CN115916828A - Pd-l1-特异性抗体和抗pd-l1-car-t细胞 - Google Patents
Pd-l1-特异性抗体和抗pd-l1-car-t细胞 Download PDFInfo
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Abstract
本发明涉及单克隆抗人PD‑L1抗体或单链可变片段(scFv),其包括具有SEQ ID NO:3所示氨基酸的VH和具有SEQ ID NO:5所示氨基酸的VL。本发明还涉及嵌合抗原受体融合蛋白,其自N‑末端到C‑末端包括:(i)本发明的单链可变片段(scFv),(ii)跨膜结构域,(iii)至少一个共刺激结构域,和(iv)激活结构域。发明人已经表明,本发明的PD‑L1CAR‑T细胞在杀伤若干癌细胞系方面比阿维鲁单抗PD‑L1CAR‑T细胞更有效。PD‑L1CAR‑T在免疫疗法中可单独使用或者与其他药物联合使用。
Description
序列表、表格或计算机程序的引用
序列表以ASCII格式的文本文件通过EFS-Web与说明书同时提交,文件名为Sequence Listing.txt,创建日期为2021年6月15日,大小为31.1千字节。通过EFS-Web提交的序列表是说明书的一部分,并在此通过引用全文并入本文。
技术领域
本发明涉及PD-L1(程序性死亡配体-1)-特异性抗体和抗PD-L1-CAR-T细胞,它们对于肿瘤的过继免疫基因治疗领域中是有用的。
背景技术
免疫疗法正在成为一种非常有前途的癌症治疗方法。T细胞或T淋巴细胞是我们免疫系统的武装力量,不断寻找外来抗原并将异常(癌症或经感染细胞)和正常细胞区分开来。利用CAR(嵌合抗原受体)构建体对T细胞进行基因修饰已成为设计肿瘤特异性T细胞最常见的方法。将靶向肿瘤相关抗原(TAA)的CAR-T细胞输入患者体内(称为过继细胞转移或ACT)是一种有效的免疫治疗方法[1,2]。与化疗或抗体相比,CAR-T技术的优点在于经重新编程的工程化T细胞能在患者体内实现增殖和持续存在(“一种活的药物”)[1,3,4]。
CAR通常由在N-末端部分的单克隆抗体来源的单链可变片段(scFv)、铰链、跨膜结构域和若干胞内共刺激结构域:(i)CD28,(ii)CD137(4-1BB)、CD27或其他共刺激结构域,与CD3ζ结构域串联组成(图1)[1,2]。CAR的演变经历了从第一代(无共刺激结构域)到第二代(有一个共刺激结构域)再到第三代CAR(有若干个共刺激结构域)。产生具有多个共刺激结构域的CAR(所谓的第三代CAR)增强了CAR-T细胞毒活性,显著改善CAR-T细胞的持久性,从而增强其抗肿瘤活性。
图1示出了CAR的结构。左侧示出了第一代(无共刺激结构域)的结构,中间示出了第二代(一个共刺激结构域CD28或4-1BB)的结构,以及右侧示出了第三代(两个或若干个共刺激结构域)。该图来自于Golubovskaya,Wu,Cancers,2016[5]。
PD-L1,也称为分化簇274、CD274或B7同源物1、B7-H1,是一种40kDa的跨膜蛋白,在疾病或其他事件期间在抑制免疫系统中起重要作用。PD-L1结构域与PD-1蛋白的结合阻断了负责免疫防御的CD8+T细胞的增殖和活性。PD-L1/PD-1的相互作用在体内,特别是在肿瘤微环境中于抑制T细胞响应中起主导作用。
若干类型的癌症会过表达PD-L1。在临床试验中测试了抗PD-L1单克隆抗体(mAbs)和抗PD-1mAbs免疫疗法[3]。PD-L1在正常组织的细胞表面通常不表达,但在许多肿瘤组织中表达升高。此外,PD-L1表达通过免疫细胞,主要通过其的产生IFN-γ而被显著上调。
美国食品药品监督管理局(FDA)于2017年加速批准阿维鲁单抗(avelumab)用于治疗患有转移性默克尔细胞瘤的成人和12岁及以上儿童患者。阿维鲁单抗是一种阻断PD-L1的人IgG1λ单克隆抗体。
需要一种具有高特异性和活性的抗PD-L1抗体。
附图说明
图1.CAR的结构。
图2.PD-L1 CAR构建体的结构,其中以CD28(上图)或4-1BB(下图)作为共刺激结构域。FLAG标签是可选的。
图3.PD-L1抗体通过ELISA和蛋白质印迹检测PD-L1抗原。
图4.针对不同癌细胞系的PD-L1抗体的FACS检测。HepG2,SKOV-3表达高水平PD-L1。
图5A至图5E.Promab PD-L1-CAR-T细胞(PMC159,CD28;PMC804,4-1BB)对PD-L1-阳性癌细胞具有高细胞毒性。效应细胞与靶细胞的比例为10:1。图5A:PMC159,A1847靶细胞;图5B:PMC159,BxPC3靶细胞;图5C:PMC159,Hela-CD19靶细胞;图5D:PMC159,SKOV靶细胞;图5E:PMC804,A431靶细胞。
图6A至图6B.阿维鲁单抗PD-L1 scFv-CAR-T细胞对靶癌细胞(6A:BxPC3细胞;6B:SKOV-3细胞)的细胞毒活性。效应细胞与靶细胞的比例等于10:1。
图7A至图7B.CD24-CAR-T细胞与Promab的PD-L1-CAR-T细胞的组合靶向癌细胞。通过该组合,在BxPC3细胞中观察到100%的杀伤,在SKOV-3细胞中观察到>90%的杀伤。
具体实施方式
定义
如本文所使用的,“嵌合抗原受体(CAR)”是指一种经过改造后可以赋予T细胞新的能力靶向一种特定蛋白的受体蛋白。该受体是嵌合的,因为它们将抗原结合功能和T细胞激活功能结合成单一的受体。CAR是一种融合蛋白,其包括能够与抗原结合的胞外结构域、跨膜结构域和至少一个胞内结构域。“嵌合抗原受体(CAR)”有时也称为“嵌合受体”、“T小体”,或“嵌合免疫受体(CIR)”。
“能与抗原结合的胞外结构域”指的是能与某一抗原结合的任何寡肽或多肽。“胞内结构域”指的是任何已知作为结构域起作用的寡肽或多肽,该结构域传递信号以激活或抑制细胞内的生物过程。
如本文所使用的,“结构域”指的是多肽中的一个区域,该区域独立于其他区域折叠成特定结构。
如本文所使用的,FLAG-标签,或FLAG八肽,或FLAG表位,是能使用重组DNA技术添加到蛋白的多肽蛋白标签,其具有序列基序DYKDDDDK(SEQ ID NO:1)。它可以融合到蛋白的C-末端或N-末端,或者插入到蛋白中。
如本文所使用的,“单链可变片段(scFv)”指的是来源于保留与抗原结合能力的抗体的单链多肽。scFv的一个示例包括通过重组DNA技术形成的抗体多肽,并且其中免疫球蛋白重链(H链)和轻链(L链)片段的Fv区域通过间隔序列连接。本领域技术人员已知用于工程化scFv的各种方法。
如本文所使用的,“肿瘤抗原”指的是具有抗原性的生物分子,其表达导致癌症。
发明人已经生成了特异性靶向PD-L1的小鼠抗人单克隆抗体(Promab抗PD-L1)。单克隆抗人PD-L1抗体是针对人PD-L1的纯化重组片段生成的。
发明人已经生成了PD-L1-CAR-T细胞来靶向过表达PD-L1肿瘤抗原的癌细胞。本发明的PD-L1-CAR-T细胞针对若干癌细胞系具有高细胞毒活性和体内抗肿瘤活性。
本发明涉及抗人PD-L1抗体或其抗原结合片段,包括具有SEQ ID NO:3所示氨基酸的VH和具有SEQ ID NO:5所示氨基酸的VL。抗原结合片段包括Fab单体或Fab二聚体(Fab’)2或scFv。在一个实施方式中,单克隆抗人PD-L1抗体是单链可变片段(scFv)。
本发明还涉及嵌合抗原受体融合蛋白,其自N-末端到C-末端包含:(i)靶向PD-L1的单链可变片段(scFv),(ii)跨膜结构域,(iii)至少一个共刺激结构域,和(iv)激活结构域。
图2示出了PD-L1 CAR构建体的两种结构。示出的第二代CAR具有CD28(上图)或4-1BB(下图)作为共刺激结构域。缩写:Flag-FLAG标签;TM-跨膜。
在PD-L1 CAR构建体中,ScFv可以是VH-接头-VL或VL-接头-VH。
