CN114616239B - 嵌合抗原受体和其中表达有嵌合抗原受体的t细胞 - Google Patents
嵌合抗原受体和其中表达有嵌合抗原受体的t细胞 Download PDFInfo
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Abstract
本发明公开了嵌合抗原受体和其中表达有嵌合抗原受体的T细胞,具体公开了靶向CD3的嵌合抗原受体,该嵌合抗原受体包括CD3结合结构域;铰链区和跨膜结构域;共刺激结构域;信号转导结构域。本发明还公开了编码嵌合抗原受体的核酸分子、表达载体,宿主细胞和包含其的药物组合物和试剂盒。本发明的嵌合抗原受体可用于免疫治疗和抗移植排异反应中,具有巨大的市场应用价值。
Description
技术领域
本发明涉及免疫治疗领域,涉及嵌合抗原受体和其中表达有嵌合抗原受体的T细胞。
背景技术
免疫疗法正在成为一种非常有前景的癌症治疗方法。T细胞或T淋巴细胞是我们免疫系统的武装力量,其不断寻找外来抗原并区分异常(癌症或感染细胞)与正常细胞。用CAR遗传修饰T细胞是设计肿瘤特异性T细胞的常用方法。靶向肿瘤相关抗原的CAR-T细胞可以输注到患者体内(称为过继性T细胞疗法),代表了一种有效的免疫治疗方法。与化学疗法或抗体相比,CAR-T技术的优势在于重编程的工程化T细胞可以增殖并持续存在于患者体内,像活的药物一样起作用。
肿瘤免疫治疗的CAR-T疗法,CAR-T,全称Chimeric Antigen Receptor T-CellImmunotherapy,即嵌合抗原受体T细胞免疫疗法;原理在于经嵌合抗原受体修饰的T细胞,可以特异性地识别肿瘤相关抗原,使效应T细胞的靶向性、杀伤活性和持久性均较常规应用的免疫细胞高,并可克服肿瘤局部免疫抑制微环境并打破宿主免疫耐受状态。嵌合抗原受体(CAR)是CAR-T的核心部件,赋予T细胞HLA非依赖的方式识别肿瘤抗原能力,这使得经过CAR改造的T细胞相较于天然T细胞表面受体TCR能够识别更广泛的目标。CAR(ChimericAntigen Receptor)主要由三个功能域构成,分别是胞外结构域、跨膜结构域和胞内结构域。胞外结构域由负责识别并结合抗原的单克隆抗体的单链可变片段(single-chainvariable fragment,scFv)及一段起连接作用的铰链区(Hinge)构成。胞内结构域由共刺激结构域(Costimulatory Domain)和信号转导结构域(Signaling Domain)构成。在晚期CLL和ALL患者中采用靶向CD19的CAR-T时取得了成功(Porter等人,2011,N Engl J Med,365:725-33;Kalos等人,2011,Science Transl Med,3:
95ra73;Grupp和Kalos,2013,N Engl J Med,368:1509-18)显示,这些细胞可以在单次输注后根除巨大肿瘤负荷,缓解作用迄今持续长达3年,从而强调了CAR T细胞疗法的巨大潜力。
迄今为止,还未见靶向CD3的CAR-T及在治疗恶性肿瘤中的应用的报道。
发明内容
本发明的目的之一在于提供CD3在制备靶向CD3的嵌合抗原受体中的应用。
本发明的目的之二在于提供针对CD3的抗体或其抗原结合片段在制备靶向CD3的嵌合抗原受体中的应用。
本发明的目的之三在于提供一种靶向CD3的嵌合抗原受体或包含其的CAR-T。
本发明的目的之四在于提供前面所述的靶向CD3的嵌合抗原受体或CAR-T细胞在免疫治疗中的应用。
本发明的目的之五在于提供前面所述的靶向CD3的嵌合抗原受体或CAR-T细胞在抗移植排异反应中的应用。
为了实现上述目的,本发明采用了如下技术方案:
根据本发明的第一个方面,本发明提供了CD3在制备靶向CD3的嵌合抗原受体中的应用。
根据本发明的第二个方面,本发明提供了针对CD3的抗体或其抗原结合片段在制备靶向CD3的嵌合抗原受体中的应用。
抗原结合片段可以是Fab片段(Fab)、F(ab’)2片段、双链抗体、三链抗体、四链抗体、单链可变区片段(scFv)或二硫化物稳定的可变区片段(dsFv)。在优选的实施方案中,抗原结合片段为scFv。scFv为截短的Fab片段,其包含经由合成肽与抗体轻链的可变(V)结构域连接的抗体重链的V结构域,其可以使用常规的重组DNA技术生成。
根据本发明的第三个方面,本发明提供了一种靶向CD3的嵌合抗原受体,所述嵌合抗原受体包括CD3结合结构域。
进一步,所述嵌合抗原受体从N端到C端包括:CD3结合结构域、铰链区、跨膜结构域、信号传导结构域。
可选择地,所述嵌合抗原受体从N端到C端包括:CD3结合结构域、铰链区、跨膜结构域、共刺激结构域、信号传导结构域。
在本发明的具体实施方案中,所述嵌合抗原受体从N端到C端包括:CD3结合结构域、铰链区、跨膜结构域、共刺激结构域、信号传导结构域。
CD3结合结构域可以包含CD3抗体的任何抗原结合部分。例如,CD3结合结构域可以是Fab片段(Fab)、F(ab’)2片段、双链抗体、三链抗体、四链抗体、单链可变区片段(scFv)或二硫化物稳定的可变区片段(dsFv)。在优选的实施方案中,CD3结合结构域为scFv。scFv为截短的Fab片段,其包含经由合成肽与抗体轻链的可变(V)结构域连接的抗体重链的V结构域,其可以使用常规的重组DNA技术生成。然而,用于本发明CAR的CD3结合结构域不限于这些示例性类型的抗体片段。
CD3结合结构域可以包含轻链可变区和/或重链可变区。在本发明的实施方案中,重链可变区包含互补决定区(CDR)1、CDR2和CDR3中的一个或多个。在优选的实施方案中,CD3结合结构域包含人重链CDR1、人重链CDR2和人重链CDR3。
重链CDR1具有与SEQ ID NO:1、SEQ ID NO:17、SEQ ID NO:28、SEQ ID NO:39、SEQID NO:50中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列;
重链CDR2具有与SEQ ID NO:2、SEQ ID NO:18、SEQ ID NO:29、SEQ ID NO:40、SEQID NO:51中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列;
重链CDR3具有与SEQ ID NO:3、SEQ ID NO:19、SEQ ID NO:30、SEQ ID NO:41、SEQID NO:52中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列。
在本发明的实施方案中,轻链可变区包含互补决定区(CDR)1、CDR2和CDR3。在优选的实施方案中,CD3结合结构域包含人轻链CDR1、人轻链CDR2和人轻链CDR3。
轻链CDR1具有与SEQ ID NO:4、SEQ ID NO:20、SEQ ID NO:31、SEQ ID NO:42、SEQID NO:53中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列;
轻链CDR2具有与SEQ ID NO:5、SEQ ID NO:21、SEQ ID NO:32、SEQ ID NO:43、SEQID NO:54中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列;
轻链CDR3具有与SEQ ID NO:6、SEQ ID NO:22、SEQ ID NO:33、SEQ ID NO:44、SEQID NO:55中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列。
在本发明的实施方案中,CD3结合结构域包含重链可变区和轻链可变区。在优选的实施方案中,CD3结合结构域包含人重链可变区和人轻链可变区。CD3结合结构域的重链可变区具有与SEQ ID NO:7、SEQ ID NO:23、SEQ ID NO:34、SEQ ID NO:45、SEQ ID NO:56中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列。CD3结合结构域的轻链可变区具有与SEQ ID NO:8、SEQ ID NO:24、SEQ ID NO:35、SEQ ID NO:46、SEQ ID NO:57中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列。
在本发明的实施方案中,轻链可变区和重链可变区可以通过接头(Linker)连接。接头可以包含任何合适的氨基酸序列。在本发明的实施方案中,接头可以包含SEQ ID NO:9或其同源序列。所述同源序列与原序列的同源性优选为95%或以上、97%或以上、98%或以上、99%或以上、99.1%或以上、99.2%或以上、99.3%或以上、99.4%或以上、99.5%或以上、99.6%或以上、99.7%或以上、99.8%或以上、或99.9%或以上。
在本发明的一个实施方案中,CD3结合结构域包含具有与SEQ ID NO:10、SEQ IDNO:25、SEQ ID NO:36、SEQ ID NO:47、SEQ ID NO:58中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列的scFv。
在本发明的实施方案中,CD3结合结构域还可以包含前导序列,或称为信号肽序列。前导序列可以位于轻链可变区或重链可变区的氨基末端。优选地,前导序列位于重链可变区的氨基末端。前导序列可以包含任何合适的前导序列。例如,CD3结合结构域可以包含这样的前导序列,其含有SEQ ID NO:11或其同源序列。所述同源序列与原序列的同源性优选为95%或以上、97%或以上、98%或以上、99%或以上、99.1%或以上、99.2%或以上、99.3%或以上、99.4%或以上、99.5%或以上、99.6%或以上、99.7%或以上、99.8%或以上、或99.9%或以上。在本发明的实施方案中,虽然前导序列可以促进CAR在细胞表面上的表达,但是在表达的CAR中存在前导序列可以不是CAR发挥功能所必需的。在本发明的实施方案中,CAR在细胞表面上表达后,前导序列的全部或部分可以从CAR上切除。
在本发明的一个实施方案中,含有信号肽序列或前导序列的CD3结合结构域具有与SEQ ID NO:16、SEQ ID NO:27、SEQ ID NO:38、SEQ ID NO:49、SEQ ID NO:60中的任一个所示的氨基酸序列具有至少95%序列同一性的氨基酸序列。
铰链区作用是促进抗原受体与抗原结合;跨膜结构域用来固定CAR。在本发明的实施方案中,铰链区为人铰链区,并且跨膜结构域为人跨膜结构域。铰链区和跨膜结构域可以包含以下任一种或多种分子的铰链区和跨膜结构域:CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD134、CD137、ICOS和CD154。在本发明的具体实施方案中,选择的铰链区和跨膜结构域可以包含SEQ ID NO:12的氨基酸序列或其同源序列。所述同源序列与原序列的同源性优选为95%或以上、97%或以上、98%或以上、99%或以上、99.1%或以上、99.2%或以上、99.3%或以上、99.4%或以上、99.5%或以上、99.6%或以上、99.7%或以上、99.8%或以上、或99.9%或以上。
信号传导结构域又可称为T细胞激活结构域,提供T细胞活化的第一信号,最常用的信号传导结构域是CD3ζ胞内结构域。在本发明的实施方案中,CD3ζ胞内结构域可以包含SEQ ID NO:13的氨基酸序列或其同源序列。所述同源序列与原序列的同源性优选为95%或以上、97%或以上、98%或以上、99%或以上、99.1%或以上、99.2%或以上、99.3%或以上、99.4%或以上、99.5%或以上、99.6%或以上、99.7%或以上、99.8%或以上、或99.9%或以上。
共刺激结构域提供T细胞活化的第二信号,包含共刺激因子的细胞内结构域,所述共刺激因子包括CD27、CD28、4-1BB、OX40、CD30、CD40、ICOS、NKG2C、B7-H3。在本发明的实施方案中,共刺激结构域可以包含含SEQ ID NO:14的氨基酸序列或其同源序列。所述同源序列与原序列的同源性优选为95%或以上、97%或以上、98%或以上、99%或以上、99.1%或以上、99.2%或以上、99.3%或以上、99.4%或以上、99.5%或以上、99.6%或以上、99.7%或以上、99.8%或以上、或99.9%或以上。
在本发明的一个具体实施方案中,本发明的所述嵌合抗原受体包含SEQ ID NO:15、SEQ ID NO:26、SEQ ID NO:37、SEQ ID NO:48、SEQ ID NO:59所示的氨基酸序列。
本发明的实施方案的CAR可以包含合成的氨基酸代替一个或多个天然存在的氨基酸。此类合成的氨基酸为本领域已知的,并且包括例如,氨基环己羧酸、正亮氨酸、α-氨基n-癸酸、高丝氨酸、S-乙酰氨甲基-半胱氨酸、反式-3-羟脯氨酸和反式-4-羟脯氨酸、4-氨基苯丙氨酸、4-硝基苯丙氨酸、4-氯苯丙氨酸、4-羧基苯丙氨酸、β-苯基丝氨酸、β-羟基苯丙氨酸、苯基甘氨酸、α-萘基丙氨酸、环己基丙氨酸、环己基甘氨酸、吲哚啉-2-羧酸、1,2,3,4-四氢异喹啉-3-羧酸、氨基丙二酸、氨基丙二酸单酰胺、N’-苯甲基-N’-甲基-赖氨酸、N’,N’-二苄基-赖氨酸、6-羟赖氨酸、鸟氨酸、d-氨基环戊烷羧酸、α-氨基环己羧酸、α-氨基环庚烷羧酸、α-(2-氨基-2-降莰烷)-羧酸、α,γ-二氨基丁酸、α,βv二氨基丙酸、高苯丙氨酸以及α-叔-丁基甘氨酸。
本发明的实施方案的CAR可以被糖基化、酰胺化、羧酸化、磷酸化、酯化、N-酰化、经由例如二硫桥环化、或者转变为酸加成盐和/或任选地二聚化或多聚化。
本发明的实施方案的CAR可以通过本领域已知的方法获得。可以通过制备多肽或蛋白质的任何合适的方法制得CAR。从头合成多肽和蛋白质的合适方法为本领域已知的。另外,可以使用例如Green and Sambrook,Molecular Cloning:A Laboratory Manual(第4版),Cold Spring Harbor Laboratory Press(2012)中所述的标准重组方法,使用本文所述的核酸重组产生CAR。可选地,本文所述的CAR可以通过公司商业合成。在这方面,本发明的CAR可以是合成的和/或重组的。
根据本发明的第四个方面,本发明提供了编码前面所述的嵌合抗原受体或其组成部分的核酸分子。
本发明的核酸分子可以包含编码本文所述的前导序列、CD3结合结构域、铰链区和跨膜结构域、信号传导结构域、共刺激结构域、嵌合抗原受体中一种或多种的核苷酸序列。
本文使用的“核酸”包括“多核苷酸”、“寡核苷酸”和“核酸分子”,并且通常意为DNA或RNA的聚合物,其可以是单链或双链,合成的或从天然来源获得的(例如分离的和/或纯化的),其可以含有天然的、非天然的或改变的核苷酸,并且其可以含有天然的、非天然的或改变的核苷酸间连键,如氨基磷酸酯键或硫代磷酸酯键,替代存在于未修饰的寡核苷酸的核苷酸之间的磷酸二酯。在一些实施方案中,核酸不包含任何插入、缺失、倒位和/或置换。然而,在一些情况下核酸包含一个或多个插入、缺失、倒位和/或置换可能是合适的。
本发明的实施方案的核酸可以是重组体。本文使用的术语“重组体”指(i)通过将天然的或合成的核酸区段与可在活细胞中复制的核酸分子连接而在活细胞外构建的分子,或者(ii)由以上(i)中所述的那些分子的复制而产生的分子。出于本文的目的,复制可以是体外复制或体内复制。
核酸可以基本上由本文所述的一条或多条指定的核苷酸序列组成,以使其它组分(例如其它核苷酸)不实质性改变编码的CAR的生物活性。
重组核酸可以是具有非天然存在的序列或者具有通过序列的两个原本分离的区段的人工组合而制备的序列的核酸。该人工组合通常通过化学合成来完成,或者更通常通过人工操纵分离的核酸区段来完成,例如通过基因工程技术来完成,诸如以上的Green等人中所述的那些技术。可以利用本领域已知的程序,基于化学合成和/或酶连接反应构建核酸。参见,例如以上的Green等人。例如,可以利用天然存在的核苷酸或者设计以增加分子的生物稳定性或者增加杂交时所形成的双链体的物理稳定性的不同修饰的核苷酸(例如硫代磷酸酯衍生物和吖啶取代的核苷酸)来化学合成核酸。可用于产生核酸的修饰的核苷酸的实例包括但不限于:5-氟尿嘧啶、5-溴尿嘧啶、5-氯尿嘧啶、5-碘尿嘧啶、次黄嘌呤、黄嘌呤、4-乙酰胞嘧啶、5-(羧基羟甲基)尿嘧啶、5-羧基甲基氨基甲基-2-硫脲苷、5-羧基甲基氨基甲基尿嘧啶、二氢尿嘧啶、β-D半乳糖基Q核苷(beta-D-galactosylqueosine)、肌酐、N6-异戊烯腺嘌呤、1-甲基鸟嘌呤、1-甲基肌苷、2,2-二甲基鸟嘌呤、2-甲基腺嘌呤、2-甲基鸟嘌呤、3-甲基胞嘧啶、5-甲基胞嘧啶、N 6-取代的腺嘌呤、7-甲基鸟嘌呤、5-甲基氨基甲基尿嘧啶、5-甲氧基氨基甲基-2-硫脲嘧啶、β-D-甘露糖基Q核苷(beta-D-mannosylqueosine)、5′-甲氧基羧甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N 6-异戊烯腺嘌呤、尿嘧啶-5-羟乙酸(v)、怀丁苷(wybutoxosine)、假尿嘧啶、Q核苷(queosine)、2-巯基胞嘧啶、5-甲基-2-硫脲嘧啶、2-硫脲嘧啶、4-硫脲嘧啶、5-甲基尿嘧啶、尿嘧啶-5-羟乙酸甲酯、3-(3-氨基-3-N-2-羧丙基)尿嘧啶以及2,6-二氨基嘌呤。
核酸可以包含编码本文所述的任何CAR的任何分离或纯化的核苷酸序列。可选地,核苷酸序列可包含任何序列简并的核苷酸序列或简并序列的组合。
本发明的实施方案还提供分离或纯化的核酸,其包含与本文所述的任何核酸的核苷酸序列互补的核苷酸序列或者包含在严紧条件下与本文所述的任何核酸的核苷酸序列杂交的核苷酸序列。
