CN111849910B - 工程化免疫细胞及其用途 - Google Patents
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Abstract
本发明涉及一种工程化免疫细胞,其表达(i)特异性识别配体的细胞表面分子,(ii)外源性的白细胞介素,和(iii)外源性的Flt3L、XCL2和/或XCL1。本发明还提供了该工程化免疫细胞在治疗癌症、感染或自身免疫性疾病中的用途。与传统的工程化免疫细胞细胞相比,本发明的工程化免疫细胞具有显著提高的肿瘤杀伤活性。
Description
技术领域
本发明属于免疫治疗领域。更具体地,本发明涉及一种工程化免疫细胞,其表达(i)特异性识别配体的细胞表面分子,(ii)外源性的白细胞介素,和(iii)外源性的Flt3L、XCL2和/或XCL1基因。更优选地,所述特异性识别配体的细胞表面分子是嵌合抗原受体。
背景技术
肿瘤免疫治疗主要是通过调节人体免疫系统和肿瘤微环境,最终依靠自身免疫来清除肿瘤细胞。免疫系统是一个统一的整体,固有免疫在肿瘤免疫中也起到十分重要的作用。
一些抗原递呈细胞,如树突状细胞及巨噬细胞是固有免疫和获得性免疫的连接桥梁。抗原递呈细胞可以对肿瘤抗原进行识别并递呈给获得性免疫系统,激活肿瘤特异性T细胞,进而对肿瘤进行清除。因而通过增强抗原递呈过程来增加免疫系统杀伤肿瘤的效果是肿瘤免疫的重要研究方向。
CAR细胞治疗是重要的肿瘤细胞免疫疗法。CAR细胞成功控制肿瘤一般而言需要经过以下几个过程:免疫系统激活、CAR细胞的活化和扩增、活化的CAR细胞浸润肿瘤组织并杀死肿瘤细胞。然而,目前CAR细胞疗法普遍存在一个问题,即肿瘤微环境对CAR细胞有抑制作用,使得CAR细胞无法浸润肿瘤组织。因此,如何降低肿瘤微环境对CAR细胞的抑制作用,提高CAR细胞的存活时间,或者招募其他免疫细胞与CAR细胞协同作用,对于提高CAR细胞的治疗效果非常重要。
已经报道,白细胞介素IL-7和趋化因子CCL-19通过招募内源性的树突状细胞进入肿瘤组织,激活肿瘤反应性的内源性T细胞并使其分化为记忆T细胞,从而促进常规TCR-T细胞(参见CN109153989A)或CAR-T细胞的抗肿瘤活性(Adachi, K., Kano, Y., Nagai, T.et al. IL-7 and CCL19 expression in CAR-T cells improves immune cellinfiltration and CAR-T cell survival in the tumor. Nat Biotechnol 36, 346–351(2018))。
传统1型树突状细胞(conventional DC1,cDC1)是树突状细胞的一类亚群,为提呈肿瘤抗原的主要免疫细胞。研究结果显示cDC1可以有效递呈肿瘤相关抗原,尤其是坏死细胞相关抗原,有效诱导抗原特异性CD8+T细胞应答,在体内肿瘤杀伤过程中发挥极其重要的作用。在小鼠及人的研究中均显示,cDC1在肿瘤微环境中的分布与抗肿瘤免疫应答呈正相关,是一个重要的肿瘤相关免疫评分的评价参数。cDC1在小鼠及人体内分布较少,在肿瘤免疫应答率低的小鼠及人肿瘤微环境中几乎不可见。优化cDC1在肿瘤治疗中的作用是提高肿瘤免疫治疗效果的一个重要研究方向。
CCL-19具有招募树突状细胞和内源T细胞进入肿瘤的能力,但其对cDC1树突状细胞招募能力有限,因此,需要一种新的免疫治疗手段,可以有效分化或招募cDC1树突状细胞,以提高肿瘤抗原提呈效率,诱导机体过继性免疫反应,解决肿瘤的异质性问题,从而提高CAR细胞治疗的疗效。
发明内容
在第一个方面,本发明提供一种新的工程化免疫细胞,其表达(i)特异性识别配体的细胞表面分子,(ii)外源性的白细胞介素,和(iii)外源性的Flt3L、XCL2和/或XCL1基因。
在一个实施方案重,所述特异性识别配体的细胞表面分子是嵌合抗原受体或T细胞受体,优选是嵌合抗原受体。
在一个实施方案中,所述白细胞介素是IL-2、IL-7、IL-12、IL-15、IL-21、IL-17、IL-18、IL-23、或其亚基、或其组合、或其亚基的组合,优选是IL-7。
在一个实施方案中,所述白细胞介素、Flt3L、XCL2或XCL1蛋白是可以抵抗蛋白酶水解的融合蛋白或者突变体。
在一个实施方案中,所述免疫细胞是选自T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞或NKT细胞。优选地,所述T细胞是CD4+/CD8+ T细胞、CD4+辅助T细胞、CD8+T细胞、肿瘤浸润细胞、记忆T细胞、幼稚T细胞、γδ-T细胞或αβ-T细胞。
在一个实施方案中,所述特异性识别配体的细胞表面分子是嵌合抗原受体,其包含配体结合结构域、跨膜结构域、共刺激结构域和胞内信号传导结构域。其中,配体结合结构域可以选自scFv、Fab、单结构域抗体、纳米抗体、抗原结合配体、重组纤连蛋白结构域、anticalin和DARPIN。优选地,所述配体结合结构域选自scFv、Fab、单结构域抗体和纳米抗体。
在一个实施方案中,所述特异性识别配体的细胞表面分子与选自以下的靶标结合:TSHR、CD19、CD123、CD22、BAFF-R、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII 、GD2、GD3、BCMA、GPRC5D、Tn Ag、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、间皮素、IL-l lRa、PSCA、PRSS21、 VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、AFP、Folate 受体α、ERBB2 (Her2/neu)、MUC1、EGFR、CS1、CD138、NCAM、Claudin18.2、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gploo、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD 179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、豆荚蛋白、HPV E6、E7、MAGE Al、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG (TMPRSS2 ETS融合基因)、NA17、PAX3、雄激素受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D和它们的任意组合。优选地,所述靶标选自CD19、CD20、CD22、CD30、CD33、CD38、CD123、CD138、CD171、MUC1、AFP、Folate 受体α、CEA、PSCA、PSMA、Her2、EGFR、IL13Ra2、GD2、NKG2D、EGFRvIII、CS1、BCMA、间皮素和它们的任意组合。
在一个实施方案中,所述跨膜结构域选自以下蛋白质的跨膜结构域:TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137和CD154。优选地,跨膜结构域选自CD8α、CD4、CD28和CD278的跨膜结构域。
在一个实施方案中,所述胞内信号传导结构域选自以下蛋白的信号传导结构域:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d。优选地,所述胞内信号传导结构域是包含CD3ζ的信号传导结构域。
在一个实施方案中,所述共刺激结构域是一个或多个选自以下蛋白质的共刺激信号传导结构域:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18(LFA-1)、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70以及它们的组合。优选地,所述共刺激结构域是CD27、CD28、CD134、CD137或CD278的共刺激信号传导结构域或它们的组合。
在一个实施方案中,外源性的白细胞介素、Flt3L、XCL2和/或XCL1的表达或活性是组成型表达。在另一个实施方案中,外源性的白细胞介素、Flt3L、XCL2和/或XCL1的表达或活性是条件型表达。例如,通过将外源性基因与诱导型、阻遏型或组织特异性启动子可操作连接从而实现条件型表达。
在一个实施方案中,白细胞介素、Flt3L、XCL2和/或XCL1可以与定位结构域可操作连接,所述定位结构域可以将本发明的外源性基因定位在特定的细胞位置上表达,例如细胞膜、细胞质中的特定细胞器例如内质网、高尔基体、细胞核等。定位结构域包括但不限于核定位信号、引导肽、跨膜结构域等。在一个实施方案中,本发明的外源性基因白细胞介素、Flt3L、XCL2和/或XCL1与跨膜结构域可操作连接,从而锚定在工程化免疫细胞的表面表达。
在第二个方面,本发明提供一种核酸分子,(i)编码特异性识别配体的细胞表面分子的核酸序列,(ii)编码白细胞介素的核酸序列,和(iii)编码Flt3L、XCL2和/或XCL1的核酸序列。优选地,所述特异性识别配体的细胞表面分子是嵌合抗原受体或T细胞受体,更优选嵌合抗原受体。优选地,所述白细胞介素是IL-2、IL-7、IL-12、IL-15、IL-21、IL-17、IL-18、IL-23、或其亚基、或其组合、或其亚基的组合,更优选是IL-7、其亚基或其组合。优选地,所述核酸是DNA或RNA。
本发明还提供包含上述核酸分子的载体。具体地,所述载体选自质粒、逆转录病毒、慢病毒、腺病毒、牛痘病毒、劳氏肉瘤病毒(RSV)、多瘤病毒和腺相关病毒(AAV)。在一些实施方案中,该载体还包含在免疫细胞中自主复制的起点、选择标记、限制酶切割位点、启动子、多聚腺苷酸尾(polyA)、3’UTR、5’UTR、增强子、终止子 、绝缘子、操纵子、选择标记、报告基因、靶向序列和/或蛋白质纯化标签等元件。在一个具体的实施方案中,所述载体是体外转录的载体。
在一个实施方案中,本发明还提供一种试剂盒,其包含本发明所述的工程化免疫细胞、核酸分子或载体。
在一个实施方案中,本发明还提供一种药物组合物,其包含本发明所述的工程化免疫细胞、核酸分子或载体,和一种多种药学上可接受的赋型剂。
在第三个方面,本发明还提供一种制备工程化免疫细胞的方法,包括将以下引入所述免疫细胞:(a)编码特异性识别配体的细胞表面分子的第一核酸序列或其编码的特异性识别配体的细胞表面分子;(b)编码白细胞介素的第二核酸序列或其编码的白细胞介素;(c)编码XCL1、XCL2和/或Flt3L的第三核酸序列或其编码的XCL1、XCL2和/或Flt3L蛋白。优选地,所述特异性识别配体的细胞表面分子是嵌合抗原受体或嵌合T细胞受体,更优选嵌合抗原受体。优选地,所述白细胞介素是IL-2、IL-7、IL-12、IL-15、IL-21、IL-17、IL-18、IL-23、或其亚基、或其组合、或其亚基的组合,更优选是IL-7、其亚基或其亚基的组合。
在一个实施方案中,可以将上述组分(a)、(b)和(c)以任何顺序先后依次引入免疫细胞。在另一个实施方案中,可以将上述组分(a)、(b)和(c)同时引入免疫细胞,例如将(a)、(b)和(c)克隆在一个或多个载体中。
在第四个方面,本发明还提供一种治疗患有癌症、感染或自身免疫性疾病的受试者的方法,包括向所述受试者施用有效量的根据本发明所述的免疫细胞、核酸分子、载体或药物组合物。
在一个实施方案中,所述癌症是实体瘤或血液肿瘤。更具体地,所述癌症选自:脑神经胶质瘤、胚细胞瘤、肉瘤、白血病、基底细胞癌、胆道癌、膀胱癌、骨癌、脑和CNS癌症、乳腺癌、腹膜癌、宫颈癌、绒毛膜癌、结肠和直肠癌、结缔组织癌症、消化系统的癌症、子宫内膜癌、食管癌、眼癌、头颈癌、胃癌、胶质母细胞瘤(GBM)、肝癌、肝细胞瘤、上皮内肿瘤、肾癌、喉癌、肝肿瘤、肺癌、淋巴瘤、黑色素瘤、骨髓瘤、神经母细胞瘤、口腔癌、卵巢癌、胰腺癌、前列腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸系统的癌症、唾液腺癌、皮肤癌、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌、子宫或子宫内膜癌、泌尿系统的恶性肿瘤、外阴癌以及其它癌和肉瘤、以及B细胞淋巴瘤、套细胞淋巴瘤、AIDS相关淋巴瘤、以及Waldenstrom巨球蛋白血症、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、B细胞急性淋巴细胞白血病(B-ALL)、T细胞急性淋巴细胞白血病(T-ALL)、B细胞幼淋巴细胞白血病、母细胞性浆细胞样树突状细胞瘤、伯基特氏淋巴瘤、弥散性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性骨髓性白血病(CML)、恶性淋巴组织增生疾病、MALT淋巴瘤、毛细胞白血病、边缘区淋巴瘤、多发性骨髓瘤、骨髓发育不良、浆母细胞性淋巴瘤、白血病前期、浆细胞样树突状细胞瘤、以及移植后淋巴细胞增生性紊乱(PTLD)。
在一个实施方案中,所述感染包括但不限于由病毒、细菌、真菌和寄生虫引起的感染。
在一个实施方案中,所述自身免疫性疾病包括但不限于I型糖尿病、腹腔疾病、格雷夫斯病、炎症性肠病、多发性硬化症、银屑病、类风湿性关节炎、艾迪生病、干燥综合征、桥本甲状腺炎、重症肌无力、血管炎、恶性贫血与系统性红斑狼疮等。
本发明的工程化免疫细胞的优势之处在于,共表达的白细胞介素以及Flt3L、XCL2和/或XCL1能够有效促进DC细胞在肿瘤部位的分化或募集,增加DC细胞数量,增加工程化免疫细胞的增殖及存活时间,从而一方面降低肿瘤微环境对工程化免疫细胞的抑制作用,提高工程化免疫细胞的肿瘤杀伤能力,另一方面增加的DC细胞能够激活机体自身T细胞的过继性免疫识别,与工程化免疫细胞形成协同效应,最终增强对肿瘤的抑制。
附图说明
图1:重组逆转录病毒载体mCD19-CAR-Flt3L的结构示意图。
图2:重组逆转录病毒载体mCD19-CAR-XCL1的结构示意图。
图3:Panc02-mCD19细胞的CD19表达率。
图4:通过流式细胞术测定的CAR-T细胞的CAR表达水平。
图5:通过ELISA测定的CAR-T细胞的XCL1表达水平。
图6:通过ELISA测定的CAR-T细胞的IL-7表达水平。
图7:通过ELISA测定的CAR-T细胞的CCL19表达水平。
图8:通过ELISA测定的CAR-T细胞的Flt3L表达水平。
图9:CAR-T细胞分别与靶细胞和非靶细胞共培养后的IFN-γ释放水平。
图10:用CAR-T细胞治疗小鼠胰腺癌后,小鼠的体重变化曲线。
图11:用CAR-T细胞治疗小鼠胰腺癌后,小鼠的肿瘤生长曲线。
图12:用CAR-T细胞治疗小鼠胰腺癌后,小鼠的存活曲线。
发明详述
除非另有说明,否则本文中所使用的所有科学技术术语的含义与本发明所属领域的普通技术人员通常所了解的相同。
特异性识别配体的细胞表面分子
如本文所用,术语“特异性识别配体的细胞表面分子”是指在细胞表面表达的能够与靶分子(例如配体)特异性结合的分子。此类表面分子一般包含能够与配体特异性结合的配体结合结构域、将表面分子锚定在细胞表面的跨膜结构域,以及负责信号传递的胞内结构域。常见的此类表面分子的实例包括例如T细胞受体或嵌合抗原受体。
如本文所用,术语“T细胞受体”或“TCR”是指响应于抗原呈递并参与T细胞活化的膜蛋白复合体。TCR的刺激由抗原呈递细胞上的主要组织相容性复合体分子(MHC)触发,所述抗原呈递细胞将抗原肽呈递至T细胞并且结合至TCR复合体以诱发一系列胞内信号传导。TCR由分别形成异二聚体的六条肽链组成,其一般分为αβ型和γδ型。每条肽链包括恒定区和可变区,其中可变区负责结合特异性的特定的抗原和MHC分子。TCR的可变区可以包含配体结合结构域或与配体结合结构域可操作连接,其中配体结合结构域的定义如下所述。
如本文所用,术语“嵌合抗原受体”或“CAR”是指人工构建的杂合多肽,该杂合多肽一般包括配体结合结构域(例如抗体的抗原结合部分)、跨膜结构域、共刺激结构域和细胞内信号传导结构域,各个结构域之间通过接头连接。CAR能够利用单克隆抗体的抗原结合特性以非MHC限制性的方式将T细胞和其它免疫细胞的特异性和反应性重定向至所选择的靶标。非MHC限制性的抗原识别给予CAR细胞与抗原处理无关的识别抗原的能力,因此绕过了肿瘤逃逸的主要机制。此外,当在T细胞内表达时,CAR有利地不与内源性T细胞受体(TCR)的α链和β链二聚化。
如本文所用,“配体结合结构域”是指可以与配体(例如抗原)结合的任何结构或其功能性变体。配体结合结构域可以是抗体结构,包括但不限于单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体、鼠源抗体、嵌合抗体及其功能性片段。例如,配体结合结构域包括但不限于Fab、Fab’、Fv片段、F(ab’)2、单链抗体(Single Chain Antibody Fragment,scFv)、单结构域抗体(Single Domain Antibody, sdAb)、纳米抗体(Nanobody,Nb)、抗原结合配体、重组纤连蛋白结构域、anticalin和DARPIN等,优选选自Fab、scFv、sdAb和纳米抗体。在本发明中,配体结合结构域可以是单价或二价,且可以是单特异性、双特异性或多特异性的抗体。在另一个实施方案中,配体结合结构域也可以是特定蛋白的特异性结合多肽或受体结构,所述特定蛋白是例如PD1、PDL1、PDL2、TGFβ、APRIL和NKG2D。
“Fab”是指免疫球蛋白分子被木瓜蛋白酶裂解后产生的两个相同片段中的任一个,由通过二硫键连接的完整轻链和重链N端部分组成,其中重链N端部分包括重链可变区和CH1。与完整的IgG相比,Fab没有Fc片段,流动性和组织穿透能力较高,并且无需介导抗体效应即可单价结合抗原。
“单链抗体”或“scFv”是由抗体重链可变区(VH)和轻链可变区(VL)通过接头连接而成的抗体。可以选择接头的最佳长度和/或氨基酸组成。接头的长度会明显影响scFv的可变区折叠和相互作用情况。事实上,如果使用较短的接头(例如在5-10个氨基酸之间),则可以防止链内折叠。关于接头的大小和组成的选择,参见例如,Hollinger等人,1993ProcNatl Acad .Sci .U .S .A .90:6444-6448;美国专利申请公布号2005/0100543、2005/0175606、2007/0014794;以及PCT公布号WO2006/020258和WO2007/024715,其全文通过引用并入本文。scFv可以包含以任何顺序连接的VH和VL,例如VH-接头-VL或VL-接头-VH。
“单结构域抗体”或“sdAb”是指一种天然缺失轻链的抗体,该抗体只包含一个重链可变区(VHH)和两个常规的CH2与CH3区,也称为“重链抗体”。
“纳米抗体”或“Nb”是指单独克隆并表达出来的VHH结构,其具有与原重链抗体相当的结构稳定性以及与抗原的结合活性,是目前已知的可结合目标抗原的最小单位。
术语“功能性变体”或“功能性片段”是指基本上包含亲本的氨基酸序列但与该亲本氨基酸序列相比含有至少一个氨基酸修饰(即取代、缺失或插入)的变体,条件是所述变体保留亲本氨基酸序列的生物活性。在一个实施方案中,所述氨基酸修饰优选是保守型修饰。
如本文所用,术语“保守性修饰”是指不会明显影响或改变含有该氨基酸序列的抗体或抗体片段的结合特征的氨基酸修饰。这些保守修饰包括氨基酸取代、添加及缺失。修饰可以通过本领域中已知的标准技术,如定点诱变和PCR介导的诱变而引入本发明的嵌合抗原受体中。保守氨基酸取代是氨基酸残基被具有类似侧链的氨基酸残基置换的取代。具有类似侧链的氨基酸残基家族已在本领域中有定义,包括碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)及芳香族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。保守性修饰可以例如基于极性、电荷、溶解度、疏水性、亲水性和/或所涉及残基的两亲性质的相似性来进行选择。
因此,“功能性变体”或“功能性片段”与亲本氨基酸序列具有至少75%,优选至少76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性,并且保留亲本氨基酸的生物活性,例如结合活性。
如本文所用,术语“序列同一性”表示两个(核苷酸或氨基酸)序列在比对中在相同位置处具有相同残基的程度,并且通常表示为百分数。优选地,同一性在被比较的序列的整体长度上确定。因此,具有完全相同序列的两个拷贝具有100%同一性。本领域技术人员将认识到,一些算法可以用于使用标准参数来确定序列同一性,例如Blast (Altschul等(1997)Nucleic Acids Res.25:3389-3402)、Blast2(Altschul等(1990)J.Mol.Biol.215:403-410)、Smith-Waterman(Smith等(1981)J.Mol.Biol .147:195-197)和ClustalW。
