Glu Ser Val Glu Tyr Phe Gly Thr Thr Leu Met Gln
1 5 10 15
<210> 23
<211> 7
<212> PRT
<213> 人工序列
<400> 23
Ala Ala Ser Asn Val Glu Ser
1 5
<210> 24
<211> 9
<212> PRT
<213> 人工序列
<400> 24
Gln Gln Ser Arg Lys Val Pro Tyr Thr
1 5
<210> 25
<211> 10
<212> PRT
<213> 人工序列
<400> 25
Gly Tyr Thr Phe Thr Ser Tyr Val Met His
1 5 10
<210> 26
<211> 17
<212> PRT
<213> 人工序列
<400> 26
Tyr Ile Asn Pro His Asn Asp Gly Asn Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 27
<211> 5
<212> PRT
<213> 人工序列
<400> 27
Gln Thr Met Asp Tyr
1 5
<210> 28
<211> 15
<212> PRT
<213> 人工序列
<400> 28
Arg Ala Ser Glu Ser Val Glu Phe Tyr Gly Thr Thr Leu Met Gln
1 5 10 15
<210> 29
<211> 7
<212> PRT
<213> 人工序列
<400> 29
Ala Ala Ser Asn Val Glu Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列
<400> 30
Gln Gln Ser Arg Lys Val Pro Tyr Thr
1 5
<210> 31
<211> 9
<212> PRT
<213> 人工序列
<400> 31
Gly Asp Ser Ile Thr Ser Asp Tyr Trp
1 5
<210> 32
<211> 16
<212> PRT
<213> 人工序列
<400> 32
Tyr Ile Ser Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 33
<211> 10
<212> PRT
<213> 人工序列
<400> 33
Gln Gly Gly Trp Leu Asn Ala Met Asp Tyr
1 5 10
<210> 34
<211> 17
<212> PRT
<213> 人工序列
<400> 34
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Ser Leu
1 5 10 15
Ala
<210> 35
<211> 7
<212> PRT
<213> 人工序列
<400> 35
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 36
<211> 9
<212> PRT
<213> 人工序列
<400> 36
Gln Gln Tyr Tyr Gly Tyr Pro Tyr Thr
1 5
<210> 37
<211> 10
<212> PRT
<213> 人工序列
<400> 37
Gly Asp Ser Ile Thr Ser Gly Tyr Trp Asn
1 5 10
<210> 38
<211> 16
<212> PRT
<213> 人工序列
<400> 38
Tyr Ile Ser Tyr Thr Gly Ser Thr Tyr Gln Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 39
<211> 11
<212> PRT
<213> 人工序列
<400> 39
Ser Arg Ala Trp Ile Arg Thr Tyr Phe Asp Tyr
1 5 10
<210> 40
<211> 12
<212> PRT
<213> 人工序列
<400> 40
Ser Val Ser Ser Ser Ile Ser Ser Ser Asn Leu His
1 5 10
<210> 41
<211> 7
<212> PRT
<213> 人工序列
<400> 41
Gly Thr Ser Asn Leu Ala Ser
1 5
<210> 42
<211> 9
<212> PRT
<213> 人工序列
<400> 42
Gln Gln Trp Ser Ser Tyr Pro Leu Thr
1 5
Claims (11)
1.抗PD-L1抗体或其抗原结合片段,其特征在于,所述抗体含有以下互补决定区CDRs:
HCDR1、HCDR2、HCDR3的氨基酸序列如SEQ ID NO:37、38、39所示,LCDR1、LCDR2、LCDR3的氨基酸序列如SEQ ID NO:40、41、42所示。
2.一种抗PD-L1抗体或其抗原结合片段,其特征在于,所述抗体含有重链可变区和轻链可变区;
所述重链可变区的氨基酸序列如SEQ ID NO:17所示,所述轻链可变区的氨基酸序列如SEQ ID NO:18所示。