在一个实施方式中,共刺激结构域选自由CD28、4-1BB、GITR、ICOS-1、CD27、OX-40和DAP10组成的组。优选的共刺激结构域是CD28。
优选的激活结构域是CD3泽塔(CD3 Z或CD3ζ)。
跨膜结构域可以源自天然多肽,或者可以是人工设计的。源自天然多肽的跨膜结构域能从任何膜结合蛋白或跨膜蛋白获得。例如,可以使用T细胞受体α或β链、CD3ζ链、CD28、CD3ε.、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、ICOS、CD154或GITR的跨膜结构域。人工设计的跨膜结构域是主要包含疏水性残基(诸如亮氨酸和缬氨酸)的多肽。优选的是,苯丙氨酸、色氨酸和缬氨酸的三联体位于合成跨膜结构域的每一端。任选地,短寡肽接头或多肽接头,例如,具有2至10个氨基酸长度的接头可以置于跨膜结构域和胞内结构域之间。在一个实施方式中,可以使用具有甘氨酸-丝氨酸连续序列的接头序列。
本发明提供了编码PD-L1 CAR的核酸。编码CAR的核酸可以通过常规方法由特定CAR的氨基酸序列来制备。对于每个结构域的氨基酸序列,编码氨基酸序列的碱基序列可以从NCBI RefSeq ID或GenBank的登录号获得,并且本发明的核酸可以使用标准分子生物学和/或化学方法制备。例如,基于该碱基序列,可以合成核酸,并且本发明的核酸可以通过使用聚合酶链式反应(PCR)组合从cDNA文库获得的DNA片段来制备。
编码本发明CAR的核酸可以插入到载体中,并且该载体可以被引入到细胞中。例如,可以使用病毒载体,诸如逆转录病毒载体(包括致癌逆转录病毒载体、慢病毒载体和假型载体)、腺病毒载体、腺相关病毒(AAV)载体、猿猴病毒载体、痘苗病毒载体或仙台病毒载体、爱泼斯坦-巴尔病毒(EBV)载体和HSV载体。优选使用缺乏复制能力从而不能在感染细胞中自我复制的病毒载体。
例如,当使用逆转录病毒载体时,可以基于LTR序列和载体所具有的包装信号序列(packaging signal sequence)选择合适的包装细胞,该包装细胞用于制备逆转录病毒颗粒。包装细胞的示例包括PG13(ATCC CRL-10686)、PA317(ATCC CRL-9078)、GP+E-86和GP+envAm-12以及Psi-Crip。也可以使用具有高转染效率的293细胞或293T细胞来制备逆转录病毒颗粒。基于逆转录病毒生产的多种逆转录病毒载体和可用于包装逆转录病毒载体的包装细胞可从许多公司广泛地商购获得。
CAR-T细胞通过该CAR与特定抗原结合,从而将信号传递到细胞中,并且细胞因而被激活。表达CAR的细胞的激活依据宿主细胞的种类和CAR的胞内结构域而变化,并且可以基于例如细胞因子的释放、细胞增殖速率的改善、细胞表面分子的变化等作为指标来确认。例如,从激活细胞释放细胞毒性细胞因子(肿瘤坏死因子、淋巴毒素等)会引起表达抗原的靶细胞的破坏。此外,细胞因子的释放或细胞表面分子的变化会刺激其他免疫细胞,例如B细胞、树突细胞、NK细胞和巨噬细胞。
表达CAR的细胞可用作疾病的治疗剂。治疗剂包含表达CAR的细胞作为活性成分,并且它可进一步包含合适的赋形剂。
发明人已经生成了靶向过表达PD-L1的不同癌细胞(卵巢癌、胰腺癌和其他癌症)的PD-L1-CAR-T(PD-L1-CAR-T)细胞。发明人提供了证明PD-L1在不同类型的癌症(卵巢癌、胰腺癌和其他)中有效表达的数据。与未转导的T细胞和模拟-CAR-T(Mock-CAR-T)细胞相比,PD-L1-CAR-T细胞针对PL-1阳性癌细胞表达更高的细胞毒活性。在一个实施方式中,将FLAG标签添加到ScFv的C-末端,这使得能够检测细胞中的CAR。PD-L1抗体作为治疗剂在许多临床应用中是非常有效的。
本发明的PD-L1单克隆抗体或PD-L1-ScFv相对于已知的抗PD-L1抗体(诸如阿维鲁单抗)的优势在于,该抗体针对PD-L1阳性癌细胞(卵巢、胰腺和其他)具有高度特异性。此外,Promab PD-L1-CAR-T的活性高于阿维鲁单抗-PD-L1-CAR-T细胞。发明人已经表明,Promab PD-L1 CAR-T细胞在杀伤若干癌细胞系方面比阿维鲁单抗PD-L1 CAR-T细胞更有效。
本发明的单克隆小鼠抗人PD-L1抗体检测PD-L1阳性癌细胞中的PD-L1。
本发明的PD-L1抗体可用于免疫治疗应用:毒素/药物偶联的Ab、单克隆治疗性抗体、PD-L1抗体的人源化、CAR-T细胞免疫治疗。
使用本发明PD-L1抗体的PD-L1-CAR-T细胞可有效地用于靶向PD-L1阳性细胞系(诸如卵巢癌、胰腺癌和宫颈癌)中的PD-L1抗原。
PD-L1-CAR-T可以与不同的化学疗法联合使用:检查点抑制剂;靶向疗法、小分子抑制剂和抗体。
PD-L1抗体可以用定点突变进行修饰以进行亲和性调节;它可用于人源化和完全人抗体产生。
PD-L1-CAR-T细胞可在临床上用于靶向PD-L1阳性细胞。
共激活结构域:CD28、4-1BB和其他的修饰可用于增加其功效。标签偶联的PD-L1scFv可用于CAR生成。
第三代CAR-T或其他共刺激信号结构域可用于CAR内的相同PD-L1-scFv。
PD-L1与靶向其他肿瘤抗原或肿瘤微环境(VEGFR-1-3)的其他CAR的组合或者与双特异性scFv-CAR的组合可用于增强单一疗法PD-L1-CAR的活性。
可以生成具有PD-L1和CD3或其他抗原的双特异性抗体,其用于治疗。
PD-L1 scFv、PD-L1抗体或PD-L1 CAR-T细胞可以与另一种CAR一起使用以增加其活性。双靶向PD-L1和另一肿瘤抗原可以增强治疗。此外,PD-L1-CAR-T细胞与其他CAR-T细胞的共转染可用于抑制检查点信号传导并增加CAR-T细胞的活性。CD24-CAR-T和PD-L1CAR-T的组合在两种不同细胞系的细胞毒性测定中显示出相似的杀伤活性。当PD-L1通路在肿瘤微环境中被激活时,这可以应用于体内两条通路的共同抑制。此外,具有两个利用接头结合的scFv的双特异性CAR-T细胞可用于增强单一scFv CAR-T细胞的功效。
PD-L1单克隆抗体可以作为单一药剂使用,或者可以与其他疗法联合使用。这种联合治疗方法将提高CAR-T的疗效。
PD-L1-CAR-T细胞可用于针对对化疗最具耐药性并形成侵袭性肿瘤的癌症干细胞。
PD-L1-CAR可用于生成其他类型的细胞,诸如CAR-自然杀伤(NK)细胞、iPS(诱导多能)-NK或iPS-T细胞、巨噬细胞、γ-δT细胞和其他造血细胞,它们可靶向PD-L1阳性癌症。本发明提供了经修饰以表达PD-L1-CAR的T细胞,或NK细胞,或巨噬细胞,或造血细胞。
以下实施例进一步说明本发明。这些实施例仅旨在说明本发明,而不应理解为限制本发明。
实施例
实施例1.PD-L1抗体和活性
我们使用杂交瘤(克隆7D2A10)生成小鼠单克隆抗人PD-L1抗体。该杂交瘤是针对利用大肠杆菌(E.coli)表达的人PD-L1的纯化重组片段(24至153个氨基酸序列)而生成的。杂交瘤技术是标准的且描述在[4]中。该抗体检测PD-L1胞外结构域,并且为IgG2b型。
图3示出了这种抗人PD-L1抗体通过ELISA和蛋白印迹检测PD-L1抗原。在图3A中,从底部到顶部示出了对照抗原(100ng)、PD-L-1抗原(10ng)、PDL-1抗原(50ng)、PD-L-1抗原(100ng)的ELISA结果。ELISA表明,与对照抗原(100ng)无结合,与PD-L1抗原(10ng)、PD-L1抗原(50ng)和PD-L1抗原(100ng)的结合呈剂量依赖性增加。在图3B中,蛋白印迹分析表明,该抗体与PD-L1胞外结构域(AA:24至153,预期分子量为40.1kDa)结合。在图3C中,蛋白印迹分析表明,这种抗体不与(1)HEK293细胞裂解物中的PD-L1结合,而与(2)融合有人Fc的PD-L1胞外结构域(PD-L1-hFc)转染的HEK293细胞裂解物存在结合。
