CN114853900A - 新型嵌合抗原受体及其用途 - Google Patents
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- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16041—Use of virus, viral particle or viral elements as a vector
- C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
Abstract
本发明提供一种新型的嵌合抗原受体,其包含抗原结合区、跨膜结构域和胞内信号传导区,所述抗原结合区包含特异性靶向CD7的抗体,所述胞内信号传导区由共刺激结构域、初级信号传导结构域,和γc链或其胞内区组成。本发明还涉及包含本发明的新型嵌合抗原受体的工程化免疫细胞及其药物组合物,以及所述工程化免疫细胞/药物组合物在治疗癌症中的用途。
Description
技术领域
本发明属于免疫治疗领域。更具体地,本发明涉及靶向CD7的新型嵌合抗原受体,及其在治疗疾病中的用途。
背景技术
CD7是一种细胞表面糖蛋白,分子量为约40kDa,属于免疫球蛋白超家族的一员。CD7在大多数的T细胞、NK细胞、髓细胞、T细胞急性淋巴细胞白血病/淋巴瘤、急性粒细胞性白血病和慢性粒细胞白血病中均有表达。据报道,CD7分子通过与其配体K12/SECTM1的结合在T细胞活化期间起到共刺激信号的作用。并且,破坏小鼠T祖细胞中的CD7分子依然会产生正常的T细胞发育和体内平衡,表明CD7似乎对T细胞的发育和功能不会产生关键性的影响,这使其成为治疗急性淋巴细胞白血病(ALL)的非常合适的治疗靶点。实际上,CD7作为治疗白血病和淋巴瘤的细胞毒性分子的靶标已被广泛研究。
目前针对CD7的CAR-T疗法非常有限。因此,本发明旨在提供一种高效的靶向CD7的CAR细胞疗法。
发明概述
在第一个方面,本发明提供一种新型嵌合抗原受体,其包含抗原结合区、跨膜结构域和胞内信号传导区,所述抗原结合区包含特异性靶向CD7的抗体,所述胞内信号传导区由共刺激结构域、初级信号传导结构域,和γc链或其胞内区组成。
在一个优选的实施方案中,γc链的氨基酸序列如SEQ ID NO:14所示;其胞内区的氨基酸序列如SEQ ID NO:16所示。
在一个实施方案中,所述抗体选自IgG、Fab、Fab'、F(ab')2、Fd、Fd′、Fv、scFv、sdFv、线性抗体、单结构域抗体、纳米抗体和双体,优选选自Fab、scFv、单结构域抗体和纳米抗体,最优选是scFv。
在一个实施方案中,所述抗体选自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体、鼠源抗体和嵌合抗体。
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、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、CD94、LTB以及ZAP70。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。
在一个实施方案中,所述初级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,所述初级信号传导结构域包含CD3ζ的信号传导结构域。
在一个实施方案中,所述嵌合抗原受体的抗原结合区还包含靶向第二抗原的抗体,所述第二抗原选自: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、Folate受体α、ERBB2(Her2/neu)、MUC1、EGFR、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。
在第二个方面,本发明还提供包含编码本发明的嵌合抗原受体的序列的核酸、包含所述核酸的载体、以及包含所述核酸或载体的免疫细胞。
在一个实施方案中,本发明提供一种核酸,其包含编码本发明的嵌合抗原受体的序列。优选地,所述核酸是DNA或RNA。
在一个实施方案中,本发明提供包含上述核酸的载体。具体地,所述载体选自线性核酸分子、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)、噬菌体、噬菌粒、粘粒或人工染色体。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,本发明提供包含本发明的核酸或载体的工程化免疫细胞,其能够表达本发明的嵌合抗原受体。在一个具体的实施方案中,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。优选地,所述T细胞是CD4+/CD8+双阳性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、CD4-CD8-T细胞、调节性T细胞、γδ-T细胞或αβ-T细胞。
在一个实施方案中,所述工程化免疫细胞包含内源性CD7和至少一种TCR/CD3基因的表达被抑制或沉默。优选地,所述免疫细胞进一步包含至少一种MHC-II类相关基因的表达被抑制或沉默。
在一个实施方案中,所述TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ和它们的组合;所述MHC-II类相关基因选自:HLA-DPA、HLA-DQ、HLA-DRA、RFX5、RFXAP、RFXANK、CIITA和它们的组合。在一个具体的实施方案中,所述工程化免疫细胞的内源性CD7、选自TRAC和TRBC的至少一种TCR/CD3基因和选自RFX5、RFXAP、RFXANK和CIITA的至少一种MHC-II类基因的表达被抑制或沉默。
在第三个方面,本发明提供一种药物组合物,包含如上定义的本发明的嵌合抗原受体或其编码核酸、载体或包含它们的工程化免疫细胞,和一种或多种药学上可接受的赋型剂。
在第四个方面,在一个方面,本发明还提供一种治疗与CD7表达相关的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工程化免疫细胞或药物组合物。因此,本发明还涵盖工程化免疫细胞及包含其的组合物在制备用于治疗与CD7表达相关的疾病的药物中的用途。
在一个实施方案中,与CD7表达相关的疾病优选选自急性淋巴细胞白血病(ALL,例如T-ALL、NK-ALL)、急性髓细胞白血病(AML)、慢性粒细胞性白血病、慢性淋巴细胞白血病、慢性骨髓性白血病、T淋巴母细胞性淋巴瘤(T-LBL)、非霍奇金淋巴瘤、外周T细胞淋巴瘤(PTCL)、结外NK/T细胞淋巴瘤、γδT细胞淋巴瘤和早期前T淋巴母细胞白血病(ETP-ALL)。
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。
嵌合抗原受体
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,该杂合多肽的基础结构包括抗原结合区(例如抗体的抗原结合部分)、跨膜结构域、共刺激结构域和初级信号传导结构域。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表达CAR的T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。
在一个实施方案中,本发明提供的新型嵌合抗原受体包含抗原结合区、跨膜结构域和胞内信号传导区,所述抗原结合区包含特异性靶向CD7的抗体,所述胞内信号传导区由共刺激结构域、初级信号传导结构域,和γc链或其胞内区组成。换言之,本发明的嵌合抗原受体的胞内区除了共刺激结构域、初级信号传导结构域,以及γc链或其胞内区,并不包含其他具有信号传导作用的结构。因此,与传统的CAR结构的胞内区(包含初级信号传导结构域,或初级信号传导结构域和共刺激结构域)相比,本发明的新型嵌合抗原受体的胞内区还包含γc链或其胞内区。在一个实施方案中,所述胞内信号传导区包含的共刺激结构域、初级信号传导结构域以及γc链或其胞内区按照与细胞膜的距离从近到远依次排列。即共刺激结构域离细胞膜最近,而γc链或其胞内区离细胞膜最远。如本文所用,“抗原结合区”是指可以与抗原结合的任何结构或其功能性变体。抗原结合区可以是抗体或其抗原结合部分。如本文所用,术语“抗体”具有本领域技术人员所理解的最广泛的含义,并且包括单克隆抗体(包含完整抗体)、多克隆抗体、多价抗体、多特异性抗体(例如双特异性抗体)、和能够表现期望的生物活性的携带一个或多个CDR序列的抗体片段或合成多肽。本发明的抗体也包含重组抗体、人抗体、人源化抗体、鼠源抗体、嵌合抗体及其抗原结合部分。“抗体片段”或“抗原结合部分”是指完整抗体的一部分,一般包含完整抗体的抗原结合位点并因此保留结合抗原的能力。本发明中的抗体片段的实例包括但不限于:Fab、Fab'、F(ab')2、Fd片段、Fd′、Fv片段、scFv、二硫键-连接的Fv(sdFv)、抗体的重链可变区(VH)或轻链可变区(VL)、线性抗体、具有两个抗原结合位点的“双体”、单结构域抗体、纳米抗体、所述抗原的天然配体或其功能性片段等。因此,本发明的“抗体”涵盖如上定义的抗体的抗体片段或抗原结合部分。
因此,在一个实施方案中,本发明的抗体选自IgG、Fab、Fab'、F(ab')2、Fd、Fd′、Fv、scFv、sdFv、线性抗体、单结构域抗体、纳米抗体和双体,优选选自Fab、scFv、单结构域抗体和纳米抗体,最优选是scFv。在本发明中,抗体可以是单价或二价,且可以是单特异性、双特异性或多特异性的抗体。
“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。常用的接头例如GSTSGSGKPGSGEGSTKG(SEQ ID NO:66)、GGGGSGGGGSGGGGS(SEQ ID NO:67)。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。
在一个实施方案中,本发明的嵌合抗原受体包含的靶向CD7的抗体包含如SEQ IDNO:1、2、和3所示的CDR-L1、CDR-L2和CDR-L3,和如SEQ ID NO:4、5和6所示的CDR-H1、CDR-H2和CDR-H3。优选地,本发明的靶向CD7的抗体包含与选自SEQ ID NO:7、10、13、16和19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%、98%、99%或100%序列同一性的轻链可变区和与选自SEQ ID NO:8、11、14、17和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%、98%、99%或100%序列同一性的重链可变区。更优选地,本发明的嵌合抗原受体包含抗CD7抗体,其氨基酸序列如SEQ ID NO:9、12、15、18或21所示。
在一个实施方案中,除了靶向CD7的抗体外,本发明的嵌合抗原受体的抗原结合区还包含靶向第二抗原的抗体,所述第二抗原选自: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/Galectin 8、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、CYP1B1、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,所述第二抗原选自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。本领域已知的靶向上述肿瘤抗原的抗体均可用于本发明。
在一个优选的实施方案中,所述靶向第二抗原的抗体是靶向CD19的抗体,其包含:
(1)如SEQ ID NO:44所示的CDR-L1、如SEQ ID NO:45所示的CDR-L2、如SEQ ID NO:46所示的CDR-L3、如SEQ ID NO:47所示的CDR-H1、如SEQ ID NO:48所示的CDR-H2和如SEQID NO:49所示的CDR-H3;或
(2)如SEQ ID NO:50所示的CDR-L1、如SEQ ID NO:51所示的CDR-L2、如SEQ ID NO:52所示的CDR-L3、如SEQ ID NO:53所示的CDR-H1、如SEQ ID NO:54所示的CDR-H2和如SEQID NO:55所示的CDR-H3。
在一个优选的实施方案中,所述靶向第二抗原的抗体是靶向CD19的抗体,其包含与SEQ ID NO:56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%、99%或100%序列同一性的轻链可变区序列和与SEQ ID NO:57或60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%、99%或100%序列同一性的重链可变区序列。更优选地,本发明的嵌合抗原受体包含靶向CD7的抗体和靶向CD19的抗体,所述靶向CD19的抗体的氨基酸序列如SEQ ID NO:58或61所示。
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。当嵌合受体多肽与靶抗原结合时,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人CD8α链,其与SEQ ID NO:22所示的氨基酸序列或与SEQ ID NO:23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抗原结合区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抗原结合区的任何寡肽或多肽。具体地,铰链区用来为抗原结合区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、CD28、CD4、FcγRIIIα受体、IgG4或IgG1的铰链区部分,更优选CD8α、CD28或IgG4铰链,其与SEQ ID NO:38、40或42所示的氨基酸序列或与SEQ ID NO:39、41或43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“初级信号传导结构域”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。初级信号传导结构域负责在抗原结合区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,初级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初级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。初级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)。本发明的初级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的初级信号转导结构域可以包含CD3ζ信号传导结构域,该信号传导结构域与SEQ ID NO:30或32所示的氨基酸序列或SEQ ID NO:31或33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的胞内信号传导区可以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、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、CD94、LTB以及ZAP70。
