CN110386987B - 一种抑制性的合成Notch和双靶点系统及其制备方法和应用 - Google Patents
一种抑制性的合成Notch和双靶点系统及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种抑制性的合成Notch和双靶点系统及其制备方法和应用,其包含有Notch1序列与CSK激酶结合的融合蛋白。利用抑制性的合成Notch得到双靶点系统可以同时靶向两种肿瘤相关抗原,提高T细胞杀伤肿瘤细胞的准确性,有效克服靶向单一肿瘤相关抗原所导致的脱靶毒性。
Description
技术领域
本发明涉及基因工程技术领域,具体涉及一种抑制性的合成Notch和双靶点系统及其制备方法和应用。
背景技术
近几年,肿瘤免疫疗法发展迅速,成为继手术、化疗和放疗之后的第四种治疗手段。肿瘤免疫疗法通过激活或增强人体免疫系统功能而达到杀伤肿瘤的目的,包括肿瘤疫苗、细胞因子、溶瘤病毒、免疫检查点抑制剂和过继免疫细胞治疗(adoptive celltherapy,ACT)等。免疫检查点抑制剂和嵌合抗原受体T细胞 (chimeric antigen receptorT cell,CAR-T),在治疗肿瘤试验中取得重大进展,显示出根治肿瘤的潜力。2013年,《科学》杂志将肿瘤免疫疗法列为年度十大科学突破之首。2017年,美国FDA先后批准两款CD19CAR-T细胞上市,Novartis 的Kymriah治疗儿童和青少年难治/复发急B性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)),以及Kite的Yescarta治疗成人复发性/难治性弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL),成为过继免疫细胞治疗肿瘤的里程碑事件。
经过多年的研究改进,CAR-T细胞已发展至第四代。嵌合抗原受体包括胞外单链可变片段(single-chain variable fragments,scFv)、铰链区(hinge,H)、跨膜区(transmembrane,TM)、胞内共刺激结构域(costimulatory molecule,CM) 和CD3ζ激活结构域。第一代CAR-T细胞内部只具有CD3ζ或FcRγ的激活结构域,增殖能力不足,抗肿瘤效果差。在第一代CAR基础上,增加一个或两个共刺激结构域,如CD28、4-1BB和OX40等,为第二代或第三代CAR-T细胞,大幅提高CAR-T细胞分泌的细胞因子水平和杀伤效果。第四代CAR-T细胞,又称通用细胞因子杀伤的重定向T细胞(T cells redirected for universalcytokine killing, TRUCK),在第二代或第三代CAR-T细胞基础上,表达IL-12等促炎细胞因子或4-1BBL、CD40L等共刺激配体,解除免疫抑制,募集其它免疫细胞迁移到肿瘤微环境(tumor microenvironment,TME),引发广泛的抗肿瘤反应,且杀伤抗原阴性的肿瘤细胞。
迄今为止,CAR-T细胞的临床试验及研究进展主要集中在白血病和淋巴瘤等液体肿瘤领域。CD19 CAR-T细胞获得FDA批准上市,标志CAR-T细胞由临床研究向临床应用转化。然而,CAR-T细胞治疗实体瘤的临床研究进展迟缓,主要原因有实体瘤复杂的异质性、组织隔离屏障、免疫抑制和脱靶毒性(on target/off tumor)等。其中,脱靶毒性问题是一个不可回避的重大挑战。
根据表达组织的专一性程度,肿瘤抗原分为肿瘤特异性抗原(tumor specificantigen,TSA)和肿瘤相关抗原(tumor-associated antigen,TAA)。TSA是指肿瘤细胞所特有的抗原,不表达于任何正常细胞和组织中,如突变蛋白和肿瘤新抗原。TAA是指肿瘤细胞高表达,而正常细胞低表达的抗原。目前,CAR-T细胞识别的肿瘤抗原,特别是实体瘤抗原,只有少数是TSA,绝大部分是TAA,因此普遍存在脱靶毒性问题。CAR-T细胞治疗实体瘤的脱靶毒性的严重程度可危及患者生命。在一项HER2 CAR-T细胞治疗直肠癌合并肝肺转移的试验中,患者发生急性肺水肿,最终死于呼吸衰竭,主要原因是肺血管等组织低表达HER2,引发HER2 CAR-T细胞攻击肺组织。CAIX CAR-T细胞治疗转移性肾细胞癌,患者发生严重的黄疸和胆管炎,因为胆管上皮细胞低表达CAIX,造成CAIX CAR-T 细胞浸润至胆管上皮组织。随着CAR-T细胞的发展和杀伤活性增强,其脱靶毒性更加受到关注。
为解决CAR-T细胞的脱靶毒性问题,已报道的相关策略如下。
(1)选择肿瘤特异性抗原、正常组织表达水平非常低而能够承受脱靶毒性的抗原和肿瘤新抗原,如EGFRvIII、CSPG4和WT1-HLA-A*02:01。
(2)亲和力调节的CAR-T细胞。通过降低scFv的亲和力,使CAR-T细胞杀伤抗原高表达的肿瘤细胞,而避免攻击抗原低表达的正常组织。
(3)组合型双靶点CAR(biCAR)。T细胞表达两种结构不完全的CAR,其中一种CAR具有降低亲和力的scFv和CD3ζ激活结构域,另一种CAR具有高亲和力的scFv和共刺激信号结构域。只有肿瘤细胞同时表达两种抗原,才能充分激活CAR-T细胞的杀伤功能。
(4)抑制性CAR(inhibitory CAR,iCAR)。采用scFv与程序性死亡蛋白 -1(PD-1)或细胞毒性T淋巴细胞相关抗原4(CTLA-4)的抑制性结构域构建嵌合受体,即iCAR,与常规的CAR组成双靶点CAR系统。iCAR识别正常组织抗原,抑制常规CAR的激活和杀伤功能。肿瘤细胞缺少iCAR结合的抗原,iCAR 不能抑制常规CAR的激活,CAR-T细胞杀伤肿瘤细胞。