这种PD-L1抗体通过流式细胞术检测肿瘤组织和若干癌细胞系中高水平的PD-L1。
该抗体在肝癌中检测到中度PD-L1表达,在正常肝、肺、子宫和脑下垂体(hypohysis)中检测到一些结合。通过该抗体,大多数正常组织(结肠、十二指肠、直肠、睾丸、食管、脑、肌肉、胰腺、肾、胃、前列腺、扁桃体和脾)显示出阴性PD-L1表达。
在大多数正常组织中不存在染色对于以CAR-T形式使用该抗体是有利的,因为非靶向和非肿瘤活性更低。
实施例2.PD-L1 VH、VL和scFv序列
我们对来自杂交瘤克隆(#7D2A10)的抗PD-L1抗体(通过ELISA检测与PD-L1抗原结合呈阳性)进行了测序。抗PD-L1 scFv的结构为:VH-接头-VL。
PD-L1 VH核苷酸序列(SEQ ID NO:2)
CAGATCCAGTTGGTGCAGTCTGGACCTGAGCTGAAGAACCCTGGAGAGACAGTCAAGATCTCCTGCAAGGCTTCTGGGTATACCTTCACAAACTATGGAATGAACTGGGTGAAGCAGGCTCCAGGAAAGGGTTTAAAGTGGATGGGGTGGATAAACACCCACACTGGAGAGCCAACATATGCTGATGACTTCAAGGGACGGTTTGCCTTCTCTTCGGAAACCTCTGCCAGCTCTGCCTATTTGCAGATCAACAACCTCAAAAATGATGACATGGCTACATATTTCTGTGCAAAAGGTACCCACAGAGAAGAAATTCCGGCCTGGTTCGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA
PD-L1 VH氨基酸序列(SEQ ID NO:3)
Q I Q L V Q S G P E L K N P G E T V K I S C K A S G Y T F T N Y G M NW V K Q A P G K G L K W M G W I N T H T G E P T Y A D D F K G R F A F S S E TS A S S A Y L Q I N N L K N D D M A T Y F C A K G T H R E E I P A W F A Y W GQ G T L V T V S A
PD-L1 VL核苷酸序列(SEQ ID NO:4)
GATGTTTTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCATTGTACATAGTAATGGAAACACCTATTTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAGAGCTCCTGATCTACAAAGTTTCCAACCTATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGCTTTCAAGGTTCACATGTTCCTCCCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGG
PD-L1 VL氨基酸序列(SEQ ID NO:5)
D V L M T Q T P L S L P V S L G D Q A S I S C R S S Q S I V H S N G NT Y L E W Y L Q K P G Q S P E L L I Y K V S N L F S G V P D R F S G S G S G TD F T L K I S R V E A E D L G V Y Y C F Q G S H V P P T F G A G T K L E L K R
接头核苷酸序列(SEQ ID NO:6)
GGTGGCGGTGGTTCT GGTGGCGGTGGTTCT GGTGGCGGTGGTTCT
接头氨基酸序列(SEQ ID NO:7)
PD-L1 scFv核苷酸序列(SEQ ID NO:8)
粗体、较大的字体突出了VH的核苷酸序列;下划线突出了VL的核苷酸序列;中间(斜体)是编码接头的核苷酸序列。
PD-L1 scFv氨基酸序列(SEQ ID NO:9)
实施例3.PD-L1慢病毒CAR构建体
发明人在慢病毒载体内生成了PD-L1 CAR构建体,克隆到慢病毒载体的Xba I和Eco R I位点。pCD510-FMC63-28z慢病毒CAR构建体包括在CMV启动子下的Xba I和EcoR I克隆位点之间的PD-L1 ScFv-Flag标签-CD8铰链、CD28跨膜/激活-CD3ζ插入物(PMC159)。为了更容易检测CAR阳性T细胞,插入了Flag标签。发明人还生成了具有相同的PD-L1-CAR scfv的PMC804 CAR,其scfv在含有41BB共刺激结构域而不是CD28,之后没有FLAG标签,并通过MNDU3启动子调节用于CAR的更高表达。
慢病毒在293T细胞中生成,并通过RT-PCR建立滴度。然后用等剂量的慢病毒转导T细胞。
实施例4A.具有CD28作为共刺激结构域的PD-L1 CAR(PMC159)
PD-L1-CAR构建体的方案如图2所示。慢病毒载体Lenti CMV-MCS-EF1a-puro用于所有scFv CAR序列的克隆。
下列核苷酸和氨基酸序列示出了本发明的PD-L1 ScFv Flag-CD8铰链-TM28-CD28-CD3ζ。该结构包括人CD8信号肽(CD8 signaling peptide)(CD8信号肽(CD8leader))、PD-L1 scFv(VH-接头3x(G4S)-VL)、FLAG、CD8铰链、CD28跨膜、激活结构域、CD3ζ(图2)。
<CD8信号肽>
核苷酸序列(SEQ ID NO:10)
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCG
氨基酸序列(SEQ ID NO:11)
MALPVTALLLPLALLLHAARP
<Nhe限制性位点I>
GCTAGC
氨基酸序列
<AS>
<PD-L1 scFV>
参见实施例2,SEQ ID NO:8和SEQ ID NO:9。
<FLAG>
核苷酸序列(SEQ ID NO:12)
GACTACAAAGACGATGACGACAAG
氨基酸序列(SEQ ID NO:1)
DYKDDDDK
<XhoI限制性位点>
核苷酸序列
CTCGAG
氨基酸序列
LE
<CD8铰链>
核苷酸序列(SEQ ID NO:13)
AAGCCCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGAGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCAGTGAT
氨基酸序列(SEQ ID NO:14)
KPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFASD
<间隔子>
核苷酸序列
aagccc
氨基酸序列
KP
<CD28 TM/共刺激>
核苷酸序列(SEQ ID NO:15)
TTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
氨基酸序列(SEQ ID NO:16)
FWVLVVVGGVLACYSLLVTVAFIIFWV/RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
<CD3ζ>
核苷酸序列(SEQ ID NO:17)
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTAA
氨基酸序列(SEQ ID NO:18)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