在严紧条件下杂交的核苷酸序列可以在高度严紧条件下杂交。“高度严紧条件”意为核苷酸序列以可检测地比非特异性杂交更强的量与靶序列(本文所述的任何核酸的核苷酸序列)特异性杂交。高度严紧条件包括将含有准确互补序列的多核苷酸或者仅含有一些分散的错配的多核苷酸与恰巧具有匹配核苷酸序列的一些小的区域(例如3-10个碱基)的随机序列区分开的条件。此类小的互补区域比14-17个或者更多个碱基的全长互补体更易解链,并且高度严紧杂交使其易于区分。相对高度严紧的条件将包括,例如低盐和/或高温条件,如由约0.02-0.1M NaCl或等同物,在约50-70℃的温度下所提供的条件。此类高度严紧条件容忍极少(如果存在)核苷酸序列与模板或靶标链之间的错配,并且特别适合于检测本文所述的任何本发明的CAR的表达。普遍认为通过添加增加量的甲酰胺可以导致更严紧的条件。
在本发明的实施方案中,核酸包含编码CAR的密码子优化的核苷酸序列。不受特定理论或机制的束缚,认为核苷酸序列的密码子优化增加mRNA转录本的翻译效率。核苷酸序列的密码子优化可以涉及将天然密码子置换为编码相同氨基酸,但可以由细胞内更容易获得的tRNA翻译的另一密码子,从而提高翻译效率。核苷酸序列的优化还可以降低会干扰翻译的二级mRNA结构,从而提高翻译效率。就这点而言,编码CAR的核酸可以包含SEQ ID NO:16-25中任一项的密码子优化的核苷酸序列。
本发明还提供这样的核酸,其包含与本文所述的任何核酸的核苷酸序列具有至少约95%或者更多,例如约96%、约97%、约98%或约99%同一性的核苷酸序列。
根据本发明的第五个方面,本发明提供了包含前面所述的核酸分子的重组表达载体。在实施方案中,可以将本发明的核酸并入重组表达载体中。就这点而言,本发明的实施方案提供包含本发明的任何核酸的重组表达载体。出于本文的目的,术语“重组表达载体”意为遗传修饰的寡核苷酸或多核苷酸构建体,当构建体包含编码mRNA、蛋白、多肽或肽的核苷酸序列,并且在足以使mRNA、蛋白、多肽或肽在宿主细胞内表达的条件下将载体与细胞接触时,其允许细胞表达mRNA、蛋白、多肽或肽。本发明的载体作为整体不是天然存在的。
然而,载体的部分可以是天然存在的。本发明的重组表达载体可以包含任何类型的核苷酸,包括但不限于DNA和RNA,其可以是单链的或双链的,合成的或者部分由天然来源获得的,并且其可以含有天然的、非天然的或改变的核苷酸。重组表达载体可以包含天然存在的或非天然存在的核苷酸间连键或者这两种类型的连键。优选地,非天然存在的或改变的核苷酸或核苷酸间连键不妨碍载体的转录或复制。
在实施方案中,本发明的重组表达载体可以是任何合适的重组表达载体,并且可以被用于转化或转染任何合适的宿主细胞。合适的载体包括设计以用于增殖和扩增或者用于表达或者用于这两种的那些载体,如质粒和病毒。载体可以选自:pUC系列(FermentasLife Sciences,Glen Burnie,MD)、pBluescript系列(Stratagene,LaJolla,CA)、pET系列(Novagen,Madison,WI)、pGEX系列(Pharmacia Biotech,Uppsala,Sweden)以及pEX系列(Clontech,Palo Alto,CA)。也可使用诸如λGT10、λGT11、λZapII(Stratagene)、λEMBL4和λNM1149的噬菌体载体。植物表达载体的实例包括pBI01、pBI101.2、pBI101.3、pBI121和pBIN19(Clontech)。动物表达载体的实例包括pEUK-Cl、pMAM和pMAMneo(Clontech)。重组表达载体可以是病毒载体,例如逆转录病毒载体。在本发明的实施方案中,载体为γ逆转录病毒载体、慢病毒载体或转座子。
在实施方案中,可以使用例如以上Green等人中所述的标准重组DNA技术来制备本发明的重组表达载体。可以将环状或线性表达载体的构建体制备为含有在原核或真核宿主细胞中发挥功能的复制系统。复制系统可以来源于,例如ColEl、2μ质粒、λ、SV40、牛乳头瘤病毒等。
重组表达载体可以包含调控序列,如转录和翻译起始和终止密码子,视情况而定并且考虑载体是基于DNA的还是基于RNA的,其对于待引入载体的宿主细胞的类型(例如细菌、真菌、植物或动物)是特异的。重组表达载体可以包含限制位点以促进克隆。
重组表达载体可以包含允许对转化或转染的宿主细胞进行选择的一种或多种标志物基因。标志物基因包括抗微生物剂抗性(例如对抗生素、重金属等的抗性),在营养缺陷型宿主中互补以提供原营养等。用于本发明的表达载体的合适的标志物基因包括,例如新霉素/G418抗性基因、潮霉素抗性基因、组氨醇抗性基因、四环素抗性基因以及氨苄西林抗性基因。
重组表达载体可以包含与以下序列可操作地连接的天然或非天然的启动子:编码本发明的CAR的核苷酸序列或者与编码本发明的CAR的核苷酸序列互补或杂交的核苷酸序列。启动子的选择,例如强、弱、可诱导的、组织特异性的和发育特异性的,在本领域普通技术人员的能力内。类似地,核苷酸序列与启动子的组合也在本领域普通技术人员的能力内。启动子可以是非病毒启动子或病毒启动子,例如巨细胞病毒(CMV)启动子、SV40启动子、RSV启动子或鼠干细胞病毒的长末端重复中存在的启动子。
可以将本发明的重组表达载体设计为瞬时表达、稳定表达或者设计为这两种。另外,可以将重组表达载体制备为组成型表达或诱导型表达。
此外,可以将重组表达载体制备为包含自杀基因。本文使用的术语“自杀基因”指引起表达自杀基因的细胞死亡的基因。自杀基因可以是这样的基因,其赋予基因在其中表达的细胞针对试剂(例如药物)的敏感性,并且当细胞与所述试剂接触或者暴露于所述试剂时引起细胞死亡。自杀基因为本领域已知的,并且包括例如单纯疱疹病毒(HSV)胸苷激酶(TK)基因、胞嘧啶脱氨酶、嘌呤核苷磷酸化酶和硝基还原酶。
根据本发明的第六个方面,本发明提供了一种宿主细胞,所述宿主细胞包含前面所述的嵌合抗原受体、前面所述的核酸分子、或前面所述的重组表达载体。
在本发明的实施方案中还提供包含本文所述的任何重组表达载体的宿主细胞。本文使用的术语“宿主细胞”指可以含有本发明的重组表达载体的任何类型的细胞。宿主细胞可以是真核细胞,例如植物、动物、真菌或藻类;或者可以是原核细胞,例如细菌或原生动物。宿主细胞可以是培养的细胞或原代细胞,即直接由生物体如人分离到的细胞。宿主细胞可以是贴壁细胞或悬浮细胞,即悬浮生长的细胞。合适的宿主细胞为本领域已知的,并且包括,例如DH5α大肠杆菌细胞、中国仓鼠卵巢细胞、猴VERO细胞、COS细胞、HEK293细胞等。出于扩增或复制重组表达载体的目的,宿主细胞可以是原核细胞,例如DH5α细胞。出于产生CAR的目的,宿主细胞可以是哺乳动物细胞。宿主细胞可以是人细胞。尽管宿主细胞可以是任何类型的细胞、可以来源于任何类型的组织,并且可以处于任何发育阶段,但是宿主细胞可以是外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。宿主细胞可以是B细胞、自然杀伤(NK)细胞或T细胞。
出于本文的目的,T细胞可以是任何T细胞,如培养的T细胞,例如原代T细胞;或者是来自培养的T细胞系的T细胞,例如Jurkat、SupT1等;或者是获自哺乳动物的T细胞。如果获自哺乳动物,T细胞可以获自多种来源,包括但不限于血液、骨髓、淋巴结、胸腺或者其它组织或液体。T细胞也可以是富集的或纯化的。T细胞可以是人T细胞。T细胞可以是分离自人的T细胞。T细胞可以是任何类型的T细胞,并且可以处于任何发育阶段,包括但不限于CD4+/CD8+双阳性T细胞、CD4+辅助T细胞(例如Th 1和Th 2细胞)、CD8+T细胞(例如细胞毒性T细胞)、肿瘤浸润细胞、记忆T细胞、初始T细胞等。
T细胞可以是自体的或同种异体的。“自体”是指要用于治疗方法或用途(即要用核酸或载体转导)的细胞来源于或者获自要进行治疗方法的受试者。因此,从受试者获得自体细胞,用核酸或载体转导并返回相同的受试者。
“同种异体”是指要用于治疗方法或用途(即要用核酸或载体转导)的细胞来源于或获自与要进行治疗方法的受试者的不同受试者。因此,同种异体细胞从第一个受试者获得,用核酸或载体转导并施用于第二个受试者。
还应当理解,本发明的宿主细胞可包含超过一种核酸或载体。特别地,本发明的细胞可包含2,3,4或5种或更多种核酸或载体,其各自表达不同的嵌合抗原受体分子。因此,本发明的细胞可包含不同的嵌合抗原受体分子,其能够结合CD3,例如在CD3的相同或不同的位置。在这方面,本发明的细胞可包含嵌合抗原受体分子,其包含结合CD3的scFv和嵌合抗原受体分子,所述嵌合抗原受体分子包含结合CD3的配体。
此外,除了本发明的表达的嵌合抗原受体之外,本发明的细胞可以包含至少一种其他受体(特别是外源的)(例如多种受体),其可以与CAR一起以组合方式用于结合靶物,在此类方法中,可以需要CAR和至少一种其他受体与靶细胞的结合来刺激针对靶细胞的免疫应答(例如,每种CAR/受体可以仅提供免疫细胞刺激的部分信号,其单独可以不足以免疫细胞刺激,但一起允许免疫细胞刺激)。在本发明的细胞是T细胞的情况下,可以必需CAR结合CD3和至少一种其他受体结合CD3表达细胞上的其配体两者来刺激T细胞。至少一种其他受体可以是另外的CAR分子。
可以使用另外的受体与本发明的CAR组合,其中两种受体结合不同的靶物并诱导不同的效果来治疗疾病。因此,两种受体的作用可以完全彼此独立,但是一起可以呈现针对疾病的有效疗法。
根据本发明的第七个方面,本发明提供了一种制备前面所述的宿主细胞的方法,所述方法包括将前面所述的核酸分子或前面所述的重组表达载体导入宿主细胞,并在适合细胞表达所述核酸分子或载体的条件下培养宿主细胞。
根据本发明的第八个方面,本发明提供了一种细胞群,所述细胞群包括前面所述的宿主细胞。
细胞群可以是除了至少一种其它细胞外还包含含有任何所述重组表达载体的宿主细胞的异质群,所述其它细胞为例如不包含任何重组表达载体的宿主细胞(例如T细胞)或者除了T细胞之外的细胞,例如B细胞、巨噬细胞、嗜中性粒细胞、红细胞、肝细胞、内皮细胞、上皮细胞、肌细胞、脑细胞等。可选地,细胞群可以是基本同质的群体,其中所述群体主要包含含有重组表达载体的宿主细胞(例如基本上由含有重组表达载体的宿主细胞组成)。群体也可以是克隆细胞群,其中群体的所有细胞均为含有重组表达载体的单个宿主细胞的克隆,以使群体的所有细胞均包含重组表达载体。在本发明的一个实施方案中,细胞群为包含含有本文所述的重组表达载体的宿主细胞的克隆群体。
在本发明的实施方案中,群体中细胞的数目可以快速扩增。表达CAR的细胞的数目的扩增可以通过如以下中所述的本领域已知的多种方法中的任一种来完成,例如美国专利8,034,334;美国专利8,383,099;美国专利申请公开号2012/0244133;Dudley等人,J.Immunother.,26:332-42(2003);以及Riddell等人,J.Immunol.Methods,128:189-201(1990)。
CAR、核酸、重组表达载体和宿主细胞(包括其群体)在下文中统称为“CAR材料”。
根据本发明的第九个方面,本发明提供了一种药物组合物,所述药物组合物包括前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、或前面所述的细胞群。
进一步,所述药物组合物包括药学上可接受的载体。就药物组合物而言,载体可以是常规用于所考虑的具体的本发明的CAR材料的那些载体中的任何载体。制备可施用组合物的方法为本领域技术人员已知的或显而易见的,并且更详细地描述于,例如,Remington:The Science and Practice ofPharmacy,第22版,Pharmaceutical Press(2012)。优选地,药学上可接受的载体是在使用条件下,无有害副作用或毒性的载体。
载体的选择将部分由具体的本发明的CAR材料以及由用于施用本发明的CAR材料的具体方法决定。因此,存在多种合适的本发明的药物组合物的制剂。合适的制剂可以包括用于肠胃外、皮下、静脉内、肌肉内、动脉内、鞘内、瘤内或腹膜内施用的那些制剂中的任何制剂。可以使用多于一种途径来施用本发明的CAR材料,并且在某些情况下,特定途径可以比另一途径提供更直接以及更有效的应答。
优选地,通过注射,例如静脉内施用本发明的CAR材料。当本发明的CAR材料为表达本发明的CAR的宿主细胞(或其群体)时,用于注射的细胞的药学可接受的载体可以包括任何等张载体,如例如生理盐水(含约0.90%w/v NaCl的水,含约300mOsm/L NaCl的水,或者每升水约9.0g NaCl)、NORMOSOL R电解质溶液(Abbott,Chicago,IL)、PLASMA-LYTE A(Baxter,Deerfield,IL)、含约5%葡萄糖的水或者乳酸林格氏液。在实施方案中,用人血清白蛋白补充药学可接受的载体。
本发明的药物组合物还可包括与本发明的CAR材料联合施用的其它药学活性剂或药物,所述其它药学活性剂或药物如化疗剂,例如天冬酰胺酶、白消安、卡铂、顺铂、道诺霉素、多柔比星、氟尿嘧啶、吉西他滨、羟基脲、甲氨蝶呤、紫杉酚、利妥昔单抗、长春花碱、长春新碱等。
当将本发明的CAR材料与一种或多种另外的治疗剂一起施用时,一种或多种另外的治疗剂可以共施用至哺乳动物。“共施用”意为在时间上足够接近地施用一种或多种另外的治疗剂和本发明的CAR材料,以使本发明的CAR材料可以增强一种或多种另外的治疗剂的作用,反之亦然。就这点而言,可以首先施用本发明的CAR材料,之后施用一种或多种另外的治疗剂,反之亦然。可选地,可以同时施用本发明的CAR材料和一种或多种另外的治疗剂。可以增强表达CAR的细胞功能的另外的治疗剂可以包括,例如,一种或多种细胞因子或者一种或多种抗体(例如,抑制PD-1功能的抗体)。
考虑可以将本发明的CAR材料和药物组合物用于治疗或预防哺乳动物中的病况的方法中。不受特定理论或机制的束缚,本发明的CAR材料具有生物活性,例如识别CD3的能力,以使当由细胞表达时,CAR能够介导针对表达CD3的细胞的免疫应答。就这点而言,本发明的实施方案提供治疗或预防哺乳动物中的病况的方法,其包括向哺乳动物施用有效治疗或预防哺乳动物中的病况的量的本发明的CAR、核酸、重组表达载体、宿主细胞、细胞群和/或药物组合物中的任一种。病况可以为以CD3的表达或过表达为特征的任何病况。在优选的实施方案中,病况为癌症。
出于施用宿主细胞或细胞群的本发明的方法的目的,细胞可以是与哺乳动物同种异体的细胞或是其自体的细胞。在“自体的”施用方法中,将细胞从哺乳动物中取出,储存(并任选地进行修饰),并返回至同一哺乳动物中。在“同种异体的”施用方法中,哺乳动物接受来自基因相似但不同供体的细胞。优选地,细胞为哺乳动物自体的。在本发明的实施方案中,向哺乳动物施用的细胞已经经历了基因编辑。
本文提及的哺乳动物可以是任何哺乳动物。本文使用的术语“哺乳动物”指任何哺乳动物,包括但不限于啮齿目的哺乳动物,如小鼠和仓鼠;以及兔形目的哺乳动物,如兔。哺乳动物可以来自食肉目,包括猫科(猫)和犬科(狗)。哺乳动物可以来自偶蹄目,包括牛科(牛)和猪科(猪);或者来自奇蹄目,包括马科(马)。哺乳动物可以来自灵长目、猿(Ceboids)目或猴(Simoids)目(猴),或者来自类人猿目(人和类人猿)。优选地,哺乳动物为人。
本文使用的术语“治疗”和“预防”以及由其衍生的词语不一定意指100%或完全的治疗或预防。而是,存在本领域普通技术人员认为具有潜在益处或治疗效果的不同程度的治疗或预防。在这方面,本发明的方法可以提供任何量任何水平的哺乳动物中病况的治疗或预防。此外,本发明的方法提供的治疗或预防可以包括被治疗或预防的疾病(例如癌症)的一种或多种病况或症状的治疗或预防。另外,出于本文的目的,“预防”可以涵盖延迟疾病,例如癌症或其症状或病况的发作。可选地或另外,“预防”可以涵盖延迟疾病,例如癌症或其症状或病况的复发。
根据本发明的第十个方面,本发明提供了一种试剂盒,所述试剂盒包含前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、前面所述的细胞群、或前面所述的药物组合物。
试剂盒的一些组分可以以水性介质或冻干形式包装。试剂盒的容器装置通常包括至少一个小瓶,试管,烧瓶,瓶子,注射器或其它容器装置,其中可以放置组分,优选适当地分装。如果试剂盒中有多个组分,则试剂盒通常还将包含第二个,第三个或其它附加容器,其中附加组分可以单独放置在容器中。然而,组分的各种组合可以包括在小瓶中。本发明的试剂盒通常还将包括用于容纳商业销售的密封限制组分的装置。这种容器可以包括注塑或吹塑塑料容器,其中保持所需的小瓶。
当试剂盒的组分提供在一种和/或多种液体溶液中时,液体溶液是水溶液,无菌水溶液是特别有用的。在一些情况下,容器装置本身可以是注射器,移液器和/或其它类似的装置,制剂可以从该装置施用到身体的感染区域,注射到动物中,和/或甚至施用到试剂盒的其它组分和/或与其混合。
然而,试剂盒的组分可以以干燥粉末提供。当试剂和/或组分作为干燥粉末提供时,可以通过加入合适的溶剂来重构粉末。可以设想,溶剂也可以在另一个容器装置中提供。试剂盒还可以包含用于容纳无菌的药学上可接受的缓冲剂和/或其它稀释剂的第二容器装置。
根据本发明的第十一个方面,本发明提供了一种免疫治疗方法,所述免疫治疗方法包括给有需要者施用前面所述的宿主细胞、前面所述的细胞群或前面所述的药物组合物。
进一步,所述方法适用疾病包括自身免疫性疾病、癌症。
所述癌症包括急性髓系白血病、慢性髓系白血病、急性淋巴细胞白血病、霍奇金淋巴瘤、神经母细胞瘤、尤文肉瘤、多发性骨髓瘤、骨髓增生异常综合征、BPDCN、胶质瘤,或其他实体瘤:包括胰腺癌、肺癌、结直肠癌、乳腺癌、膀胱癌。
根据本发明的第十二个方面,本发明提供了一种抗移植排异反应的方法,所述方法包括给有需要者施用前面所述的宿主细胞、前面所述的细胞群或前面所述的药物组合物。
进一步,所述移植排异反应包括移植物抗宿主反应、宿主抗移植物反应。
根据本发明的第十三个方面,本发明提供了前面所述的核酸分子、或前面所述的重组表达载体在制备前面所述的宿主细胞或前面所述的细胞群中的应用。
根据本发明的第十四个方面,本发明提供了前面所述的核酸分子、或前面所述的重组表达载体在制备CAR或CAR-T中的应用。
根据本发明的第十五个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体或前面所述的宿主细胞在制备前面所述的药物组合物中的应用。