配体结合结构域的选择取决于待识别的与具体疾病状态相关的靶细胞上的细胞表面标记,例如肿瘤特异性抗原或肿瘤相关抗原。因此,在一个实施方案中,本发明的配体结合结构域与选自以下的一个或多个靶标结合:TSHR、CD19、CD123、CD22、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、GD2、GD3、BCMA、Tn Ag、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、间皮素、IL-l lRa、PSCA、PRSS21、 VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、Folate 受体α、ERBB2 (Her2/neu)、MUC1、EGFR、NCAM、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gplOO、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD 179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、豆荚蛋白、HPV E6、E7、MAGE Al、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG (TMPRSS2 ETS融合基因)、NA17、PAX3、雄激素受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D和它们的任意组合。优选地,所述靶标选自:CD19、CD20、CD22、BAFF-R、CD33、EGFRvIII、BCMA、GPRC5D、PSMA、ROR1、FAP、ERBB2 (Her2/neu)、MUC1、EGFR、CAIX、WT1、NY-ESO-1、CD79a、CD79b、GPC3、Claudin18.2、NKG2D和它们的任意组合。根据待靶向的抗原,本发明的CAR可以被设计为包括对该抗原具有特异性的配体结合结构域。例如,如果CD19是待靶向的抗原,则CD19抗体可用作本发明的配体结合结构域。在优选的实施方式中,本发明CAR包含CD19 scFv,其包含与SEQ ID NO: 2第1-107位或SEQID NO:14第1-107位所示的氨基酸序列具有至少90%、95%、97%或99%或100%序列同一性的轻链可变区序列和与SEQ ID NO:2第123-242位或SEQ ID NO:14第123-238位所示的氨基酸序列具有至少90%、95%、97%或99%或100%序列同一性的重链可变区序列。
如本文所用,术语“跨膜结构域”是指能够使嵌合抗原受体在免疫细胞(例如淋巴细胞、NK细胞或NKT细胞)表面上表达,并且引导免疫细胞针对靶细胞的细胞应答的多肽结构。跨膜结构域可以是天然或合成的,也可以源自任何膜结合蛋白或跨膜蛋白。当嵌合抗原受体与靶抗原结合时,跨膜结构域能够进行信号传导。特别适用于本发明中的跨膜结构域可以源自例如TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137、CD154及其功能性片段。或者,跨膜结构域可以是合成的并且可以主要地包含疏水性残基如亮氨酸和缬氨酸。优选地,所述跨膜结构域源自CD8α链,其与SEQ ID NO:4或16所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或所述CD8α跨膜结构域的编码序列与SEQ ID NO:3或15所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的嵌合抗原受体还可以包含位于配体结合结构域和跨膜结构域之间的铰链区。如本文所用,术语“铰链区”一般是指作用为连接跨膜结构域至配体结合结构域的任何寡肽或多肽。具体地,铰链区用来为配体结合结构域提供更大的灵活性和可及性。铰链区可以包含最多达300个氨基酸,优选10至100个氨基酸并且最优选25至50个氨基酸。铰链区可以全部或部分源自天然分子,如全部或部分源自CD8、CD4或CD28的胞外区,或全部或部分源自抗体恒定区。或者,铰链区可以是对应于天然存在的铰链序列的合成序列,或可以是完全合成的铰链序列。在优选的实施方式中,所述铰链区包含CD8α链、FcγRIIIα受体、IgG4或IgG1的铰链区部分,更优选CD8α铰链,其与SEQ ID NO:12或22所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或者CD8α铰链的编码序列与SEQ ID NO:11或21所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
如本文所用,术语“胞内信号传导结构域”是指转导效应子功能信号并指导细胞进行指定功能的蛋白质部分。胞内信号传导结构域负责在配体结合结构域结合抗原以后的细胞内初级信号传递,从而导致免疫细胞和免疫反应的活化。换言之,胞内信号传导结构域负责活化其中表达CAR的免疫细胞的正常的效应子功能的至少一种。例如,T细胞的效应子功能可以是细胞溶解活性或辅助活性,包括细胞因子的分泌。
在一个实施方案中,本发明的嵌合抗原受体包含的胞内信号传导结构域可以是T细胞受体和共受体的细胞质序列,其在抗原受体结合以后一同起作用以引发初级信号传导,以及这些序列的任何衍生物或变体和具有相同或相似功能的任何合成序列。胞内信号传导结构域可以包含许多免疫受体酪氨酸激活基序(Immunoreceptor Tyrosine-basedActivation Motifs, ITAM)。本发明的胞内信号传导结构域的非限制性施例包括但不限于源自FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d的那些。在优选的实施方式中,本发明CAR的信号传导结构域可以包含CD3ζ信号传导结构域,该信号传导结构域与SEQ ID NO:8或20所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:7或19所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的嵌合抗原受体包含一个或多个共刺激结构域。共刺激结构域可以是来自共刺激分子的细胞内功能性信号传导结构域,其包含所述共刺激分子的整个细胞内部分,或其功能片段。“共刺激分子”是指在T细胞上与共刺激配体特异性结合,由此介导T细胞的共刺激反应(例如增殖)的同源结合配偶体。共刺激分子包括但不限于1类MHC分子、BTLA和Toll配体受体。本发明的共刺激结构域的非限制性施例包括但不限于源自以下蛋白质的共刺激信号传导结构域:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18(LFA-1)、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM以及ZAP70。优选地,本发明CAR的共刺激结构域来自4-1BB、CD28、CD27、OX40或其组合。在一个实施方案中,本发明的CAR包含的共刺激结构域与SEQ ID NO:6或18所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或该共刺激结构域的编码序列与SEQ ID NO:5或17所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的CAR还可以包含信号肽,使得当其在细胞例如T细胞中表达时,新生蛋白质被引导至内质网并随后引导至细胞表面。信号肽的核心可以含有长的疏水性氨基酸区段,其具有形成单个α-螺旋的倾向。在信号肽的末端,通常有被信号肽酶识别和切割的氨基酸区段。信号肽酶可以在移位期间或完成后切割,以产生游离信号肽和成熟蛋白。然后,游离信号肽被特定蛋白酶消化。可用于本发明的信号肽是本领域技术人员熟知的,例如衍生自CD8α、IgG1、GM-CSFRα等的信号肽。在一个实施方案中,可用于本发明的信号肽与SEQ ID NO:10或34所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或该信号肽的编码序列与SEQ ID NO:9或33所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的CAR还可以包含开关结构,以调控CAR的表达时间。例如,开关结构可以是二聚化结构域的形式,通过与其相应配体的结合引起构象变化,暴露胞外结合结构域,使其与被靶向抗原结合,从而激活信号传导通路。或者,也可以使用开关结构域分别连接结合结构域和信号传导结构域,仅当开关结构域互相结合(例如在诱导化合物的存在下)时,结合结构域和信号传导结构域才能通过二聚体连接在一起,从而激活信号通路。开关结构还可以是掩蔽肽的形式。掩蔽肽可以遮蔽胞外结合结构域,阻止其与被靶向抗原的结合,当通过例如蛋白酶切割掩蔽肽后,就可以暴露胞外结合结构域,使其成为一个“普通”的CAR结构。本领域技术人员知晓的各种开关结构均可用于本发明。
在一个实施方案中,本发明的CAR还可以包含自杀基因,即,使其表达一个可通过外源物质诱导的细胞死亡信号,以在需要时(例如产生严重的毒副作用时)清除CAR细胞。例如,自杀基因可以是插入的表位的形式,例如CD20表位、RQR8等,当需要时,可以通过加入靶向这些表位的抗体或试剂来消除CAR细胞。自杀基因也可以是单纯疱疹病毒胸苷激酶(HSV-TK),该基因可使细胞在接受更昔洛韦治疗诱导下死亡。自杀基因还可以是iCaspase-9,可以通过化学诱导药物如AP1903、AP20187等诱导iCaspase-9发生二聚化,从而激活下游的Caspase3分子,导致细胞凋亡。本领域技术人员知晓的各种自杀基因均可用于本发明。
在一个实施方案中,所述嵌合抗原受体包含:(a)4-1BB共刺激结构域和CD3ζ胞内信号传导结构域,(b)CD27共刺激结构域和CD3ζ胞内信号传导结构域,(c)CD28共刺激结构域和CD3ζ胞内信号传导结构域,(d)OX40共刺激结构域和CD3ζ胞内信号传导结构域,(e)CD28共刺激结构域、4-1BB共刺激结构域和CD3ζ胞内信号传导结构域,(f)OX40共刺激结构域、4-1BB共刺激结构域和CD3ζ胞内信号传导结构域,或(g)CD28共刺激结构域、OX40共刺激结构域和CD3ζ胞内信号传导结构域。
白细胞介素
白细胞介素是由白细胞产生,且在白细胞间发挥功能的一类细胞因子,在传递信息,激活与调节免疫细胞,介导T、B细胞活化、增殖与分化及在炎症反应中起重要作用。一般而言,白细胞介素的生物学效应通过其与相应受体的结合来实现,例如IL -7的生物学特性通过IL-7与其受体IL-7R的结合来实现。
在一个实施方案中,可用于本发明的白细胞介素包括但不限于IL-2、IL-7、IL-12、IL-15、IL-21、IL-17、IL-18、IL-23、或其亚基、或其组合、或其亚基的组合。IL-2主要由T细胞产生,通过自分泌和旁分泌的方式发挥作用。IL-2不仅能维持T细胞生长,促进细胞因子的产生,而且能够诱导CD8+ T细胞和CD4+ T细胞发挥细胞毒性作用。此外,IL-2还能够刺激NK细胞增殖,增强NK杀伤活性,促进NK细胞产生IFNγ、TNFβ、TGFβ等因子,以及激活巨噬细胞,增强巨噬细胞的抗原呈递能力和靶细胞杀伤能力。IL-7主要由骨髓及胸腺基质细胞产生,其主要功能涉及以下几个方面:促进前体B细胞生长;抑制外周T细胞凋亡,诱导细胞增殖、持续存活;以及影响树突状细胞、巨噬细胞的发育和功能,诱导巨噬细胞分泌多种细胞因子。IL-12主要作用于T细胞和NK细胞。具体而言,IL-12可以刺激活化型T细胞增殖,促进Th0细胞向Th1细胞分化;诱导CTL和NK细胞的细胞毒性活性并促进其分泌IFNγ、TNFα、GMCSF等细胞因子;促进NK细胞和IL-2Rα、TNF受体以及CD56的表达,增强对肿瘤细胞的ADCC效应。IL-15可由活化的巨噬细胞、表皮细胞和呈现为细胞等多种细胞产生。由于IL-15的分子结构与IL-2比较相似,可以利用IL-2R的β链和γ链与靶细胞结合,发挥与IL-2类似的生物学活性,例如刺激T细胞和NK细胞的增殖,诱导B细胞增殖和分化等。IL-21由活化的CD4+T细胞、NKT细胞、Tfh细胞和Th17细胞产生,与IL-2、IL-15均具有较高的同源性。IL-21具有广泛的免疫调节功能,激活它可以增强活化型CD8+ T细胞的增殖,增强NK细胞的细胞毒性活性,促进B细胞的增殖与分化。IL-17由Th17细胞分泌,为促炎性分子,能够抑制调节性T细胞,并且招募和激活中性粒细胞和巨噬细胞。IL-18同样为促炎性分子,由T细胞和NK细胞分泌,激活的巨噬细胞也会分泌大量IL-18。有报道显示,IL-18在固有免疫和过继性免疫过程中发挥重要作用。IL-23同样由T细胞和NK细胞分泌,IL-23可以促进Th17细胞分化。树突状细胞、单核细胞、巨噬细胞同样表达低水平IL-23受体,可被IL-23激活。研究表明,这些白细胞介素单独或组合能够发挥有效的抗肿瘤作用。
在一个实施方案中,本发明使用的白细胞介素与SEQ ID NO:23、27、39、41、43、45、47、49、51、53、55、57或59 所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:24、28、40、42、44、46、48、50、52、54、56、58、或60所示的核酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
基因
酪氨酸激酶受体3配体(Fms-like tyrosine kinase 3 ligand, Flt3L)是一种细胞因子,其可以与Fms样酪氨酸激酶受体3(Fms-like tyrosine kinase 3 receptor,Flt3R)特异性结合,从而促进DC细胞、自然杀伤细胞、细胞毒性T淋巴细胞等的增殖、分化和成熟。Flt3L广泛存在于任和鼠的组织和器官中。Flt3L在人的外周血的单核细胞中表达最高,其次是在心脏、胎盘、肺、脾脏、胸腺、卵巢、小肠、肝脏、肾脏和胰腺中,在脑组织中表达最低。
研究表明,Flt3L可以与细胞因子,如IL-6、IL-7、IL-13等促进T细胞增殖。此外,Flt3L对B细胞的早期分化、NK细胞、DC等血源性前体细胞的分化具有重要影响。特别地,由于只有不成熟的DC才能表达受体Flt3R,因此Flt3L可以选择性地扩增DC前体细胞,促进DC的分化。已有研究表明,向小鼠皮下注射Flt3L可以显著增加其淋巴和非淋巴组织中的DC数量。据报道,携带Flt3L的重组腺病毒载体和化疗药物5-氟尿嘧啶联合应用在肝癌或直肠癌的小鼠模型中取得显著的抗肿瘤效果。具体地,Flt3L通过刺激骨髓免疫细胞的增殖和分化,有效保护了化疗药物引起的骨髓损伤,而肿瘤局部增殖的DC则有效地呈递了被5-氟尿嘧啶和NK细胞杀伤的肿瘤细胞的碎片,从而激起特异性抗肿瘤免疫反应。
在一个实施方案中,本发明使用的Flt3L与SEQ ID NO:36或38所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或Flt3L的编码序列与SEQ ID NO:35或37所示的核酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
和XCL2基因
C型趋化因子家族又称淋巴趋化因子,包括两个成员XCL1和XCL2,主要由CD8+T细胞和自然杀伤细胞产生。XCL1具有独特的序列特征以及两种可相互转换的蛋白空间构象,使得XCL1有别于其他趋化因子并发挥独特的功能。XCL1特异性受体XCR1是G蛋白偶联受体家族成员,二者相互作用不仅在胸腺的阴性选择和建立自身免疫耐受中发挥重要作用,而且能启动交叉抗原呈递并介导细胞毒性免疫反应。XCL1不仅能调节免疫系统平衡,维持肠道免疫稳态,而且与多种疾病相关,如自身免疫病、肾炎、结核和人类免疫缺陷病毒感染等。XCL2与XCL1的核酸序列具有97%同一性,其中第7位和第8位两个氨基酸残基不同:XCL1中为Asp和Lys,XCL2中为His和Arg。研究发现,XCL2与XCL1在表达谱、结构和功能上均非常相似,例如与XCL1一样,XCL2也具有单体型和二聚体型两种可相互转换的蛋白空间构象,其中单体型构象结合并激活XCR1,二聚体型构象对葡糖氨基聚糖类(Glycosaminoglycan,GAG)中的发夹结构具有更高的亲和力。XCL1和XCL2的受体XCR1选择性地表达在具有抗原呈递能力的DC(cDC1)细胞上,有研究发现引入XCL1可有效提高抗肿瘤免疫治疗和靶向疫苗的疗效。
在一个实施方案中,本发明使用的XCL1与SEQ ID NO:26或30所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或XCL1的编码序列与SEQ ID NO:25或29所示的核酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明使用的XCL2与SEQ ID NO:68所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或XCL2的编码序列与SEQ ID NO:67所示的核酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
外源基因的表达
本发明中的外源性基因,例如白细胞介素、Flt3L、XCL2和/或XCL1的表达可以是组成型表达或条件型表达。
在一个实施方案中,外源性的白细胞介素、Flt3L、XCL2和/或XCL1的表达是条件型表达。例如,根据需要,可以将本发明的外源基因与诱导型、阻遏型或组织特异性启动子可操作连接,从而在特定的时间或特定的组织、细胞类型内调控引入的外源基因的表达水平。在一个实施方案中中,启动子是诱导型启动子,即,仅在特定环境条件、发育条件或诱导物存在下启动转录的启动子。此类环境条件包括例如肿瘤酸性微环境、肿瘤低氧微环境等。此类诱导物包括例如西环素、四环素或其类似物,四环素的类似物包括例如金霉素、土霉素、去甲基氯四环素、甲烯土霉素、多西环素和米诺环素。诱导型启动子包括例如Lac操纵子序列、四环素操纵子序列、半乳糖操纵子序列或多西环素操纵子序列等。在另一个实施方案中,启动子是阻遏型启动子,即,在存在对阻遏型启动子具有特异性的阻遏物的情况下,外源基因在细胞中的表达被抑制或不表达。阻遏型启动子包括例如Lac阻遏型元件或四环素阻遏型元件。本领域技术人源熟知的诱导型/阻遏型表达系统可用于本发明,包括但不限于Tet-on系统、Tet-off系统、Cre/loxP系统等。
在一个实施方案中,白细胞介素、Flt3L、XCL2和/或XCL1可以与定位结构域可操作连接,所述定位结构域可以将本发明的外源性基因定位在特定的细胞位置上表达,例如细胞膜、细胞质中的特定细胞器例如内质网、高尔基体、细胞核等。定位结构域包括但不限于核定位信号、引导肽、跨膜结构域等。在一个实施方案中,本发明的外源性基因白细胞介素、Flt3L、XCL2和/或XCL1与跨膜结构域可操作连接,从而锚定在工程化免疫细胞的表面表达。
在一个实施方案中,本发明中的外源性基因,例如白细胞介素、Flt3L、XCL2或XCL1蛋白可以是野生型或具有特定性能(例如抵抗蛋白酶水解)的融合蛋白或者突变体。
核酸
本发明还提供一种核酸分子,其包含(i)编码特异性识别配体的细胞表面分子的核酸序列,(ii)编码白细胞介素的核酸序列,和(iii)编码Flt3L、XCL2和/或XCL1的核酸序列。
在一个实施方案重,所述特异性识别配体的细胞表面分子是T细胞受体或嵌合抗原受体,优选嵌合抗原受体。嵌合抗原受体的定义如上所述。
如本文所用,术语 “核酸分子”包括核糖核苷酸和脱氧核糖核苷酸的序列,如经修饰的或未经修饰的RNA或DNA,各自为单链和/或双链形式的线性或环状,或它们的混合物(包括杂合分子)。因此,根据本发明的核酸包括DNA (比如dsDNA、ssDNA、cDNA)、RNA(比如dsRNA、ssRNA、mRNA、ivtRNA),它们的组合或衍生物(比如PNA)。优选地,所述核酸是DNA或RNA,更优选mRNA。
核酸可以包含常规的磷酸二酯键或非常规的键(如酰胺键,比如在肽核酸(PNA)中发现的)。本发明的核酸还可含有一种或多种经修饰的碱基,比如,例如三苯甲基化的碱基和不常见的碱基(比如肌苷)。也可以想到其它修饰,包括化学、酶促或代谢修饰,只要本发明的多链CAR可以从多核苷酸表达即可。核酸可以以分离的形式提供。在一个实施方案中,核酸也可以包括调节序列,比如转录控制元件(包括启动子、增强子、操纵子、抑制子和转录终止信号)、核糖体结合位点、内含子等。
可以对本发明的核酸序列进行密码子优化以在所需的宿主细胞(如,免疫细胞)中进行最佳表达;或者用于在细菌、酵母菌或昆虫细胞中表达。密码子优化是指将目标序列中存在的在给定物种的高度表达的基因中一般罕见的密码子替换为在这类物种的高度表达的基因中一般常见的密码子,而替换前后的密码子编码相同的氨基酸。因此,最佳密码子的选择取决于宿主基因组的密码子使用偏好。
载体
本发明还提供一种载体,包含如本发明所述的核酸。其中,编码特异性识别配体的细胞表面分子的核酸序列、编码IL-7的核酸序列,编码XCL1的核酸、编码XCL2的核酸和/或编码Flt3L的核酸序列可以位于一个或多个载体中。
如本文所用,术语“载体”是用作将(外源)遗传材料转移到宿主细胞中的媒介核酸分子,在该宿主细胞中所述核酸分子可以例如复制和/或表达。