3.根据权利要求1所述抗PD-L1抗体或其抗原结合片段,其特征在于,所述抗体具有恒定区,重链恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgD、IgE或IgM中的任一种;轻链恒定区为κ链或λ链。
4.根据权利要求1-3任一项所述抗PD-L1抗体或其抗原结合片段,其特征在于,所述抗体为双特异性抗体、CDR移植抗体或多聚体抗体中的任一种或几种;所述抗原结合片段为scFv、Fab、Fab’、F(ab’)2和Fv中的任一种或几种。
5.一种核酸,其特征在于,编码权利要求1~4任一项所述的抗PD-L1的抗体或其抗原结合片段的序列。
6.根据权利要求5所述的核酸,其特征在于,所述核酸包括:编码所述抗体或其抗原结合片段的重链可变区的第一核酸,和/或,编码所述抗体或其抗原结合片段的轻链可变区的第二核酸。
7. 根据权利要求6所述核酸,其特征在于,所述第一核酸的碱基序列如SEQ ID NO:15所示或与SEQ ID NO:15所示具有至少95%同一性的序列;
所述第二核酸的碱基序列如SEQ ID NO:16所示或与SEQ ID NO:16所示具有至少95%同一性的序列。
8.一种载体,其特征在于,所述载体包含权利要求5~7任一项所述核酸。
9.一种细胞,其特征在于,所述细胞包含权利要求5~7任一项所述核酸、或权利要求8所述载体。
10.一种药物组合物,其特征在于,所述药物组合物含有权利要求1~4任一项所述抗PD-L1抗体或其抗原结合片段、权利要求5~7任一项所述核酸、权利要求8所述载体或权利要求9所述细胞。
11.权利要求1~4任一项所述抗PD-L1抗体或其抗原结合片段、权利要求5~7任一项所述核酸、权利要求8所述载体、权利要求9所述细胞或权利要求10所述药物组合物在制备用于治疗PD-L1介导的疾病或病症的药物中的应用,所述疾病或病症选自结直肠癌、肾癌、胃癌、尿道上皮癌、卵巢癌和黑色素瘤。
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CN202011541107 | 2020-12-23 |
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CN109641971A (zh) * | 2016-08-25 | 2019-04-16 | Jcr制药股份有限公司 | 抗体融合蛋白的制造方法 |
CN111662383A (zh) * | 2019-03-08 | 2020-09-15 | 珠海市丽珠单抗生物技术有限公司 | 抗pd-l1抗体及其应用 |
CN111676196A (zh) * | 2012-05-25 | 2020-09-18 | 塞勒克提斯公司 | 工程化异体和免疫抑制耐受性t细胞的方法 |
CN114867493A (zh) * | 2019-10-04 | 2022-08-05 | 阿尔伯特爱因斯坦医学院 | Kir3dl3是免疫系统的抑制性受体及其用途 |
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JP6448533B2 (ja) * | 2012-05-15 | 2019-01-09 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Pd−1/pd−l1シグナル伝達を破壊することによる癌免疫療法 |
TWI680138B (zh) * | 2014-01-23 | 2019-12-21 | 美商再生元醫藥公司 | 抗pd-l1之人類抗體 |
CN105777906B (zh) * | 2014-12-19 | 2019-04-23 | 苏州丁孚靶点生物技术有限公司 | 抗pd-l1全人抗体及其应用 |
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CN106939050B (zh) * | 2017-03-27 | 2019-05-10 | 顺昊细胞生物技术(天津)股份有限公司 | 抗pd1和cd19双特异性抗体及其应用 |
CN107384933A (zh) * | 2017-08-31 | 2017-11-24 | 西北大学 | pD1蛋白C端9个氨基酸多克隆抗体、核苷酸序列、制备方法及应用 |
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CN111676196A (zh) * | 2012-05-25 | 2020-09-18 | 塞勒克提斯公司 | 工程化异体和免疫抑制耐受性t细胞的方法 |
CN109641971A (zh) * | 2016-08-25 | 2019-04-16 | Jcr制药股份有限公司 | 抗体融合蛋白的制造方法 |
CN111662383A (zh) * | 2019-03-08 | 2020-09-15 | 珠海市丽珠单抗生物技术有限公司 | 抗pd-l1抗体及其应用 |
CN114867493A (zh) * | 2019-10-04 | 2022-08-05 | 阿尔伯特爱因斯坦医学院 | Kir3dl3是免疫系统的抑制性受体及其用途 |
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