根据本发明的第十六个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、前面所述的细胞群、或前面所述的药物组合物在制备前面所述的试剂盒中的应用。
根据本发明的第十七个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、前面所述的细胞群、前面所述的药物组合物、前面所述的试剂盒在前面所述的免疫治疗中的应用。
根据本发明的第十八个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、前面所述的细胞群、前面所述的药物组合物、前面所述的试剂盒在前面所述的抗移植排异反应中的应用。
根据本发明的第十九个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、前面所述的细胞群、或前面所述的药物组合物在免疫治疗中的应用。
根据本发明的第二十个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、前面所述的细胞群、或前面所述的药物组合物在抗移植排异反应中的应用。
根据本发明的第个二十一个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、前面所述的细胞群、或前面所述的药物组合物在制备用于免疫治疗的药物中的应用。
根据本发明的第二十二个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、或前面所述的细胞群、或前面所述的药物组合物在制备抗移植排异反应的药物中的应用。
根据本发明的第二十三个方面,本发明提供了前面所述的核酸分子、前面所述的重组表达载体、前面所述的宿主细胞、或前面所述的细胞群、或前面所述的药物组合物在制备抗癌症药物中的应用。
本发明所述的癌症可以为任何癌症,包括但不限于急性髓系白血病、慢性髓系白血病、急性淋巴细胞白血病、霍奇金淋巴瘤、神经母细胞瘤、尤文肉瘤、多发性骨髓瘤、骨髓增生异常综合征、BPDCN、胶质瘤,或其他实体瘤:包括胰腺癌、肺癌、结直肠癌、乳腺癌、膀胱癌。
优选地,癌症为淋巴瘤。在特别优选的实施方案中,癌症为T细胞淋巴瘤(如例如,间变性大细胞淋巴瘤(ALCL)、外周T细胞淋巴瘤-非特指型(PTCL-NOS)、血管免疫母细胞性T细胞淋巴瘤(AITL)和其它T细胞淋巴瘤)。优选地,癌症的特征在于CD3的表达或过表达。
附图说明
图1显示本发明构建的LV-CD3CAR质粒示意图;
图2显示利用流式细胞仪检测慢病毒LV-CD3CAR-291转导率的结果图;
图3显示利用流式细胞仪检测慢病毒LV-CD3CAR-cel转导率的结果图;
图4显示利用流式细胞仪检测慢病毒LV-CD3CAR-OKT31转导率的结果图;
图5显示利用流式细胞仪检测LV-CD3CAR-291-T中TCR敲除效果的结果图;
图6显示利用流式细胞仪检测LV-CD3CAR-cel-T中TCR敲除效果的结果图;
图7显示利用流式细胞仪检测LV-CD3CAR-OKT31-T中TCR敲除效果的结果图;
图8显示利用流式细胞仪检测LV-CD3CAR-291-T细胞对Jurkat-GFP细胞的杀伤作用结果图;
图9显示利用流式细胞仪检测LV-CD3CAR-cel-T细胞对Jurkat-GFP细胞的杀伤作用结果图;
图10显示利用流式细胞仪检测LV-CD3CAR-OKT31-T细胞对Jurkat-GFP细胞的杀伤作用结果图;
图11显示利用流式细胞仪检测LV-CD3CAR-sp34-T细胞对Jurkat-GFP细胞的杀伤作用结果图;
图12显示利用流式细胞仪检测LV-CD3CAR-UCHT1-T细胞对Jurkat-GFP细胞的杀伤作用结果图;
图13显示利用动物模型研究本发明构建的LV-CD3CAR-cel-T细胞对肿瘤影响的结果图;
图14显示小鼠体内荧光强度统计图;
图15显示小鼠生存时间统计图;
图16显示LV-CD3CAR-T对CD3阳性细胞的清除效果统计图。
具体实施方式
以下实施例进一步说明本发明。下述实施例只是为了说明本发明,而不应被解释为是限制性的。
实施例1 靶向CD3的CAR表达
1、合成靶向CD3的CAR的核酸分子
合成可表达靶向CD3的CAR的核酸分子,序列代号CD3CAR-291(SEQ ID NO:61);CD3CAR-cel(SEQ ID NO:62);CD3CAR-OKT31(SEQ ID NO:63);CD3CAR-sp34(SEQ ID NO:64):CD3CAR-UCHT1(SEQ ID NO:65);
3、构建LV-CD3CAR表达质粒
将CD3CAR按照酶切连接的方式插入表达载体pLVX-Puro中(载体线性序列如SEQID NO:66所示),构建LV-CD3CAR表达质粒,LV-CD3CAR质粒示意图如图1所示(胞内共刺激域为4-1BB,EGFR D III-DVI可作为CAR表达检测标志物以及CAR-T细胞的自杀基因,增加该产品的安全性)。酶切位点:XbaI,EcoRI。转化,涂板,小提测序,确认质粒构建成功。质粒大提获得无内毒素的表达质粒,以备包装慢病毒。
4、LV-CD3CAR慢病毒包装
PEI转染法(针对T75培养瓶)步骤如下:
(1)day1复苏293T/17细胞至1*T75内,培养基体积15ml;
(2)day3将293T/17细胞传代至1*T225内,培养基体积45ml;
(3)day5将293T/17细胞传代至3*T225内,接种密度大概为6*107个细胞/T225瓶;
(4)day6下午进行病毒包装。转染前观察细胞状态,汇聚度约90%时进行转染。弃去瓶内培养基,更换为15ml新鲜的DMEM培养基(无抗生素),培养30min。
溶液A配制:取LV-CD3CAR表达质粒17.7μg,辅助质粒pRSV-REV 8.8μg、辅助质粒pMDLg/pRRE 8.8μg及辅助质粒pMD2.G 4.4μg,转染比例为4∶2∶2∶1,总量为40μg,混匀后用无血清DMEM稀释定容至0.75ml,混匀后室温静置5min。
溶液B配制:取630μl DMEM,再加入120μl PEI工作液(1mg/ml、4℃保存),充分混匀,室温静置5min。
将B液逐滴加入到A液中,并轻柔混匀,室温孵育20min。将混合液逐滴加入到细胞中,轻柔混匀,置于5%二氧化碳培养17h。
(5)day7上午弃去原培养基,加入15ml的不含血清及抗生素的DMEM培养基,培养31h后收获病毒,之后再加入培养基培养24h,再收获一次病毒。收取细胞上清液,2000rpm离心5min。之后将上清液转移至高速离心管内,配平,然后30000g,4℃离心4h,吸净上清,加入500μl无菌PBS缓冲液重悬病毒颗粒,混匀200μl/支分装并于-80℃冰箱保存。
5、T细胞分离
从中心血站或医院获得健康捐献者的血液样品。经过如下疾病的检测(不仅局限于这些检测)合格的患者。包括:甲肝,乙肝,丙肝,艾滋病,梅毒抗体,结核,遗传性疾病等。采用美天旎公司的Pan T Cell Isolation Kit human(Order no.130-096-535),按提供的protocol分离T细胞。
6、T细胞激活
T细胞完全培养基配制:OpTmizerTMCTSTMT-cell Expansion SFM+5%CTS ImmuneCell SR+1%L-glutamine+10ng/ml IL-7/15。
起始细胞数为3M+Human T-Activator CD3/CD28 Dynabeads 75ul。起始细胞浓度为1M/ml。37℃培养箱培养。激活48小时。
7、T细胞基因编辑
采用CRISPR/cas9系统,设计sgRNA,以电转方式敲除TCR。Cas9蛋白及sgRNA购买自ThermFisher公司。
电转体系:
电转条件:1600V,10ms,3pulses
其中,TCR sgRNA序列如下:
cagggttctggatatctgt(SEQ ID NO:67)
8、LV-CD3CAR慢病毒转导
T细胞基因编辑12小时以后,LV-CD3CAR慢病毒转导,病毒MOI:3-20,聚凝胺1.5μl(5-10μg/ml)。6-12小时后去除含有慢病毒的培养基,更换新鲜培养基,进行CAR-T细胞扩增。
9、CAR-T细胞扩增
更换新鲜培养基后,在IL-7/15持续存在下,以1M/ml为起始细胞密度,进行细胞传代,每2天检测细胞密度及活率,补充新鲜培养基及细胞因子。保持细胞密度在1M/ml。
10、CAR-T细胞TCR敲除效率检测
电转48小时后,采用流式细胞仪检测TCR敲除效果。结果如图2-4所示,TCR敲除率达到80-90%。LV-CD3CAR-291-T(敲除转染LV-CD3CAR-291的T细胞,CAR-T细胞)细胞残留少量CD3/αβ TCR/γδ,TCR阳性的细胞<1%。LV-CD3CAR-cel-T(敲除转染LV-CD3CAR-cel的T细胞,CAR-T细胞)细胞没有CD3/αβTCR/γδTCR阳性的细胞。LV-CD3CAR-OKT31-T(敲除转染LV-CD3CAR-OKT31的T细胞,CAR-T细胞)细胞残留少量CD3/αβ TCR/γδ,TCR阳性的细胞<1%。图中PanT代表未经处理的T细胞,PanT TCRKO代表TCR敲除的T细胞,LV-CD3CAR-291-T、LV-CD3CAR-cel-T、LV-CD3CAR-OKT31-T代表CAR-T细胞。
11、LV-CD3CAR慢病毒转导率检测
慢病毒转导之后2-7天,采用流式细胞仪检测转导率。结果如图5-7所示,慢病毒转导3天之后CAR表达率不低于50%,图中PanT代表未经处理的T细胞,PanT TCRKO代表TCR敲除的T细胞,LV-CD3CAR-291-T、LV-CD3CAR-cel-T、LV-CD3CAR-OKT31-T代表CAR-T细胞。
实施例2 CAR-T细胞体外杀伤功能检测
1、Jurkat-GFP细胞系与实施例1制备的CAR-T细胞共培养,E/T(Jurkat-GFP:CAR-T)比例分别为8∶1,4∶1,2∶1,1∶1,0.5∶1,0∶1。
2、分组如下:
Jurkat-GFP组:0.5M每孔,三个复孔;
PanT TCRKO(敲除TCR的T细胞)组:0.5M每孔,三个复孔;
PanT TCRKO(敲除TCR的T细胞)+Jurkat-GFP组:8∶1,4∶1,2∶1,1∶1,0.5∶1,0∶1;
LV-CD3CAR-T(CAR-T)+Jurkat-GFP组:8∶1,4∶1,2∶1,1∶1,0.5∶1,0∶1;
每个比例设三个复孔。
3、24小时后流式细胞仪检测Jurkat-GFP细胞的GFP荧光。
4、结果
结果如图8-12所示,CAR-T(LV-CD3CAR-291-T、LV-CD3CAR-cel-T、LV-CD3CAR-OKT31-T、LV-CD3CAR-sp34-T、LV-CD3CAR-UCHT1-T))细胞在E∶T=2∶1情况下,1天即可杀伤90%-100%的CD3/TCR阳性Jurkat-GFP细胞。
实施例3 CAR-T细胞体内杀伤功能检测
一、步骤
1、Jurkat-Fluc细胞系构建NPG鼠肿瘤模型
NPG小鼠5-8周龄,均为雌性,尾静脉注射1×106个Jurkat-Fluc细胞。一周后生物荧光检测,确认NPG鼠肿瘤模型构建成功。
2、、一周后将NPG小鼠分为肿瘤模型组(阴性对照组),LV-CD3CAR-cel-T组,LV-TCRCAR-T组,共三组,每组三只鼠。
3、经NPG小鼠尾静脉回输CAR阳性细胞1×107个。观察期限8周。
4、每周观察各组NPG鼠生物荧光强度,体重,状态,以及生存时间。
二、结果
体内有效性结果如图13所示,LV-CD3CAR-T组明显抑制肿瘤生长,生物荧光强度显著低于肿瘤组。LV-CD3CAR-T组小鼠生存时间显著延长。在观察期限内实验组小鼠仍存活。
体内有效性结果如图14所示:LV-CD3CAR-T组小鼠体内荧光强度显著低于肿瘤模型组,反映出LV-CD3CAR-T组的肿瘤负荷显著低于肿瘤模型组,证明LV-CD3CAR-T在小鼠体内可以有效杀伤肿瘤细胞。
体内有效性结果如图15所示:LV-CD3CAR-T组小鼠的生存时间明显优于肿瘤模型组,可以说明LV-CD3CAR-T组抑制肿瘤的生长,减缓病情的发展,可显著延长小鼠的生存期。
体外和体内实验证明本发明构建的靶向CD3的CAR-T可有效杀伤CD3阳性细胞,可以用于治疗T细胞来源的淋巴细胞白血病以及T细胞来源的淋巴瘤。
实施例4 CAR-T细胞抑制移植排异反应的功能检测
一、步骤
1、获取异体健康献血者的PBMC,提取Pan T细胞(未处理的T细胞),计数;
2、细胞计数确定LV-CD3CAR-cel-T的数量;
3、流式检测确定LV-CD3CAR-cel-T转导率;
4、将LV-CD3CAR-cel-T与Pan T细胞数量分别按0.5∶1,1∶1和2∶1的比例混合;
5、第0h、24h、48h流式检测CD3阳性细胞数量。
二、结果
结果如图16所示,本发明构建的CAR-T细胞可有效清除异体体内的CD3阳性细胞。因此本发明的CD3CAR-T可用于抑制移植排异反应的发生。图16中:UCAR-T代表LV-CD3CAR-T。
在此将本文引用的所有参考文献,包括出版物、专利申请和专利通过引用并入,其程度如同将各参考文献单独且明确指明通过引用并入,并且在本文整体示出一样。
术语“一个/一种(a)”和“一个/一种(an)”和“所述(the)”以及类似的指代物在描述本发明的上下文中(特别是在下述权利要求的上下文中)的使用被解释为既涵盖单数又涵盖复数,除非本文另外指明或者上下文明显矛盾。术语“包含(comprising)”、“具有(having)”、“包括(including)”以及“含有(containing)”被解释为开放式术语(即,意为“包括但不限于”)除非另外标注。本文数值范围的叙述仅意图作为单独指落入范围内的各独立数值的速记法,除非本文另外指明,并且各独立的数值并入说明书如同本文单独对其进行叙述一样。可以以任何合适的顺序实施本文所述的所有方法,除非本文另外指明或者在其它方面与上下文明显矛盾。本文提供的任何或所有实施例或者示例性语言(例如“如”)的使用仅意图更好地阐明本发明,并且不对本发明的范围构成限制,除非另外声明。说明书中的语言均不应被解释为指示任何未要求保护的元素对于本发明的实践是必要的。
本文描述了本发明的优选实施方案,包括发明人已知的实施本发明的最佳方式。经阅读前述描述,那些优选实施方案的改变对于本领域普通技术人员而言可以变得显而易见。发明人期望本领域技术人员视情况应用此类改变,并且发明人意图以与本文具体所述的不同的方式实践本发明。因此,如适用的法律所允许的,本发明包括在此所附的权利要求中所述的主题的所有修饰和等同物。此外,本发明涵盖以上所述元素的所有可能的改变的任何组合,除非本文另外指明或者在其它方面与上下文明显矛盾。
序列表
<110> 北京门罗生物科技有限公司
<120> 嵌合抗原受体和其中表达有嵌合抗原受体的T细胞
<141> 2022-04-15
<150> PCT/CN2019/111651
<151> 2019-10-17
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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 Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 14
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
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> 15
<211> 491
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Ile Ser Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Arg Ser Gly Tyr Thr His
65 70 75 80
Tyr Asn Gln Lys Leu Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Ser Ala Tyr Tyr Asp Tyr Asp Gly Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile
145 150 155 160
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
165 170 175
Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
180 185 190
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Asp Thr
195 200 205
Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
225 230 235 240
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr Phe Gly
245 250 255
Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Ser Ser Thr Thr Thr Pro
260 265 270
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
275 280 285
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
290 295 300
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
305 310 315 320
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
325 330 335
Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
340 345 350
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
355 360 365
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
370 375 380
Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
385 390 395 400
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
405 410 415
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
420 425 430
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
435 440 445
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
450 455 460
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
465 470 475 480
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
485 490
<210> 16
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Ile Ser Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Arg Ser Gly Tyr Thr His
65 70 75 80
Tyr Asn Gln Lys Leu Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Ser Ala Tyr Tyr Asp Tyr Asp Gly Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile
145 150 155 160
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
165 170 175
Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
180 185 190
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Asp Thr
195 200 205
Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
225 230 235 240
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr Phe Gly
245 250 255
Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Ser Ser
260 265
<210> 17
<211> 44
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly
35 40
<210> 18
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr
1 5 10 15
Asn Gln Lys Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
20 25 30
Asn Thr Ala Phe Leu Gln Met
35
<210> 19
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Tyr
1 5 10 15
Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Pro Val
20 25 30
Thr Val Ser Ser Asp Pro
35
<210> 20
<211> 35
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr
35
<210> 21
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser
1 5 10 15
Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
20 25 30
Thr Asp Tyr Thr Phe Thr Ile Ser Ser
35 40
<210> 22
<211> 29
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser
1 5 10 15
Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile
20 25
<210> 23
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser Asp Pro
115 120
<210> 24
<211> 105
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Gln Gly Thr Lys Leu Gln Ile
100 105
<210> 25
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Gln Gly Thr Lys Leu Gln Ile Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly
115 120 125
Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala
130 135 140
Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly
165 170 175
Tyr Thr Asn Tyr Asn Gln Lys Val Lys Asp Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ser Lys Asn Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro
195 200 205
Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp His Tyr
210 215 220
Cys Leu Asp Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Asp
225 230 235 240
Pro
<210> 26
<211> 485
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
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 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
20 25 30
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser
35 40 45
Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro
50 55 60
Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser
100 105 110
Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
130 135 140
Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg
145 150 155 160
Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His
165 170 175
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile
180 185 190
Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys Asp Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe Leu Gln Met
210 215 220
Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Tyr
225 230 235 240
Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Pro Val
245 250 255
Thr Val Ser Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
260 265 270
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
275 280 285
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
290 295 300
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
305 310 315 320
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
325 330 335
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
340 345 350
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
355 360 365
Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
370 375 380
Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
385 390 395 400
Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
405 410 415
Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
420 425 430
Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
435 440 445
Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
450 455 460
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
465 470 475 480
Ala Leu Pro Pro Arg
485
<210> 27
<211> 262
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
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 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
20 25 30
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser
35 40 45
Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro
50 55 60
Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser
100 105 110
Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
130 135 140
Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg
145 150 155 160
Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His
165 170 175
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile
180 185 190
Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys Asp Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe Leu Gln Met
210 215 220
Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Tyr
225 230 235 240
Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Pro Val
245 250 255
Thr Val Ser Ser Asp Pro
260
<210> 28
<211> 44
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly
35 40
<210> 29
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr
1 5 10 15
Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser
20 25 30
Ser Thr Ala Tyr Met Gln
35
<210> 30
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
1 5 10 15
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr
20 25 30
Leu Thr Val Ser Ser
35
<210> 31
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro
1 5 10 15
Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
20 25 30
Met Asn Trp Tyr
35
<210> 32
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser
1 5 10 15
Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly
20 25 30
Thr Ser Tyr Ser Leu Thr Ile Ser Gly
35 40
<210> 33
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser
1 5 10 15
Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn
20 25 30
<210> 34
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 35
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro
1 5 10 15
Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
20 25 30
Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile
35 40 45
Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly
50 55 60
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala
65 70 75 80
Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn
100 105
<210> 36
<211> 240
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
130 135 140
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser
145 150 155 160
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser
165 170 175
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
180 185 190
Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
195 200 205
Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
210 215 220
Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn
225 230 235 240
<210> 37
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
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 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Ser Gln Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met
165 170 175
Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln
180 185 190
Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu
195 200 205
Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser
210 215 220
Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr
245 250 255
Lys Leu Glu Ile Asn Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
260 265 270
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
275 280 285
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
290 295 300
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
305 310 315 320
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys
325 330 335
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
340 345 350
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
355 360 365
Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
370 375 380
Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
385 390 395 400
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
405 410 415
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
420 425 430
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
435 440 445
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
450 455 460
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
465 470 475 480
Leu Pro Pro Arg
<210> 38
<211> 261
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
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 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Ser Gln Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met
165 170 175
Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln
180 185 190
Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu
195 200 205
Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser
210 215 220
Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr
245 250 255
Lys Leu Glu Ile Asn
260
<210> 39
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly
35 40
<210> 40
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
1 5 10 15
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
20 25 30
Asp Asp Ser Gln Ser Ile Leu Tyr Leu Gln
35 40
<210> 41
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val Arg
1 5 10 15
His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly
20 25 30
Gln Gly Thr Leu Val Thr Val Ser Ala
35 40
<210> 42
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val
35
<210> 43
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Gln Glu Lys Pro Asp His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn
1 5 10 15
Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly
20 25 30
Asp
<210> 44
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala Ile
1 5 10 15
Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly
20 25 30
Thr Lys Leu Thr Val Leu
35
<210> 45
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 46
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala
65 70 75 80
Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 47
<211> 249
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala
65 70 75 80
Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
165 170 175
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu Gln
195 200 205
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val Arg
210 215 220
His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ala
245
<210> 48
<211> 493
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
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 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr
20 25 30
Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly
35 40 45
Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp
50 55 60
His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly
65 70 75 80
Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu
85 90 95
Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala
100 105 110
Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys
145 150 155 160
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
165 170 175
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
180 185 190
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
195 200 205
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser
210 215 220
Ile Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met
225 230 235 240
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
245 250 255
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Thr Thr
260 265 270
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
275 280 285
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
290 295 300
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
305 310 315 320
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
325 330 335
Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
340 345 350
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
355 360 365
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
370 375 380
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln
385 390 395 400
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
405 410 415
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
420 425 430
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
435 440 445
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
450 455 460
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
465 470 475 480
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
485 490
<210> 49
<211> 270
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
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 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr
20 25 30
Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly
35 40 45
Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp
50 55 60
His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly
65 70 75 80
Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu
85 90 95
Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala
100 105 110
Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys
145 150 155 160
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
165 170 175
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
180 185 190
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
195 200 205
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser
210 215 220
Ile Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met
225 230 235 240
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
245 250 255
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
260 265 270
<210> 50
<211> 44
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Glu Val Gln Leu Val 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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
35 40
<210> 51
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
Leu Glu Trp Val Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr
1 5 10 15
Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser Lys
20 25 30
Asn Thr Ala Tyr Leu Gln
35
<210> 52
<211> 40
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
1 5 10 15
Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln
20 25 30
Gly Thr Leu Val Thr Val Ser Ser
35 40
<210> 53
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr
20 25 30
Leu Asn Trp Tyr
35
<210> 54
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser
1 5 10 15
Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
20 25 30
Thr Asp Tyr Thr Leu Thr Ile Ser Ser
35 40
<210> 55
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr
1 5 10 15
Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
20 25 30
<210> 56
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 56