(5)携带亮氨酸拉链接头的zipCAR。zipCAR与识别不同肿瘤抗原的zipFv 组装成完整的CAR。通过改变zipFv的浓度或亲和力调节CAR-T细胞活性,或者通过两种zipFv竞争性结合zipCAR,达到CAR-T细胞特异性杀伤肿瘤细胞的目的。
(6)合成Notch(synthetic Notch,synNotch)条件诱导表达的CAR。构建由scFv、Notch1和转录因子组成的嵌合蛋白受体,即synNotch。当T细胞synNotch 结合肿瘤细胞的第一种抗原后,被γ-secretase切割跨膜区域,释放胞内的转录因子。转录因子转运至细胞核,启动CAR基因转录和翻译。之后,CAR识别肿瘤细胞的第二种抗原,激活CAR-T细胞的杀伤功能。synNotch条件诱导表达的 CAR,能够减少脱靶毒性,但是CAR的表达和激活存在较长的时间滞后,影响解决脱靶毒性问题的效果。
已报道的多种解决CAR-T脱靶毒性的策略,皆存在各种不足。
(1)选择肿瘤特异性抗原,在目前CAR-T细胞治疗实体瘤的靶点绝大部分是TAA情况下,寻找高特异性的TSA,面临很大的成本和时间挑战。
(2)亲和力调节的CAR-T细胞,不足之处是肿瘤细胞降低抗原表达水平后,不能被CAR-T细胞识别,发生肿瘤逃逸。
(3)组合型双靶点CAR(biCAR),两种抗原的表达水平不均衡将影响相应的CAR协同激活和杀伤效果。
(4)抑制性CAR,理论上,该策略具有解决CAR-T细胞脱靶毒性问题的潜力,但是,寻找正常细胞表达而肿瘤细胞不表达的抗原仍然是一个艰难的挑战。
(5)携带亮氨酸拉链接头的zipCAR,改变zipFv的竞争组合以调控CAR-T 细胞活性,涉及的影响因素多,体系复杂性高,实用性较差。此外,该方法仍然面临寻找正常细胞表达而肿瘤细胞不表达的抗原挑战。
(6)synNotch诱导表达CAR的双靶点系统,synNotch和CAR在结构和功能方面相对独立,通过synNotch的切割,胞内的转录因子片段入核,转录和表达CAR基因。synNotch和CAR两者与抗原靶点的结合及其激活存在先后顺序,且具有较长的时间滞后,解决CAR-T细胞的脱靶毒性问题仍然不足。
发明内容
本发明的目的是提供一种抑制性的合成Notch和双靶点系统及其制备方法和应用,解决现有技术中CAR-T细胞仍然存在脱靶毒性的问题。
本发明解决技术问题所采用的技术方案是:一种抑制性的合成Notch,其包含有Notch1序列与CSK激酶结合的融合蛋白。
该融合蛋白具有与SEQ ID NO:1所示的氨基酸序列,或为与SEQ ID NO:1 所示的氨基酸序列具有50%以上同源性的氨基酸序列。该融合蛋白具有SEQ ID NO:2所示的核苷酸序列。
在本发明的的抑制性的合成Notch中,所述抑制性的合成Notch还包含有与抗原靶点X相结合的scFv,与抗原靶点X相结合的scFv以及Notch1序列、CSK 激酶依次连接。
在本发明的抑制性的合成Notch中,所述抑制性的合成Notch还包含有CD8α信号肽(Leader,L),所述CD8α信号肽(Leader,L)、与抗原靶点X相结合的scFv以及Notch1序列、CSK激酶依次连接。
另外,所述抑制性的合成Notch还可以进一步包含有c-Myc标签。
在本发明的抑制性的合成Notch中,所述Notch1序列具有负调节域(negativeregulatory region,NRR)和跨膜区(TM),所述CD8α信号肽(Leader,L)、与抗原靶点X相结合的scFv以及负调节域(negative regulatory region,NRR)、跨膜区(TM)、CSK激酶依次连接。
其中,上述的抗原靶点X包括但不限于实体瘤的抗原靶点GPC-3、HER2、 CEA、CD147、EGFRvIII、PSMA、Mesothelin、FAP、EGFR、CD171、GD2等,以及B细胞恶性肿瘤的靶点CD22、CD20、ROR1、CD19等、以及髓系恶性肿瘤的靶点CD33、CD123、CD174等,以及复发/难治性多发性骨髓瘤的靶点BCMA、 CD19、CD123等。
本发明还提供了一种双靶点系统,其包含有上述的抑制性的合成Notch(synthetic Notch,synNotch)以及嵌合抗原受体(chimeric antigen receptor,CAR)。其中,抑制性的synNotch可以与各种CAR组合,建立双靶点系统。
该双靶点系统具有SEQ ID NO:3所示的氨基酸序列。
在本发明的双靶点系统中,所述抑制性的合成Notch(synthetic Notch,synNotch)和所述嵌合抗原受体(chimeric antigen receptor,CAR)通过P2A多肽连接。
在本发明的双靶点系统中,所述嵌合抗原受体(chimeric antigen receptor,CAR)包括依次连接的CD8α信号肽(L)、与抗原靶点Y相结合的scFv、CD8 铰链区(H)、CD28跨膜区(TM)、4-1BB和CD3ζ。
其中,上述的抗原靶点Y包括但不限于实体瘤的抗原靶点GPC-3、HER2、 CEA、CD147、EGFRvIII、PSMA、Mesothelin、FAP、EGFR、CD171、GD2 等,以及B细胞恶性肿瘤的靶点CD22、CD20、ROR1、CD19等、以及髓系恶性肿瘤的靶点CD33、CD123、CD174等、以及复发/难治性多发性骨髓瘤的靶点 BCMA、CD19、CD123等。且需要说明的是,抗原靶点Y与抗原靶点X是不同的抗原靶点。
另外,所述嵌合抗原受体(chimeric antigen receptor,CAR)还可以进一步包含有FLAG标签。