载体一般包括靶向载体和表达载体。“靶向载体”是通过例如同源重组或使用特异性靶向位点处序列的杂合重组酶将分离的核酸递送至细胞内部的介质。“表达载体”是用于异源核酸序列(例如编码本发明的嵌合抗原受体多肽的那些序列)在合适的宿主细胞中的转录以及它们的mRNA的翻译的载体。可用于本发明的合适载体是本领域已知的,并且许多可商购获得。在一个实施方案中,本发明的载体包括但不限于质粒、病毒(例如逆转录病毒、慢病毒、腺病毒、牛痘病毒、劳氏肉瘤病毒(RSV、多瘤病毒和腺相关病毒(AAV)等)、噬菌体、噬菌粒、粘粒和人工染色体(包括BAC和YAC)。载体本身通常是核苷酸序列,通常是包含插入物(转基因)的DNA序列和作为载体“骨架”的较大序列。工程化载体通常还包含在宿主细胞中自主复制的起点(如果需要多核苷酸的稳定表达)、选择标记和限制酶切割位点(如多克隆位点,MCS)。载体可另外包含启动子、多聚腺苷酸尾(polyA)、3’ UTR、增强子、终止子、绝缘子、操纵子、选择标记、报告基因、靶向序列和/或蛋白质纯化标签等元件。在一个具体的实施方案中,所述载体是体外转录的载体。
工程化免疫细胞及其制备方法
本发明还提供一种工程化免疫细胞,其包含本发明的核酸或载体。换言之,本发明的工程化免疫细胞表达特异性识别配体的细胞表面分子、外源性的IL-7基因,以及XCL1、XCL2和/或Flt3L基因。
如本文所用,术语“免疫细胞”是指免疫系统的具有一种或多种效应子功能(例如,细胞毒性细胞杀伤活性、分泌细胞因子、诱导ADCC和/或CDC)的任何细胞。例如,免疫细胞可以是T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞和/或NKT细胞,或者是从细胞脐带血等干细胞来源获得的免疫细胞。优选地,免疫细胞是T细胞。T细胞可以是任何T细胞,如体外培养的T细胞,例如原代T细胞,或者来自体外培养的T细胞系例如Jurkat、SupT1等的T细胞,或获得自受试者的T细胞。受试者的实例包括人、狗、猫、小鼠、大鼠及其转基因物种。T细胞可以从多种来源获得,包括外周血单核细胞、骨髓、淋巴结组织、脐血、胸腺组织、来自感染部位的组织、腹水、胸膜积液、脾组织及肿瘤。T细胞也可以被浓缩或纯化。T细胞可以处于任何发育阶段,包括但不限于,CD4+/CD8+ T细胞、CD4+辅助T细胞(例如Th1和Th2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、幼稚T细胞、γδ-T细胞、αβ-T细胞等。在一个优选的实施方案中,免疫细胞是人T细胞。可以使用本领域技术人员已知的多种技术,如Ficoll分离从受试者的血液获得T细胞。在本发明中,免疫细胞被工程化以表达嵌合抗原受体以及外源性的IL-7基因,和XCL1、XCL2和/或Flt3L基因。
采用本领域已知的常规方法(如通过转导、转染、转化等)可以将编码嵌合抗原受体多肽的核酸序列以及IL-7基因和XCL1、XCL2和/或Flt3L基因引入免疫细胞。“转染”是将核酸分子或多核苷酸(包括载体)引入靶细胞的过程。一个例子是RNA转染,即将RNA(比如体外转录的RNA,ivtRNA)引入宿主细胞的过程。该术语主要用于真核细胞中的非病毒方法。术语“转导”通常用于描述病毒介导的核酸分子或多核苷酸的转移。动物细胞的转染通常涉及在细胞膜中打开瞬时的孔或“洞”,以允许摄取材料。可以使用磷酸钙、通过电穿孔、通过细胞挤压或通过将阳离子脂质与材料混合以产生与细胞膜融合并将它们的运载物沉积入内部的脂质体,进行转染。用于转染真核宿主细胞的示例性技术包括脂质囊泡介导的摄取、热休克介导的摄取、磷酸钙介导的转染(磷酸钙/DNA共沉淀)、显微注射和电穿孔。术语“转化”用于描述核酸分子或多核苷酸(包括载体)向细菌中、也向非动物真核细胞(包括植物细胞)中的非病毒转移。因此,转化是细菌或非动物真核细胞的基因改变,其通过细胞膜从其周围直接摄取并随后并入外源遗传材料(核酸分子)而产生。转化可以通过人工手段实现。为了发生转化,细胞或细菌必须处于感受态的状态。对于原核转化,技术可包括热休克介导的摄取、与完整细胞的细菌原生质体融合、显微注射和电穿孔。
因此,本发明还提供一种制备工程化免疫细胞的方法,包括将以下引入所述免疫细胞:(a)编码特异性识别配体的细胞表面分子的第一核酸序列或其编码的特异性识别配体的细胞表面分子;(b)编码IL-7的第二核酸序列或其编码的IL-7蛋白;和(c)编码XCL1、XCL2和/或Flt3L的第三核酸序列或其编码的XCL1、XCL2和/或Flt3L蛋白。
在一个实施方案中,可以将上述组分(a)、(b)和(c)以任何顺序先后依次引入免疫细胞。在另一个实施方案中,可以将上述组分(a)、(b)和(c)同时引入免疫细胞,例如将(a)、(b)和(c)克隆在一个或多个载体中。
将核酸或载体引入免疫细胞后,本领域技术人员可以通过常规技术对所得免疫细胞进行扩增和活化。
还在一个实施方案中,本发明的免疫细胞还包含至少一种失活基因,其选自以下:CD52、GR、TCRα、TCRβ、CD3γ、CD3δ、CD3ε、CD247ζ、HLA-I、HLA-II、B2M、免疫检查点基因如PD1、CTLA-4、LAG3和TIM3。更特别地,免疫细胞中的至少TCR组分(包括TCRα、TCRβ基因)或CD3组分(包括CD3γ、CD3δ、CD3ε、CD247ζ)被失活。这种失活使得TCR-CD3复合物在细胞中没有功能。该策略对于避免移植物抗宿主病(GvHD)特别有用。使基因失活的方法是本领域已知的,例如通过大范围核酸酶、锌指核酸酶、TALE核酸酶或CRISPR系统中的Cas酶介导DNA断裂,从而使该基因失活。
试剂盒和药物组合物
本发明该提供一种试剂盒,其包含本发明的工程化免疫细胞、核酸分子或载体。
在一个优选的实施方案中,本发明的试剂盒还包含说明书。
本发明还提供一种药物组合物,其包含本发明所述的工程化免疫细胞、核酸分子或载体作为活性剂,和一种多种药学上可接受的赋型剂。因此,本发明还涵盖所述核酸分子、载体或工程化免疫细胞在制备药物组合物或药物中的用途。
如本文所用,术语“药学上可接受的赋型剂” 是指在药理学和/或生理学上与受试者和活性成分相容(即,能够引发所需的治疗效果而不会引起任何不希望的局部或全身作用)的载体和/或赋形剂,其是本领域公知的(参见例如Remington's PharmaceuticalSciences.Edited by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995)。药学上可接受的赋型剂的实例包括但不限于填充剂、粘合剂、崩解剂、包衣剂、吸附剂、抗粘附剂、助流剂、抗氧化剂、调味剂、着色剂、甜味剂、溶剂、共溶剂、缓冲剂、螯合剂、表面活性剂、稀释剂、润湿剂、防腐剂、乳化剂、包覆剂、等渗剂、吸收延迟剂、稳定剂和张力调节剂。本领域技术人员已知选择合适的赋型剂以制备本发明期望的药物组合物。用于本发明的药物组合物中的示例性赋型剂包括盐水、缓冲盐水、葡萄糖和水。通常,合适的赋形剂的选择尤其取决于所使用的活性剂、待治疗的疾病和药物组合物的期望剂型。
根据本发明的药物组合物可适用于多种途径施用。通常,通过胃肠外完成施用。胃肠外递送方法包括局部、动脉内、肌内、皮下、髓内、鞘内、心室内、静脉内、腹膜内、子宫内、阴道内、舌下或鼻内施用。
根据本发明的药物组合物也可以制备成各种形式,如固态、液态、气态或冻干形式,特别可以是软膏、乳膏、透皮贴剂、凝胶、粉末、片剂、溶液、气雾剂、颗粒、丸剂、混悬剂、乳剂、胶囊、糖浆、酏剂、浸膏剂、酊剂或流浸膏提取物的形式,或者是特别适用于所需施用方法的形式。本发明已知的用于生产药物的过程可包括例如常规混合、溶解、制粒、制糖衣、研磨、乳化、包封、包埋或冻干过程。包含例如本文所述的免疫细胞的药物组合物通常以溶液形式提供,并且优选包含药学上可接受的缓冲剂。
根据本发明的药物组合物还可以与一种或多种适用于治疗和/或预防待治疗疾病的其它药剂组合施用。适用于组合的药剂的优选实例包括已知的抗癌药物,比如顺铂、美登素衍生物、雷查霉素(rachelmycin)、卡里奇霉素(calicheamicin)、多西紫杉醇、依托泊苷、吉西他滨、异环磷酰胺、伊立替康、美法仑、米托蒽醌、sorfimer卟啉钠II(sorfimersodiumphotofrin II)、替莫唑胺、拓扑替康、葡萄糖醛酸曲美沙特(trimetreateglucuronate) 、奥利斯他汀E(auristatin E)、长春新碱和阿霉素;肽细胞毒素,比如蓖麻毒素、白喉毒素、假单胞菌细菌外毒素A、DNA酶和RNA酶;放射性核素,比如碘131、铼186、铟111、铱90、铋210和213、锕225和砹213;前药,比如抗体定向的酶前药;免疫刺激剂,比如血小板因子4、黑色素瘤生长刺激蛋白等;抗体或其片段,比如抗CD3抗体或其片段,补体活化剂,异种蛋白结构域,同种蛋白结构域,病毒/细菌蛋白结构域和病毒/细菌肽。此外,本发明的药物组合物也可以与其他一种或多种治疗方法,例如化疗、放疗组合使用。
治疗应用
本发明还提供一种治疗患有癌症、感染或自身免疫性疾病的受试者的方法,包括向所述受试者施用有效量的根据本发明所述的免疫细胞或药物组合物。因此,本发明还涵盖所述工程化免疫细胞在制备治疗癌症、感染或自身免疫性疾病的药物中的用途。
在一个实施方案中,直接向受试者施用有效量的本发明的免疫细胞和/或药物组合物。
在另一个实施方案中,本发明的治疗方法是离体治疗。具体地,该方法包括以下步骤:(a)提供样品,所述样品包含免疫细胞;(b)在体外将本发明的嵌合抗原受体以及待表达的外源性基因引入所述免疫细胞,获得经修饰的免疫细胞,(c)向有此需要的受试者施用所述经修饰的免疫细胞。优选地,步骤(a)中提供的免疫细胞选自巨噬细胞、树突状细胞、单核细胞、T细胞、NK细胞和/或NKT细胞;并且所述免疫细胞可以通过本领域已知的常规方法从受试者的样品(特别是血液样品)中获得。然而,也可以使用能够表达本发明的嵌合抗原受体和外源性基因并发挥如本文所述的所需生物效应功能的其它免疫细胞。此外,通常选择的免疫细胞与受试者的免疫系统相容,即优选所述免疫细胞不引发免疫原性响应。例如,可以使用“通用接受体细胞”,即发挥所需生物效应功能的普遍相容的可在体外生长和扩增的淋巴细胞。使用此类细胞将不需要获得和/或提供受试者自身淋巴细胞。步骤(c)的离体引入可以通过经由电穿孔将本文所述的核酸或载体引入免疫细胞或通过用病毒载体感染免疫细胞来实施,所述病毒载体为如前所述的慢病毒载体、腺病毒载体、腺相关病毒载体或逆转录病毒载体。其它可想到的方法包括使用转染试剂(比如脂质体)或瞬时RNA转染。
在一个实施方案中,所述免疫细胞是自体或同种异体的细胞,优选T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞和/或NKT细胞,更优选T细胞、NK细胞或NKT细胞。
如本文所用,术语“自体”是指来源于个体的任何材料稍后将被再引入该相同个体中。
如本文所用,术语“同种异体”是指任何材料来源于与引入该材料的个体相同物种的不同动物或不同患者。当在一个或多个基因座处的基因不同时,认为两个或更多个体彼此为同种异体的。在一些情况下,来自同一物种的各个体的同种异体材料在基因上的不同可能足以发生抗原相互作用。
如本文所用,术语“受试者”是哺乳动物。哺乳动物可以是人、非人灵长类动物、小鼠、大鼠、狗、猫、马或牛,但不限于这些实例。除人以外的哺乳动物可以有利地用作代表癌症动物模型的受试者。优选地,所述受试者是人。
在一个实施方案中,所述癌症是与配体结合结构域结合的靶标表达有关的癌症。例如,所述癌症包括但不限于:脑神经胶质瘤、胚细胞瘤、肉瘤、白血病、基底细胞癌、胆道癌、膀胱癌、骨癌、脑和CNS癌症、乳腺癌、腹膜癌、宫颈癌、绒毛膜癌、结肠和直肠癌、结缔组织癌症、消化系统的癌症、子宫内膜癌、食管癌、眼癌、头颈癌、胃癌(包括胃肠癌)、胶质母细胞瘤(GBM)、肝癌、肝细胞瘤、上皮内肿瘤、肾癌、喉癌、肝肿瘤、肺癌(例如小细胞肺癌、非小细胞肺癌、腺状肺癌和鳞状肺癌)、淋巴瘤(包括霍奇金淋巴瘤和非霍奇金淋巴瘤)、黑色素瘤、骨髓瘤、神经母细胞瘤、口腔癌(例如唇、舌、口和咽)、卵巢癌、胰腺癌、前列腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸系统的癌症、唾液腺癌、皮肤癌、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌、子宫或子宫内膜癌、泌尿系统的恶性肿瘤、外阴癌以及其它癌和肉瘤、以及B细胞淋巴瘤(包括低级/滤泡性非霍奇金淋巴瘤(NHL)、小淋巴细胞性(SL)NHL、中间级/滤泡性NHL、中间级扩散性NHL、高级成免疫细胞性NHL、高级成淋巴细胞性NHL、高级小型非裂化细胞性NHL、大肿块病NHL)、套细胞淋巴瘤、AIDS相关淋巴瘤、以及Waldenstrom巨球蛋白血症、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、B细胞急性淋巴细胞白血病(B-ALL)、T细胞急性淋巴细胞白血病(T-ALL)、B细胞幼淋巴细胞白血病、母细胞性浆细胞样树突状细胞瘤、伯基特氏淋巴瘤、弥散性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性骨髓性白血病(CML)、恶性淋巴组织增生疾病、MALT淋巴瘤、毛细胞白血病、边缘区淋巴瘤、多发性骨髓瘤、骨髓发育不良、浆母细胞性淋巴瘤、白血病前期、浆细胞样树突状细胞瘤、以及移植后淋巴细胞增生性紊乱(PTLD);以及其他与靶标表达有关的疾病。优选地,可以用本发明的工程化免疫细胞或药物组合物治疗的疾病选自:白血病、淋巴瘤、多发性骨髓瘤、脑神经胶质瘤、胰腺癌、胃癌等。
在一个实施方案中,所述感染包括但不限于由病毒、细菌、真菌和寄生虫引起的感染。
在一个实施方案中,所述自身免疫性疾病包括但不限于I型糖尿病、腹腔疾病、格雷夫斯病、炎症性肠病、多发性硬化症、银屑病、类风湿性关节炎、艾迪生病、干燥综合征、桥本甲状腺炎、重症肌无力、血管炎、恶性贫血与系统性红斑狼疮等。
在一个实施方案中,所述方法还进一步包括向所述受试者施用一种或多种额外的化疗剂、生物制剂、药物或治疗。在该实施方案 中,化疗剂、生物制剂、药物或治疗选自放射疗法、手术、抗体试剂和/或小分子和它们的任意组合。
下面将参考附图并结合实例来详细说明本发明。需要说明的是,本领域的技术人员应该理解本发明的附图及其实施例仅仅是为了例举的目的,并不能对本发明构成任何限制。在不矛盾的情况下,本申请中的实施例及实施例中的特征可以相互组合。
具体实施方式
实施例1 构建小鼠胰腺癌细胞系Panc02-mCD19
1. 制备pLV-mCD19质粒
以小鼠脾脏总mRNA为模板,通过反转录PCR得到小鼠脾脏总cDNA序列后,再通过PCR获得含有XbaI及SalI酶切位点的小鼠mCD19序列。然后,将mCD19基因重组至pLV-BHAm质粒中,得到pLV-BHAm-mCD19质粒。
2.慢病毒包装
在T175培养瓶中,以30×106个细胞/瓶的密度将293T细胞接种于30ml含有10% 胎牛血清的DMEM培养基中,于37℃、5% CO2培养箱中培养过夜。
在无菌管中加入3ml Opti-MEM(Gibco,货号31985-070)、34 μg pLV-BHAm-mCD19质粒、8.5 μg pMD2.G载体(Addgene,货号12259)和17 μg psPAX2载体(Addgene,货号12260)。然后加入120μl X-treme GENE HP DNA转染试剂(Roche,货号06366236001),立即混匀,室温孵育15 min。然后将该质粒/载体/转染试剂混合物逐滴加入到预先准备好的293T细胞的培养瓶中,于37℃,5% CO2条件下培养过夜。在转染后24小时和48小时收集培养物,合并后超速离心(25000g,4℃,2.5h),获得浓缩的pLV-BHAm-mCD19慢病毒,将其保存于-80℃。
3. 筛选Panc02-mCD19细胞系
在6孔细胞培养板的每个孔中,加入含10%胎牛血清的RPMI-1640培养基(Gibco,货号C12430500BT)、1×106个小鼠胰腺癌细胞Panc02(来自中国药科大学实验室馈赠)和200μl pLV-BHAm-mCD19慢病毒,于37℃、5% CO2条件下孵育48 h。然后用0.25%胰酶将细胞消化成单细胞悬液,并将细胞稀释后转移至96孔板中继续培养,直至出现单克隆细胞。挑选单克隆细胞,再次用0.25%胰酶消化成单细胞,并用200μl opti-MEM培养基重悬细胞。用APCanti-mouse CD19抗体(Biolegend,货号115512),通过流式细胞术检测感染效率,并筛选出CD19阳性克隆。将阳性克隆传代3-4次后,再用流式细胞术检测CD19表达水平。未经病毒感染的Panc02细胞用作对照。
结果如图3所示。最后筛选的Panc02-mCD19细胞系中,CD19表达率为100%。
实施例2. 制备CAR-T细胞
1. 构建逆转录病毒质粒
人工合成依次连接的mCD19-scFv、mCD8a铰链区及跨膜区、鼠41bb胞内域和鼠CD3ζ胞内域的编码序列片段,并在两端加入XhoI/EcoRI酶切位点。将片段克隆入MSCV载体,获得MSCV-mCD19-CAR质粒。
人工合成依次连接T2A和鼠IL-7的编码序列片段,并在两端加入EcoRI/SalI酶切位点。将片段克隆入MSCV-mCD19-CAR载体,获得MSCV-mCD19-CAR-IL-7质粒。
人工合成依次连接T2A和鼠XCL1的编码序列片段,并在两端加入EcoRI/SalI酶切位点。将片段克隆入MSCV-mCD19-CAR载体,获得MSCV-mCD19-CAR-XCL1质粒。
人工合成依次连接T2A和鼠CCL19的编码序列片段,并在两端加入EcoRI/SalI酶切位点。将片段克隆入MSCV-mCD19-CAR载体,获得MSCV-mCD19-CAR-CCL19质粒。
人工合成依次连接T2A和鼠Flt3L的编码序列片段,并在两端加入EcoRI/SalI酶切位点。将片段克隆入MSCV-mCD19-CAR载体,获得MSCV-mCD19-CAR-Flt3L质粒。
2. 制备逆转录病毒
在T175培养瓶中,以30×106个细胞/瓶的密度将293T细胞接种于30ml含有10% 胎牛血清的DMEM培养基中,于37℃、5% CO2培养箱中培养过夜,用于病毒包装。
在无菌管中加入3ml Opti-MEM(Gibco,货号31985-070)、45μg 逆转录病毒质粒(MSCV-mCD19-CAR质粒、MSCV- mCD19-CAR-IL-7质粒、MSCV- mCD19-CAR-XCL1质粒、MSCV-mCD19-CAR-CCL19或MSCV-mCD19-CAR-Flt3L质粒)和15 μg包装载体pCL-Eco(上海禾午生物科技有限公司,货号P3029)。然后加入120μl X-treme GENE HP DNA转染试剂(Roche,货号06366236001),立即混匀,室温孵育15 min。然后将该质粒/载体/转染试剂混合物逐滴加入到预先准备好的293T细胞的培养瓶中,于37℃,5% CO2条件下培养过夜。在转染后72小时收集培养物,离心(2000g,4℃,10分钟),获得逆转录病毒上清液。
3. 制备CAR-T细胞
从小鼠脾脏分离T淋巴细胞,并用DynaBeads CD3/CD28 CTSTM(Gibco,货号40203D)激活T细胞,然后在37℃和5%CO2下培养1天。
以每孔3×106个细胞/mL的密度将激活的T细胞接种至预先用RetroNectin包被过夜的24孔板中,然后分别加入500 μL完全培养基(NT,对照)、MSCV-mCD19-CAR病毒, MSCV-mCD19-CAR-XCL1病毒,MSCV-mCD19-CAR-Flt3L病毒,MSCV-mCD19-CAR-IL-7病毒+ MSCV-mCD19-CAR-CCL19病毒,MSCV-mCD19-CAR-IL-7病毒+ MSCV-mCD19-CAR-Flt3L病毒,或MSCV-mCD19-CAR-IL-7病毒+ MSCV-mCD19-CAR-XCL1病毒,并补充完全培养基至2mL。
将24孔板放于离心机进行离心感染,于32℃,2000 g离心2 h。然后,立刻将24孔板放置于37℃、CO2培养箱静置培养。第二天更换新鲜培养基,并调整细胞密度为1×106个细胞/mL。感染三天后,收集细胞用于后续分析。收集的细胞即为NT细胞、mCD19-CAR细胞、mCD19-CAR-XCL1细胞、mCD19-CAR-Flt3L细胞、mCD19-CAR-IL-7-CCL19细胞、mCD19-CAR-IL-7-Flt3L细胞,和mCD19-CAR-IL-7-XCL1细胞。
实施例3. 检测CAR-T细胞的表达
1. 细胞表面CAR的表达水平
取出实施例2制备的2×105个CAR-T细胞,用Goat Anti-Rat IgG (H&L)Biotin(BioVision, 货号6910-250)作为一抗,APC Streptavidin(BD Pharmingen,货号554067)作为二抗,通过流式细胞术检测CAR T细胞上的CAR的表达水平,结果如图4所示。
可以看出,与对照相比,mCD19-CAR、mCD19-CAR-XCL1、mCD19-CAR-Flt3L、mCD19-CAR-IL-7-XCL1、mCD19-CAR-IL-7-CCL19细胞、mCD19-CAR-IL-7-Flt3L细胞中的CAR阳性效率均大于50%,表明这些细胞均可有效表达CAR。
2. XCL1的表达水平
收集实施例2制备的CAR-T细胞的上清液,根据制造商的建议,用Mouse XCL1DuoSet ELISA kit试剂盒(R&D Systems, 货号 DY486)检测细胞中的XCL1分泌水平,结果如图5所示。