PD-L1-CAR的核苷酸序列(PMC 159,FLAG加下划线),SEQ ID NO:19
GATGTTTTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCATTGTACATAGTAATGGAAACACCTATTTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAGAGCTCCTGATCTACAAAGTTTCCAACCTATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGCTTTCAAGGTTCACATGTTCCTCCCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGG GACTACAAAGACGATGACGACAAG
ctcgagAAGCCCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGAGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCAGTGATaagcccttttgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaacagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctatcgctccAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTAA
PD-L1-CAR蛋白的氨基酸序列,PMC 159,SEQ ID NO:20
M A L P V T A L L L P L A L L L H A A R P A S Q I Q L V Q S G P E L KN P G E T V K I S C K A S G Y T F T N Y G M N W V K Q A P G K G L K W M G W IN T H T G E P T Y A D D F K G R F A F S S E T S A S S A Y L Q I N N L K N D DM A T Y F C A K G T H R E E I P A W F A Y W G Q G T L V T V S A G G G G S G GG G S G G G G S D V L M T Q T P L S L P V S L G D Q A S I S C R S S Q S I V HS N G N T Y L E W Y L Q K P G Q S P E L L I Y K V S N L F S G V P D R F S G SG S G T D F T L K I S R V E A E D L G V Y Y C F Q G S H V P P T F G A G T K LE L K R D Y K D D D D K L E K P T T T P A P R P P T P A P T I A S Q P L S L RP E A S R P A A G G A V H T R G L D F A S D K P F W V L V V V G G V L A C Y SL L V T V A F I I F W V R S K R S R L L H S D Y M N M T P R R P G P T R K H YQ P Y A P P R D F A A Y R S R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L NL G R R E E Y D V L D K R R G R D P E M G G K P Q R R K N P Q E G L Y N E L QK D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y DA L H M Q A L P P
实施例4B.具有4-1BB作为共刺激结构域的PD-L1 CAR(PMC 804)
该CAR的核苷酸和氨基酸序列与实施例4A的相同,除了该CAR没有FLAG标签,并且用4-1BB替代CD28作为共刺激结构域。
<41BB结构域/共刺激>
核苷酸序列,SEQ ID NO:21
AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG
氨基酸序列,SEQ ID NO:22
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
PD-L1-CAR的核苷酸序列(PMC 804,4-1BB加下划线),SEQ ID NO:23ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGgctagcCAGATCCAGTTGGTGCAGTCTGGACCTGAGCTGAAGAACCCTGGAGAGACAGTCAAGATCTCCTGCAAGGCTTCTGGGTATACCTTCACAAACTATGGAATGAACTGGGTGAAGCAGGCTCCAGGAAAGGGTTTAAAGTGGATGGGGTGGATAAACACCCACACTGGAGAGCCAACATATGCTGATGACTTCAAGGGACGGTTTGCCTTCTCTTCGGAAACCTCTGCCAGCTCTGCCTATTTGCAGATCAACAACCTCAAAAATGATGACATGGCTACATATTTCTGTGCAAAAGGTACCCACAGAGAAGAAATTCCGGCCTGGTTCGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGGTGGCGGTGGTTCT GGTGGCGGTGGTTCTGGTGGCGGTGGTTCTGATGTTTTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCATTGTACATAGTAATGGAAACACCTATTTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAGAGCTCCTGATCTACAAAGTTTCCAACCTATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGCTTTCAAGGTTCACATGTTCCTCCCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGGctcgagAAGCCCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGAGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCAGTGATaagcccttttgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaacagtggcctttattattttctgggtgAAACGGGGCAGAAAGAAACTC CTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCC AGAAGAAGAAGAAGGAGGATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTAA
PD-L1-CAR的氨基酸序列(PMC 804,4-1BB加下划线),SEQ ID NO:24