本发明还提供了上述的双靶点系统的制备方法,其特征在于,包括:
A、设计抑制性的合成Notch(synthetic Notch,synNotch)和所述嵌合抗原受体(chimeric antigen receptor,CAR)的双靶点系统,确定其结构元件和氨基酸序列;
B、合成双靶点系统的DNA序列,对编码氨基酸的密码子进行人源化优化,将基因序列连接至pWPT-GFP质粒载体,测序验证。
进一步地,该制备方法还包括:
C、采用双靶点系统pWPT-GFP表达质粒、psPAX2和pMD2.G三质粒共转染293T细胞,包装慢病毒,48小时后收集含慢病毒的培养基上清,浓缩慢病毒;
D、慢病毒转导Jurkat T细胞,筛选和分离表达抑制性synNotch和CAR的双靶点系统的Jurkat T单克隆细胞株。
本发明还提供了上述的抑制性的合成Notch在用于制备改造免疫细胞并调节免疫细胞活性的药物、药物组合物、试剂和/或试剂盒中的应用。免疫细胞包括但不限于T细胞、NK细胞、M(巨噬)细胞、CAR-T细胞、TCR-T细胞、CAR-NK 细胞和CAR-M细胞等。
本发明还提供了上述的双靶点系统在用于制备改造免疫细胞并调节免疫细胞活性的药物、药物组合物、试剂和/或试剂盒中的应用。免疫细胞包括但不限于 T细胞、NK细胞、M(巨噬)细胞、CAR-T细胞、TCR-T细胞、CAR-NK细胞和CAR-M细胞等。
本发明还提供了上述的抑制性的合成Notch在用于制备预防和/或治疗肿瘤和/或癌症的药物、药物组合物、试剂和/或试剂盒中的应用。其中,肿瘤包括但不限于实体瘤、B细胞恶性肿瘤、髓系恶性肿瘤、复发/难治性多发性骨髓瘤等。
本发明还提供了上述的双靶点系统在用于制备预防和/或治疗肿瘤和/或癌症的药物、药物组合物、试剂和/或试剂盒中的应用。其中,肿瘤包括但不限于实体瘤、B细胞恶性肿瘤、髓系恶性肿瘤、复发/难治性多发性骨髓瘤等。
实施本发明的抑制性的合成Notch和双靶点系统及其制备方法和应用,具有以下有益效果:(1)基于抑制性的synNotch和CAR的双靶点系统,同时靶向两种肿瘤相关抗原,提高T细胞杀伤肿瘤细胞的准确性,有效克服靶向单一肿瘤相关抗原所导致的脱靶毒性,该双靶点系统反应快速,及时解除抑制性synNotch 对CAR的抑制,保证T细胞迅速响应靶点抗原刺激和杀伤靶细胞,T细胞只有同时结合两种抗原靶点才会被激活,有效解决脱靶毒性问题;(2)抑制性的 synNotch可以抑制T细胞内源性TCR活性,无需敲除TCRα等基因,避免包括CAR-T细胞在内的T细胞发生移植物抗宿主病(graft-versus-host disease,GVHD),为开发适合异体移植CAR-T细胞的提供新的技术手段:(3)建立调控蛋白功能的新方法,通过刺激信号诱导抑制性的synNotch切割和改变蛋白激酶的细胞内分布,从而调节蛋白激酶的活性和功能。
附图说明
图1是本发明的双靶点系统的原理图;
图2是EGFR和EpCAM双靶点系统的结构图;
图3是双靶点系统改造的Jurkat T细胞杀伤肝癌细胞的原理图;
图4A是流式细胞术检测Jurkat T细胞表达FLAG标签的对比图;
图4B是流式细胞术检测Jurkat T单克隆细胞株的FLAG标签的对比图;
图5是流式细胞术检测肝癌细胞和293T细胞的EGFR和EpCAM的表达的检测图;
图6是共培养激活实验及流式细胞术检测CD69表达变化的检测图;
图7是ELISA检测IL-2分泌水平的方块对比图;
图8A是流式细胞术检测共培养杀伤效果的检测图;
图8B是根据图8A的检测效果制成的共培养杀伤效果的曲线对比图。
具体实施方式
下面结合附图和实施例,对本发明的抑制性的合成Notch和双靶点系统及其制备方法和应用作进一步说明:
本发明针对synNotch诱导表达CAR的双靶点系统的不足,采用不同的原理和结构,构建抑制性的synNotch和CAR双靶点系统,赋予免疫细胞具有高特异性杀伤双靶点阳性肿瘤细胞的能力,避免脱靶毒性。利用抑制性的synNotch和 CAR在免疫突触中共定位,以及抑制性的synNotch的切割、快速的磷酸化修饰,即时解除抑制性synNotch对CAR的抑制,保证T细胞迅速响应抗原刺激,且T 细胞只有同时结合两种抗原靶点才会被激活,有效解决脱靶毒性问题。
本发明构建基于抑制性的合成Notch(synthetic Notch,synNotch)和嵌合抗原受体(chimeric antigen receptor,CAR)双靶点系统模型,修饰T细胞,使其具备特异性杀伤抗原靶点双阳性肝癌细胞的能力,实验原理如图1所示。
该双靶点系统由识别X抗原靶点的抑制性的synNotch和识别Y抗原靶点的 CAR组成。当抑制性的synNotch的靶点X不存在,抑制性的synNotch阻止识别 Y靶点的CAR激活。当抑制性的synNotch与其靶点X结合,抑制性的synNotch 被切割并丧失抑制能力,CAR被Y抗原激活。该系统保证T细胞只有同时与X 和Y两种靶点结合,才会被激活和杀伤靶细胞。
其中,设计抑制性的synNotch和CAR的双靶点系统,其组成元件依次为 CD8α信号肽(L)、c-Myc标签、EGFR scFv、Notch1核心序列负调节域(NRR) 和跨膜区(TM)、CSK、P2A、CD8α信号肽(L)、FLAG标签、EpCAM scFv、 CD8铰链区(H)、CD28跨膜区(TM)、4-1BB和CD3ζ(SEQ3,含有1628 个氨基酸)。