可以看出,包含mCD19-CAR-XCL1的两种CAR T细胞均可有效分泌XCL1。
3. IL-7的表达水平
收集实施例2制备的CAR-T细胞的上清液,根据制造商的建议,用Mouse IL-7DuoSet ELISA kit试剂盒(R&D Systems, 货号 DY407)检测细胞中的IL-7分泌水平,结果如图6所示。
可以看出,包含mCD19-CAR-IL-7的三种CAR T细胞均可有效表达IL-7。
4. CCL19的表达水平
收集实施例2制备的CAR-T细胞的上清液,根据制造商的建议,用Mouse CCL19DuoSet ELISA kit试剂盒(R&D Systems, 货号 DY440)检测细胞中的CCL19分泌水平,结果如图7所示。
可以看出,包含mCD19-CAR-CCL19的CAR T细胞可有效表达CCL19。
5. Flt3L的表达水平
收集实施例2制备的CAR-T细胞的上清液,根据制造商的建议,用Mouse Flt-3Ligand DuoSet ELISA kit试剂盒(R&D Systems, 货号 DY427)检测细胞中的Flt3L分泌水平,结果如图8所示。
可以看出,包含mCD19-CAR-Flt3L的两种CAR T细胞均可有效表达Flt3L。
实施例4. 检测CAR-T细胞的IFN-γ分泌水平
在96孔圆底板中以2×105个细胞/100 μl的浓度分别加入NT细胞、mCD19-CAR细胞、mCD19-CAR-XCL1细胞,mCD19-CAR-Flt3L细胞、mCD19-CAR-IL-7-CCL19细胞,mCD19-CAR-IL-7-Flt3L细胞和mCD19-CAR-IL-7-XCL1细胞。然后在各孔中以1×104个细胞/100 μl的浓度分别加入靶标Panc02-mCD19细胞或非靶标Panc02细胞。在37℃培养24 h后,收集培养物上清液。根据制造商的建议,用Mouse IFN-gamma DuoSet ELISA试剂盒(R&D,货号DY485)检测培养物上清液中IFN-γ的表达水平。
检测结果如图9所示。可以看出,在非靶细胞Panc02中均没有检测到IFN-γ的释放,且NT细胞不表达IFN-γ,表明本实施例中的CAR T细胞的杀伤都是特异性的。并且,在杀伤靶细胞时,与仅表达CAR的T细胞相比,额外表达Flt3L、IL-7+Flt3L、IL-7+CCL19或IL-7+XCL1均可显著增加抗原特异性的IFN-γ水平。
实施例5. CAR-T 细胞的肿瘤抑制效果验证
在健康C57BL/6小鼠的左前肢腋下部位,经皮下接种5×105个实施例1制备的Panc02-mCD19胰腺癌细胞。
将接种了胰腺癌细胞的小鼠随机分为7组,每组6只。待肿瘤体积生长至100 mm3时,向每只小鼠经尾静脉注射5×106个实施例2制备的NT细胞、mCD19-CAR细胞、mCD19-CAR-XCL1细胞、mCD19-CAR-Flt3L细胞、mCD19-CAR-IL-7-CCL19细胞、mCD19-CAR-IL-7-Flt3L细胞,或mCD19-CAR-IL-7-XCL1细胞。
监测小鼠的体重和肿瘤体积变化,直至实验结束。
小鼠的体重变化如图10所示。可以看出,施用CAR-T细胞后,各组小鼠的体重与对照组相比没有显著差异,且在观察周期中,当小鼠肿瘤未超过1500mm3时,小鼠行动活泼,毛色正常,这表明,施用CAR-T细胞不会对小鼠有明显的毒副反应。
小鼠的肿瘤体积变化如图11所示。可以看出,与NT细胞和常规CAR-T细胞相比,仅表达XCL1或Flt3L的CAR-T细胞不能显著增强抗肿瘤效果,表明单独的XCL1或Flt3L不能与CAR-T细胞产生协同作用。此外,共表达IL-7和CCL19的CAR-T细胞的抗肿瘤效果明显优于常规CAR-T细胞,这与之前的报道一致。然而,出乎意料地,发明人发现,IL-7+XCL1以及IL-7+Flt3L组合不仅显著提高了CAR-T细胞的肿瘤抑制效果,并且增强效果远远优于IL-7+CCL19组合对CAR-T的增强效果。其中,共表达IL-7和XCL1的CAR-T细胞的肿瘤抑制效果最好,几乎使得肿瘤完全消失而没有明显复发。
小鼠的存活曲线如图12所示。可以看出,相较于传统CAR-T细胞治疗,额外表达的XCL1或Flt3L单独并不能明显延长小鼠的生存期,而共表达IL-7+CCL19、IL-7+Flt3L或IL-7+XCL1的CAR-T细胞则能够有效延长小鼠的生存期。其中,在IL-7+XCL1组中,5只小鼠达到完全缓解,直至实验结束一直保持无瘤生存,1只小鼠达到非常好的部分缓解,持续保持肿瘤抑制状态。在IL-7+Flt3L组中,有3只小鼠在实验结束时维持完全缓解。而在IL-7+CCL19组中,有2只小鼠在实验结束时维持完全缓解,保持无瘤生存,其余小鼠虽然在实验早期相较于常规CAR-T细胞发挥一定的抑瘤作用,但到实验后期,抑瘤效果消失,导致小鼠死亡。
以上结果表明,共表达IL-7+XCL1或IL-7+Flt3L能够有效增强工程化免疫细胞对靶标胰腺癌细胞的抑制效果,显著提高存活率,并且增强效果优于目前已知的IL-7+CCL19组合。
需要说明的是,以上仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。本领域技术人员理解的是,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
序列表
<110> 南京北恒生物科技有限公司
<120> 工程化免疫细胞及其用途
<150> 2020104607305
<151> 2020-05-27
<160> 68
<170> SIPOSequenceListing 1.0
<210> 1
<211> 726
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
gacatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atcagttgca gggcaagtca ggacattagt aaatatttaa attggtatca gcagaaacca 120
gatggaactg ttaaactcct gatctaccat acatcaagat tacactcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggagcaa 240
gaagatattg ccacttactt ttgccaacag ggtaatacgc ttccgtacac gttcggaggg 300
gggaccaagc tggagatcac aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgaaactgca ggagtcagga cctggcctgg tggcgccctc acagagcctg 420
tccgtcacat gcactgtctc aggggtctca ttacccgact atggtgtaag ctggattcgc 480
cagcctccac gaaagggtct ggagtggctg ggagtaatat ggggtagtga aaccacatac 540
tataattcag ctctcaaatc cagactgacc atcatcaagg acaactccaa gagccaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca tttactactg tgccaaacat 660
tattactacg gtggtagcta tgctatggac tactggggcc aaggaacctc agtcaccgtc 720
tcctca 726
<210> 2
<211> 242
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
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Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu
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Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys
130 135 140
Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
145 150 155 160
Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser
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Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
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Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
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Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
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Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
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Ser Ser
<210> 3
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atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
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<210> 4
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
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Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys Lys
20 25
<210> 5
<211> 120
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 60
actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 120
<210> 6
<211> 40
<212> PRT
<213> 人工序列(Artificial Sequence)
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Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
1 5 10 15
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
20 25 30
Glu Glu Glu Glu Gly Gly Cys Glu
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<210> 7
<211> 339
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 180
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300
acctacgacg cccttcacat gcaggccctg ccccctcgc 339
<210> 8
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
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Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
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Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
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Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 9
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 10
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
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> 11
<211> 135
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 12
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 13
<211> 714
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
gacatccaga tgacccagag ccctgccagc ctgtctacca gcctgggcga gacagtgacc 60
atccagtgtc aggccagcga ggacatctac tctggcctgg cttggtatca gcagaagccc 120
ggcaagagcc ctcagctgct gatctacggc gccagcgacc tgcaggacgg cgtgcctagc 180
agattcagcg gcagcggctc cggaacccag tacagcctga agatcaccag catgcagacc 240
gaggacgagg gcgtgtactt ctgccagcaa ggcctgacct accctagaac cttcggagga 300
ggcaccaagc tggaactgaa gggcggaggc ggaagtggag gcggaggatc tggcggcgga 360
ggctctgaag tgcagctgca gcagtctggc gctgaactgg tccggcctgg cactagcgtg 420
aagctgtcct gcaaggtgtc cggcgacacc atcaccttct actacatgca cttcgtgaag 480
cagaggccag gacagggcct ggaatggatc ggcagaatcg accctgagga cgagagcacc 540
aagtacagcg agaagttcaa gaacaaggcc accctgaccg ccgacaccag cagcaacacc 600
gcctacctga agctgtctag cctgacctcc gaggacaccg ccacctactt ttgcatctac 660
ggcggctact acttcgacta ctggggccag ggcgtgatgg tcaccgtgtc cagc 714
<210> 14
<211> 238
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Thr Ser Leu Gly
1 5 10 15
Glu Thr Val Thr Ile Gln Cys Gln Ala Ser Glu Asp Ile Tyr Ser Gly
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asp Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Thr Ser Met Gln Thr
65 70 75 80
Glu Asp Glu Gly Val Tyr Phe Cys Gln Gln Gly Leu Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln
115 120 125
Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Leu Ser Cys
130 135 140
Lys Val Ser Gly Asp Thr Ile Thr Phe Tyr Tyr Met His Phe Val Lys
145 150 155 160
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Glu
165 170 175
Asp Glu Ser Thr Lys Tyr Ser Glu Lys Phe Lys Asn Lys Ala Thr Leu
180 185 190
Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu Lys Leu Ser Ser Leu
195 200 205
Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys Ile Tyr Gly Gly Tyr Tyr
210 215 220
Phe Asp Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser
225 230 235
<210> 15
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
atctgggcac ccttggccgg aatctgcgtg gcccttctgc tgtccttgat catcactctc 60
atc 63
<210> 16
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Ile Trp Ala Pro Leu Ala Gly Ile Cys Val Ala Leu Leu Leu Ser Leu
1 5 10 15
Ile Ile Thr Leu Ile
20
<210> 17
<211> 126
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
aggaaaaaat tcccccacat attcaagcaa ccatttaaga agaccactgg agcagctcaa 60
gaggaagatg cttgtagctg ccgatgtcca caggaagaag aaggaggagg aggaggctat 120
gagctg 126
<210> 18
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Arg Lys Lys Phe Pro His Ile Phe Lys Gln Pro Phe Lys Lys Thr Thr
1 5 10 15
Gly Ala Ala Gln Glu Glu Asp Ala Cys Ser Cys Arg Cys Pro Gln Glu
20 25 30
Glu Glu Gly Gly Gly Gly Gly Tyr Glu Leu
35 40
<210> 19
<211> 327
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
agcaggagtg cagagactgc tgccaacctg caggacccca accagctcta caatgagctc 60
aatctagggc gaagagagga atatgacgtc ttggagaaga agcgggctcg ggatccagag 120
atgggaggca aacagcagag gaggaggaac ccccaggaag gcgtatacaa tgcactgcag 180
aaagacaaga tggcagaagc ctacagtgag atcggcacaa aaggcgagag gcggagaggc 240
aaggggcacg atggccttta ccagggtctc agcactgcca ccaaggacac ctatgatgcc 300
ctgcatatgc agaccctggc ccctcgc 327
<210> 20
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Ser Arg Ser Ala Glu Thr Ala Ala Asn Leu Gln Asp Pro Asn Gln Leu
1 5 10 15
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Glu
20 25 30