MALPVTALLLPLALLLHAARPASQIQLVQSGPELKNPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTHTGEPTYADDFKGRFAFSSETSASSAYLQINNLKNDDMATYFCAKGTHREEIPAWFAYWGQGTLVTVSAGGGGSGGGGSGGGGSDVLMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPELLIYKVSNLFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPPTFGAGTKLELKRLEKPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFASDKPFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEED GCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
实施例5.CAR慢病毒生产
合成编码PD-L1 scFv的DNA,并由Syno Biological(中国北京)将其亚克隆到第三代慢病毒载体Lenti CMV-MCS-EF1a-puro中。对慢病毒构建体进行双向测序以确认构建体序列,并将其用于慢病毒生产。将1000万生长停滞的HEK293FT细胞(Thermo Fisher)接种到T75烧瓶中并培养过夜,然后使用CalPhos转染试剂盒(Takara,Mountain View,CA)加入pPACKH1慢病毒载体包装混合物(System Biosciences,Palo Alto,CA)和10μg每种慢病毒载体进行转染。第二天,用新鲜培养基更换培养基,并于48小时后收集含慢病毒的培养基。通过以2100g离心30分钟来清除培养基中的细胞碎片。病毒颗粒通过以112000g离心100分钟来收集,使其悬浮在DMEM或AIM V培养基中,然后等分并在-80℃下冷冻。根据制造商的方案使用Lenti-X qRT-PCR试剂盒(Takara)和7900HT热循环仪(Thermo Fisher)通过定量RT-PCR确定病毒制剂的滴度。慢病毒滴度>1×108pfu/ml。
实施例6.从全血中分离外周血单核细胞(PBMC)
从个体或混合捐助者(取决于所需的血液量)以10mL的量(10mL fractions)收集全血(Stanford Hospital Blood Center,Stanford,CA),并使用Ficol-Paque PLUS进行分离。去除在稀释的血浆/Ficoll界面看到的含有外周血单核细胞(PBMC)的细胞层,并避免任何Ficoll。为了确保完全去除Ficoll、血小板和血浆蛋白,用PBS洗涤PBMC两次,总体积为40ml,将其在室温下以200×g离心10分钟。然后用血细胞计数器计数细胞。如果要立即使用经洗涤的PBMC,则用CAR-T培养基(AIM V-AlbuMAX(BSA)(Life Technologies),具有5% AB血清和1.25μg/mL两性霉素B(Gemini Bioproducts,Woodland,CA)、100U/mL青霉素和100μg/mL链霉素)洗涤一次。如果要冷冻PBMC,则将经洗涤的细胞悬在转移隔热小瓶中至-80℃下持续24小时,然后储存在液氮中。
实施例7.来自PBMC的T-细胞激活
在人白细胞介素-2 300U/mL(huIL-2,Invitrogen)的存在下,以5×105细胞/mL的浓度在CAR-T培养基(AIM V-AlbuMAX(BSA,Life Technologies),具有5% AB血清和1.25μg/mL两性霉素B(Gemini Bioproducts,Woodland,CA),100U/mL青霉素和100μg/mL链霉素)中培养PBMC分离的细胞。用CD3/CD28珠激活T,并在CO2存在下于37℃下孵育24小时,然后进行CAR病毒转导。
实施例8.T-细胞转导和扩增
PBMC激活后,细胞在37℃、5% CO2下孵育24小时。向每个孔中加入1×106细胞、5×106慢病毒和2μL/mL Transplus的培养基(Alstem,Richmond,CA)(最终稀释度为1∶500)。在重复加入病毒之前,将细胞再培养24小时。然后在300U/Ml的IL-2的持续存在下,使细胞生长12至14天。每2至3天,对细胞浓度进行分析,同时加入培养基以将细胞悬浮液稀释至1×106细胞/mL。CAR表达可以用FLAG抗体或者用抗小鼠F(ab)2检测Flag-标签化的scFv或者用未标签化的scFv表达来验证。
实施例9.细胞毒性测定
根据以下列出的制造商方案,使用ACEA机器进行细胞毒性测定。
将贴壁靶癌细胞以每孔1×104个细胞接种到96孔E板(Acea Biosciences,SanDiego,CA)中,并用基于阻抗的实时细胞分析(RTCA)iCELLigence系统(Acea Biosciences)在培养物中监测过夜。第二天,去除培养基并用含有10% FBS±1×105效应细胞(CAR-T细胞或未转导的T细胞)的AIM V-AlbuMAX培养基代替,一式三份地进行。用RTCA系统额外监测E板中的细胞2至3天,并绘制随时间的阻抗图。细胞溶解计算为(没有效应细胞的情况下靶细胞的阻抗-存在效应CAR-T细胞的情况下靶细胞的阻抗)×100/没有效应细胞的情况下靶细胞的阻抗。
实施例10.PD-L1在不同癌组织和正常组织中的表达
用PD-L1单克隆抗体进行染色证实了若干癌细胞系的高染色性:卵巢癌SKOV-3、肝细胞瘤、HepG2;以及在乳腺MCF-7细胞系的中等染色性(图4)。正常HEK-293细胞,癌细胞:HT29、MDA-231、HCT116和其他为阴性。
实施例11.Promab PD-L1-CAR表现了对PD-L1阳性癌细胞的高细胞毒活性
实时细胞毒性测定证明了Promab PD-L1-CD28-CD3 CAR细胞(PMC159)对高PD-L1阳性癌细胞的高细胞毒性活性:卵巢癌A1847细胞、胰腺癌BxpC3细胞、宫颈癌Hela-CD19细胞和卵巢癌SKOV-3(图5A至图5D)。
Promab PD-L1-CD28-CD3 CAR-T(PMC159)对卵巢癌A1847细胞具有100%的杀伤活性(图5A),对胰腺癌BxPC3细胞系具有几乎100%的杀伤活性(图5B),对宫颈癌Hela-CD19细胞具有>75%的杀伤活性(图5C)。
我们还测试了PD-L1-41BB-CD3 CAR-T细胞(PMC804)对A431表皮癌细胞的作用,发现它们杀伤了癌细胞(图5E)。因此,具有CD28或41BB共刺激结构域的CAR-T细胞对癌细胞具有活性。
实施例12.具有Promab PD-L1 scFv的CAR-T细胞与具有阿维鲁单抗PD-L1-scFv的CAR-T细胞的比较
我们比较了Promab PD-L1 scFv和来自已发表的抗体阿维鲁单抗的PD-L1 scFv,其中阿维鲁单抗被FDA批准用于治疗默克尔细胞瘤。将在C-末端没有FLAG标签的已发表的阿维鲁单抗PD-L1 scFv序列插入到CAR。阿维鲁单抗PD-L1CAR-T的一般结构如图2所示。阿维鲁单抗PD-L1 scFv的序列如下所示。
PD-L1(阿维鲁单抗)VH,核苷酸序列(SEQ ID NO:25)
gaagtgcagctgctggaaagcggcggcggcctggtgcagccgggcggcagcctgcgcctgagctgcgcggcgagcggctttacctttagcagctatattatgatgtgggtgcgccaggcgccgggcaaaggcctggaatgggtgagcagcatttatccgagcggcggcattaccttttatgcggataccgtgaaaggccgctttaccattagccgcgataacagcaaaaacaccctgtatctgcagatgaacagcctgcgcgcggaagataccgcggtgtattattgcgcgcgcattaaactgggcaccgtgaccaccgtggattattggggccagggcaccctggtgaccgtgagcagc