在一个优选的实施方案中,所述共刺激结构域包含一个或多个选自以下蛋白质的胞内区:DAP10、DAP12、CD27、CD28、CD134、4-1BB或CD278。例如,在一个实施方案中,所述共刺激结构域包含4-1BB的胞内区。在一个实施方案中,所述共刺激结构域包含CD28的胞内区。在一个实施方案中,所述共刺激结构域包含4-1BB的胞内区和CD28的胞内区。
在一个实施方案中,4-1BB的胞内区与SEQ ID NO:28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:29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,CD28的胞内区与SEQ ID NO:26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:27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,除了共刺激结构域和初级信号传导结构域用作信号传导之外,本发明的嵌合抗原受体还包含γc链或其胞内区以增强信号传导。在该实施方案中,本发明的嵌合抗原受体的胞内区(即,用于信号传导的结构)由共刺激结构域、初级信号传导结构域,和γc链或其胞内区这三种信号传导结构组成。这意味着本发明的嵌合抗原受体不包含第四种信号传导结构,例如其他细胞因子的信号传导区,如IL-2Ra、IL2Ra、IL2Rb、IL4Ra、IL7Ra、IL9Ra、IL15Ra、IL21Ra等的胞内区。
如本文所用,术语“γc链”是指细胞因子IL-2、IL-4、IL-7、IL-9、IL-15、IL-21的受体共有的γ链。γc链最初在IL-2受体中被鉴定,后来发现它也参与IL-4、IL-7、IL-9、IL-15、IL-21等受体的组成,因此也称为通用γ链。例如,IL-2受体有三种形式,由α链(也称为IL-2Rα)、β链(也称为IL-2Rβ)和γc链(也称为IL-2Rγ或IL-2Rg)的不同组合形成,其中与其他组合相比,包含全部三条链的IL-2受体与IL-2细胞因子具有最高的亲和力。IL-2受体的三条链锚定在细胞膜上,通过与IL-2的结合将生化信号传递到细胞内。在这些γ链依赖性的细胞因子中,细胞因子受体特有的组分,例如IL-2Rβ、IL-4Rα、IL-7Rα、IL-9Rα、IL-21R等负责与JAK1结合,而γc链则与JAK3结合。当这些细胞因子受体与细胞因子结合时,三个主要的信号通路被激活,包括MAP激酶、PI3激酶和JAK-STAT通路,进而调控T细胞和NK细胞的存活以及增殖。
γc链是分子量为64kD的糖蛋白,由347个氨基酸组成,其中包括232个氨基酸的胞外区,29个氨基酸的跨膜区和86个氨基酸的胞内区。胞内区中含有Src同源区,对促进细胞的生长以及IL-2介导的c-myc、c-fos、c-jun等基因的表达至关重要。在一个实施方案中,可用于本发明的γc链与SEQ ID NO:62所示的氨基酸序列或SEQ ID NO:63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,可用于本发明的γc链胞内区与SEQ ID NO:64所示的氨基酸序列或SEQID NO:65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。优选地,本发明的γc链如SEQ ID NO:63所示,其胞内区如SEQID NO:65所示。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,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,暴露胞外的抗原结合区,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分别连接抗原结合区和信号传导结构域,仅当开关结构互相结合(例如在诱导化合物的存在下)时,抗原结合区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的抗原结合区,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,就可以暴露胞外的抗原结合区,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。
核酸
本发明还提供一种核酸,其包含编码本发明的嵌合抗原受体的序列。
如本文所用,术语“核酸”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一种或多种核酸。
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线性核酸分子(例如DNA或RNA)、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
本发明提供工程化免疫细胞,其包含嵌合抗原受体或其编码核酸。
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。在一个实施方案中,免疫细胞衍生自干细胞,例如成体干细胞、胚胎干细胞、脐带血干细胞、祖细胞、骨髓干细胞、诱导多能干细胞、全能干细胞或造血干细胞等。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、CD4-CD8-T细胞、调节性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多肽。
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引入免疫细胞,使其表达本发明的嵌合抗原受体多肽。“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。
在一个实施方案中,本发明提供的工程化免疫细胞的内源性CD7的表达被抑制或沉默。在一个实施方案中,本发明提供的工程化免疫细胞的至少一种TCR/CD3基因的表达被抑制或沉默。在一个实施方案中,本发明提供的工程化免疫细胞的内源性CD7和至少一种TCR/CD3基因的表达被抑制或沉默。
CD7不仅在肿瘤细胞,例如T细胞急性淋巴细胞白血病/淋巴瘤、急性粒细胞性白血病和慢性粒细胞白血病中表达,在大多数正常T细胞和NK细胞中也有表达。因此,为了避免靶向CD7的CAR细胞之间的互相识别和杀伤,有必要抑制或沉默CAR细胞的内源性CD7基因的表达。
T细胞表面受体(T cell receptor,TCR)是所有T细胞表面的特征性标志,以非共价键与CD3结合形成TCR/CD3复合物,并通过与抗原呈递细胞表面的特异性MHC-抗原肽复合物结合,产生特异性抗原刺激信号,激活T细胞,发挥杀伤作用。因此,抑制或沉默CAR-T细胞中内源性TCR/CD3基因的表达能够避免其对患者体内正常细胞或组织的攻击,进而避免或降低发生移植物抗宿主病(GvHD)的风险。TCR是由两条不同肽链构成的异二聚体,通常分为两类:α/β型和γ/δ型,其中95%以上的外周T淋巴细胞都表达TCRα/β。TCRα链由TRAC基因编码,β链由TRBC基因编码。TCR的每条肽链包括可变区(V区)、恒定区(C区)、跨膜区和胞质区,其中胞质区很短,不具备传递抗原刺激信号的能力。TCR分子属于免疫球蛋白超家族,其抗原特异性存在于V区;V区又各有三个高变区CDR1、CDR2、CDR3,其中以CDR3变异最大,直接决定了TCR的抗原结合特异性。在TCR识别MHC-抗原肽复合物时,CDR1、CDR2识别并结合MHC分子,而CDR3直接与抗原肽相结合。CD3包括四种亚基:γ、δ、ε、ζ,通常以二聚体εγ、εδ、ζζ的形式存在。这四种亚基均包含保守的免疫受体酪氨酸激活基序(Immunoreceptortyrosine-based activation motif,ITAM),其中的2个酪氨酸残基被酪氨酸蛋白激酶磷酸化后,向T细胞传递活化信号。因此,在一个实施方案中,至少一种TCR/CD3基因选自:TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ。
在一个实施方案中,本发明提供的工程化免疫细胞的至少一种MHC-II类相关基因的表达被抑制或沉默。在一个实施方案中,本发明提供的工程化免疫细胞的内源性CD7和至少一种MHC-II类相关基因的表达被抑制或沉默。在一个实施方案中,本发明提供的工程化免疫细胞的至少一种TCR/CD3基因和至少一种MHC-II类相关基因的表达被抑制或沉默。在一个实施方案中,本发明提供的工程化免疫细胞的内源性CD7、至少一种TCR/CD3基因和至少一种MHC-II类相关基因的表达被抑制或沉默。在该实施方案中,MHC-II类相关基因包括MHC-II类基因本身,以及与MHC-II类基因相互作用或调控其表达的基因。
主要组织相容性复合物(major histocompatibility complex,MHC)最初被表征为在移植反应中起主要作用的蛋白,其在所有高等脊椎动物的表面上上表达,并且在小鼠中称为H-2,在人细胞中称为HLA。MHC主要有两类:I类和II类。I类MHC蛋白是两种蛋白质的异二聚体:一种是由MHC I基因编码的跨膜蛋白α链,另一种是由不位于MHC基因簇内的基因编码的细胞外蛋白质的β2微球蛋白链。α链包括三个结构域,外来肽与两个在N末端也最可变的结构域α1、α2结合。II类MHC蛋白也是异二聚体,包含两个由MHC复合物内的基因编码的跨膜蛋白。I类MHC/抗原复合物与细胞毒性T细胞(例如CD8+ T细胞)相互作用,而II类MHC向辅助T细胞(例如CD4+ T细胞)呈递抗原。此外,I类MHC蛋白倾向于在几乎所有有核细胞和血小板(以及小鼠中的红血细胞)中表达,而II类MHC蛋白更具选择性地表达。通常,II类MHC蛋白在B细胞、一些巨噬细胞和单核细胞、激活的T细胞、郎格罕氏细胞(Langerhans cell)和树突细胞上表达。
人的II类HLA簇包含三个主要基因座DP、DQ和DR。II类分子是由均锚定在膜中的α链和β链组成的异二聚体,其中α链为约33-35kDa,并且含有5个外显子。外显子1编码前导肽,外显子2和3编码两个细胞外结构域,外显子4编码跨膜结构域,外显子5编码细胞质尾部。因此,在一个实施方案中,MHC-II类相关基因选自:HLA-DPA、HLA-DQ和HLA-DRA。
MHC-II类基因的表达还取决于多种重要的正向调控蛋白,例如RFX复合物、CIITA等。RFX复合物由三个亚基组成:RFXANK(也称为RFXB)、RFX5和RFX辅助蛋白(也称为RFXAP)。RFX复合物通过促进其他转录因子与II类MHC分子的启动子结合并增强启动子结合的特异性来促进II类MHC分子的表达。CIITA是II类MHC表达的主控制因子。CIITA包括富含酸性氨基酸的N端,富含Pro、Ser、Thr的PST区域,中间的GTP结合区域以及富含Leu重复序列(LRR)的C端,其中N端酸性区域和PST区域是转录激活区域。因此,在一个实施方案中,MHC-II类相关基因选自:RFX5、RFXAP、RFXANK和CIITA。
因此,在一个实施方案中,MHC-II类相关基因选自:HLA-DPA、HLA-DQ、HLA-DRA、RFX5、RFXAP、RFXANK和CIITA,优选选自RFX5、RFXAP、RFXANK和CIITA,更优选RFX5或CIITA。
在一个实施方案中,CAR-T细胞中的内源性MHC-I类基因(例如HLA-A、HLA-B、HLA-C、B2M等)是功能性的。在另一个实施方案中,CAR-T细胞中的内源性MHC-I类基因的表达也被抑制或沉默。
在一个实施方案中,本发明所述的表达靶向CD7的嵌合抗原受体的工程化免疫细胞包括内源性CD7、至少一种TCR/CD3基因和至少一种MHC-II类相关基因的表达被抑制或沉默,其中所述至少一种TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ和它们的组合;所述至少一种MHC-II类相关基因选自HLA-DPA、HLA-DQ、HLA-DRA、RFX5、RFXAP、RFXANK和CIITA。在一个优选的实施方案中,本发明所述的表达靶向CD7的嵌合抗原受体的工程化免疫细胞包括内源性CD7、选自TRAC和TRBC的至少一种TCR/CD3基因和选自RFX5、RFXAP、RFXANK和CIITA的至少一种MHC-II类基因的表达被抑制或沉默。更优选地,本发明所述的表达靶向CD7的嵌合抗原受体的工程化免疫细胞包括内源性CD7、选自TRAC和TRBC的至少一种TCR/CD3基因和RFX5的表达被抑制或沉默。更优选地,本发明所述的表达靶向CD7的嵌合抗原受体的工程化免疫细胞包括内源性CD7、选自TRAC和TRBC的至少一种TCR/CD3基因和CIITA的表达被抑制或沉默。在一个实施方案中,所述工程化免疫细胞中的MHC-I类基因,例如HLA-A、HLA-B、HLA-C和B2M的表达是功能性的。
在一个实施方案中,除了CD7、MHC-II类相关基因和TCR/CD3基因,本发明的工程化免疫细胞还可以包含至少一种选自以下的基因的表达被抑制或沉默:CD52、GR、dCK和免疫检查点基因,如PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。
抑制基因表达或使基因沉默的方法是本领域技术人员熟知的,包括但不限于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、或通过反义寡核苷酸、RNAi、shRNA等技术使基因失活。
在一个实施方案中,本发明的工程化免疫细胞还表达免疫抑制分子,所述免疫抑制分子包含一个或多个免疫细胞抗原结合区、跨膜结构域和共刺激结构域。当将本发明的工程化免疫细胞向受试者施用时,所述免疫抑制分子能够抑制或降低所述受试者体内的免疫细胞(例如NK细胞、T细胞)对外源性的工程化免疫细胞的免疫反应,进而降低HvG风险。在一个实施方案中,所述免疫抑制分子不包含初级信号传导结构域。跨膜结构域、共刺激结构域和初级信号传导结构域的定义如上所述。