Lys Lys Arg Ala Arg Asp Pro Glu Met Gly Gly Lys Gln Gln Arg Arg
35 40 45
Arg Asn Pro Gln Glu Gly Val Tyr Asn Ala Leu Gln Lys Asp Lys Met
50 55 60
Ala Glu Ala Tyr Ser Glu Ile Gly Thr Lys Gly Glu Arg Arg Arg Gly
65 70 75 80
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
85 90 95
Thr Tyr Asp Ala Leu His Met Gln Thr Leu Ala Pro Arg
100 105
<210> 21
<211> 135
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
actactacca agccagtgct gcgaactccc tcacctgtgc accctaccgg gacatctcag 60
ccccagagac cagaagattg tcggccccgt ggctcagtga aggggaccgg attggacttc 120
gcctgtgata tttac 135
<210> 22
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Thr Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val His Pro Thr
1 5 10 15
Gly Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly Ser
20 25 30
Val Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr
35 40 45
<210> 23
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 23
atgttccatg tttcttttag gtatatcttt ggacttcctc ccctgatcct tgttctgttg 60
ccagtagcat catctgattg tgatattgaa ggtaaagatg gcaaacaata tgagagtgtt 120
ctaatggtca gcatcgatca attattggac agcatgaaag aaattggtag caattgcctg 180
aataatgaat ttaacttttt taaaagacat atctgtgatg ctaataaggt taaaggaaga 240
aaaccagctg ccctgggtga agcccaacca acaaagagtt tggaagaaaa taaatcttta 300
aaggaacaga aaaaactgaa tgacttgtgt ttcctaaaga gactattaca agagataaaa 360
acttgttgga ataaaatttt gatgggcact aaagaacact ga 402
<210> 24
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile
1 5 10 15
Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys
20 25 30
Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu
35 40 45
Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe
50 55 60
Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Val Lys Gly Arg
65 70 75 80
Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu
85 90 95
Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu
100 105 110
Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met
115 120 125
Gly Thr Lys Glu His
130
<210> 25
<211> 345
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 25
atgagacttc tcatcctggc cctccttggc atctgctctc tcactgcata cattgtggaa 60
ggtgtaggga gtgaagtctc agataagagg acctgtgtga gcctcactac ccagcgactg 120
ccggttagca gaatcaagac ctacaccatc acggaaggct ccttgagagc agtaattttt 180
attaccaaac gtggcctaaa agtctgtgct gatccacaag ccacgtgggt gagagacgtg 240
gtcaggagca tggacaggaa atccaacacc agaaataaca tgatccagac caagccaaca 300
ggaacccagc aatcgaccaa tacagctgtg accctgactg gctag 345
<210> 26
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Met Arg Leu Leu Ile Leu Ala Leu Leu Gly Ile Cys Ser Leu Thr Ala
1 5 10 15
Tyr Ile Val Glu Gly Val Gly Ser Glu Val Ser Asp Lys Arg Thr Cys
20 25 30
Val Ser Leu Thr Thr Gln Arg Leu Pro Val Ser Arg Ile Lys Thr Tyr
35 40 45
Thr Ile Thr Glu Gly Ser Leu Arg Ala Val Ile Phe Ile Thr Lys Arg
50 55 60
Gly Leu Lys Val Cys Ala Asp Pro Gln Ala Thr Trp Val Arg Asp Val
65 70 75 80
Val Arg Ser Met Asp Arg Lys Ser Asn Thr Arg Asn Asn Met Ile Gln
85 90 95
Thr Lys Pro Thr Gly Thr Gln Gln Ser Thr Asn Thr Ala Val Thr Leu
100 105 110
Thr Gly
<210> 27
<211> 465
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 27
atgttccatg tttcttttag atatatcttt ggaattcctc cactgatcct tgttctgctg 60
cctgtcacat catctgagtg ccacattaaa gacaaagaag gtaaagcata tgagagtgta 120
ctgatgatca gcatcgatga attggacaaa atgacaggaa ctgatagtaa ttgcccgaat 180
aatgaaccaa acttttttag aaaacatgta tgtgatgata caaaggaagc tgcttttcta 240
aatcgtgctg ctcgcaagtt gaagcaattt cttaaaatga atatcagtga agaattcaat 300
gtccacttac taacagtatc acaaggcaca caaacactgg tgaactgcac aagtaaggaa 360
gaaaaaaacg taaaggaaca gaaaaagaat gatgcatgtt tcctaaagag actactgaga 420
gaaataaaaa cttgttggaa taaaattttg aagggcagta tataa 465
<210> 28
<211> 154
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Ile Pro Pro Leu Ile
1 5 10 15
Leu Val Leu Leu Pro Val Thr Ser Ser Glu Cys His Ile Lys Asp Lys
20 25 30
Glu Gly Lys Ala Tyr Glu Ser Val Leu Met Ile Ser Ile Asp Glu Leu
35 40 45
Asp Lys Met Thr Gly Thr Asp Ser Asn Cys Pro Asn Asn Glu Pro Asn
50 55 60
Phe Phe Arg Lys His Val Cys Asp Asp Thr Lys Glu Ala Ala Phe Leu
65 70 75 80
Asn Arg Ala Ala Arg Lys Leu Lys Gln Phe Leu Lys Met Asn Ile Ser
85 90 95
Glu Glu Phe Asn Val His Leu Leu Thr Val Ser Gln Gly Thr Gln Thr
100 105 110
Leu Val Asn Cys Thr Ser Lys Glu Glu Lys Asn Val Lys Glu Gln Lys
115 120 125
Lys Asn Asp Ala Cys Phe Leu Lys Arg Leu Leu Arg Glu Ile Lys Thr
130 135 140
Cys Trp Asn Lys Ile Leu Lys Gly Ser Ile
145 150
<210> 29
<211> 345
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
atgagacttc tcctcctgac tttcctggga gtctgctgcc tcaccccatg ggttgtggaa 60
ggtgtgggga ctgaagtcct agaagagagt agctgtgtga acttacaaac ccagcggctg 120
ccagttcaaa aaatcaagac ctatatcatc tgggaggggg ccatgagagc tgtaattttt 180
gtcaccaaac gaggactaaa aatttgtgct gatccagaag ccaaatgggt gaaagcagcg 240
atcaagactg tggatggcag ggccagtacc agaaagaaca tggctgaaac tgttcccaca 300
ggagcccaga ggtccaccag cacagcagta accctgactg ggtaa 345
<210> 30
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Met Arg Leu Leu Leu Leu Thr Phe Leu Gly Val Cys Cys Leu Thr Pro
1 5 10 15
Trp Val Val Glu Gly Val Gly Thr Glu Val Leu Glu Glu Ser Ser Cys
20 25 30
Val Asn Leu Gln Thr Gln Arg Leu Pro Val Gln Lys Ile Lys Thr Tyr
35 40 45
Ile Ile Trp Glu Gly Ala Met Arg Ala Val Ile Phe Val Thr Lys Arg
50 55 60
Gly Leu Lys Ile Cys Ala Asp Pro Glu Ala Lys Trp Val Lys Ala Ala
65 70 75 80
Ile Lys Thr Val Asp Gly Arg Ala Ser Thr Arg Lys Asn Met Ala Glu
85 90 95
Thr Val Pro Thr Gly Ala Gln Arg Ser Thr Ser Thr Ala Val Thr Leu
100 105 110
Thr Gly
<210> 31
<211> 54
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
gagggcagag gaagtcttct aacatgcggt gacgtggagg agaatcccgg ccct 54
<210> 32
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
1 5 10 15
Gly Pro
<210> 33
<211> 72
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 33
atggcctcac cgttgacccg ctttctgtcg ctgaacctgc tgctgctggg tgagtcgatt 60
atcctgggga gt 72
<210> 34
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Met Ala Ser Pro Leu Thr Arg Phe Leu Ser Leu Asn Leu Leu Leu Leu
1 5 10 15
Gly Glu Ser Ile Ile Leu Gly Ser
20
<210> 35
<211> 708
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 35
atgacagtgc tggcgccagc ctggagccca acaacctatc tcctcctgct gctgctgctg 60
agctcgggac tcagtgggac ccaggactgc tccttccaac acagccccat ctcctccgac 120
ttcgctgtca aaatccgtga gctgtctgac tacctgcttc aagattaccc agtcaccgtg 180
gcctccaacc tgcaggacga ggagctctgc gggggcctct ggcggctggt cctggcacag 240
cgctggatgg agcggctcaa gactgtcgct gggtccaaga tgcaaggctt gctggagcgc 300
gtgaacacgg agatacactt tgtcaccaaa tgtgcctttc agcccccccc cagctgtctt 360
cgcttcgtcc agaccaacat ctcccgcctc ctgcaggaga cctccgagca gctggtggcg 420
ctgaagccct ggatcactcg ccagaacttc tcccggtgcc tggagctgca gtgtcagccc 480
gactcctcaa ccctgccacc cccatggagt ccccggcccc tggaggccac agccccgaca 540
gccccgcagc cccctctgct cctcctactg ctgctgcccg tgggcctcct gctgctggcc 600
gctgcctggt gcctgcactg gcagaggacg cggcggagga caccccgccc tggggagcag 660
gtgccccccg tccccagtcc ccaggacctg ctgcttgtgg agcactga 708
<210> 36
<211> 235
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Met Thr Val Leu Ala Pro Ala Trp Ser Pro Thr Thr Tyr Leu Leu Leu
1 5 10 15
Leu Leu Leu Leu Ser Ser Gly Leu Ser Gly Thr Gln Asp Cys Ser Phe
20 25 30
Gln His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu
35 40 45
Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu
50 55 60
Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln
65 70 75 80
Arg Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly
85 90 95
Leu Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala
100 105 110
Phe Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser
115 120 125
Arg Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp
130 135 140
Ile Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro
145 150 155 160
Asp Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala
165 170 175
Thr Ala Pro Thr Ala Pro Gln Pro Pro Leu Leu Leu Leu Leu Leu Leu
180 185 190
Pro Val Gly Leu Leu Leu Leu Ala Ala Ala Trp Cys Leu His Trp Gln
195 200 205
Arg Thr Arg Arg Arg Thr Pro Arg Pro Gly Glu Gln Val Pro Pro Val
210 215 220
Pro Ser Pro Gln Asp Leu Leu Leu Val Glu His
225 230 235
<210> 37
<211> 699
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 37
atgacagtgc tggcgccagc ctggagccca aattcctccc tgttgctgct gttgctgctg 60
ctgagtcctt gcctgcgggg gacacctgac tgttacttca gccacagtcc catctcctcc 120
aacttcaaag tgaagtttag agagttgact gaccacctgc ttaaagatta cccagtcact 180
gtggccgtca atcttcagga cgagaagcac tgcaaggcct tgtggagcct cttcctagcc 240
cagcgctgga tagagcaact gaagactgtg gcagggtcta agatgcaaac gcttctggag 300
gacgtcaaca ccgagataca ttttgtcacc tcatgtacct tccagcccct accagaatgt 360
ctgcgattcg tccagaccaa catctcccac ctcctgaagg acacctgcac acagctgctt 420
gctctgaagc cctgtatcgg gaaggcctgc cagaatttct ctcggtgcct ggaggtgcag 480
tgccagccgg actcctccac cctgctgccc ccaaggagtc ccatagccct agaagccacg 540
gagctcccag agcctcggcc caggcagctg ttgctcctgc tgctgctgct gctgcctctc 600
acactggtgc tgctggcagc cgcctggggc cttcgctggc aaagggcaag aaggaggggg 660
gagctccacc ctggggtgcc cctcccctcc catccctag 699
<210> 38
<211> 232
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Met Thr Val Leu Ala Pro Ala Trp Ser Pro Asn Ser Ser Leu Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Ser Pro Cys Leu Arg Gly Thr Pro Asp Cys Tyr
20 25 30
Phe Ser His Ser Pro Ile Ser Ser Asn Phe Lys Val Lys Phe Arg Glu