Notch1核心序列设计参考专利US 20190134093A1(SYSTEMS AND METHODS FORTARGETING CANCER CELLS)。EGFR scFv序列设计参考专利US6217866B1(Cetuximab,2015年6月到期)。EpCAM scFv序列设计参考专利WO1998046645A2(METHOD FOR THE PRODUCTIONOF ANTIHUMAN ANTIGEN RECEPTORS AND USES THEREOF)。
为验证该系统模型,本发明设计和构建识别表皮生长因子受体(epidermalgrowth factor receptor,EGFR)的抑制性synNotch和识别上表细胞粘附分子(epithelial cell adhesion molecule,EpCAM)的EpCAM-CAR,抑制性的synNotch 阻止EpCAM-CAR激活。(I)抑制性的synNotch的元件包括CD8α信号肽(Leader, L)、c-Myc标签、EGFR scFv、Notch1的负调节域(negative regulatory region, NRR)和跨膜区(TM)、以及CSK。(II)EpCAM CAR的元件包括CD8α信号肽(L)、FLAG标签、EpCAM scFv、CD8铰链区(H)、CD28跨膜区(TM)、 4-1BB和CD3ζ。抑制性synNotch和EpCAM CAR通过P2A多肽连接,结构如图2所示。
利用该双靶点系统改造Jurkat T细胞,使其具有特异性杀伤靶点双阳性肝癌细胞的能力。具体情况如图3所示。(A)EpCAM scFv识别HepG2肝癌细胞 (EGFR-,EpCAM+),但EpCAM CAR活性被抑制性synNotch抑制,Jurkat T 细胞不能发挥杀伤功能;(B)EGFR scFv识别SK-HEP-1细胞(EGFR+,EpCAM-),抑制性synNotch的抑制功能丧失,但EpCAM CAR因缺少可结合的抗原靶点而不能被激活,Jurkat T细胞不能发挥杀伤功能;(C)当EpCAM scFv和EGFR scFv 识别HUH-7(EGFR+,EpCAM+)相应的抗原靶点,抑制性synNotch的抑制功能丧失,EpCAM CAR激活,Jurkat T细胞发挥杀伤功能。
基于抑制性的synNotch和CAR的双靶点系统,可以交换EpCAM scFv和 EGFR scFv的位置,不影响Jurkat T细胞杀伤肝癌细胞的准确性。此外,该系统具有模块化组合的特点。采用识别其它靶点的scFv序列替换EpCAM scFv或(和) EGFR scFv,可以建立高特异性识别不同靶点组合的双靶点系统,改造T细胞,杀伤各种类型肿瘤细胞。因此,该双靶点系统具有良好的转换性和通用性。比如,也可以利用不同的scFv识别实体瘤的抗原靶点,进而杀伤实体瘤,包括但不限于GPC-3scFv、HER2 scFv、CEA scFv、CD147 scFv、EGFRvIII scFv、PSMA scFv、 Mesothelin scFv、FAP scFv、EGFR scFv、CD171 scFv、GD2 scFv等;利用不同的scFv识别B细胞恶性肿瘤的靶点,进而杀伤B细胞恶性肿瘤,包括但不限于 CD19 scFv、CD20 scFv、CD22 scFv、ROR1 scFv等;利用不同的scFv识别髓系恶性肿瘤的靶点,进而杀伤髓系恶性肿瘤,包括但不限于CD33 scFv、CD123 scFv、 CD174 scFv等;利用不同的scFv识别复发/难治性多发性骨髓瘤的靶点,进而杀伤复发/难治性多发性骨髓瘤,包括但不限于CD19 scFv、CD123 scFv、BCMA scFv 等。利用本发明的双靶点系统治疗上述各种肿瘤的原理与前述相同,这里不再进行详细赘述,其均视为本发明的保护范围之内。
下面通过具体实施方式详细说明。实验设计如下:
(1)设计抑制性的synNotch和CAR的双靶点系统,如图2所示,确定其结构元件和氨基酸序列;
(2)合成双靶点系统的DNA序列,对编码氨基酸的密码子进行人源化优化,将基因序列连接至pWPT-GFP质粒载体,测序验证;
(3)采用双靶点系统pWPT-GFP表达质粒、psPAX2和pMD2.G三质粒共转染293T细胞,包装慢病毒,48小时后收集含慢病毒的培养基上清,浓缩慢病毒;
(4)慢病毒转导Jurkat T细胞,筛选和分离表达抑制性的synNotch和CAR 的双靶点系统的Jurkat T单克隆细胞株;
(5)检测293T、HepG2、HUH-7和SK-HEP-1细胞的EGFR和EpCAM表达水平,验证其作为实验靶细胞的可行性;
(6)激活实验:将双靶点修饰Jurkat T单克隆细胞分别与293T、HepG2、 HUH-7和SK-HEP-1共培养,效应细胞(E)和靶细胞(T)的比例设置为1:1、 1:3和1:10,检测双靶点修饰Jurkat T的CD69和IL-2表达水平;
(7)杀伤肝癌细胞实验:将双靶点修饰Jurkat T单克隆细胞分别与HepG2、 HUH-7和SK-HEP-1共培养,效应细胞(E)和靶细胞(T)的比例设置为1:0、 1:1、3:1和10:1,检测双靶点修饰Jurkat T单克隆细胞杀伤的肝癌细胞效率。
实施例1:
根据该双靶点系统氨基酸序列,合成相应的基因序列,对密码子进行人源化优化,并在5’-端添加BamHI酶切位点,在3’-端添加SalI酶切位点。取4μg含双靶点系统基因的DNA,加入2μL 10×NEBuffer 3.1,14μL ddH2O,混匀,之后加入1μL BamHI和1μL SalI,混匀,置于37℃恒温箱静置4小时。采用相同的方法,取2μg pWPT-GFP质粒,加入2μL 10×NEBuffer 3.1,14μL ddH2O,混匀,之后加入1μL BamHI和1μL SalI,混匀,置于37℃恒温箱静置4小时。将经过双酶切的DNA片段,经Sybergreen预染后,转移至1%的琼脂糖凝胶上样孔,在80V电压下进行电泳。在紫外灯下,将目的条带切割,回收和纯化。经双酶切的双靶点系统基因的DNA片段和pWPT-GFP质粒各取1μg,加入1μL 10×T4 ligase buffer,6μLddH2O,混匀,之后加入1μL T4 ligase,混匀,置于37℃恒温箱静置1小时。将连接产物转化感受态大肠杆菌细胞TOP10,挑选单克隆,扩大培养。收集大肠杆菌,提取质粒,进行PCR鉴定和酶切鉴定,以及测序分析,获得双靶点系统pWPT-GFP表达质粒。
实施例2:
293T细胞和HUH-7细胞培养基为含10%胎牛血清,100×稀释青链霉素的 DMEM培养基。HepG2细胞和SK-HEP-1细胞培养基为含10%胎牛血清,100×稀释青链霉素的MEM培养基。Jurkat T细胞培养基为含10%胎牛血清,100μg/mL 硫酸庆大霉素的RPMI-1640培养基。上述细胞均置于37℃,5%CO2培养箱中培养。293T、HepG2、HUH-7和SK-HEP-1细胞均采用0.25%胰蛋白酶消化传代。
取双靶点系统pWPT-GFP表达质粒、psPAX2和pMD2.G质粒各5μg,溶于 480μL 1×HBS(HEPES缓冲盐溶液)。取36μL PEI(聚乙烯亚胺,2.5mg/mL, pH7.4),用1×HBS稀释至360μL,滴加至质粒溶液中,边加边混匀,静置20 分钟。将质粒-PEI混合物滴加至接种293T细胞的10厘米培养皿中,8小时后更换新鲜培养基。48小时后收集含慢病毒的培养基上清,在4℃,12000×g离心 10分钟。先后采用0.45μm和0.22μm滤膜过滤。将滤液转移至截留分子量为50 kD超滤管,在4℃,6000×g离心30分钟,浓缩病毒上清。检测病毒滴度,调整至感染复数(multiplicity of infection,MOI)为20。
在24孔板中接种5×104Jurkat T细胞,加入250μL培养基、750μL病毒上清和1μLpolybrene,轻轻混匀,置于37℃,5%CO2培养箱中。培养8小时后,离心收集细胞,更换培养基。72小时后,流式细胞术检测双靶点系统的FLAG 标签表达水平。取105双靶点系统修饰Jurkat T细胞,用预冷PBS洗涤2次。400× g离心3分钟,用500μL PBS悬浮细胞。加入5μLFITC-mouse anti-FLAG IgG1 抗体溶液或FITC-mouse IgG1同型对照抗体,4℃,避光孵育0.5小时。用PBS洗涤2次,加入500μL PBS悬浮细胞,进行流式细胞术检测。FITC选择的激发波长为488nm,检测波长为525nm。结果如图4A所示,Jurkat T细胞表达FLAG 标签的比例为27.48%。根据抑制性Notch与EpCAM CAR所在信使RNA(message RNA,mRNA)为单顺反子,FLAG表达表明双靶点系统表达正常。
加入终浓度为400μg/mL的G418,继续培养14天。取存活的细胞转移至96 孔细胞培养板,进行有限稀释,挑选稳定表达双靶点系统的Jurkat T单克隆细胞株。将Jurkat T单克隆细胞株进行扩大培养,流式细胞术检测FLAG标签表达水平。检测结果如图4B所示,JurkatT单克隆细胞株的FLAG标签阳性率达到 99.53%,表明成功建立双靶点系统修饰Jurkat T单克隆细胞株。
实施例3:
将293T、SK-HEP-1、HepG2、HUH-7细胞吸去培养基,加入1mL 0.25%胰蛋白酶消化。待细胞消化完全,加入含胎牛血清的培养基终止消化,400×g离心 3分钟,用PBS洗涤2次,加入500μL PBS悬浮细胞。加入5μL FITC-mouse anti-EGFR IgG1抗体、FITC-mouse anti-EpCAM IgG1抗体或FITC-mouse IgG1同型对照抗体,4℃,避光孵育0.5小时。用PBS洗涤2次,用500μL PBS悬浮细胞,进行流式细胞术检测。检测结果如图5所示,293T细胞为EGFR-EpCAM-, SK-HEP-1细胞为EGFR+EpCAM-,HepG2细胞为EGFR-EpCAM+,HUH-7细胞为EGFR+EpCAM+,符合验证双靶点系统杀伤实验的要求。
实施例4:
激活实验:将培养的293T、SK-HEP-1、HepG2、HUH-7细胞用0.25%胰蛋白酶消化,加入含胎牛血清的培养基终止消化,400g离心3分钟。用培养基悬浮细胞,进行细胞计数,调整细胞浓度至105/mL,取100μL转移至96孔细胞培养板孔中,每孔10000个细胞。培养过夜。加入双靶点修饰的Jurkat T单克隆细胞,分别与SK-HEP-1、HepG2和HUH-7共培养,靶细胞(T)和效应细胞(E) 的比例设置为1:1、1:3和1:10,置于37℃,5%CO2培养箱中,共培养12小时。吸取培养液,400×g离心3分钟,收集细胞,培养基上清用于检测人白细胞介素 2(IL-2)浓度。收集的细胞用PBS洗涤2次。加入FITC-mouse anti-CD69 IgG1 抗体溶液,4℃孵育1小时,用PBS洗涤2次,用PBS悬浮细胞,进行流式细胞术检测。流式检测结果如图6所示,与HUH-7细胞共培养,随着T:E比增加,双靶点修饰Jurkat T单克隆细胞的激活标志分子CD69表达水平逐步增加。当T:E 比为10,CD69阳性Jurkat T细胞达到43.55%。此外,与HepG2细胞共培养,当T:E比为10,Jurkat T细胞被轻度激活。