在一个实施方案中,所述免疫细胞抗原结合区是靶向免疫细胞抗原的抗体、免疫细胞抗原的配体或其组合。优选地,所述抗体选自Fab、Fab'、F(ab')2、Fd、Fd′、Fv、scFv、sdFv、线性抗体、单结构域抗体、纳米抗体和双体。优选地,所述免疫细胞抗原选自NKG2A、NKG2B、NKG2C、NKG2D、NKG2E、NKP46、LIR1、LIR2、LIR3、LIR5、LIR8、PD-1、TIGIT、TIM3、LAG3、KIR、CEACAM1、LAIR1、SIGLEC7、SIGLCE9、KLRG1、CD2、CD3、CD4、CD5、CD8、CD16a、CD16b、CD25、CD27、CD28、CD30、CD38、CD45、CD48、CD50、CD52、CD56、CD57、CD62L、CD69、CD94、CD96、CD100、CD102、CD122、CD127、CD132、CD137、CD160、CD161、CD178、CD218、CD226、CD244、CD279、CD305、CD337、CS1和它们的组合。优选地,所述免疫细胞抗原选自NKG2A、NKG2B、CD94、LIR1、LIR2、LIR3、SIGLEC7、SIGLCE9、KIR、CEACAM1、LAIR1、KLRG1和它们的组合。在一个实施方案中,所述免疫细胞抗原的配体选自HLA-E、HLA-F、HLA-G、钙黏素(例如E-钙黏素、N-钙黏素、R-钙黏素)、胶原蛋白、OCIL、唾液酸、PD-L1、PD-L2、CD155、CTLA4、CD112、CD113、Gal-9、FGL1或其胞外区。优选地,所述免疫细胞抗原的配体选自HLA-E、HLA-F、HLA-G、E-钙黏素、PD-L1、PD-L2或其胞外区。在一个实施方案中,所述免疫细胞抗原结合区包含抗NKG2A抗体、抗LIR1抗体、抗SIGLEC7抗体、抗SIGLCE9抗体、抗KIR抗体、抗KLRG1抗体、PD-L1胞外区、PD-L2胞外区、E-钙黏素胞外区、HLA-E胞外区、HLA-G胞外区或它们的组合。在一个实施方案中,所述工程化免疫细胞还包含靶向第二抗原的第二嵌合抗原受体,所述第二抗原的定义如上所述。在该实施方案中,所述第二嵌合抗原受体可以包含或不包含γc链或其胞内区。
在一个实施方案中,提供多种免疫细胞,每种免疫细胞被改造为表达一种或多种嵌合抗原受体。例如,在一些实施方案中,将一种免疫细胞改造为表达结合和/或靶向CD7的嵌合抗原受体(例如包含本发明所述抗CD7抗体的CAR),并且将另一种细胞改造为表达结合和/或靶向其他抗原的嵌合抗原受体。在一个实施方案中,免疫细胞也可以表达多特异性嵌合抗原受体,其靶向包括CD7在内的一种或多种抗原。例如,这种多特异性嵌合抗原受体可以包含靶向CD7的多特异性抗体,或者同时包含本发明所述的抗CD7抗体和靶向其他抗原的抗体。在此类实施方案中,所述多种工程化免疫细胞可以一起或单独施用。在一个实施方案中,所述多种免疫细胞可以在同一组合物中或在不同组合物中。细胞的示例性组合物包括本申请以下章节中所描述的组合物。
药物组合物
本发明还提供一种药物组合物,其包含本发明所述的嵌合抗原受体、核酸、载体或工程化免疫细胞作为活性剂,和一种或多种药学上可接受的赋型剂。因此,本发明还涵盖所述嵌合抗原受体、核酸、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'sPharmaceuticalSciences.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IL-2,趋化因子比如IL-8、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页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与CD7表达相关的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以及药物组合物在制备治疗与CD7表达相关的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其他外源性基因(如有)引入所述免疫细胞,并抑制或沉默所述免疫细胞中特定基因的表达(例如内源性CD7、TCR/CD3基因和MHC-II类相关基因),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,与CD7表达相关的疾病包括非实体瘤(诸如血液学肿瘤,例如白血病和淋巴瘤)和实体瘤。血液学肿瘤是血液或骨髓的癌症,包括但不限于急性白血病,诸如急性淋巴细胞白血病(ALL,例如T-ALL、NK-ALL)、急性髓细胞白血病(AML)、急性骨髓性白血病和成髓细胞性、前髓细胞性、粒-单核细胞型、单核细胞性和红白血病;慢性白血病,诸如慢性粒细胞性白血病、慢性骨髓性白血病和慢性淋巴细胞白血病;真性红细胞增多症、淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤(无痛和高等级形式)、外周T细胞淋巴瘤(PTCL)、血管免疫母细胞T细胞淋巴瘤(AITL)、间变性大细胞淋巴瘤(ALCL)、结外NK/T细胞淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症、骨髓增生异常综合征、多毛细胞白血病、伯基特淋巴瘤、弥漫性大细胞淋巴瘤、套细胞淋巴瘤、T淋巴母细胞性淋巴瘤(T-LBL)、γδT细胞淋巴瘤、早期前T淋巴母细胞白血病(ETP-ALL)、小淋巴细胞淋巴瘤(SLL)和脊髓发育不良。实体瘤是通常不包含囊肿或液体区的组织的异常肿块,其可以是良性或恶性的。不同类型的实体瘤以形成它们的细胞类型命名(诸如肉瘤、癌和淋巴瘤)。实体瘤的实例包括但不限于纤维肉瘤、粘液肉瘤、脂肪肉瘤间皮瘤、胰腺癌、卵巢癌、腹膜、大网膜和肠系膜癌、咽癌、前列腺癌、直肠癌、肾癌、皮肤癌、小肠癌、黑素瘤、肾癌,喉癌、软组织癌、胃癌、睾丸癌、结肠癌,食道癌,宫颈癌、腺泡型横纹肌肉瘤、膀胱癌、骨癌、脑癌、乳腺癌、肛门癌、眼癌、肝内胆管癌、关节癌、颈癌、胆囊癌、胸膜癌、鼻癌、中耳癌、口腔癌、外阴癌、甲状腺癌和输尿管癌。
在一个实施方案中,与CD7表达相关的疾病优选选自急性淋巴细胞白血病(ALL,例如T-ALL、NK-ALL)、急性髓细胞白血病(AML)、慢性粒细胞性白血病、慢性淋巴细胞白血病、慢性骨髓性白血病、T淋巴母细胞性淋巴瘤(T-LBL)、非霍奇金淋巴瘤、外周T细胞淋巴瘤(PTCL)、结外NK/T细胞淋巴瘤、γδT细胞淋巴瘤和早期前T淋巴母细胞白血病(ETP-ALL)。
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。
附图说明
图1:示出了bbz-dKO T细胞和bbzg-dKO T细胞上scFv的表达水平。
图2:示出了bbz-dKO T细胞和bbzg-dKO T细胞对靶细胞的杀伤能力。
图3:示出了bbz-dKO T细胞和bbzg-dKO T细胞与靶细胞共培养后的细胞因子释放水平。
图4:示出了bbz-tKO T细胞和bbzg-tKO T细胞上scFv的表达水平。
图5:示出了bbz-tKO T细胞和bbzg-tKO T细胞对靶细胞的杀伤能力。
图6:示出了bbz-tKO T细胞和bbzg-tKO T细胞与靶细胞共培养后的细胞因子释放水平。
图7:示出了CAR7X19 T细胞对两种靶细胞的杀伤能力。
图8:示出了CAR7x19 T细胞与两种靶细胞共培养后的细胞因子释放水平。
图9:表达免疫抑制分子No.1(A)、No.2-3(B)、No.4-10(C)的UNKi-T细胞对NK细胞杀伤效果的抑制作用。Mock T:敲除TRAC/B2M/RFX5三基因的T细胞。
图10:表达免疫抑制分子No.11-13(A,Mock T:敲除B2M的T细胞)和No.14(B,MockT:敲除B2M的T细胞)的UNKi-T细胞对NK细胞杀伤效果的抑制作用。
图11:bbzg-EA CAR-T细胞和bbzg-PA CAR-T细胞对靶细胞Jurkat的杀伤能力。
图12:bbzg-EA CAR-T细胞对NK细胞杀伤作用的抑制效果。
图13:bbzg-PA CAR-T细胞对T细胞杀伤作用的抑制效果。
具体实施方式
实施例1:制备双基因敲除的CD7-UCAR T细胞
合成以下蛋白的编码序列,并将其依次克隆至pLVX载体(Public Protein/Plasmid Library(PPL),货号:PPL00157-4a):CD8α信号肽(SEQ ID NO:36)、抗CD7 scFv(SEQ ID NO:12)、CD8α铰链区(SEQ ID NO:38)、CD8α跨膜区(SEQ ID NO:22)、4-1BB共刺激结构域(SEQ ID NO:28)、CD3ζ初级信号传导结构域(SEQ ID NO:32),获得传统的bbz-CAR质粒,并通过测序确认目标序列的正确插入。用同样的方法获得bbzg-CAR质粒,其与bbz-CAR质粒的唯一区别在于,还包括与CD3ζ初级信号传导结构域连接的γ链胞内区(SEQ ID NO:65),其中γ链胞内区位于CD3ζ的C端。
在无菌管中加入3ml Opti-MEM(Gibco,货号31985-070)稀释上述质粒后,再根据质粒:病毒包装载体:病毒包膜载体=4:2:1的比例加入包装载体psPAX2(Addgene,货号12260)和包膜载体pMD2.G(Addgene,货号12259)。然后,加入120ul X-treme GENE HP DNA转染试剂(Roche,货号06366236001),立即混匀,于室温下孵育15min,然后将质粒/载体/转染试剂混合物逐滴加入到293T细胞的培养瓶中。在24小时和48小时收集病毒,将其合并后,超速离心(25000g,4℃,2.5小时)获得浓缩的bbz-CAR慢病毒和bbzg-CAR慢病毒。
用DynaBeads CD3/CD28 CTSTM(Gibco,货号40203D)激活T细胞,并在37℃和5%CO2下培养1天。然后采用CRISPR/Cas9系统敲除野生型T细胞中的TCR/CD3组分(具体为TRAC基因)和CD7基因,获得TCR/CD7双敲除的dKO-T细胞。未敲除基因的野生型T细胞(即,NT细胞)作为对照。
使用FITC Mouse Anti-Human CD3(BD Pharmingen,货号555916)抗体和PE mouseanti-human CD7(biolegend货号395604),通过流式细胞仪检测T细胞中的TCR和CD7的基因编辑效率,结果如表1所示。
表1.T细胞中的基因表达效率
名称 | TCR/CD3 | CD7 |
dKO-T | 3.7% | 7.6% |
NT | 99% | 96% |
从表1可以看出,本发明制备的dKO-T细胞中相关基因的表达被有效抑制或沉默。
将浓缩后的慢病毒加入dKO-T细胞,获得两种UCAR-T细胞(即,bbz-dKO T细胞和bbzg-dKO T细胞)。在37℃和5%CO2下培养11天之后,使用Biotin-SP(long spacer)AffiniPure Goat Anti-Mouse IgG,F(ab')2Fragment Specific(min X Hu,Bov,Hrs SrProt)(jackson immunoresearch,货号115-065-072)作为一抗,APC Streptavidin(BDPharmingen,货号554067)或PE Streptavidin(BD Pharmingen,货号554061)作为二抗,通过流式细胞仪检测UCAR T细胞上的scFv的表达水平,结果如图1所示。
可以看出,本实施例制备的UCAR-T细胞中的scFv均可以有效表达,表明γ链胞内区的加入不会影响CAR结构的表面表达。
实施例2:UCAR T细胞对靶细胞的杀伤效果和细胞因子释放
2.1UCAR-T细胞对靶细胞的杀伤效果
为了检测CAR-T细胞对靶细胞的杀伤能力,首先以1x104/孔将携带荧光素基因的Jurkat靶细胞铺入96孔板中,然后以2.5:1的效靶比将两种CAR T细胞和NT细胞铺入到96孔板进行共培养,8小时后利用酶标仪测定荧光值。根据计算公式:(靶细胞荧光均值-样品荧光均值)/靶细胞荧光均值×100%,计算得到杀伤效率,结果如图2所示。
可以看出,与NT相比,bbz-dKO T细胞和bbzg-dKO T细胞对靶细胞均有特异性杀伤,并且本发明的bbzg-dKO T细胞对靶细胞的杀伤效果显著高于传统bbz-dKO T细胞。
2.2UCAR-T细胞的细胞因子释放
T细胞杀伤靶细胞时,靶细胞数量减少的同时也会释放细胞因子IL2和IFN-γ等。根据以下步骤,使用酶联免疫吸附法(ELISA)来测定本发明的UCAR T细胞杀伤靶细胞时细胞因子IL2的释放水平。
(1)收集细胞共培养上清液
以1x105/孔将Jurkat靶细胞铺于96孔板中,然后以1:1的比例将两种UCAR T细胞和NT细胞(阴性对照)分别与靶细胞共培养,8小时后收集细胞共培养上清液。
(2)ELISA检测上清中IL2分泌量
使用捕获抗体Purified anti-human IL-2Antibody(Biolegend,货号500302)包被96孔板4℃孵育过夜,然后移除抗体溶液,加入250μL含有2%BSA(sigma,货号V900933-1kg)的PBST(含0.1%吐温的1XPBS)溶液,37℃孵育2小时。然后用250μL PBST(含0.1%吐温的1XPBS)清洗板3次。每孔加入50μL细胞共培养上清液或标准品,并在37℃孵育1小时,然后用250μL PBST(含0.1%吐温的1XPBS)清洗板3次。然后向各孔分别加入50μL检测抗体Anti-IL-2抗体,在37℃孵育1小时后,用250μL PBST(含0.1%吐温的1XPBS)清洗板3次。再加入HRP Streptavidin(Biolegend,货号405210),在37℃孵育30分钟后,弃上清液,加入250μLPBST(含0.1%吐温的1XPBS),清洗5次。向各孔加入50μL TMB底物溶液。使反应在室温下于暗处发生30分钟,之后向各孔中加入50μL 1mol/LH2SO4以停止反应。在停止反应的30分钟内,使用酶标仪检测450nm处吸光度,并根据标准曲线(根据标准品的读值和浓度绘制)计算细胞因子的含量,结果如图3所示。
可以看出,bbz-dKO T细胞和bbzg-dKO T细胞对靶细胞的因子释放均显著高于对照NT组,且bbzg-dKO T细胞的释放水平显著高于bbz-dKO T细胞。
实施例3制备三基因敲除的CD7-UCAR T细胞并验证其功能
用DynaBeads CD3/CD28 CTSTM(Gibco,货号40203D)激活T细胞,并在37℃和5%CO2下培养1天。然后采用CRISPR/Cas9系统敲除野生型T细胞中的TCR/CD3组分(具体为TRAC基因)、CD7基因和MHC-II类相关基因(具体为RFX5),获得TCR/CD7/RFX5三敲除的tKO-T细胞。未敲除基因的野生型T细胞(即,NT细胞)作为对照。
使用FITC Mouse Anti-Human CD3(BD Pharmingen,货号555916)抗体、PE mouseanti-human CD7(biolegend货号395604)和APC anti-human DR,DP,DQ(biolegend,货号361714)抗体,通过流式细胞仪检测T细胞中的TCR/CD7/RFX5的基因编辑效率,结果如表2所示。
表2.T细胞中的基因表达效率
名称 | TCR/CD3 | CD7 | RFX5/MHC-II |
tKO-T | 3.8% | 10.7% | 15.8% |