35 40 45
Leu Thr Asp His Leu Leu Lys Asp Tyr Pro Val Thr Val Ala Val Asn
50 55 60
Leu Gln Asp Glu Lys His Cys Lys Ala Leu Trp Ser Leu Phe Leu Ala
65 70 75 80
Gln Arg Trp Ile Glu Gln Leu Lys Thr Val Ala Gly Ser Lys Met Gln
85 90 95
Thr Leu Leu Glu Asp Val Asn Thr Glu Ile His Phe Val Thr Ser Cys
100 105 110
Thr Phe Gln Pro Leu Pro Glu Cys Leu Arg Phe Val Gln Thr Asn Ile
115 120 125
Ser His Leu Leu Lys Asp Thr Cys Thr Gln Leu Leu Ala Leu Lys Pro
130 135 140
Cys Ile Gly Lys Ala Cys Gln Asn Phe Ser Arg Cys Leu Glu Val Gln
145 150 155 160
Cys Gln Pro Asp Ser Ser Thr Leu Leu Pro Pro Arg Ser Pro Ile Ala
165 170 175
Leu Glu Ala Thr Glu Leu Pro Glu Pro Arg Pro Arg Gln Leu Leu Leu
180 185 190
Leu Leu Leu Leu Leu Leu Pro Leu Thr Leu Val Leu Leu Ala Ala Ala
195 200 205
Trp Gly Leu Arg Trp Gln Arg Ala Arg Arg Arg Gly Glu Leu His Pro
210 215 220
Gly Val Pro Leu Pro Ser His Pro
225 230
<210> 39
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 39
atgtgtccag cgcgcagcct cctccttgtg gctaccctgg tcctcctgga ccacctcagt 60
ttggccagaa acctccccgt ggccactcca gacccaggaa tgttcccatg ccttcaccac 120
tcccaaaacc tgctgagggc cgtcagcaac atgctccaga aggccagaca aactctagaa 180
ttttaccctt gcacttctga agagattgat catgaagata tcacaaaaga taaaaccagc 240
acagtggagg cctgtttacc attggaatta accaagaatg agagttgcct aaattccaga 300
gagacctctt tcataactaa tgggagttgc ctggcctcca gaaagacctc ttttatgatg 360
gccctgtgcc ttagtagtat ttatgaagac ttgaagatgt accaggtgga gttcaagacc 420
atgaatgcaa agcttctgat ggatcctaag aggcagatct ttctagatca aaacatgctg 480
gcagttattg atgagctgat gcaggccctg aatttcaaca gtgagactgt gccacaaaaa 540
tcctcccttg aagaaccgga tttttataaa actaaaatca agctctgcat acttcttcat 600
gctttcagaa ttcgggcagt gactattgac agagtgacga gctatctgaa tgcttcctaa 660
<210> 40
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Met Cys Pro Ala Arg Ser Leu Leu Leu Val Ala Thr Leu Val Leu Leu
1 5 10 15
Asp His Leu Ser Leu Ala Arg Asn Leu Pro Val Ala Thr Pro Asp Pro
20 25 30
Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val
35 40 45
Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys
50 55 60
Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser
65 70 75 80
Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys
85 90 95
Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala
100 105 110
Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr
115 120 125
Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys
130 135 140
Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu
145 150 155 160
Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr
165 170 175
Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys
180 185 190
Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr
195 200 205
Ile Asp Arg Val Thr Ser Tyr Leu Asn Ala Ser
210 215
<210> 41
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 41
atgtgtcaat cacgctacct cctctttttg gccacccttg ccctcctaaa ccacctcagt 60
ttggccaggg tcattccagt ctctggacct gccaggtgtc ttagccagtc ccgaaacctg 120
ctgaagacca cagatgacat ggtgaagacg gccagagaaa aactgaaaca ttattcctgc 180
actgctgaag acatcgatca tgaagacatc acacgggacc aaaccagcac attgaagacc 240
tgtttaccac tggaactaca caagaacgag agttgcctgg ctactagaga gacttcttcc 300
acaacaagag ggagctgcct gcccccacag aagacgtctt tgatgatgac cctgtgcctt 360
ggtagcatct atgaggactt gaagatgtac cagacagagt tccaggccat caacgcagca 420
cttcagaatc acaaccatca gcagatcatt ctagacaagg gcatgctggt ggccatcgat 480
gagctgatgc agtctctgaa tcataatggc gagactctgc gccagaaacc tcctgtggga 540
gaagcagacc cttacagagt gaaaatgaag ctctgcatcc tgcttcacgc cttcagcacc 600
cgcgtcgtga ccatcaacag ggtgatgggc tatctgagct ccgcctga 648
<210> 42
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Met Cys Gln Ser Arg Tyr Leu Leu Phe Leu Ala Thr Leu Ala Leu Leu
1 5 10 15
Asn His Leu Ser Leu Ala Arg Val Ile Pro Val Ser Gly Pro Ala Arg
20 25 30
Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val
35 40 45
Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp
50 55 60
Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr
65 70 75 80
Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg
85 90 95
Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr
100 105 110
Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys
115 120 125
Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His
130 135 140
Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp
145 150 155 160
Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys
165 170 175
Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys
180 185 190
Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val
195 200 205
Met Gly Tyr Leu Ser Ser Ala
210 215
<210> 43
<211> 462
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 43
atgtacagga tgcaactcct gtcttgcatt gcactaagtc ttgcacttgt cacaaacagt 60
gcacctactt caagttctac aaagaaaaca cagctacaac tggagcattt actgctggat 120
ttacagatga ttttgaatgg aattaataat tacaagaatc ccaaactcac caggatgctc 180
acatttaagt tttacatgcc caagaaggcc acagaactga aacatcttca gtgtctagaa 240
gaagaactca aacctctgga ggaagtgcta aatttagctc aaagcaaaaa ctttcactta 300
agacccaggg acttaatcag caatatcaac gtaatagttc tggaactaaa gggatctgaa 360
acaacattca tgtgtgaata tgctgatgag acagcaacca ttgtagaatt tctgaacaga 420
tggattacct tttgtcaaag catcatctca acactgactt ga 462
<210> 44
<211> 153
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu
20 25 30
Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile
35 40 45
Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe
50 55 60
Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu
65 70 75 80
Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys
85 90 95
Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile
100 105 110
Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala
115 120 125
Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe
130 135 140
Cys Gln Ser Ile Ile Ser Thr Leu Thr
145 150
<210> 45
<211> 510
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 45
atgtacagca tgcagctcgc atcctgtgtc acattgacac ttgtgctcct tgtcaacagc 60
gcacccactt caagctccac ttcaagctct acagcggaag cacagcagca gcagcagcag 120
cagcagcagc agcagcagca cctggagcag ctgttgatgg acctacagga gctcctgagc 180
aggatggaga attacaggaa cctgaaactc cccaggatgc tcaccttcaa attttacttg 240
cccaagcagg ccacagaatt gaaagatctt cagtgcctag aagatgaact tggacctctg 300
cggcatgttc tggatttgac tcaaagcaaa agctttcaat tggaagatgc tgagaatttc 360
atcagcaata tcagagtaac tgttgtaaaa ctaaagggct ctgacaacac atttgagtgc 420
caattcgatg atgagtcagc aactgtggtg gactttctga ggagatggat agccttctgt 480
caaagcatca tctcaacaag ccctcaataa 510
<210> 46
<211> 169
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
1 5 10 15
Leu Val Asn Ser Ala Pro Thr Ser Ser Ser Thr Ser Ser Ser Thr Ala
20 25 30
Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln His Leu
35 40 45
Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser Arg Met Glu Asn
50 55 60
Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe Lys Phe Tyr Leu
65 70 75 80
Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys Leu Glu Asp Glu
85 90 95
Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln Ser Lys Ser Phe
100 105 110
Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile Arg Val Thr Val
115 120 125
Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys Gln Phe Asp Asp
130 135 140
Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp Ile Ala Phe Cys
145 150 155 160
Gln Ser Ile Ile Ser Thr Ser Pro Gln
165
<210> 47
<211> 408
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 47
atggtattgg gaaccataga tttgtgcagc tgtttcagtg cagggcttcc taaaacagaa 60
gccaactggg tgaatgtaat aagtgatttg aaaaaaattg aagatcttat tcaatctatg 120
catattgatg ctactttata tacggaaagt gatgttcacc ccagttgcaa agtaacagca 180
atgaagtgct ttctcttgga gttacaagtt atttcacttg agtccggaga tgcaagtatt 240
catgatacag tagaaaatct gatcatccta gcaaacaaca gtttgtcttc taatgggaat 300
gtaacagaat ctggatgcaa agaatgtgag gaactggagg aaaaaaatat taaagaattt 360
ttgcagagtt ttgtacatat tgtccaaatg ttcatcaaca cttcttga 408
<210> 48
<211> 135
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Met Val Leu Gly Thr Ile Asp Leu Cys Ser Cys Phe Ser Ala Gly Leu
1 5 10 15
Pro Lys Thr Glu Ala Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys
20 25 30
Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr
35 40 45
Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe
50 55 60
Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile
65 70 75 80
His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser
85 90 95
Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu
100 105 110
Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val
115 120 125
Gln Met Phe Ile Asn Thr Ser
130 135
<210> 49
<211> 489
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 49
atgaaaattt tgaaaccata tatgaggaat acatccatct cgtgctactt gtgtttcctt 60
ctaaacagtc actttttaac tgaggctggc attcatgtct tcattttggg ctgtgtcagt 120
gtaggtctcc ctaaaacaga ggccaactgg atagatgtaa gatatgacct ggagaaaatt 180
gaaagcctta ttcaatctat tcatattgac accactttat acactgacag tgactttcat 240
cccagttgca aagttactgc aatgaactgc tttctcctgg aattgcaggt tattttacat 300
gagtacagta acatgactct taatgaaaca gtaagaaacg tgctctacct tgcaaacagc 360
actctgtctt ctaacaagaa tgtagcagaa tctggctgca aggaatgtga ggagctggag 420
gagaaaacct tcacagagtt tttgcaaagc tttatacgca ttgtccaaat gttcatcaac 480
acgtcctga 489
<210> 50
<211> 162