PD-L1(阿维鲁单抗)VH,氨基酸序列(SEQ ID NO:26)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYIMMWVRQA PGKGLEWVSS IYPSGGITFYADTVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARIK LGTVTTVDYW GQGTLVTVSS
接头核苷酸序列(SEQ ID NO:27)
ggcggcggcggcagcggcggcggcggcagcggcggcggcggcagc
接头氨基酸序列(SEQ ID NO:7)
GGGGS GGGGS GGGGS
PD-L1(阿维鲁单抗)VL,核苷酸序列(SEQ ID NO:28)
cagagcgcgctgacccagccggcgagcgtgagcggcagcccgggccagagcattaccattagctgcaccggcaccagcagcgatgtgggcggctataactatgtgagctggtatcagcagcatccgggcaaagcgccgaaactgatgatttatgatgtgagcaaccgcccgagcggcgtgagcaaccgctttagcggcagcaaaagcggcaacaccgcgagcctgaccattagcggcctgcaggcggaagatgaagcggattattattgcagcagctataccagcagcagcacccgcgtgtttggcaccggcaccaaagtgaccgtgctg
PD-L1(阿维鲁单抗)VL,氨基酸序列(SEQ ID NO:29)
Q S A L T Q P A S V S G S P G Q S I T I S C T G T S S D V G G Y N Y VS W Y Q Q H P G K A P K L Met I Y D V S N R P S G V S N R F S G S K S G N T AS L T I S G L Q A E D E A D Y Y C S S Y T S S S T R V F G T G T K V T V L
PD-L1(阿维鲁单抗)ScFv,核苷酸序列(SEQ ID NO:30)
gaagtgcagctgctggaaagcggcggcggcctggtgcagccgggcggcagcctgcgcctgagctgcgcggcgagcggctttacctttagcagctatattatgatgtgggtgcgccaggcgccgggcaaaggcctggaatgggtgagcagcatttatccgagcggcggcattaccttttatgcggataccgtgaaaggccgctttaccattagccgcgataacagcaaaaacaccctgtatctgcagatgaacagcctgcgcgcggaagataccgcggtgtattattgcgcgcgcattaaactgggcaccgtgaccaccgtggattattggggccagggcaccctggtgaccgtgagcagcggcggcggcggcagcggcggcggcggcagcggcggcggcggcagccagagcgcgctgacccagccggcgagcgtgagcggcagcccgggccagagcattaccattagctgcaccggcaccagcagcgatgtgggcggctataactatgtgagctggtatcagcagcatccgggcaaagcgccgaaactgatgatttatgatgtgagcaaccgcccgagcggcgtgagcaaccgctttagcggcagcaaaagcggcaacaccgcgagcctgaccattagcggcctgcaggcggaagatgaagcggattattattgcagcagctataccagcagcagcacccgcgtgtttggcaccggcaccaaagtgaccgtgctg
PD-L1(阿维鲁单抗)ScFv,氨基酸序列(SEQ ID NO:31)
E V Q L L E S G G G L V Q P G G S L R L S C A A S G F T F S S Y I M MW V R Q A P G K G L E W V S S I Y P S G G I T F Y A D T V K G R F T I S R D NS K N T L Y L Q M N S L R A E D T A V Y Y C A R I K L G T V T T V D Y W G Q GT L V T V S S G G G G S G G G G S G G G G S Q S A L T Q P A S V S G S P G Q SI T I S C T G T S S D V G G Y N Y V S W Y Q Q H P G K A P K L M I Y D V S N RP S G V S N R F S G S K S G N T A S L T I S G L Q A E D E A D Y Y C S S Y T SS S T R V F G T G T K V T V L
按照实施例5生成阿维鲁单抗PD-L1 CAR-T细胞。
阿维鲁单抗PD-L1 CAR-T细胞用于细胞毒性测定(图6)。结果表明,Promab PD-L1CAR-T细胞比阿维鲁单抗PD-L1 CAR-T细胞更有效地杀伤相同的癌细胞系。阿维鲁单抗PD-L1 CAR-T细胞对BxPC3细胞具有约25%的杀伤活性,而PMC159 PD-L1 CAR-T细胞对相同细胞具有几乎100%的杀伤活性(参见实施例11,图5B)。阿维鲁单抗PD-L1 CAR-T细胞对SKOV-3细胞具有约<35%的杀伤活性,而PMC159PD-L1 CAR-T细胞对相同细胞具有>67%的杀伤活性(参见实施例11,图5D)。
实施例13.CD24和Promab PD-L1-CAR-T细胞的组合靶向癌细胞
图7A至7B示出了CD24-CAR-T细胞和PMC159 PD-L1-CAR-T细胞的组合靶向癌细胞。在BxPC3细胞中观察到100%的杀伤,在SKOV-3细胞中观察到>80%的杀伤。
结果表明,PD-L1 CAR-T细胞可以与其他CAR-T细胞一起使用。当PD-L1通路在肿瘤微环境中被激活时,PD-L1 CAR-T细胞和CD24 CAR-T细胞的组合可用于体内两条通路的共同抑制。
参考文献
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2.Maus,M.V.,Grupp,S.A.,Porter,D.L.,and June,C.H.(2014).Antibody-modified T cells:CARs take the front seat for hematologic malignancies.Blood123,2625-2635.
3.Sgambato,A.,Casaluce,F.,Sacco,P.C.,Palazzolo,G.,Maione,P.,Rossi,A.,Ciardiello,F.,and Gridelli,C.(2016).Anti PD-1and PD-L1 Immunotherapy in theTreatment ofAdvanced Non-Small Cell Lung Cancer(NSCLC):A Review on ToxicityProfile and its Management.Curr Drug Saf 11,62-68.