NT | 99% | 92% | 92% |
从表2可以看出,本发明制备的tKO-T细胞中相关基因的表达被有效抑制或沉默。
将实施例1制备的bbz-CAR慢病毒和bbzg-CAR慢病毒加入tKO-T细胞,获得两种UCAR-T细胞(即,bbz-tKO T细胞和bbzg-tKO T细胞),并通过流式细胞仪检测UCAR T细胞上的scFv的表达水平,结果如图4所示。可以看出,本实施例制备的UCAR T细胞中的scFv均可以有效表达。
根据实施例2所述的方法检测UCAR-T细胞对靶细胞的特异性杀伤活性(效靶比为5:1、2.5:1和1.25:1)和细胞因子IL-2的释放水平,结果分别如图5和图6所示。bbz-tKO T细胞和bbzg-tKO T细胞对靶细胞的特异性杀伤和细胞因子释放均显著高于对照NT组,且bbzg-tKO T细胞的释放水平高于bbz-tKO T细胞。
实施例4.制备双靶点UCAR-T细胞并验证其功能
合成编码以下蛋白的序列,并将其依次克隆至pLVX载体(Public Protein/Plasmid Library(PPL),货号:PPL00157-4a):CD8α信号肽(SEQ ID NO:36)、抗CD7scFv(SEQID NO:12)、连接肽(SEQ ID NO:67)、抗CD19 scFv(SEQ ID NO:58)、CD8α铰链区(SEQ IDNO:38)、CD8α跨膜区(SEQ ID NO:22)、4-1BB胞内区(SEQ ID NO:28)、CD3ζ胞内信号传导结构域(SEQ ID NO:32)和γ链胞内区(SEQ ID NO:65),并通过测序确认目标序列的正确插入。
按照实施例1的方法将上述质粒载体包装为慢病毒,并感染tkO-T细胞,获得CAR7X19 T细胞。未经修饰的野生型T细胞用作阴性对照(NT)。
根据实施例2中所述的方法,检测CAR7X19 T细胞对靶细胞(Nalm6和Jurkat)的杀伤功能,结果如图7所示;用Purified anti-human IFN-γAntibody(Biolegend,货号506502)检测细胞因子IFN-γ的释放水平,结果如图8所示。
可以看出,与NT细胞相比,CAR7X19 T细胞对Nalm6和Jurkat两种靶细胞均具有显著升高的特异性杀伤活性和细胞因子释放水平。
实施例5.免疫抑制分子对NK细胞杀伤作用的抑制效果
按表3所示合成免疫抑制分子No.1-14,并根据实施例1所述的方法,将其克隆至pLVX载体质粒(Public Protein/Plasmid Library(PPL),货号:PPL00157-4a),然后转染进慢病毒,并感染激活的T细胞,获得表达免疫抑制分子的T细胞。采用CRISPR系统敲除表达免疫抑制分子No.1-10的细胞中的TCR/CD3组分(具体为TRAC基因)和MHC相关基因(具体为B2M和RFX5),敲除表达免疫抑制分子No.11-14的细胞中的B2M基因,并用流式细胞仪确认各基因被有效敲除,获得UNKi-T细胞。
表3.免疫抑制分子结构
其中,抗KIR scFv的氨基酸序列如SEQ ID NO:71所示;抗LIR1 scFv-1的氨基酸序列如SEQ ID NO:72所示;抗LIR1 scFv-2的氨基酸序列如SEQ ID NO:73所示;E钙黏素胞外区的氨基酸序列如SEQ ID NO:74所示;提呈肽的氨基酸序列如SEQ ID NO:75所示;突变型B2M的核酸序列如SEQ ID NO:76所示,氨基酸序列如SEQ ID NO:77所示;HLA-E胞外区的氨基酸序列如SEQ ID NO:78所示;HLA-G的氨基酸序列如SEQ ID NO:79所示;抗NKG2A scFv的氨基酸序列如SEQ ID NO:80所示;抗SIGLEC7 scFv的氨基酸序列如SEQ ID NO:81所示;抗SIGLEC7/SIGLEC9 scFv的氨基酸序列如SEQ ID NO:82所示;抗KLRG1 scFv的氨基酸序列如SEQ ID NO:83所示;PDL1信号肽的氨基酸序列如SEQ ID NO:68所示;PDL1胞外区的氨基酸序列如SEQ ID NO:69所示;PDL1跨膜区的氨基酸序列如SEQ ID NO:70所示;IgG4铰链区的氨基酸序列如SEQ ID NO:42所示;CD28铰链区的氨基酸序列如SEQ ID NO:40所示;CD8α跨膜区的氨基酸序列如SEQ ID NO:22所示;CD28跨膜区的氨基酸序列如SEQ ID NO:24所示;CD28共刺激结构域的氨基酸序列如SEQ ID NO:26所示;B2M信号肽的的氨基酸序列如SEQID NO:34所示;CD8α信号肽的的氨基酸序列如SEQ ID NO:36所示。
然后根据以下方法检测表达免疫抑制分子No.1-13的UNKi-T细胞对NK细胞杀伤作用的抑制效果:用Far-Red(invitrogen,货号C34564)标记本发明制备的UNKi-T细胞和Mock-T细胞。然后按照1x104个细胞/孔的浓度将标记好的UNKi-T细胞和NT细胞铺入96孔板,并以2:1的效靶比加入NK92细胞(用于表达免疫抑制分子No.3-10的UNKi-T细胞和MockT细胞)或NK92-KLRG1细胞(用于表达免疫抑制分子No.1-2和11-13的UNKi-T细胞,通过将KLRG1基因引入NK92细胞来制备)进行共培养。16-18小时后,用流式细胞仪检测培养物中T细胞的比例,进而计算NK细胞对T细胞的杀伤效果,结果如图9和图10A所示。
用以下方法检测表达免疫抑制分子No.14的T细胞对NK细胞杀伤作用的抑制效果:将T细胞进行培养并经细胞丝裂霉素C处理,同时将两个异体来源的PBMC(donor1和donor2)采用Far-Red进行标记后,按照T细胞:PBMC=1:2的比例进行共培养。每2-3天进行半换液处理。8d后细胞计数并采用PE anti-human CD3(厂家biolegend,货号:317308)和FITC anti-human CD56(厂家:biolegend,货号:362546)染色,然后通过流式细胞术检测NK细胞群比例。通过细胞总量*NK细胞群比例来计算NK细胞数量,结果如图10B所示。
从图9和图10可以看出,与不表达免疫抑制分子的T细胞相比,表达免疫抑制分子No.1-14的UNKi-T细胞均能显著降低NK细胞对T细胞的杀伤作用。并且,与仅表达免疫细胞抗原结合区和跨膜结构域(即,不包含共刺激结构域)的T细胞(G0、E0、Ecad0)相比,共刺激结构域的加入可以进一步显著增强T细胞对NK细胞杀伤的抑制(G28、E28、ECad28,见图9C)。因此,上述免疫抑制分子可以显著降低NK细胞对UNKi-T细胞的杀伤作用,从而能够有效降低HvGD风险。
实施例6.表达两种免疫抑制分子的CAR-T细胞的杀伤活性以及对免疫细胞杀伤作用的抑制效果
在实施例1制备的bbzg-CAR质粒中进一步包含表1所示的免疫抑制分子No.5和10(通过2A肽连接),获得bbzg-EA质粒;或者进一步包含免疫抑制分子No.14和10(通过2A肽连接),获得bbzg-PA质粒。根据实施例1所述的方法,将上述两种质粒包装入病毒,并转染进敲除TCR/CD7/CIITA三基因的T细胞中,获得表达bbzg-EA和bbzg-PA的通用型CAR-T细胞。敲除TCR/CD7/CIITA三基因的T细胞作为对照(Mock T细胞)。
根据实施例2所述方法检测上述通用型CAR-T细胞对Jurkat靶细胞的杀伤效果,结果如图11所示。可以看出,在各种效靶比下,表达bbzg-EA和bbzg-PA的通用型CAR-T细胞对Jurkat靶细胞都显示出强烈的杀伤效果。
通过以下方法检测上述表达bbzg-EA的通用型CAR-T细胞对NK细胞杀伤作用的抑制效果:用Far-Red(invitrogen,货号C34564)标记本发明制备的bbzg-EA-CAR T细胞和NT细胞。然后按照1x104个细胞/孔的浓度将标记好的bbzg-EA-CAR T细胞和NT细胞铺入96孔板,并以4:1、2:1或1:1的效靶比加入NK92细胞进行共培养。16-18小时后,用流式细胞仪检测培养物中T细胞的比例,进而计算NK细胞对T细胞的杀伤率,结果如图12所示。可以看出,在不同效靶比下,该通用型CAR-T细胞均可以显著抑制NK细胞对其的杀伤效果。
此外,通过以下方法检测上述表达bbzg-PA的通用型CAR-T细胞对T细胞杀伤作用的抑制效果:将CAR-T细胞和NT细胞进行培养并经细胞丝裂霉素C处理,同时将三个异体来源的PBMC(donor1、donor2和donor3)采用Far-Red进行标记后,按照T细胞:PBMC=1:2的比例进行共培养。每2-3天进行半换液处理。8d后细胞计数并采用PE anti-human CD8(厂家biolegend,货号:344706)染色,然后通过流式细胞术检测T细胞群比例。通过细胞总量*T细胞群比例来计算T细胞数量。结果如图13所示。可以看出,表达两种免疫抑制分子组合的通用型CAR-T细胞可以显著抑制T细胞的杀伤作用。
综上,免疫抑制分子不会影响CAR-T细胞的杀伤活性,同时可以显著抑制免疫细胞(例如NK细胞、T细胞等)对其的杀伤作用。
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。
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<120> 新型嵌合抗原受体及其用途
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<213> Artificial Sequence(Artificial Sequence)
<220>
<223> h189-3 scFv
<400> 18
Asp Val Val Met Thr Gln Ser Pro Ala Phe Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ala Pro Lys Leu Leu Ile
35 40 45
Lys Ser Ala Ser Gln Ser Ile Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Ala
65 70 75 80
Glu Asp Ala Ala Met Tyr Phe Cys Gln Gln Ser Asn Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Ser Thr Ser
100 105 110
Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Val
115 120 125
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val
130 135 140
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met
145 150 155 160
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Lys
165 170 175
Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Ala Gln Lys Phe Gln Gly
180 185 190
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
195 200 205
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
210 215 220
Gly Gly Val Tyr Tyr Asp Leu Tyr Tyr Tyr Ala Leu Asp Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser
245
<210> 19
<211> 108
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> h189-4 VL
<400> 19
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Ser Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Asn Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 20
<211> 123
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> h189-4 VH
<400> 20
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Lys Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Val Tyr Tyr Asp Leu Tyr Tyr Tyr Ala Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 21
<211> 249
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> h189-4 scFv
<400> 21
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Ser Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Asn Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Ser Thr Ser
100 105 110
Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Val
115 120 125
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val
130 135 140
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met
145 150 155 160
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Lys
165 170 175
Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Ala Gln Lys Phe Gln Gly
180 185 190
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
195 200 205
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
210 215 220
Gly Gly Val Tyr Tyr Asp Leu Tyr Tyr Tyr Ala Leu Asp Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser
245
<210> 22
<211> 25
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α跨膜结构域
<400> 22
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> 23
<211> 75
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α跨膜结构域
<400> 23
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gcaaa 75
<210> 24
<211> 27
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28跨膜结构域
<400> 24
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 25
<211> 81
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28跨膜结构域
<400> 25
ttttgggtcc tcgtcgtagt tggaggggta cttgcctgtt atagcctcct ggttaccgta 60
gcatttatta tattctgggt g 81
<210> 26
<211> 41
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28共刺激结构域
<400> 26
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 27
<211> 123
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28共刺激结构域
<400> 27
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120
tcc 123
<210> 28
<211> 40
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 28
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
35 40
<210> 29
<211> 120
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 29
cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 60
actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 120
<210> 30
<211> 113
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 30
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
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 31
<211> 339
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 31
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> 32
<211> 114
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 32
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 Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Phe Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
50 55 60
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
65 70 75 80
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser
85 90 95
Thr Ala Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro
100 105 110
Pro Arg
<210> 33
<211> 342
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 33
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctttaacg agctcaatct aggacgaaga gaggagttcg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg cagagaagga agaaccctca ggaaggcctg 180
tacaatgaac tgcagaaaga taagatggcg gaggcctaca gtgagattgg gatgaaaggc 240
gagcgccgga ggggcaaggg gcacgatggc cttttccagg gtctcagtac agccaccaag 300
gacacctttg acgcccttca catgcaggcc ctgccccctc gc 342
<210> 34
<211> 20
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> B2M信号肽
<400> 34
Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
1 5 10 15
Gly Leu Glu Ala
20
<210> 35
<211> 60
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> B2M信号肽
<400> 35
atgtcccgct ctgttgcttt ggctgtgctg gcccttttgt cccttagcgg actggaggcc 60
<210> 36
<211> 21
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α信号肽
<400> 36
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> 37
<211> 63
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α信号肽
<400> 37
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 38
<211> 45
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α铰链区
<400> 38
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> 39
<211> 135
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α铰链区
<400> 39
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 40
<211> 39
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28铰链区
<400> 40
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 41
<211> 117
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28铰链区
<400> 41
attgaagtta tgtatcctcc tccttaccta gacaatgaga agagcaatgg aaccattatc 60
catgtgaaag ggaaacacct ttgtccaagt cccctatttc ccggaccttc taagccc 117
<210> 42
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 42
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 43
<211> 36
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 43
gaaagcaaat acgggccgcc gtgtccaccc tgtccg 36
<210> 44
<211> 11
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1 CDR-L1
<400> 44
Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
1 5 10
<210> 45
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1 CDR-L2
<400> 45
His Thr Ser Arg Leu His Ser
1 5
<210> 46
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1 CDR-L3
<400> 46
Gln Gln Gly Asn Thr Leu Pro Tyr Thr
1 5
<210> 47
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1 CDR-H1
<400> 47
Gly Val Ser Leu Pro Asp Tyr
1 5
<210> 48
<211> 5
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1 CDR-H2
<400> 48
Trp Gly Ser Glu Thr
1 5
<210> 49
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1 CDR-H3
<400> 49
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
1 5 10
<210> 50
<211> 11
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2 CDR-L1
<400> 50
Gln Ala Ser Glu Asp Ile Tyr Ser Gly Leu Ala
1 5 10
<210> 51
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2 CDR-L2
<400> 51
Gly Ala Ser Asp Leu Gln Asp
1 5
<210> 52
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2 CDR-L3
<400> 52
Gln Gln Gly Leu Thr Tyr Pro Arg Thr
1 5
<210> 53
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2 CDR-H1
<400> 53
Gly Asp Thr Ile Thr Phe Tyr
1 5
<210> 54
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2 CDR-H2
<400> 54
Asp Pro Glu Asp Glu Ser
1 5
<210> 55
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2 CDR-H3
<400> 55
Gly Gly Tyr Tyr Phe Asp Tyr
1 5
<210> 56
<211> 107
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1 VL
<400> 56
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
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 57
<211> 120
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1 VH
<400> 57
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Cys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 58
<211> 242
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-1
<400> 58
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
85 90 95
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
115 120 125
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
165 170 175
Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
180 185 190
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
195 200 205
Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
210 215 220
Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
225 230 235 240
Ser Ser
<210> 59
<211> 107
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2 VL
<400> 59
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
100 105
<210> 60
<211> 116
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2 VH