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Met Lys Ile Leu Lys Pro Tyr Met Arg Asn Thr Ser Ile Ser Cys Tyr
1 5 10 15
Leu Cys Phe Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His
20 25 30
Val Phe Ile Leu Gly Cys Val Ser Val Gly Leu Pro Lys Thr Glu Ala
35 40 45
Asn Trp Ile Asp Val Arg Tyr Asp Leu Glu Lys Ile Glu Ser Leu Ile
50 55 60
Gln Ser Ile His Ile Asp Thr Thr Leu Tyr Thr Asp Ser Asp Phe His
65 70 75 80
Pro Ser Cys Lys Val Thr Ala Met Asn Cys Phe Leu Leu Glu Leu Gln
85 90 95
Val Ile Leu His Glu Tyr Ser Asn Met Thr Leu Asn Glu Thr Val Arg
100 105 110
Asn Val Leu Tyr Leu Ala Asn Ser Thr Leu Ser Ser Asn Lys Asn Val
115 120 125
Ala Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Thr Phe
130 135 140
Thr Glu Phe Leu Gln Ser Phe Ile Arg Ile Val Gln Met Phe Ile Asn
145 150 155 160
Thr Ser
<210> 51
<211> 489
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 51
atgagatcca gtcctggcaa catggagagg attgtcatct gtctgatggt catcttcttg 60
gggacactgg tccacaaatc aagctcccaa ggtcaagatc gccacatgat tagaatgcgt 120
caacttatag atattgttga tcagctgaaa aattatgtga atgacttggt ccctgaattt 180
ctgccagctc cagaagatgt agagacaaac tgtgagtggt cagctttttc ctgttttcag 240
aaggcccaac taaagtcagc aaatacagga aacaatgaaa ggataatcaa tgtatcaatt 300
aaaaagctga agaggaaacc accttccaca aatgcaggga gaagacagaa acacagacta 360
acatgccctt catgtgattc ttatgagaaa aaaccaccca aagaattcct agaaagattc 420
aaatcacttc tccaaaagat gattcatcag catctgtcct ctagaacaca cggaagtgaa 480
gattcctga 489
<210> 52
<211> 162
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
Met Arg Ser Ser Pro Gly Asn Met Glu Arg Ile Val Ile Cys Leu Met
1 5 10 15
Val Ile Phe Leu Gly Thr Leu Val His Lys Ser Ser Ser Gln Gly Gln
20 25 30
Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Gln
35 40 45
Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro
50 55 60
Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln
65 70 75 80
Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile
85 90 95
Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala
100 105 110
Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr
115 120 125
Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu
130 135 140
Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu
145 150 155 160
Asp Ser
<210> 53
<211> 441
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 53
atggagagga cccttgtctg tctggtagtc atcttcttgg ggacagtggc ccataaatca 60
agcccccaag ggccagatcg cctcctgatt agacttcgtc accttattga cattgttgaa 120
cagctgaaaa tctatgaaaa tgacttggat cctgaacttc tatcagctcc acaagatgta 180
aaggggcact gtgagcatgc agcttttgcc tgttttcaga aggccaaact caagccatca 240
aaccctggaa acaataagac attcatcatt gacctcgtgg cccagctcag gaggaggctg 300
cctgccagga ggggaggaaa gaaacagaag cacatagcta aatgcccttc ctgtgattcg 360
tatgagaaaa ggacacccaa agaattccta gaaagactaa aatggctcct tcaaaagatg 420
attcatcagc atctctccta g 441
<210> 54
<211> 146
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
Met Glu Arg Thr Leu Val Cys Leu Val Val Ile Phe Leu Gly Thr Val
1 5 10 15
Ala His Lys Ser Ser Pro Gln Gly Pro Asp Arg Leu Leu Ile Arg Leu
20 25 30
Arg His Leu Ile Asp Ile Val Glu Gln Leu Lys Ile Tyr Glu Asn Asp
35 40 45
Leu Asp Pro Glu Leu Leu Ser Ala Pro Gln Asp Val Lys Gly His Cys
50 55 60
Glu His Ala Ala Phe Ala Cys Phe Gln Lys Ala Lys Leu Lys Pro Ser
65 70 75 80
Asn Pro Gly Asn Asn Lys Thr Phe Ile Ile Asp Leu Val Ala Gln Leu
85 90 95
Arg Arg Arg Leu Pro Ala Arg Arg Gly Gly Lys Lys Gln Lys His Ile
100 105 110
Ala Lys Cys Pro Ser Cys Asp Ser Tyr Glu Lys Arg Thr Pro Lys Glu
115 120 125
Phe Leu Glu Arg Leu Lys Trp Leu Leu Gln Lys Met Ile His Gln His
130 135 140
Leu Ser
145
<210> 55
<211> 468
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 55
atgactcctg ggaagacctc attggtgtca ctgctactgc tgctgagcct ggaggccata 60
gtgaaggcag gaatcacaat cccacgaaat ccaggatgcc caaattctga ggacaagaac 120
ttcccccgga ctgtgatggt caacctgaac atccataacc ggaataccaa taccaatccc 180
aaaaggtcct cagattacta caaccgatcc acctcacctt ggaatctcca ccgcaatgag 240
gaccctgaga gatatccctc tgtgatctgg gaggcaaagt gccgccactt gggctgcatc 300
aacgctgatg ggaacgtgga ctaccacatg aactctgtcc ccatccagca agagatcctg 360
gtcctgcgca gggagcctcc acactgcccc aactccttcc ggctggagaa gatactggtg 420
tccgtgggct gcacctgtgt caccccgatt gtccaccatg tggcctaa 468
<210> 56
<211> 155
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 56
Met Thr Pro Gly Lys Thr Ser Leu Val Ser Leu Leu Leu Leu Leu Ser
1 5 10 15
Leu Glu Ala Ile Val Lys Ala Gly Ile Thr Ile Pro Arg Asn Pro Gly
20 25 30
Cys Pro Asn Ser Glu Asp Lys Asn Phe Pro Arg Thr Val Met Val Asn
35 40 45
Leu Asn Ile His Asn Arg Asn Thr Asn Thr Asn Pro Lys Arg Ser Ser
50 55 60
Asp Tyr Tyr Asn Arg Ser Thr Ser Pro Trp Asn Leu His Arg Asn Glu
65 70 75 80
Asp Pro Glu Arg Tyr Pro Ser Val Ile Trp Glu Ala Lys Cys Arg His
85 90 95
Leu Gly Cys Ile Asn Ala Asp Gly Asn Val Asp Tyr His Met Asn Ser
100 105 110
Val Pro Ile Gln Gln Glu Ile Leu Val Leu Arg Arg Glu Pro Pro His
115 120 125
Cys Pro Asn Ser Phe Arg Leu Glu Lys Ile Leu Val Ser Val Gly Cys
130 135 140
Thr Cys Val Thr Pro Ile Val His His Val Ala
145 150 155
<210> 57
<211> 477
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 57
atgagtccag ggagagcttc atctgtgtct ctgatgctgt tgctgctgct gagcctggcg 60
gctacagtga aggcagcagc gatcatccct caaagctcag cgtgtccaaa cactgaggcc 120
aaggacttcc tccagaatgt gaaggtcaac ctcaaagtct ttaactccct tggcgcaaaa 180
gtgagctcca gaaggccctc agactacctc aaccgttcca cgtcaccctg gactctccac 240
cgcaatgaag accctgatag atatccctct gtgatctggg aagctcagtg ccgccaccag 300
cgctgtgtca atgcggaggg aaagctggac caccacatga attctgttct catccagcaa 360
gagatcctgg tcctgaagag ggagcctgag agctgcccct tcactttcag ggtcgagaag 420
atgctggtgg gtgtgggctg cacctgcgtg gcctcgattg tccgccaggc agcctaa 477
<210> 58
<211> 158
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 58
Met Ser Pro Gly Arg Ala Ser Ser Val Ser Leu Met Leu Leu Leu Leu
1 5 10 15
Leu Ser Leu Ala Ala Thr Val Lys Ala Ala Ala Ile Ile Pro Gln Ser
20 25 30
Ser Ala Cys Pro Asn Thr Glu Ala Lys Asp Phe Leu Gln Asn Val Lys
35 40 45
Val Asn Leu Lys Val Phe Asn Ser Leu Gly Ala Lys Val Ser Ser Arg
50 55 60
Arg Pro Ser Asp Tyr Leu Asn Arg Ser Thr Ser Pro Trp Thr Leu His
65 70 75 80
Arg Asn Glu Asp Pro Asp Arg Tyr Pro Ser Val Ile Trp Glu Ala Gln
85 90 95
Cys Arg His Gln Arg Cys Val Asn Ala Glu Gly Lys Leu Asp His His
100 105 110
Met Asn Ser Val Leu Ile Gln Gln Glu Ile Leu Val Leu Lys Arg Glu
115 120 125
Pro Glu Ser Cys Pro Phe Thr Phe Arg Val Glu Lys Met Leu Val Gly
130 135 140
Val Gly Cys Thr Cys Val Ala Ser Ile Val Arg Gln Ala Ala
145 150 155
<210> 59
<211> 582
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 59
atggctgctg aaccagtaga agacaattgc atcaactttg tggcaatgaa atttattgac 60
aatacgcttt actttatagc tgaagatgat gaaaacctgg aatcagatta ctttggcaag 120
cttgaatcta aattatcagt cataagaaat ttgaatgacc aagttctctt cattgaccaa 180
ggaaatcggc ctctatttga agatatgact gattctgact gtagagataa tgcaccccgg 240
accatattta ttataagtat gtataaagat agccagccta gaggtatggc tgtaactatc 300
tctgtgaagt gtgagaaaat ttcaactctc tcctgtgaga acaaaattat ttcctttaag 360
gaaatgaatc ctcctgataa catcaaggat acaaaaagtg acatcatatt ctttcagaga 420
agtgtcccag gacatgataa taagatgcaa tttgaatctt catcatacga aggatacttt 480
ctagcttgtg aaaaagagag agaccttttt aaactcattt tgaaaaaaga ggatgaattg 540
ggggatagat ctataatgtt cactgttcaa aacgaagact ag 582
<210> 60
<211> 193
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
Met Ala Ala Glu Pro Val Glu Asp Asn Cys Ile Asn Phe Val Ala Met
1 5 10 15
Lys Phe Ile Asp Asn Thr Leu Tyr Phe Ile Ala Glu Asp Asp Glu Asn
20 25 30
Leu Glu Ser Asp Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile
35 40 45
Arg Asn Leu Asn Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro
50 55 60
Leu Phe Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg
65 70 75 80
Thr Ile Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met
85 90 95
Ala Val Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys
100 105 110
Glu Asn Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile
115 120 125
Lys Asp Thr Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly
130 135 140
His Asp Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe
145 150 155 160
Leu Ala Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys
165 170 175
Glu Asp Glu Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu
180 185 190
Asp
<210> 61
<211> 579
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 61
atggctgcca tgtcagaaga ctcttgcgtc aacttcaagg aaatgatgtt tattgacaac 60
acgctttact ttatacctga agaaaatgga gacctggaat cagacaactt tggccgactt 120
cactgtacaa ccgcagtaat acggaatata aatgaccaag ttctcttcgt tgacaaaaga 180
cagcctgtgt tcgaggatat gactgatatt gatcaaagtg ccagtgaacc ccagaccaga 240
ctgataatat acatgtacaa agacagtgaa gtaagaggac tggctgtgac cctctctgtg 300
aaggatagta aaatgtctac cctctcctgt aagaacaaga tcatttcctt tgaggaaatg 360
gatccacctg aaaatattga tgatatacaa agtgatctca tattctttca gaaacgtgtt 420
ccaggacaca acaagatgga gtttgaatct tcactgtatg aaggacactt tcttgcttgc 480
caaaaggaag atgatgcttt caaactcatt ctgaaaaaaa aggatgaaaa tggggataaa 540
tctgtaatgt tcactctcac taacttacat caaagttag 579
<210> 62
<211> 192
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 62
Met Ala Ala Met Ser Glu Asp Ser Cys Val Asn Phe Lys Glu Met Met
1 5 10 15
Phe Ile Asp Asn Thr Leu Tyr Phe Ile Pro Glu Glu Asn Gly Asp Leu
20 25 30
Glu Ser Asp Asn Phe Gly Arg Leu His Cys Thr Thr Ala Val Ile Arg
35 40 45