Glu Val Gln Leu Val 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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 57
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 58
<211> 244
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 58
Glu Val Gln Leu Val 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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
130 135 140
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu
180 185 190
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Val Glu Ile Lys
<210> 59
<211> 488
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
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 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr
35 40 45
Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser
85 90 95
Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp
115 120 125
Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
165 170 175
Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr
195 200 205
Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
210 215 220
Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
225 230 235 240
Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe
245 250 255
Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg
260 265 270
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
275 280 285
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
290 295 300
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
305 310 315 320
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg
325 330 335
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
340 345 350
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
355 360 365
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
370 375 380
Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
385 390 395 400
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
405 410 415
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg
485
<210> 60
<211> 265
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
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 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr
35 40 45
Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser
85 90 95
Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp
115 120 125
Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
165 170 175
Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr
195 200 205
Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
210 215 220
Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
225 230 235 240
Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe
245 250 255
Gly Gln Gly Thr Lys Val Glu Ile Lys
260 265
<210> 61
<211> 1473
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 61
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccgcaggtcc agcttgtcca gtctggggct gaagtcaaga aacctggcgc cagcgtgaag 120
gtctcctgca aggcttctgg ctacaccttt attagttaca cgatgcattg ggtaaggcag 180
gcccctggac agggtctgga atggatggga tatattaatc cgagaagtgg gtatactcat 240
tacaatcaga agttaaagga caaggcaaca cttaccgcgg acaaatccgc gagcacagcc 300
tacatggaac tgagcagcct gagatctgag gacaccgcag tctattactg tgcaagatcg 360
gcctactatg attatgacgg ctttgcttac tggggccaag gaaccctggt caccgtctca 420
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagatatt 480
cagatgaccc agtctccatc ttccctctct gctagcgtcg gggatagggt caccataacc 540
tgctctgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc aggcaaagct 600
cccaagagac taatttatga cacatccaaa ctggcttctg gagtcccttc taggttcagt 660
ggcagtggat ctgggaccga tttcaccctc acaatcagct ctctgcagcc agaagatttc 720
gccacttatt actgccagca atggagtagt aacccaccca cgttcggtgg agggaccaag 780
gtggagatca aacgaacctc gagtaccacg acgccagcgc cgcgaccacc aacaccggcg 840
cccaccatcg cgtcgcagcc cctgtccctg cgcccagagg cgtgccggcc agcggcgggg 900
ggcgcagtgc acacgagggg gctggacttc gcctgtgata tctacatctg ggcgcccttg 960
gccgggactt gtggggtcct tctcctgtca ctggttatca ccctttactg caaacggggc 1020
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 1080
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgaga 1140
gtgaagttca gcaggagcgc agacgccccc gcgtacaagc agggccagaa ccagctctat 1200
aacgagctca atctaggacg aagagaggag tacgatgttt tggacaagag acgtggccgg 1260
gaccctgaga tggggggaaa gccgagaagg aagaaccctc aggaaggcct gtacaatgaa 1320
ctgcagaaag ataagatggc ggaggcctac agtgagattg ggatgaaagg cgagcgccgg 1380
aggggcaagg ggcacgatgg cctttaccag ggtctcagta cagccaccaa ggacacctac 1440
gacgcccttc acatgcaggc cctgccccct cgc 1473
<210> 62
<211> 1455
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 62
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggatattc agatgaccca gtccccctcc tccctgtccg cttccgtcgg cgatagagtc 120
accattacct gttcagccag tagttccgtg tcttacatga actggtatca gcagacccca 180
ggcaaggcac ctaagcggtg gatctacgac acatccaagc tggcctctgg agtgcccagc 240
cggttctccg gctctggcag cggcaccgac tataccttta caatcagctc cctgcagcct 300
gaggacatcg ccacatacta ttgccagcag tggtctagca atccattcac ctttggccag 360
ggaacaaagc tgcagatcgg aggaggaggc agcggcggag gaggctccgg cggcggcggc 420
tctcaggtgc agctggtgca gtccggagga ggagtggtgc agcccggcag aagcctgcgg 480
ctgagctgta aggccagcgg ctacaccttc acacggtata ccatgcactg ggtgagacag 540
gcaccaggca agggcctgga gtggatcggc tacatcaacc ccagcagagg ctacacaaac 600
tataatcaga aggtgaagga caggttcacc atctcccgcg ataactctaa gaatacagcc 660
tttctgcaga tggactccct gaggcctgag gataccggcg tgtatttttg cgcccgctat 720
tatgatgacc attactgtct ggactattgg gggcagggaa cacccgtgac tgtgagctcg 780
gatcccacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 840
cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 900
gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 960
cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 1020
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1080
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1140
gcagacgccc ccgcgtacaa gcagggccag aaccagctct ataacgagct caatctagga 1200
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1260
aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1320
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1380
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1440
gccctgcccc ctcgc 1455
<210> 63
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 63
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccgcaggtcc agctgcagca gtctggggct gaactggcaa gacctggggc ctcagtgaag 120
atgtcctgca aggcttctgg ctacaccttt actaggtaca cgatgcactg ggtaaaacag 180
aggcctggac agggtctgga atggattgga tacattaatc ctagccgtgg ttatactaat 240
tacaatcaga agttcaagga caaggccaca ttgactacag acaaatcctc cagcacagcc 300
tacatgcaac tgagcagcct gacatctgag gactctgcag tctattactg tgcaagatat 360
tatgatgatc attactgcct tgactactgg ggccaaggca ccactctcac agtctcctca 420
gggggaggtg gcagcggggg aggtggcagc ggcggcggga gctcccaaat tgttctcacc 480
cagtctccag caatcatgtc tgcatctcca ggggagaagg tcaccatgac ctgcagtgcc 540
agctcaagtg taagttacat gaactggtac cagcagaagt caggcacctc ccccaaaaga 600
tggatttatg acacatccaa actggcttct ggagtccctg ctcacttcag gggcagtggg 660
tctgggacct cttactctct cacaatcagc ggcatggagg ctgaagatgc tgccacttat 720
tactgccagc agtggagtag taacccattc acgttcggct cggggacaaa gttggaaata 780
aacaccacga cgccagcgcc gcgaccacca acaccggcgc ccaccatcgc gtcgcagccc 840
ctgtccctgc gcccagaggc gtgccggcca gcggcggggg gcgcagtgca cacgaggggg 900
ctggacttcg cctgtgatat ctacatctgg gcgcccttgg ccgggacttg tggggtcctt 960
ctcctgtcac tggttatcac cctttactgc aaacggggca gaaagaaact cctgtatata 1020
ttcaaacaac catttatgag accagtacaa actactcaag aggaagatgg ctgtagctgc 1080
cgatttccag aagaagaaga aggaggatgt gaactgagag tgaagttcag caggagcgca 1140
gacgcccccg cgtacaagca gggccagaac cagctctata acgagctcaa tctaggacga 1200
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 1260
ccgagaagga agaaccctca ggaaggcctg tacaatgaac tgcagaaaga taagatggcg 1320
gaggcctaca gtgagattgg gatgaaaggc gagcgccgga ggggcaaggg gcacgatggc 1380
ctttaccagg gtctcagtac agccaccaag gacacctacg acgcccttca catgcaggcc 1440
ctgccccctc gc 1452
<210> 64
<211> 1479