<400> 60
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Val Ser Gly Asp Thr Ile Thr Phe Tyr
20 25 30
Tyr Met His Phe Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Glu Ser Thr Lys Tyr Ser Glu Lys Phe
50 55 60
Lys Asn Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Lys Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ile Tyr Gly Gly Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Val Met Val
100 105 110
Thr Val Ser Ser
115
<210> 61
<211> 238
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv-2
<400> 61
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> 62
<211> 1107
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> γc链
<400> 62
atgttgaagc catcattacc attcacatcc ctcttattcc tgcagctgcc cctgctggga 60
gtggggctga acacgacaat tctgacgccc aatgggaatg aagacaccac agctgatttc 120
ttcctgacca ctatgcccac tgactccctc agtgtttcca ctctgcccct cccagaggtt 180
cagtgttttg tgttcaatgt cgagtacatg aattgcactt ggaacagcag ctctgagccc 240
cagcctacca acctcactct gcattattgg tacaagaact cggataatga taaagtccag 300
aagtgcagcc actatctatt ctctgaagaa atcacttctg gctgtcagtt gcaaaaaaag 360
gagatccacc tctaccaaac atttgttgtt cagctccagg acccacggga acccaggaga 420
caggccacac agatgctaaa actgcagaat ctggtgatcc cctgggctcc agagaaccta 480
acacttcaca aactgagtga atcccagcta gaactgaact ggaacaacag attcttgaac 540
cactgtttgg agcacttggt gcagtaccgg actgactggg accacagctg gactgaacaa 600
tcagtggatt atagacataa gttctccttg cctagtgtgg atgggcagaa acgctacacg 660
tttcgtgttc ggagccgctt taacccactc tgtggaagtg ctcagcattg gagtgaatgg 720
agccacccaa tccactgggg gagcaatact tcaaaagaga atcctttcct gtttgcattg 780
gaagccgtgg ttatctctgt tggctccatg ggattgatta tcagccttct ctgtgtgtat 840
ttctggctgg aacggacgat gccccgaatt cccaccctga agaacctaga ggatcttgtt 900
actgaatacc acgggaactt ttcggcctgg agtggtgtgt ctaagggact ggctgagagt 960
ctgcagccag actacagtga acgactctgc ctcgtcagtg agattccccc aaaaggaggg 1020
gcccttgggg aggggcctgg ggcctcccca tgcaaccagc atagccccta ctgggccccc 1080
ccatgttaca ccctaaagcc tgaaacc 1107
<210> 63
<211> 369
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> γc链
<400> 63
Met Leu Lys Pro Ser Leu Pro Phe Thr Ser Leu Leu Phe Leu Gln Leu
1 5 10 15
Pro Leu Leu Gly Val Gly Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly
20 25 30
Asn Glu Asp Thr Thr Ala Asp Phe Phe Leu Thr Thr Met Pro Thr Asp
35 40 45
Ser Leu Ser Val Ser Thr Leu Pro Leu Pro Glu Val Gln Cys Phe Val
50 55 60
Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro
65 70 75 80
Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn
85 90 95
Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu Ile Thr
100 105 110
Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln Thr Phe
115 120 125
Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln
130 135 140
Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu Asn Leu
145 150 155 160
Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn
165 170 175
Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp
180 185 190
Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe
195 200 205
Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg
210 215 220
Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp
225 230 235 240
Ser His Pro Ile His Trp Gly Ser Asn Thr Ser Lys Glu Asn Pro Phe
245 250 255
Leu Phe Ala Leu Glu Ala Val Val Ile Ser Val Gly Ser Met Gly Leu
260 265 270
Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro
275 280 285
Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu Val Thr Glu Tyr His
290 295 300
Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala Glu Ser
305 310 315 320
Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro
325 330 335
Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Ala Ser Pro Cys Asn
340 345 350
Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu
355 360 365
Thr
<210> 64
<211> 258
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> γc链胞内区
<400> 64
gaacggacga tgccccgaat tcccaccctg aagaacctag aggatcttgt tactgaatac 60
cacgggaact tttcggcctg gagtggtgtg tctaagggac tggctgagag tctgcagcca 120
gactacagtg aacgactctg cctcgtcagt gagattcccc caaaaggagg ggcccttggg 180
gaggggcctg gggcctcccc atgcaaccag catagcccct actgggcccc cccatgttac 240
accctaaagc ctgaaacc 258
<210> 65
<211> 86
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> γc链胞内区
<400> 65
Glu Arg Thr Met Pro Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu
1 5 10 15
Val Thr Glu Tyr His Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys
20 25 30
Gly Leu Ala Glu Ser Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu
35 40 45
Val Ser Glu Ile Pro Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly
50 55 60
Ala Ser Pro Cys Asn Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr
65 70 75 80
Thr Leu Lys Pro Glu Thr
85
<210> 66
<211> 18
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 接头
<400> 66
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 67
<211> 15
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 接头
<400> 67
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 68
<211> 18
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> PDL1信号肽
<400> 68
Met Arg Ile Phe Ala Val Phe Ile Phe Met Thr Tyr Trp His Leu Leu
1 5 10 15
Asn Ala
<210> 69
<211> 223
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> PDL1胞外区
<400> 69
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
50 55 60
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His Leu
210 215 220
<210> 70
<211> 20
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> PDL1跨膜结构域
<400> 70
Val Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr Phe
1 5 10 15
Ile Phe Arg Leu
20
<210> 71
<211> 246
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv
<400> 71
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Ile Pro Ile Phe Gly Ala Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Pro Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Val Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser
145 150 155 160
Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg
180 185 190
Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr
210 215 220
Tyr Cys Gln Gln Arg Ser Asn Trp Met Tyr Thr Phe Gly Gln Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys Arg
245
<210> 72
<211> 243
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1
<400> 72
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Leu Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Leu Pro Ser
50 55 60
Leu Lys Ser Gln Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Thr Glu Leu Gly Arg Gly Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Ala Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly
115 120 125
Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile Leu Leu Thr Gln Ser Pro
130 135 140
Ala Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg
145 150 155 160
Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr
165 170 175
Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser
180 185 190
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys
210 215 220
Gln Gln Ser Tyr Ser Trp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 73
<211> 244
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2
<400> 73
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln
115 120 125
Gln Ser Gly Thr Val Leu Pro Arg Pro Gly Ala Ser Val Lys Met Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr Trp Met His Trp Val
145 150 155 160
Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro
165 170 175
Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe Glu Gly Lys Ala Lys
180 185 190
Leu Thr Ala Val Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys Thr Thr Tyr Asp Gly
210 215 220
Tyr Tyr Ser Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ala Ala
<210> 74
<211> 356
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> E-钙黏素 EC1-EC2
<400> 74
Trp Leu Cys Gln Glu Pro Glu Pro Cys His Pro Gly Phe Asp Ala Glu
1 5 10 15
Ser Tyr Thr Phe Thr Val Pro Arg Arg His Leu Glu Arg Gly Arg Val
20 25 30
Leu Gly Arg Val Asn Phe Glu Asp Cys Thr Gly Arg Gln Arg Thr Ala
35 40 45
Tyr Phe Ser Leu Asp Thr Arg Phe Lys Val Gly Thr Asp Gly Val Ile
50 55 60
Thr Val Lys Arg Pro Leu Arg Phe His Asn Pro Gln Ile His Phe Leu
65 70 75 80
Val Tyr Ala Trp Asp Ser Thr Tyr Arg Lys Phe Ser Thr Lys Val Thr
85 90 95
Leu Asn Thr Val Gly His His His Arg Pro Pro Pro His Gln Ala Ser
100 105 110
Val Ser Gly Ile Gln Ala Glu Leu Leu Thr Phe Pro Asn Ser Ser Pro
115 120 125
Gly Leu Arg Arg Gln Lys Arg Asp Trp Val Ile Pro Pro Ile Ser Cys
130 135 140
Pro Glu Asn Glu Lys Gly Pro Phe Pro Lys Asn Leu Val Gln Ile Lys
145 150 155 160
Ser Asn Lys Asp Lys Glu Gly Lys Val Phe Tyr Ser Ile Thr Gly Gln
165 170 175
Gly Ala Asp Thr Pro Pro Val Gly Val Phe Ile Ile Glu Arg Glu Thr
180 185 190
Gly Trp Leu Lys Val Thr Glu Pro Leu Asp Arg Glu Arg Ile Ala Thr
195 200 205
Tyr Thr Leu Phe Ser His Ala Val Ser Ser Asn Gly Asn Ala Val Glu
210 215 220
Asp Pro Met Glu Ile Leu Ile Thr Val Thr Asp Gln Asn Asp Asn Lys
225 230 235 240
Pro Glu Phe Thr Gln Glu Val Phe Lys Gly Ser Val Met Glu Gly Ala
245 250 255
Leu Pro Gly Thr Ser Val Met Glu Val Thr Ala Thr Asp Ala Asp Asp
260 265 270
Asp Val Asn Thr Tyr Asn Ala Ala Ile Ala Tyr Thr Ile Leu Ser Gln
275 280 285
Asp Pro Glu Leu Pro Asp Lys Asn Met Phe Thr Ile Asn Arg Asn Thr
290 295 300
Gly Val Ile Ser Val Val Thr Thr Gly Leu Asp Arg Glu Ser Phe Pro
305 310 315 320
Thr Tyr Thr Leu Val Val Gln Ala Ala Asp Leu Gln Gly Glu Gly Leu
325 330 335
Ser Thr Thr Ala Thr Ala Val Ile Thr Val Thr Asp Thr Asn Asp Asn
340 345 350
Pro Pro Ile Phe
355
<210> 75
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 75
Val Met Ala Pro Arg Thr Leu Ile Leu
1 5
<210> 76
<211> 297
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 同义突变的B2M
<400> 76
atccagagga ccccgaagat ccaggtttat tctcggcatc ctgccgaaaa tggaaaaagc 60
aattttctca actgttatgt gtctggattt cacccatctg acatagaggt tgaccttctt 120
aagaatggcg agagaatcga gaaggtcgaa cattcagact tgagcttcag caaggattgg 180
agcttttatc ttctttatta tactgaattt actcccactg aaaaggatga atacgcctgc 240
agggtaaacc atgtaacact cagtcagcca aagatcgtaa aatgggaccg agacatg 297
<210> 77
<211> 99
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> B2M
<400> 77
Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu
1 5 10 15
Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro
20 25 30
Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys
35 40 45
Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu
50 55 60
Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys
65 70 75 80
Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp
85 90 95
Arg Asp Met
<210> 78
<211> 284
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> HLA-E胞外区
<400> 78
Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly
1 5 10 15
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
20 25 30
Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg
35 40 45
Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr
50 55 60
Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr
65 70 75 80
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
85 90 95
Trp Met His Gly Cys Glu Leu Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu
130 135 140
Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Arg Ala Tyr Leu
145 150 155 160
Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys
165 170 175
Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Val Thr Leu
260 265 270
Arg Trp Lys Pro Ala Ser Gln Pro Thr Ile Pro Ile
275 280
<210> 79
<211> 283
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> HLA-G胞外区
<400> 79
Gly Ser His Ser Met Arg Tyr Phe Ser Ala Ala Val Ser Arg Pro Gly
1 5 10 15
Arg Gly Glu Pro Arg Phe Ile Ala Met Gly Tyr Val Asp Asp Thr Gln
20 25 30
Phe Val Arg Phe Asp Ser Asp Ser Ala Cys Pro Arg Met Glu Pro Arg
35 40 45
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Glu Glu Glu Thr
50 55 60
Arg Asn Thr Lys Ala His Ala Gln Thr Asp Arg Met Asn Leu Gln Thr
65 70 75 80
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Ser Ser His Thr Leu Gln
85 90 95
Trp Met Ile Gly Cys Asp Leu Gly Ser Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Glu Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Leu Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Ser Lys
130 135 140
Arg Lys Cys Glu Ala Ala Asn Val Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu His Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Met Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Phe Asp Tyr Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Ile Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Val Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Met Leu
260 265 270
Arg Trp Lys Gln Ser Ser Leu Pro Thr Ile Pro
275 280
<210> 80
<211> 244
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv
<400> 80
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Ser Tyr
20 25 30
Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Leu Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Lys Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile
165 170 175
Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His
210 215 220
Gly Asp Tyr Pro Arg Phe Phe Asp Val Trp Gly Gln Gly Thr Thr Val
225 230 235 240
Thr Val Ser Ser
<210> 81
<211> 241