Asn Ile Asn Asp Gln Val Leu Phe Val Asp Lys Arg Gln Pro Val Phe
50 55 60
Glu Asp Met Thr Asp Ile Asp Gln Ser Ala Ser Glu Pro Gln Thr Arg
65 70 75 80
Leu Ile Ile Tyr Met Tyr Lys Asp Ser Glu Val Arg Gly Leu Ala Val
85 90 95
Thr Leu Ser Val Lys Asp Ser Lys Met Ser Thr Leu Ser Cys Lys Asn
100 105 110
Lys Ile Ile Ser Phe Glu Glu Met Asp Pro Pro Glu Asn Ile Asp Asp
115 120 125
Ile Gln Ser Asp Leu Ile Phe Phe Gln Lys Arg Val Pro Gly His Asn
130 135 140
Lys Met Glu Phe Glu Ser Ser Leu Tyr Glu Gly His Phe Leu Ala Cys
145 150 155 160
Gln Lys Glu Asp Asp Ala Phe Lys Leu Ile Leu Lys Lys Lys Asp Glu
165 170 175
Asn Gly Asp Lys Ser Val Met Phe Thr Leu Thr Asn Leu His Gln Ser
180 185 190
<210> 63
<211> 570
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 63
atgctgggga gcagagctgt aatgctgctg ttgctgctgc cctggacagc tcagggcaga 60
gctgtgcctg ggggcagcag ccctgcctgg actcagtgcc agcagctttc acagaagctc 120
tgcacactgg cctggagtgc acatccacta gtgggacaca tggatctaag agaagaggga 180
gatgaagaga ctacaaatga tgttccccat atccagtgtg gagatggctg tgacccccaa 240
ggactcaggg acaacagtca gttctgcttg caaaggatcc accagggtct gattttttat 300
gagaagctgc taggatcgga tattttcaca ggggagcctt ctctgctccc tgatagccct 360
gtggcgcagc ttcatgcctc cctactgggc ctcagccaac tcctgcagcc tgagggtcac 420
cactgggaga ctcagcagat tccaagcctc agtcccagcc agccatggca gcgtctcctt 480
ctccgcttca aaatccttcg cagcctccag gcctttgtgg ctgtagccgc ccgggtcttt 540
gcccatggag cagcaaccct gagtccctaa 570
<210> 64
<211> 189
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 64
Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr
1 5 10 15
Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln
20 25 30
Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His
35 40 45
Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr
50 55 60
Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln
65 70 75 80
Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly
85 90 95
Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu
100 105 110
Pro Ser Leu Leu Pro Asp Ser Pro Val Ala Gln Leu His Ala Ser Leu
115 120 125
Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr
130 135 140
Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu
145 150 155 160
Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala
165 170 175
Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro
180 185
<210> 65
<211> 591
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 65
atgctggatt gcagagcagt aataatgcta tggctgttgc cctgggtcac tcagggcctg 60
gctgtgccta ggagtagcag tcctgactgg gctcagtgcc agcagctctc tcggaatctc 120
tgcatgctag cctggaacgc acatgcacca gcgggacata tgaatctact aagagaagaa 180
gaggatgaag agactaaaaa taatgtgccc cgtatccagt gtgaagatgg ttgtgaccca 240
caaggactca aggacaacag ccagttctgc ttgcaaagga tccgccaagg tctggctttt 300
tataagcacc tgcttgactc tgacatcttc aaaggggagc ctgctctact ccctgatagc 360
cccatggagc aacttcacac ctccctacta ggactcagcc aactcctcca gccagaggat 420
cacccccggg agacccaaca gatgcccagc ctgagttcta gtcagcagtg gcagcgcccc 480
cttctccgtt ccaagatcct tcgaagcctc caggcctttt tggccatagc tgcccgggtc 540
tttgcccacg gagcagcaac tctgactgag cccttagtgc caacagctta a 591
<210> 66
<211> 196
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 66
Met Leu Asp Cys Arg Ala Val Ile Met Leu Trp Leu Leu Pro Trp Val
1 5 10 15
Thr Gln Gly Leu Ala Val Pro Arg Ser Ser Ser Pro Asp Trp Ala Gln
20 25 30
Cys Gln Gln Leu Ser Arg Asn Leu Cys Met Leu Ala Trp Asn Ala His
35 40 45
Ala Pro Ala Gly His Met Asn Leu Leu Arg Glu Glu Glu Asp Glu Glu
50 55 60
Thr Lys Asn Asn Val Pro Arg Ile Gln Cys Glu Asp Gly Cys Asp Pro
65 70 75 80
Gln Gly Leu Lys Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile Arg Gln
85 90 95
Gly Leu Ala Phe Tyr Lys His Leu Leu Asp Ser Asp Ile Phe Lys Gly
100 105 110
Glu Pro Ala Leu Leu Pro Asp Ser Pro Met Glu Gln Leu His Thr Ser
115 120 125
Leu Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Asp His Pro Arg Glu
130 135 140
Thr Gln Gln Met Pro Ser Leu Ser Ser Ser Gln Gln Trp Gln Arg Pro
145 150 155 160
Leu Leu Arg Ser Lys Ile Leu Arg Ser Leu Gln Ala Phe Leu Ala Ile
165 170 175
Ala Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Thr Glu Pro Leu
180 185 190
Val Pro Thr Ala
195
<210> 67
<211> 345
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 67
atgagacttc tcatcctggc cctccttggc atctgctctc tcactgcata cattgtggaa 60
ggtgtaggga gtgaagtctc acataggagg acctgtgtga gcctcactac ccagcgactg 120
ccagttagca gaatcaagac ctacaccatc acggaaggct ccttgagagc agtaattttt 180
attaccaaac gtggcctaaa agtctgtgct gatccacaag ccacgtgggt gagagacgtg 240
gtcaggagca tggacaggaa atccaacacc agaaataaca tgatccagac caagccaaca 300
ggaacccagc aatcgaccaa tacagctgtg accctgactg gctag 345
<210> 68
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 68
Met Arg Leu Leu Ile Leu Ala Leu Leu Gly Ile Cys Ser Leu Thr Ala
1 5 10 15
Tyr Ile Val Glu Gly Val Gly Ser Glu Val Ser His Arg Arg Thr Cys
20 25 30
Val Ser Leu Thr Thr Gln Arg Leu Pro Val Ser Arg Ile Lys Thr Tyr
35 40 45
Thr Ile Thr Glu Gly Ser Leu Arg Ala Val Ile Phe Ile Thr Lys Arg
50 55 60
Gly Leu Lys Val Cys Ala Asp Pro Gln Ala Thr Trp Val Arg Asp Val
65 70 75 80
Val Arg Ser Met Asp Arg Lys Ser Asn Thr Arg Asn Asn Met Ile Gln
85 90 95
Thr Lys Pro Thr Gly Thr Gln Gln Ser Thr Asn Thr Ala Val Thr Leu
100 105 110
Thr Gly
Claims (29)
1.一种工程化免疫细胞,其表达(i)特异性识别配体的细胞表面分子,(ii)外源性的IL-7,和(iii)外源性的Flt3L、XCL2和/或XCL1基因。
2.权利要求1所述的工程化免疫细胞,其中所述特异性识别配体的细胞表面分子是嵌合抗原受体或T细胞受体。
3.权利要求2所述的工程化免疫细胞,其中所述特异性识别配体的细胞表面分子是包含以下的嵌合抗原受体:配体结合结构域、跨膜结构域、共刺激结构域和胞内信号传导结构域。
4.权利要求1所述的工程化免疫细胞,其中所述Flt3L基因如SEQ ID NO:35或37所示,或者所述Flt3L基因编码的多肽如SEQ ID NO:36或38所示。
5.权利要求1所述的工程化免疫细胞,其中所述IL-7的编码基因如SEQ ID NO:23或27所示,或者所述IL-7如SEQ ID NO:24或28所示。
6.权利要求1所述的工程化免疫细胞,其中所述XCL1基因如SEQ ID NO:25或29所示,或者所述XCL1基因编码的多肽如SEQ ID NO:26或30所示。
7.权利要求1所述的工程化免疫细胞,其中所述XCL2基因如SEQ ID NO:67所示,或者所述XCL2基因编码的多肽如SEQ ID NO:68所示。
8.权利要求1所述的工程化免疫细胞,其中所述免疫细胞选自T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞、或NKT细胞。
9.权利要求8所述的工程化免疫细胞,其中所述T细胞是CD4+/CD8+ T细胞、CD4+辅助T细胞、CD8+T细胞、肿瘤浸润细胞、记忆T细胞、幼稚T细胞、γδ-T细胞或αβ-T细胞。
10.权利要求3所述的工程化免疫细胞,其中所述配体结合结构域可以选自scFv、Fab、单结构域抗体、纳米抗体、抗原结合配体、重组纤连蛋白结构域、anticalin和DARPIN。
11.权利要求3所述的工程化免疫细胞,其中所述配体结合结构域与选自以下的靶标结合:TSHR、CD19、CD123、CD22、BAFF-R、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、GD2、GD3、BCMA、GPRC5D、Tn抗原、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、间皮素、IL-l lRa、PSCA、PRSS21、 VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、AFP、Folate 受体α、ERBB2 (Her2/neu)、MUC1、EGFR、CS1、CD138、NCAM、Claudin18.2、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gploo、bcr-abl、酪氨酸酶、EphA2、FucosylGMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD 179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、豆荚蛋白、HPV E6、E7、MAGE Al、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、TMPRSS2 ETS融合基因、NA17、PAX3、雄激素受体、CyclinBl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D或它们的任意组合。
12.权利要求3-11任一项所述的工程化免疫细胞,其中所述跨膜结构域选自以下蛋白质的跨膜结构域:TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137和CD154。
13.权利要求3-11任一项所述的工程化免疫细胞,其中所述胞内信号传导结构域选自以下蛋白的信号传导结构域:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d。
14.权利要求3-11任一项所述的工程化免疫细胞,其中所述共刺激结构域是一个或多个选自以下蛋白质的共刺激信号传导结构域:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70。
15.权利要求1所述的工程化免疫细胞,其中所述免疫细胞还包含至少一种失活基因,其选自以下:CD52、GR、TCRα、TCRβ、CD3γ、CD3δ、CD3ε、CD247ζ、HLA-I、HLA-II、B2M、PD1、CTLA-4、LAG3和TIM3。
16.权利要求1所述的工程化免疫细胞,其中所述IL-7、Flt3L、XCL2和/或XCL1基因的表达是条件型表达。
17.权利要求16所述的工程化细胞,其中所述IL-7、Flt3L、XCL2和/或XCL1基因与诱导型、阻遏型或组织特异性启动子可操作连接从而被条件型表达。
18.权利要求1所述的工程化免疫细胞,其中所述IL-7、Flt3L、XCL2和/或XCL1基因与定位结构域可操作连接。
19.一种核酸分子,其包含:(i)编码特异性识别配体的细胞表面分子的核酸序列,(ii)编码IL-7的核酸序列,和(iii)编码Flt3L、XCL2和/或XCL1的核酸序列。
20.权利要求19所述的核酸分子,其中所述特异性识别配体的细胞表面分子是嵌合抗原受体。
21.一种载体,其包含权利要求19-20任一项所述的核酸分子。
22.权利要求21所述的载体,其中所述载体选自质粒、逆转录病毒、慢病毒、腺病毒、牛痘病毒、劳氏肉瘤病毒(RSV)、多瘤病毒和腺相关病毒(AAV)。
23.一种试剂盒,其包含权利要求1-18任一项所述的工程化免疫细胞、权利要求19-20任一项所述的核酸分子或权利要求21-22任一项所述的载体。
24.一种药物组合物,其包含权利要求1-18任一项所述的工程化免疫细胞、权利要求19-20任一项所述的核酸分子或权利要求21-22任一项所述的载体,和一种多种药学上可接受的赋型剂。
25.一种制备工程化免疫细胞的方法,包括将以下引入所述免疫细胞:(a)编码特异性识别配体的细胞表面分子的第一核酸序列或其编码的特异性识别配体的细胞表面分子;(b)编码IL-7的第二核酸序列或其编码的IL-7;和(c)编码Flt3L、XCL2和/或XCL1的第三核酸序列或其编码的Flt3L、XCL2和/或XCL1蛋白。
26.权利要求25所述的方法,其中所述特异性识别配体的细胞表面分子是嵌合抗原受体。
27.权利要求25所述的方法,其中所述(a)、(b)和(c)以任何顺序先后依次引入免疫细胞。
28.权利要求25所述的方法,其中所述(a)、(b)和(c)同时引入免疫细胞。
29.权利要求1-18任一项所述的工程化免疫细胞、权利要求19-20任一项所述的核酸分子、权利要求21-22任一项所述的载体、权利要求23所述的试剂盒或权利要求24所述的药物组合物在制备治疗癌症、感染或自身免疫性疾病的药物中的用途。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP21813383.3A EP4089174A4 (en) | 2020-05-27 | 2021-05-24 | MODIFIED IMMUNE CELL AND ITS USE |
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CN114149505B (zh) * | 2021-01-12 | 2022-11-04 | 北京门罗生物科技有限公司 | 治疗b细胞相关疾病的免疫细胞、制备方法及其应用 |
CN115216449A (zh) * | 2021-04-16 | 2022-10-21 | 南京北恒生物科技有限公司 | 工程化免疫细胞及其用途 |
CN115232797A (zh) * | 2021-04-23 | 2022-10-25 | 南京北恒生物科技有限公司 | 工程化免疫细胞及其用途 |
CN113072648B (zh) * | 2021-06-04 | 2021-08-24 | 诺未科技(北京)有限公司 | 一种靶向afp的肝癌疫苗 |
TW202330598A (zh) * | 2021-06-30 | 2023-08-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | 特異性結合baff和il-12/23的抗原結合分子及用途 |
CN115704010A (zh) * | 2021-08-11 | 2023-02-17 | 南京北恒生物科技有限公司 | 工程化免疫细胞及其用途 |
CN115873801A (zh) * | 2021-09-29 | 2023-03-31 | 南京北恒生物科技有限公司 | 工程化免疫细胞及其用途 |
TW202332771A (zh) * | 2021-12-21 | 2023-08-16 | 大陸商深圳市菲鵬生物治療股份有限公司 | 轉基因免疫細胞及其構建方法和應用 |
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CA3169656C (en) | 2023-09-19 |
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