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 64
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccgcaggctg tcgtgacaca ggaaagcgcc ctgaccacca gccctggcga gacagtgacc 120
ctgacctgca gatctagcac aggcgccgtg accacaagca actacgccaa ctgggtgcag 180
gaaaagcccg accacctgtt caccggcctg atcggcggca ccaacaaaag ggctccaggc 240
gtgccagcca gattcagcgg cagcctgatt ggcgataagg ccgccctgac aatcactggc 300
gcccagaccg aggacgaggc catctacttt tgcgccctgt ggtacagcaa cctgtgggtg 360
ttcggcggag gcaccaagct gacagtgctg ggaggcggag gatctggcgg aggcggaagt 420
ggcggagggg gatctgaagt gcagctggtg gaatctggcg gcggactggt gcagcctaag 480
ggctctctga agctgagctg tgccgccagc ggcttcacct tcaacaccta cgccatgaat 540
tgggtgcgcc aggcccctgg caagggactg gaatgggtgg cccggatcag aagcaagtac 600
aacaattacg ccacctacta cgccgacagc gtgaaggacc ggttcaccat cagccgggac 660
gacagccaga gcatcctgta tctgcagatg aacaacctga aaaccgagga caccgccatg 720
tactactgcg tgcggcacgg caacttcggc aacagctatg tgtcttggtt tgcctactgg 780
ggccagggca ccctcgtgac agtgtctgct accacgacgc cagcgccgcg accaccaaca 840
ccggcgccca ccatcgcgtc gcagcccctg tccctgcgcc cagaggcgtg ccggccagcg 900
gcggggggcg cagtgcacac gagggggctg gacttcgcct gtgatatcta catctgggcg 960
cccttggccg ggacttgtgg ggtccttctc ctgtcactgg ttatcaccct ttactgcaaa 1020
cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 1080
actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 1140
ctgagagtga agttcagcag gagcgcagac gcccccgcgt acaagcaggg ccagaaccag 1200
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 1260
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 1320
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 1380
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 1440
acctacgacg cccttcacat gcaggccctg ccccctcgc 1479
<210> 65
<211> 1464
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 65
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggatatcc agatgaccca gtccccgagc tccctgtccg cctctgtggg cgatagggtc 120
accatcacct gtcgtgccag tcaggacatc cgtaattatc tcaactggta tcaacagaaa 180
ccaggaaaag ctccgaaact actgatttac tatacctccc gcctggagtc tggagtccct 240
tctcgcttct ctggttctgg ttctgggacg gattacactc tgaccatcag cagtctgcaa 300
ccggaggact tcgcaactta ttactgtcag caaggtaata ctctgccgtg gacgttcgga 360
cagggcacca aggtggagat caaaggtgga ggcggttcag gcggaggtgg ctctggcggt 420
ggcggatcgg aggttcagct ggtggagtct ggcggtggcc tggtgcagcc agggggctca 480
ctccgtttgt cctgtgcagc ttctggctac tcctttaccg gctacactat gaactgggtg 540
cgtcaggccc caggtaaggg cctggaatgg gttgcactga ttaatcctta taaaggtgtt 600
tccacctata accagaaatt caaggatcgt ttcacgatat ccgtagataa atccaaaaac 660
acagcctacc tgcaaatgaa cagcctgcgt gctgaggaca ctgccgtcta ttattgtgct 720
agaagcggat actacggcga tagcgactgg tattttgacg tctggggtca aggaaccctg 780
gtcaccgtct cctcgaccac gacgccagcg ccgcgaccac caacaccggc gcccaccatc 840
gcgtcgcagc ccctgtccct gcgcccagag gcgtgccggc cagcggcggg gggcgcagtg 900
cacacgaggg ggctggactt cgcctgtgat atctacatct gggcgccctt ggccgggact 960
tgtggggtcc ttctcctgtc actggttatc accctttact gcaaacgggg cagaaagaaa 1020
ctcctgtata tattcaaaca accatttatg agaccagtac aaactactca agaggaagat 1080
ggctgtagct gccgatttcc agaagaagaa gaaggaggat gtgaactgag agtgaagttc 1140
agcaggagcg cagacgcccc cgcgtacaag cagggccaga accagctcta taacgagctc 1200
aatctaggac gaagagagga gtacgatgtt ttggacaaga gacgtggccg ggaccctgag 1260
atggggggaa agccgagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa 1320
gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag 1380
gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta cgacgccctt 1440
cacatgcagg ccctgccccc tcgc 1464
<210> 66
<211> 8102
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 66
tggaagggct aattcactcc caaagaagac aagatatcct tgatctgtgg atctaccaca 60
cacaaggcta cttccctgat tagcagaact acacaccagg gccaggggtc agatatccac 120
tgacctttgg atggtgctac aagctagtac cagttgagcc agataaggta gaagaggcca 180
ataaaggaga gaacaccagc ttgttacacc ctgtgagcct gcatgggatg gatgacccgg 240
agagagaagt gttagagtgg aggtttgaca gccgcctagc atttcatcac gtggcccgag 300
agctgcatcc ggagtacttc aagaactgct gatatcgagc ttgctacaag ggactttccg 360
ctggggactt tccagggagg cgtggcctgg gcgggactgg ggagtggcga gccctcagat 420
cctgcatata agcagctgct ttttgcctgt actgggtctc tctggttaga ccagatctga 480
gcctgggagc tctctggcta actagggaac ccactgctta agcctcaata aagcttgcct 540
tgagtgcttc aagtagtgtg tgcccgtctg ttgtgtgact ctggtaacta gagatccctc 600
agaccctttt agtcagtgtg gaaaatctct agcagtggcg cccgaacagg gacttgaaag 660
cgaaagggaa accagaggag ctctctcgac gcaggactcg gcttgctgaa gcgcgcacgg 720
caagaggcga ggggcggcga ctggtgagta cgccaaaaat tttgactagc ggaggctaga 780
aggagagaga tgggtgcgag agcgtcagta ttaagcgggg gagaattaga tcgcgatggg 840
aaaaaattcg gttaaggcca gggggaaaga aaaaatataa attaaaacat atagtatggg 900
caagcaggga gctagaacga ttcgcagtta atcctggcct gttagaaaca tcagaaggct 960
gtagacaaat actgggacag ctacaaccat cccttcagac aggatcagaa gaacttagat 1020
cattatataa tacagtagca accctctatt gtgtgcatca aaggatagag ataaaagaca 1080
ccaaggaagc tttagacaag atagaggaag agcaaaacaa aagtaagacc accgcacagc 1140
aagcggccgg ccgctgatct tcagacctgg aggaggagat atgagggaca attggagaag 1200
tgaattatat aaatataaag tagtaaaaat tgaaccatta ggagtagcac ccaccaaggc 1260
aaagagaaga gtggtgcaga gagaaaaaag agcagtggga ataggagctt tgttccttgg 1320
gttcttggga gcagcaggaa gcactatggg cgcagcgtca atgacgctga cggtacaggc 1380
cagacaatta ttgtctggta tagtgcagca gcagaacaat ttgctgaggg ctattgaggc 1440
gcaacagcat ctgttgcaac tcacagtctg gggcatcaag cagctccagg caagaatcct 1500
ggctgtggaa agatacctaa aggatcaaca gctcctgggg atttggggtt gctctggaaa 1560
actcatttgc accactgctg tgccttggaa tgctagttgg agtaataaat ctctggaaca 1620
gatttggaat cacacgacct ggatggagtg ggacagagaa attaacaatt acacaagctt 1680
aatacactcc ttaattgaag aatcgcaaaa ccagcaagaa aagaatgaac aagaattatt 1740
ggaattagat aaatgggcaa gtttgtggaa ttggtttaac ataacaaatt ggctgtggta 1800
tataaaatta ttcataatga tagtaggagg cttggtaggt ttaagaatag tttttgctgt 1860
actttctata gtgaatagag ttaggcaggg atattcacca ttatcgtttc agacccacct 1920
cccaaccccg aggggacccg acaggcccga aggaatagaa gaagaaggtg gagagagaga 1980
cagagacaga tccattcgat tagtgaacgg atctcgacgg tatcgccttt aaaagaaaag 2040
gggggattgg ggggtacagt gcaggggaaa gaatagtaga cataatagca acagacatac 2100
aaactaaaga attacaaaaa caaattacaa aaattcaaaa ttttcgggtt tattacaggg 2160
acagcagaga tccagtttat cgataagctt gggagttccg cgttacataa cttacggtaa 2220
atggcccgcc tggctgaccg cccaacgacc cccgcccatt gacgtcaata atgacgtatg 2280
ttcccatagt aacgccaata gggactttcc attgacgtca atgggtggag tatttacggt 2340
aaactgccca cttggcagta catcaagtgt atcatatgcc aagtacgccc cctattgacg 2400
tcaatgacgg taaatggccc gcctggcatt atgcccagta catgacctta tgggactttc 2460
ctacttggca gtacatctac gtattagtca tcgctattac catggtgatg cggttttggc 2520
agtacatcaa tgggcgtgga tagcggtttg actcacgggg atttccaagt ctccacccca 2580
ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg ggactttcca aaatgtcgta 2640
acaactccgc cccattgacg caaatgggcg gtaggcgtgt acggtgggag gtctatataa 2700
gcagagctcg tttagtgaac cgtcagatcg cctggagacg ccatccacgc tgttttgacc 2760
tccatagaag acaccgactc tactagagga tcgctagcgc taccggactc agatctcgag 2820
ctcaagcttc gaattctgca gtcgacggta ccgcgggccc gggatcccgc gactctagat 2880
aattctaccg ggtaggggag gcgcttttcc caaggcagtc tggagcatgc gctttagcag 2940
ccccgctggg cacttggcgc tacacaagtg gcctctggcc tcgcacacat tccacatcca 3000
ccggtaggcg ccaaccggct ccgttctttg gtggcccctt cgcgccacct tctactcctc 3060
ccctagtcag gaagttcccc cccgccccgc agctcgcgtc gtgcaggacg tgacaaatgg 3120
aagtagcacg tctcactagt ctcgtgcaga tggacagcac cgctgagcaa tggaagcggg 3180
taggcctttg gggcagcggc caatagcagc tttgctcctt cgctttctgg gctcagaggc 3240
tgggaagggg tgggtccggg ggcgggctca ggggcgggct caggggcggg gcgggcgccc 3300
gaaggtcctc cggaggcccg gcattctgca cgcttcaaaa gcgcacgtct gccgcgctgt 3360
tctcctcttc ctcatctccg ggcctttcga cctgcagccc aagcttacca tgaccgagta 3420
caagcccacg gtgcgcctcg ccacccgcga cgacgtcccc agggccgtac gcaccctcgc 3480
cgccgcgttc gccgactacc ccgccacgcg ccacaccgtc gatccggacc gccacatcga 3540