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv
<400> 81
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 Ser Ala Ser Gln Gly Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Ile 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 Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Lys Pro Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Glu Glu
115 120 125
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Met Lys Val Ser Cys
130 135 140
Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr Trp Met Asn Trp Val Arg
145 150 155 160
Gln Ser Pro Glu Lys Gly Leu Glu Trp Val Ala Gln Ile Arg Leu Lys
165 170 175
Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser Val Tyr Leu Gln Met Asn
195 200 205
Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr Tyr Cys Thr Glu Gly Asp
210 215 220
Tyr Asp Ile Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ala
<210> 82
<211> 237
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv
<400> 82
Asp Val Gln Leu Gln Glu Ser Gly Pro Leu Val Lys Pro Ser Gln Ser
1 5 10 15
Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Gly Gly Phe
20 25 30
Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Thr Leu Glu Trp Met
35 40 45
Gly Tyr Ile Gly Tyr Gly Gly Ser Thr Ser Tyr Asn Pro Ser Leu Asn
50 55 60
Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn His Phe Phe Leu
65 70 75 80
Gln Phe Asn Ser Val Thr Thr Asp Asp Ser Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Gly Asp Tyr Leu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser
130 135 140
Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn
145 150 155 160
Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu
165 170 175
Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe
180 185 190
Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val
195 200 205
Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr
210 215 220
Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 83
<211> 241
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv
<400> 83
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Phe Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Arg Ser Asn Asn Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Phe Arg Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Thr Val Glu Pro Leu Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met
130 135 140
Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser
145 150 155 160
Ser Val Ser Ser Asn Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala
165 170 175
Ser Pro Lys Ile Trp Ile Tyr Ser Thr Ser Asn Leu Ala Ser Ala Val
180 185 190
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr
195 200 205
Ile Ser Ser Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Tyr Ser Gly Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys
Claims (31)
1.一种嵌合抗原受体,其包含抗原结合区、跨膜结构域和胞内信号传导区,所述抗原结合区包含特异性靶向CD7的抗体,所述胞内信号传导区由共刺激结构域、初级信号传导结构域,和γc链或其胞内区组成。
2.根据权利要求1所述的嵌合抗原受体,其中所述抗体选自IgG、Fab、Fab'、F(ab')2、Fd、Fd′、Fv、scFv、sdFv、线性抗体、单结构域抗体、纳米抗体和双体。
3.根据权利要求1所述的嵌合抗原受体,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、CD8、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137和CD154。
4.根据权利要求1所述的嵌合抗原受体,其中所述初级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。
5.根据权利要求1所述的嵌合抗原受体,其中所述共刺激结构域是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、CD137、CD150、CD152、CD223、CD270、CD272、CD273、CD274、CD276、CD278、CD357、DAP10、LAT、NKG2C、SLP76、LIGHT、TRIM、CD94、LTB以及ZAP70。
6.根据权利要求1所述的嵌合抗原受体,其中所述γc链与SEQ ID NO:63或65具有至少95%的序列同一性。
7.根据权利要求1所述的嵌合抗原受体,其中所述靶向CD7的抗体包含如SEQ ID NO:1所示的CDR-L1、如SEQ ID NO:2所示的CDR-L2、如SEQ ID NO:3所示的CDR-L3、如SEQ ID NO:4所示的CDR-H1、如SEQ ID NO:5所示的CDR-H2和如SEQ ID NO:6所示的CDR-H3。
8.根据权利要求7所述的嵌合抗原受体,其中所述靶向CD7的抗体包含与选自SEQ IDNO:7、10、13、16和19所示的氨基酸序列具有至少95%序列同一性的轻链可变区和与选自SEQ ID NO:8、11、14、17和20所示的氨基酸序列具有至少95%序列同一性的重链可变区。
9.根据权利要求1所述的嵌合抗原受体,其中所述抗原结合区还包含靶向第二抗原的抗体,所述第二抗原选自: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、Folate受体α、ERBB2(Her2/neu)、MUC1、EGFR、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(TMPRSS2ETS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。
10.根据权利要求9所述的嵌合抗原受体,其中所述靶向第二抗原的抗体是靶向CD19的抗体,其包含:
(1)如SEQ ID NO:44所示的CDR-L1、如SEQ ID NO:45所示的CDR-L2、如SEQ ID NO:46所示的CDR-L3、如SEQ ID NO:47所示的CDR-H1、如SEQ ID NO:48所示的CDR-H2和如SEQ IDNO:49所示的CDR-H3;或
(2)如SEQ ID NO:50所示的CDR-L1、如SEQ ID NO:51所示的CDR-L2、如SEQ ID NO:52所示的CDR-L3、如SEQ ID NO:53所示的CDR-H1、如SEQ ID NO:54所示的CDR-H2和如SEQ IDNO:55所示的CDR-H3。
11.根据权利要求10所述的嵌合抗原受体,其中所述靶向CD19的抗体包含与SEQ IDNO:56或59所示的氨基酸序列具有至少95%序列同一性的轻链可变区和与SEQ ID NO:57或60所示的氨基酸序列具有至少95%序列同一性的重链可变区。
12.一种核酸,其包含编码根据权利要求1-11任一项所述的嵌合抗原受体。
13.一种载体,包含根据权利要求12所述的核酸。
14.根据权利要求13所述的载体,其中所述载体是线性核酸分子、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、腺相关病毒(AAV)、噬菌体、粘粒或人工染色体。
15.一种工程化免疫细胞,其包含根据权利要求1-11任一项所述的嵌合抗原受体、根据权利要求12所述的核酸,或根据权利要求13或14所述的载体。
16.根据权利要求15所述的工程化免疫细胞,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。
17.根据权利要求16所述的工程化免疫细胞,其中所述免疫细胞是选自以下的T细胞:CD4+/CD8+双阳性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、CD4-CD8-T细胞、调节性T细胞、γδ-T细胞和αβ-T细胞。
18.根据权利要求15-17任一项所述的工程化免疫细胞,所述免疫细胞包含内源性CD7的表达被抑制或沉默。
19.根据权利要求15-18任一项所述的工程化免疫细胞,所述免疫细胞包含至少一种TCR/CD3基因的表达被抑制或沉默。
20.根据权利要求15-19任一项所述的工程化免疫细胞,所述免疫细胞包含至少一种MHC-II类相关基因的表达被抑制或沉默。
21.根据权利要求19-20任一项所述的工程化免疫细胞,其中所述TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ和它们的组合。
22.根据权利要求20所述的工程化免疫细胞,其中所述MHC-II类相关基因选自:HLA-DPA、HLA-DQ、HLA-DRA、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
23.根据权利要求22所述的工程化免疫细胞,其中所述工程化免疫细胞的内源性CD7、选自TRAC和TRBC的至少一种TCR/CD3基因和选自RFX5、RFXAP、RFXANK和CIITA的至少一种MHC-II类基因的表达被抑制或沉默。
24.权利要求15-23任一项所述的工程化免疫细胞,其进一步表达免疫抑制分子,所述免疫抑制分子包含一个或多个免疫细胞抗原结合区、跨膜结构域和共刺激结构域。
25.权利要求24所述的工程化免疫细胞,其中所述免疫抑制分子不包含初级信号传导结构域。
26.权利要求24所述的工程化免疫细胞,其中所述免疫细胞抗原结合区是靶向免疫细胞抗原的抗体、免疫细胞抗原的配体或其组合。
27.权利要求24所述的工程化免疫细胞,其中所述免疫细胞抗原选自NKG2A、NKG2B、NKG2C、NKG2D、NKG2E、NKP46、LIR1、LIR2、LIR3、LIR5、LIR8、PD-1、TIGIT、TIM3、LAG3、KIR、CEACAM1、LAIR1、SIGLEC7、SIGLCE9、KLRG1、CD2、CD3、CD4、CD5、CD8、CD16a、CD16b、CD25、CD27、CD28、CD30、CD38、CD45、CD48、CD50、CD52、CD56、CD57、CD62L、CD69、CD94、CD96、CD100、CD102、CD122、CD127、CD132、CD137、CD160、CD161、CD178、CD218、CD226、CD244、CD279、CD305、CD337、CS1和它们的组合。
28.权利要求26所述的工程化免疫细胞,其中所述免疫细胞抗原的配体选自HLA-E、HLA-F、HLA-G、钙黏素(例如E-钙黏素、N-钙黏素、R-钙黏素)、胶原蛋白、OCIL、唾液酸、PD-L1、PD-L2、CD155、CTLA4、CD112、CD113、Gal-9、FGL1或其胞外区。
29.一种药物组合物,包含根据权利要求1-11任一项所述的嵌合抗原受体、根据权利要求12所述的核酸、根据权利要求13或14所述的载体或根据权利要求15-28任一项所述的工程化免疫细胞,和一种或多种药学上可接受的赋型剂。
30.根据权利要求1-11任一项所述的嵌合抗原受体、根据权利要求12所述的核酸、根据权利要求13或14所述的载体、根据权利要求15-28任一项所述的工程化免疫细胞或权利要求29所述的药物组合物在制备用于治疗与CD7表达相关的疾病的药物中的用途。
31.根据权利要求30所述的用途,其中所述与CD7表达相关的疾病选自:急性淋巴细胞白血病、急性髓细胞白血病、慢性粒细胞性白血病、慢性淋巴细胞白血病、慢性骨髓性白血病、T淋巴母细胞性淋巴瘤、非霍奇金淋巴瘤、外周T细胞淋巴瘤、结外NK/T细胞淋巴瘤、γδT细胞淋巴瘤和早期前T淋巴母细胞白血病。
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