将收集的培养基上清,在4℃,8000×g离心10分钟。取100μL上清,按照人IL-2高敏ELISA试剂盒的说明书检测IL-2浓度。分光光度计检测波长为450 nm,参比波长为630nm,根据OD值建立标准曲线,计算IL-2浓度。ELISA检测结果如图7所示,与HUH-7细胞共培养,随着T:E比增加,双靶点修饰Jurkat T单克隆细胞的IL-2表达水平增加,显著高于与293T、SK-HEP-1或HepG2共培养组(p<0.001)。
实施例5:
杀伤实验:将培养的SK-HEP-1和HepG2、HUH-7肝癌细胞用0.25%胰蛋白酶消化,加入含胎牛血清的培养基终止消化,400×g离心3分钟,用PBS洗涤 2次,进行计数。用含羧基荧光素二乙酸琥珀酰亚胺酯(CFSE)的溶液悬浮细胞,调整细胞浓度至107/mL。置于37℃,5%CO2培养箱中孵育20分钟。加10倍体积含胎牛血清的培养基终止标记,400×g离心3分钟,收集细胞,用无血清培养基洗涤细胞2次。加入含胎牛血清培养基悬浮细胞,取1mL细胞悬液转移至 24孔细胞培养板中,使每孔接种20000个细胞。加入双靶点系统修饰的JurkatT 单克隆细胞,E:T设置为1:0、1:1、3:1和10:1,置于37℃,5%CO2培养箱中4 小时。收集细胞,400×g离心3分钟,用500μL PBS悬浮细胞。加入10μL碘化丙碇(PI)染色液,混匀,在4℃避光孵育10分钟。400×g离心3分钟,收集细胞,用500μL PBS悬浮细胞。进行流式细胞术检测。CFSE的激发波长选择 488nm,检测波长为516nm。PI的激发波长选择488nm,检测波长为647nm。被杀伤的肝癌细胞位于CFSE+PI+区域,而存活的肝癌细胞位于CFSE+PI-区域,据此可以获得双靶点系统修饰的Jurkat T细胞杀伤肝癌细胞的百分率。
如图8A所示,当E:T为10:1,双靶点系统修饰的Jurkat T细胞对SK-HEP-1、 HepG2和HUH-7肝癌细胞的杀伤百分比分别为5.99%、16.05%和54.00%,显示出高特异性区分单靶点阳性和双靶点阳性肝癌细胞的能力。不同E:T值条件下,双靶点系统修饰的Jurkat T细胞对三株肝癌细胞的杀伤曲线如图8B所示,可见本发明构建的双靶点系统能够高特异性区分抗原靶点双阳性和单阳性的肝癌细胞,并对靶点双阳性的HUH-7细胞具有最强的杀伤效果。
应当理解的是,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进或变换都应属于本发明所附权利要求的保护范围之内。
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cggaagcacc ccattaagag agccgctgaa ggctgggctg ctcccgatgc acttctggga 660
caagtgaagg cctctctgct gcctggtgga tctgaaggcg gcagacgtag aagagaactg 720
gaccccatgg atgtgcgggg cagcatcgtg tacctggaaa tcgacaaccg gcagtgcgtg 780
caggccagct ctcagtgttt tcagagcgct acagacgtgg ccgcctttct gggagcactg 840
gcttctctgg gctccctgaa catcccctac aagatcgagg ccgtgcagag cgagacagtg 900
gaacctcctc ctcctgctca actgcacttt atgtacgtgg cagccgccgc tttcgtgctg 960
ctgttttttg ttggctgcgg agtgctgctg agccggaaga gaagaaggca gcacggacag 1020
ctgtggttcc ccgagggctt taaagtgtcc ggcggcggag gatctggcgg aggtggaagc 1080
ggaggcggtg gatctcatat gtccgccatc caggcagcat ggccttctgg aaccgagtgc 1140
atcgccaagt acaacttcca cggcacagcc gagcaggacc tgcccttttg taagggcgat 1200
gtgctgacca tcgtggccgt gacaaaggac cctaactggt acaaggccaa gaataaggtc 1260
ggccgcgagg gcatcatccc agccaattat gtgcagaaga gggagggagt gaaggcagga 1320
accaagctga gcctgatgcc atggttccac ggcaagatca cacgcgagca ggcagagcgg 1380
ctgctgtacc cacctgagac cggcctgttt ctggtgcgcg agagcaccaa ctaccccggc 1440
gactatacac tgtgcgtgtc ctgtgatggc aaggtggagc actaccggat catgtatcac 1500
gcctctaagc tgagcatcga cgaggaggtg tacttcgaga atctgatgca gctggtggag 1560
cactatacct ccgacgccga tggcctgtgc acaagactga tcaagcccaa agtgatggag 1620
ggcacagtgg ccgcccagga tgagttctac aggtctggct gggccctgaa catgaaggag 1680