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序列表
<110> 普洛迈博生物技术公司
湖南远泰生物技术有限公司
<120> PD-L1-特异性抗体和抗PD-L1-CAR-T细胞
<130> 119995-8010.WO01
<150> 63/044,115
<151> 2020-06-25
<160> 31
<170> PatentIn version 3.5
<210> 1
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 1
Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
<210> 2
<211> 366
<212> DNA
<213> 小鼠
<400> 2
cagatccagt tggtgcagtc tggacctgag ctgaagaacc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaca aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatggggtgg ataaacaccc acactggaga gccaacatat 180
gctgatgact tcaagggacg gtttgccttc tcttcggaaa cctctgccag ctctgcctat 240
ttgcagatca acaacctcaa aaatgatgac atggctacat atttctgtgc aaaaggtacc 300
cacagagaag aaattccggc ctggttcgct tactggggcc aagggactct ggtcactgtc 360
tctgca 366
<210> 3
<211> 122
<212> PRT
<213> 小鼠
<400> 3
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Asn Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr His Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Ser Glu Thr Ser Ala Ser Ser Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Asp Asp Met Ala Thr Tyr Phe Cys
85 90 95
Ala Lys Gly Thr His Arg Glu Glu Ile Pro Ala Trp Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 4
<211> 339
<212> DNA
<213> 小鼠
<400> 4
gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccagag ctcctgatct acaaagtttc caacctattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcct 300
cccacgttcg gtgctgggac caagctggag ctgaaacgg 339
<210> 5
<211> 113
<212> PRT
<213> 小鼠
<400> 5
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Glu Leu Leu Ile Tyr Lys Val Ser Asn Leu Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg
<210> 6
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 6
ggtggcggtg gttctggtgg cggtggttct ggtggcggtg gttct 45
<210> 7
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 7
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 8
<211> 750
<212> DNA
<213> 小鼠
<400> 8
cagatccagt tggtgcagtc tggacctgag ctgaagaacc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaca aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatggggtgg ataaacaccc acactggaga gccaacatat 180
gctgatgact tcaagggacg gtttgccttc tcttcggaaa cctctgccag ctctgcctat 240
ttgcagatca acaacctcaa aaatgatgac atggctacat atttctgtgc aaaaggtacc 300
cacagagaag aaattccggc ctggttcgct tactggggcc aagggactct ggtcactgtc 360
tctgcaggtg gcggtggttc tggtggcggt ggttctggtg gcggtggttc tgatgttttg 420
atgacccaaa ctccactctc cctgcctgtc agtcttggag atcaagcctc catctcttgc 480
agatctagtc agagcattgt acatagtaat ggaaacacct atttagaatg gtacctgcag 540
aaaccaggcc agtctccaga gctcctgatc tacaaagttt ccaacctatt ttctggggtc 600
ccagacaggt tcagtggcag tggatcaggg acagatttca cactcaagat cagcagagtg 660
gaggctgagg atctgggagt ttattactgc tttcaaggtt cacatgttcc tcccacgttc 720
ggtgctggga ccaagctgga gctgaaacgg 750
<210> 9
<211> 250
<212> PRT
<213> 小鼠
<400> 9
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Asn Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr His Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Ser Glu Thr Ser Ala Ser Ser Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Asp Asp Met Ala Thr Tyr Phe Cys
85 90 95
Ala Lys Gly Thr His Arg Glu Glu Ile Pro Ala Trp Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Leu Met Thr Gln Thr
130 135 140
Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys
145 150 155 160
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
165 170 175
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile Tyr Lys
180 185 190
Val Ser Asn Leu Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp
210 215 220
Leu Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Pro Thr Phe
225 230 235 240
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
245 250
<210> 10
<211> 63
<212> DNA
<213> 智人
<400> 10
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 11
<211> 21
<212> PRT
<213> 智人
<400> 11
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 12
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 12
gactacaaag acgatgacga caag 24
<210> 13
<211> 141
<212> DNA
<213> 智人
<400> 13
aagcccacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 60
cccctgtccc tgcgcccaga ggcgagccgg ccagcggcgg ggggcgcagt gcacacgagg 120
gggctggact tcgccagtga t 141
<210> 14
<211> 47
<212> PRT
<213> 智人
<400> 14
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
1 5 10 15
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Ser Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Ser Asp
35 40 45
<210> 15
<211> 204
<212> DNA
<213> 智人
<400> 15
ttttgggtgc tggtggtggt tggtggagtc ctggcttgct atagcttgct agtaacagtg 60
gcctttatta ttttctgggt gaggagtaag aggagcaggc tcctgcacag tgactacatg 120
aacatgactc cccgccgccc cgggcccacc cgcaagcatt accagcccta tgccccacca 180
cgcgacttcg cagcctatcg ctcc 204
<210> 16
<211> 68
<212> PRT
<213> 智人
<400> 16
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser
20 25 30
Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly
35 40 45
Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala
50 55 60
Ala Tyr Arg Ser
65
<210> 17
<211> 342
<212> DNA
<213> 智人
<400> 17
agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
cgggaccctg agatgggggg aaagccgcag agaaggaaga accctcagga aggcctgtac 180
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300
acctacgacg cccttcacat gcaggccctg ccccctcgct aa 342
<210> 18
<211> 113
<212> PRT
<213> 智人
<400> 18
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 19
<211> 1542
<212> DNA
<213> 小鼠
<400> 19
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggctagcc agatccagtt ggtgcagtct ggacctgagc tgaagaaccc tggagagaca 120
gtcaagatct cctgcaaggc ttctgggtat accttcacaa actatggaat gaactgggtg 180
aagcaggctc caggaaaggg tttaaagtgg atggggtgga taaacaccca cactggagag 240
ccaacatatg ctgatgactt caagggacgg tttgccttct cttcggaaac ctctgccagc 300
tctgcctatt tgcagatcaa caacctcaaa aatgatgaca tggctacata tttctgtgca 360
aaaggtaccc acagagaaga aattccggcc tggttcgctt actggggcca agggactctg 420
gtcactgtct ctgcaggtgg cggtggttct ggtggcggtg gttctggtgg cggtggttct 480
gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 540
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 600
tacctgcaga aaccaggcca gtctccagag ctcctgatct acaaagtttc caacctattt 660
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 720
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcct 780
cccacgttcg gtgctgggac caagctggag ctgaaacggg actacaaaga cgatgacgac 840
aagctcgaga agcccaccac gacgccagcg ccgcgaccac caacaccggc gcccaccatc 900
gcgtcgcagc ccctgtccct gcgcccagag gcgagccggc cagcggcggg gggcgcagtg 960
cacacgaggg ggctggactt cgccagtgat aagccctttt gggtgctggt ggtggttggt 1020
ggagtcctgg cttgctatag cttgctagta acagtggcct ttattatttt ctgggtgagg 1080
agtaagagga gcaggctcct gcacagtgac tacatgaaca tgactccccg ccgccccggg 1140
cccacccgca agcattacca gccctatgcc ccaccacgcg acttcgcagc ctatcgctcc 1200
agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 1260
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 1320
cgggaccctg agatgggggg aaagccgcag agaaggaaga accctcagga aggcctgtac 1380
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 1440
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 1500
acctacgacg cccttcacat gcaggccctg ccccctcgct aa 1542
<210> 20
<211> 512
<212> PRT
<213> 小鼠
<400> 20
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Ala Ser Gln Ile Gln Leu Val Gln Ser Gly Pro
20 25 30
Glu Leu Lys Asn Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser
35 40 45
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro
50 55 60
Gly Lys Gly Leu Lys Trp Met Gly Trp Ile Asn Thr His Thr Gly Glu
65 70 75 80
Pro Thr Tyr Ala Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Ser Glu
85 90 95
Thr Ser Ala Ser Ser Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Asp
100 105 110
Asp Met Ala Thr Tyr Phe Cys Ala Lys Gly Thr His Arg Glu Glu Ile
115 120 125
Pro Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
130 135 140
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
145 150 155 160
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
165 170 175
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
180 185 190
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
195 200 205
Pro Glu Leu Leu Ile Tyr Lys Val Ser Asn Leu Phe Ser Gly Val Pro
210 215 220
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
225 230 235 240
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
245 250 255
Ser His Val Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
260 265 270
Arg Asp Tyr Lys Asp Asp Asp Asp Lys Leu Glu Lys Pro Thr Thr Thr
275 280 285
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
290 295 300
Leu Ser Leu Arg Pro Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val
305 310 315 320
His Thr Arg Gly Leu Asp Phe Ala Ser Asp Lys Pro Phe Trp Val Leu
325 330 335
Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val