gcgggtcacc gagctgcaag aactcttcct cacgcgcgtc gggctcgaca tcggcaaggt 3600
gtgggtcgcg gacgacggcg ccgcggtggc ggtctggacc acgccggaga gcgtcgaagc 3660
gggggcggtg ttcgccgaga tcggcccgcg catggccgag ttgagcggtt cccggctggc 3720
cgcgcagcaa cagatggaag gcctcctggc gccgcaccgg cccaaggagc ccgcgtggtt 3780
cctggccacc gtcggcgtct cgcccgacca ccagggcaag ggtctgggca gcgccgtcgt 3840
gctccccgga gtggaggcgg ccgagcgcgc cggggtgccc gccttcctgg agacctccgc 3900
gccccgcaac ctccccttct acgagcggct cggcttcacc gtcaccgccg acgtcgaggt 3960
gcccgaagga ccgcgcacct ggtgcatgac ccgcaagccc ggtgcctgac cgcgtctgga 4020
acaatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt aactatgttg 4080
ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct attgcttccc 4140
gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt tatgaggagt 4200
tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac gcaaccccca 4260
ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct ttccccctcc 4320
ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca ggggctcggc 4380
tgttgggcac tgacaattcc gtggtgttgt cggggaagct gacgtccttt ccatggctgc 4440
tcgcctgtgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc ccttcggccc 4500
tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct cttccgcgtc 4560
ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg cctggaatta 4620
attctgcagt cgagacctag aaaaacatgg agcaatcaca agtagcaata cagcagctac 4680
caatgctgat tgtgcctggc tagaagcaca agaggaggag gaggtgggtt ttccagtcac 4740
acctcaggta cctttaagac caatgactta caaggcagct gtagatctta gccacttttt 4800
aaaagaaaag aggggactgg aagggctaat tcactcccaa cgaagacaag atatccttga 4860
tctgtggatc taccacacac aaggctactt ccctgattag cagaactaca caccagggcc 4920
aggggtcaga tatccactga cctttggatg gtgctacaag ctagtaccag ttgagccaga 4980
taaggtagaa gaggccaata aaggagagaa caccagcttg ttacaccctg tgagcctgca 5040
tgggatggat gacccggaga gagaagtgtt agagtggagg tttgacagcc gcctagcatt 5100
tcatcacgtg gcccgagagc tgcatccgga gtacttcaag aactgctgat atcgagcttg 5160
ctacaaggga ctttccgctg gggactttcc agggaggcgt ggcctgggcg ggactgggga 5220
gtggcgagcc ctcagatcct gcatataagc agctgctttt tgcctgtact gggtctctct 5280
ggttagacca gatctgagcc tgggagctct ctggctaact agggaaccca ctgcttaagc 5340
ctcaataaag cttgccttga gtgcttcaag tagtgtgtgc ccgtctgttg tgtgactctg 5400
gtaactagag atccctcaga cccttttagt cagtgtggaa aatctctagc agtagtagtt 5460
catgtcatct tattattcag tatttataac ttgcaaagaa atgaatatca gagagtgaga 5520
ggccttgaca ttgctagcgt tttaccgtcg acctctagct agagcttggc gtaatcatgg 5580
tcatagctgt ttcctgtgtg aaattgttat ccgctcacaa ttccacacaa catacgagcc 5640
ggaagcataa agtgtaaagc ctggggtgcc taatgagtga gctaactcac attaattgcg 5700
ttgcgctcac tgcccgcttt ccagtcggga aacctgtcgt gccagctgca ttaatgaatc 5760
ggccaacgcg cggggagagg cggtttgcgt attgggcgct cttccgcttc ctcgctcact 5820
gactcgctgc gctcggtcgt tcggctgcgg cgagcggtat cagctcactc aaaggcggta 5880
atacggttat ccacagaatc aggggataac gcaggaaaga acatgtgagc aaaaggccag 5940
caaaaggcca ggaaccgtaa aaaggccgcg ttgctggcgt ttttccatag gctccgcccc 6000
cctgacgagc atcacaaaaa tcgacgctca agtcagaggt ggcgaaaccc gacaggacta 6060
taaagatacc aggcgtttcc ccctggaagc tccctcgtgc gctctcctgt tccgaccctg 6120
ccgcttaccg gatacctgtc cgcctttctc ccttcgggaa gcgtggcgct ttctcatagc 6180
tcacgctgta ggtatctcag ttcggtgtag gtcgttcgct ccaagctggg ctgtgtgcac 6240
gaaccccccg ttcagcccga ccgctgcgcc ttatccggta actatcgtct tgagtccaac 6300
ccggtaagac acgacttatc gccactggca gcagccactg gtaacaggat tagcagagcg 6360
aggtatgtag gcggtgctac agagttcttg aagtggtggc ctaactacgg ctacactaga 6420
agaacagtat ttggtatctg cgctctgctg aagccagtta ccttcggaaa aagagttggt 6480
agctcttgat ccggcaaaca aaccaccgct ggtagcggtg gtttttttgt ttgcaagcag 6540
cagattacgc gcagaaaaaa aggatctcaa gaagatcctt tgatcttttc tacggggtct 6600
gacgctcagt ggaacgaaaa ctcacgttaa gggattttgg tcatgagatt atcaaaaagg 6660
atcttcacct agatcctttt aaattaaaaa tgaagtttta aatcaatcta aagtatatat 6720
gagtaaactt ggtctgacag ttaccaatgc ttaatcagtg aggcacctat ctcagcgatc 6780
tgtctatttc gttcatccat agttgcctga ctccccgtcg tgtagataac tacgatacgg 6840
gagggcttac catctggccc cagtgctgca atgataccgc gagacccacg ctcaccggct 6900
ccagatttat cagcaataaa ccagccagcc ggaagggccg agcgcagaag tggtcctgca 6960
actttatccg cctccatcca gtctattaat tgttgccggg aagctagagt aagtagttcg 7020
ccagttaata gtttgcgcaa cgttgttgcc attgctacag gcatcgtggt gtcacgctcg 7080
tcgtttggta tggcttcatt cagctccggt tcccaacgat caaggcgagt tacatgatcc 7140
cccatgttgt gcaaaaaagc ggttagctcc ttcggtcctc cgatcgttgt cagaagtaag 7200
ttggccgcag tgttatcact catggttatg gcagcactgc ataattctct tactgtcatg 7260
ccatccgtaa gatgcttttc tgtgactggt gagtactcaa ccaagtcatt ctgagaatag 7320
tgtatgcggc gaccgagttg ctcttgcccg gcgtcaatac gggataatac cgcgccacat 7380
agcagaactt taaaagtgct catcattgga aaacgttctt cggggcgaaa actctcaagg 7440
atcttaccgc tgttgagatc cagttcgatg taacccactc gtgcacccaa ctgatcttca 7500
gcatctttta ctttcaccag cgtttctggg tgagcaaaaa caggaaggca aaatgccgca 7560
aaaaagggaa taagggcgac acggaaatgt tgaatactca tactcttcct ttttcaatat 7620
tattgaagca tttatcaggg ttattgtctc atgagcggat acatatttga atgtatttag 7680
aaaaataaac aaataggggt tccgcgcaca tttccccgaa aagtgccacc tgacgtcgac 7740
ggatcgggag atcaacttgt ttattgcagc ttataatggt tacaaataaa gcaatagcat 7800
cacaaatttc acaaataaag catttttttc actgcattct agttgtggtt tgtccaaact 7860
catcaatgta tcttatcatg tctggatcaa ctggataact caagctaacc aaaatcatcc 7920
caaacttccc accccatacc ctattaccac tgccaattac ctgtggtttc atttactcta 7980
aacctgtgat tcctctgaat tattttcatt ttaaagaaat tgtatttgtt aaatatgtac 8040
tacaaactta gtagttttta aagaaattgt atttgttaaa tatgtactac aaacttagta 8100
gt 8102
<210> 67
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 67
cagggttctg gatatctgt 19
Claims (19)
1.一种靶向CD3的嵌合抗原受体,其特征在于,所述嵌合抗原受体从N端到C端包括:
CD3结合结构域;
铰链区和跨膜结构域;
共刺激结构域;
信号传导结构域;
所述CD3结合结构域的氨基酸序列如SEQ ID NO:10所示;
所述铰链区和跨膜结构域的氨基酸序列如SEQ ID NO:12所示;
所述信号传导结构域的氨基酸序列如SEQ ID NO:13所示;
所述共刺激结构域的氨基酸序列如SEQ ID NO:14所示。
2.根据权利要求1所述的嵌合抗原受体,其特征在于,所述CD3结合结构域还包括信号肽序列,所述信号肽序列位于所述CD3结合结构域的氨基末端。
3.根据权利要求2所述的嵌合抗原受体,其特征在于,所述信号肽序列的氨基酸序列如SEQ ID NO:11所示。
4.根据权利要求3所述的嵌合抗原受体,其特征在于,所述CD3结合结构域的氨基酸序列如SEQ ID NO:16所示。
5.根据权利要求1-4中任一项所述的嵌合抗原受体,其特征在于,所述嵌合抗原受体的氨基酸序列如SEQ ID NO:15所示。
6.编码权利要求1-4中任一项所述的嵌合抗原受体的核酸分子。
7.包含权利要求6所述的核酸分子的重组表达载体。
8.一种宿主细胞,其特征在于,所述宿主细胞包含权利要求1-4中任一项所述的嵌合抗原受体、权利要求6所述的核酸分子、或权利要求7所述的重组表达载体。
9.一种制备权利要求8所述的宿主细胞的方法,其特征在于,所述方法包括将权利要求6所述的核酸分子或权利要求7所述的重组表达载体导入细胞,并在适合细胞表达所述核酸分子或载体的条件下培养细胞。
10.一种细胞群,其特征在于,所述细胞群包括权利要求8所述的宿主细胞。
11.一种药物组合物,其特征在于,所述药物组合物包括权利要求1-4中任一项所述的嵌合抗原受体、权利要求6所述的核酸分子、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞、或权利要求10所述的细胞群。
12.一种试剂盒,其特征在于,所述试剂盒包括权利要求1-4中任一项所述的嵌合抗原受体、权利要求6所述的核酸分子、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞、权利要求10所述的细胞群、权利要求11所述的药物组合物。
13.权利要求6所述的核酸分子、或权利要求7所述的重组表达载体在制备权利要求8所述的宿主细胞或权利要求10所述的细胞群中的应用。
14.权利要求6所述的核酸分子、或权利要求7所述的重组表达载体在制备CAR或CAR-T中的应用。
15.权利要求6所述的核酸分子、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞,或权利要求10所述的细胞群在制备权利要求11所述的药物组合物中的应用。
16.权利要求6所述的核酸分子、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞、权利要求10所述的细胞群,或权利要求11所述的药物组合物在制备权利要求12所述的试剂盒中的应用。
17.权利要求6所述的核酸分子、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞、权利要求10所述的细胞群,或权利要求11所述的药物组合物在制备用于白血病免疫治疗的药物中的应用。
18.权利要求6所述的核酸分子、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞、权利要求10所述的细胞群,或权利要求11所述的药物组合物在制备抗移植排异反应的药物中的应用。
19.权利要求6所述的核酸分子、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞、权利要求10所述的细胞群,或权利要求11所述的药物组合物在制备抗白血病药物中的应用。
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CN102958942A (zh) * | 2009-12-29 | 2013-03-06 | 新兴产品开发西雅图有限公司 | 异二聚体结合蛋白及其应用 |
CN107249602A (zh) * | 2015-02-27 | 2017-10-13 | 美商生物细胞基因治疗有限公司 | 靶向血液恶性肿瘤之嵌合抗原受体(car)、其组合物及使用方法 |
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CN109777782A (zh) * | 2019-02-15 | 2019-05-21 | 北京门罗生物科技有限公司 | 一种通用型car-t细胞及其制备方法和用途 |
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CN107249602A (zh) * | 2015-02-27 | 2017-10-13 | 美商生物细胞基因治疗有限公司 | 靶向血液恶性肿瘤之嵌合抗原受体(car)、其组合物及使用方法 |
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