ctgaagctgc tgcagaccat cggcaagggc gagtttggcg acgtgatgct gggcgattat 1740
agaggcaaca aggtggccgt gaagtgtatc aagaatgatg caaccgcaca ggcctttctg 1800
gcagaggcaa gcgtgatgac acagctgagg cactccaatc tggtgcagct gctgggcgtg 1860
atcgtggagg agaagggcgg cctgtacatc gtgacagagt atatggccaa gggctctctg 1920
gtggactacc tgcggagcag aggcaggtcc gtgctgggag gcgactgcct gctgaagttc 1980
agcctggacg tgtgcgaggc catggagtat ctggagggca acaattttgt gcacagagat 2040
ctggccgcca ggaacgtgct ggtgtctgag gacaatgtgg ccaaggtgag cgatttcggc 2100
ctgaccaagg aggccagctc cacccaggac acaggcaagc tgccagtgaa gtggaccgca 2160
ccagaggccc tgagggagaa gaagttctcc acaaagtctg acgtgtggtc ctttggcatc 2220
ctgctgtggg agatctactc ttttggccgc gtgccttatc caagaatccc cctgaaggac 2280
gtggtgccac gggtggagaa gggctacaag atggacgcac cagatggatg cccaccagcc 2340
gtgtatgaag tgatgaagaa ctgttggcac ctggatgccg ccatgagacc ttccttcctg 2400
cagctgaggg agcagctgga gcacatcaag acccacgagc tgcacctg 2448
<210> 3
<211> 1628
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 3
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gln
20 25 30
Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser
35 40 45
Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly
50 55 60
Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly
65 70 75 80
Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser
85 90 95
Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys
100 105 110
Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg
115 120 125
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr
130 135 140
Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
145 150 155 160
Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu
165 170 175
Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln
180 185 190
Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser
195 200 205
Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro
210 215 220
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile
225 230 235 240
Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn
245 250 255
Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
260 265 270
Arg Thr Arg Ile Leu Asp Tyr Ser Phe Gly Gly Gly Ala Gly Arg Asp
275 280 285
Ile Pro Pro Pro Leu Ile Glu Glu Ala Cys Glu Leu Pro Glu Cys Gln
290 295 300
Glu Asp Ala Gly Asn Lys Val Cys Ser Leu Gln Cys Asn Asn His Ala
305 310 315 320
Cys Gly Trp Asp Gly Gly Asp Cys Ser Leu Asn Phe Asn Asp Pro Trp
325 330 335
Lys Asn Cys Thr Gln Ser Leu Gln Cys Trp Lys Tyr Phe Ser Asp Gly