340 345 350
Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His
355 360 365
Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys
370 375 380
His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
385 390 395 400
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
405 410 415
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
420 425 430
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
435 440 445
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
450 455 460
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
465 470 475 480
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
485 490 495
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
500 505 510
<210> 21
<211> 126
<212> DNA
<213> 智人
<400> 21
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactg 126
<210> 22
<211> 42
<212> PRT
<213> 智人
<400> 22
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 23
<211> 1521
<212> DNA
<213> 小鼠
<400> 23
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggctagcc agatccagtt ggtgcagtct ggacctgagc tgaagaaccc tggagagaca 120
gtcaagatct cctgcaaggc ttctgggtat accttcacaa actatggaat gaactgggtg 180
aagcaggctc caggaaaggg tttaaagtgg atggggtgga taaacaccca cactggagag 240
ccaacatatg ctgatgactt caagggacgg tttgccttct cttcggaaac ctctgccagc 300
tctgcctatt tgcagatcaa caacctcaaa aatgatgaca tggctacata tttctgtgca 360
aaaggtaccc acagagaaga aattccggcc tggttcgctt actggggcca agggactctg 420
gtcactgtct ctgcaggtgg cggtggttct ggtggcggtg gttctggtgg cggtggttct 480
gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 540
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 600
tacctgcaga aaccaggcca gtctccagag ctcctgatct acaaagtttc caacctattt 660
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 720
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcct 780
cccacgttcg gtgctgggac caagctggag ctgaaacggc tcgagaagcc caccacgacg 840
ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 900
ccagaggcga gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 960
agtgataagc ccttttgggt gctggtggtg gttggtggag tcctggcttg ctatagcttg 1020
ctagtaacag tggcctttat tattttctgg gtgaaacggg gcagaaagaa actcctgtat 1080
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1140
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1200
gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1260
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1320
aagccgcaga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1380
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1440
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1500
caggccctgc cccctcgcta a 1521
<210> 24
<211> 506
<212> PRT
<213> 小鼠
<400> 24
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Ala Ser Gln Ile Gln Leu Val Gln Ser Gly Pro
20 25 30
Glu Leu Lys Asn Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser
35 40 45
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro
50 55 60
Gly Lys Gly Leu Lys Trp Met Gly Trp Ile Asn Thr His Thr Gly Glu
65 70 75 80
Pro Thr Tyr Ala Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Ser Glu
85 90 95
Thr Ser Ala Ser Ser Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Asp
100 105 110
Asp Met Ala Thr Tyr Phe Cys Ala Lys Gly Thr His Arg Glu Glu Ile
115 120 125
Pro Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
130 135 140
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
145 150 155 160
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
165 170 175
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
180 185 190
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
195 200 205
Pro Glu Leu Leu Ile Tyr Lys Val Ser Asn Leu Phe Ser Gly Val Pro
210 215 220
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
225 230 235 240
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
245 250 255
Ser His Val Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
260 265 270
Arg Leu Glu Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
275 280 285
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Ser
290 295 300
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
305 310 315 320
Ser Asp Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala
325 330 335
Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys
340 345 350
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
355 360 365
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
370 375 380
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
385 390 395 400
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
405 410 415
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
420 425 430
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro
435 440 445
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
450 455 460
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
465 470 475 480
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
485 490 495
Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505
<210> 25
<211> 360
<212> DNA
<213> 智人
<400> 25
gaagtgcagc tgctggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc agctatatta tgatgtgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtgagcagc atttatccga gcggcggcat taccttttat 180
gcggataccg tgaaaggccg ctttaccatt agccgcgata acagcaaaaa caccctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgcattaaa 300
ctgggcaccg tgaccaccgt ggattattgg ggccagggca ccctggtgac cgtgagcagc 360
<210> 26
<211> 120
<212> PRT
<213> 智人
<400> 26
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 Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala 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
Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 27
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 27
ggcggcggcg gcagcggcgg cggcggcagc ggcggcggcg gcagc 45
<210> 28
<211> 330
<212> DNA
<213> 智人
<400> 28
cagagcgcgc tgacccagcc ggcgagcgtg agcggcagcc cgggccagag cattaccatt 60
agctgcaccg gcaccagcag cgatgtgggc ggctataact atgtgagctg gtatcagcag 120
catccgggca aagcgccgaa actgatgatt tatgatgtga gcaaccgccc gagcggcgtg 180
agcaaccgct ttagcggcag caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240
caggcggaag atgaagcgga ttattattgc agcagctata ccagcagcag cacccgcgtg 300
tttggcaccg gcaccaaagt gaccgtgctg 330
<210> 29
<211> 112
<212> PRT
<213> 智人
<400> 29
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Glu Thr Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn
50 55 60
Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
65 70 75 80
Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr
85 90 95
Ser Ser Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 30
<211> 735
<212> DNA
<213> 智人
<400> 30
gaagtgcagc tgctggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc agctatatta tgatgtgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtgagcagc atttatccga gcggcggcat taccttttat 180
gcggataccg tgaaaggccg ctttaccatt agccgcgata acagcaaaaa caccctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgcattaaa 300
ctgggcaccg tgaccaccgt ggattattgg ggccagggca ccctggtgac cgtgagcagc 360
ggcggcggcg gcagcggcgg cggcggcagc ggcggcggcg gcagccagag cgcgctgacc 420
cagccggcga gcgtgagcgg cagcccgggc cagagcatta ccattagctg caccggcacc 480
agcagcgatg tgggcggcta taactatgtg agctggtatc agcagcatcc gggcaaagcg 540
ccgaaactga tgatttatga tgtgagcaac cgcccgagcg gcgtgagcaa ccgctttagc 600
ggcagcaaaa gcggcaacac cgcgagcctg accattagcg gcctgcaggc ggaagatgaa 660
gcggattatt attgcagcag ctataccagc agcagcaccc gcgtgtttgg caccggcacc 720
aaagtgaccg tgctg 735
<210> 31
<211> 245
<212> PRT
<213> 智人
<400> 31
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 Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala 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
Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser
130 135 140
Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr
145 150 155 160
Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His
165 170 175
Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg Pro
180 185 190
Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala
195 200 205
Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
210 215 220
Cys Ser Ser Tyr Thr Ser Ser Ser Thr Arg Val Phe Gly Thr Gly Thr
225 230 235 240
Lys Val Thr Val Leu
245
Claims (11)
1.一种单克隆抗人PD-L1抗体或其抗原结合片段,包括:具有SEQ ID NO:3所示氨基酸的VH和具有SEQ ID NO:5所示氨基酸的VL,其中所述抗体结合至人PD-L1蛋白。
2.一种单链可变片段(scFv),包括:具有SEQ ID NO:3所示氨基酸的VH和具有SEQ IDNO:5所示氨基酸的VL,其中所述scFv结合至人PD-L1蛋白。
3.根据权利要求2所述的scFv,进一步包括位于VH与VL之间的接头。
4.根据权利要求2所述的scFv,其具有SEQ ID NO:9所示氨基酸序列。
5.一种嵌合抗原受体融合蛋白(CAR),所述嵌合抗原受体融合蛋白自N-末端到C-末端包括:
(i)权利要求2所述的scFv,
(ii)跨膜结构域,
(iii)至少一个共刺激结构域,和
(iv)激活结构域。
6.根据权利要求5所述的CAR,其中,所述scFv进一步包括位于VH与VL之间的接头。
7.根据权利要求5所述的CAR,其中,所述共刺激结构域是CD28或4-1BB。
8.根据权利要求5所述的CAR,其中,所述激活结构域是CD3ζ。
9.根据权利要求5所述的CAR,其具有SEQ ID NO:20或SEQ ID NO:24所示氨基酸序列。
10.一种编码权利要求5所述的CAR的核酸。
11.经修饰以表达权利要求5所述的CAR的T细胞或自然杀伤细胞。
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