340 345 350
His Cys Asp Ser Gln Cys Asn Ser Ala Gly Cys Leu Phe Asp Gly Phe
355 360 365
Asp Cys Gln Arg Ala Glu Gly Gln Cys Asn Pro Leu Tyr Asp Gln Tyr
370 375 380
Cys Lys Asp His Phe Ser Asp Gly His Cys Asp Gln Gly Cys Asn Ser
385 390 395 400
Ala Glu Cys Glu Trp Asp Gly Leu Asp Cys Ala Glu His Val Pro Glu
405 410 415
Arg Leu Ala Ala Gly Thr Leu Val Val Val Val Leu Met Pro Pro Glu
420 425 430
Gln Leu Arg Asn Ser Ser Phe His Phe Leu Arg Glu Leu Ser Arg Val
435 440 445
Leu His Thr Asn Val Val Phe Lys Arg Asp Ala His Gly Gln Gln Met
450 455 460
Ile Phe Pro Tyr Tyr Gly Arg Glu Glu Glu Leu Arg Lys His Pro Ile
465 470 475 480
Lys Arg Ala Ala Glu Gly Trp Ala Ala Pro Asp Ala Leu Leu Gly Gln
485 490 495
Val Lys Ala Ser Leu Leu Pro Gly Gly Ser Glu Gly Gly Arg Arg Arg
500 505 510
Arg Glu Leu Asp Pro Met Asp Val Arg Gly Ser Ile Val Tyr Leu Glu
515 520 525
Ile Asp Asn Arg Gln Cys Val Gln Ala Ser Ser Gln Cys Phe Gln Ser
530 535 540
Ala Thr Asp Val Ala Ala Phe Leu Gly Ala Leu Ala Ser Leu Gly Ser
545 550 555 560
Leu Asn Ile Pro Tyr Lys Ile Glu Ala Val Gln Ser Glu Thr Val Glu
565 570 575
Pro Pro Pro Pro Ala Gln Leu His Phe Met Tyr Val Ala Ala Ala Ala
580 585 590
Phe Val Leu Leu Phe Phe Val Gly Cys Gly Val Leu Leu Ser Arg Lys
595 600 605
Arg Arg Arg Gln His Gly Gln Leu Trp Phe Pro Glu Gly Phe Lys Val
610 615 620
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
625 630 635 640
His Met Ser Ala Ile Gln Ala Ala Trp Pro Ser Gly Thr Glu Cys Ile
645 650 655
Ala Lys Tyr Asn Phe His Gly Thr Ala Glu Gln Asp Leu Pro Phe Cys
660 665 670
Lys Gly Asp Val Leu Thr Ile Val Ala Val Thr Lys Asp Pro Asn Trp
675 680 685
Tyr Lys Ala Lys Asn Lys Val Gly Arg Glu Gly Ile Ile Pro Ala Asn
690 695 700
Tyr Val Gln Lys Arg Glu Gly Val Lys Ala Gly Thr Lys Leu Ser Leu
705 710 715 720
Met Pro Trp Phe His Gly Lys Ile Thr Arg Glu Gln Ala Glu Arg Leu
725 730 735
Leu Tyr Pro Pro Glu Thr Gly Leu Phe Leu Val Arg Glu Ser Thr Asn
740 745 750
Tyr Pro Gly Asp Tyr Thr Leu Cys Val Ser Cys Asp Gly Lys Val Glu
755 760 765
His Tyr Arg Ile Met Tyr His Ala Ser Lys Leu Ser Ile Asp Glu Glu
770 775 780
Val Tyr Phe Glu Asn Leu Met Gln Leu Val Glu His Tyr Thr Ser Asp
785 790 795 800
Ala Asp Gly Leu Cys Thr Arg Leu Ile Lys Pro Lys Val Met Glu Gly
805 810 815
Thr Val Ala Ala Gln Asp Glu Phe Tyr Arg Ser Gly Trp Ala Leu Asn
820 825 830
Met Lys Glu Leu Lys Leu Leu Gln Thr Ile Gly Lys Gly Glu Phe Gly
835 840 845
Asp Val Met Leu Gly Asp Tyr Arg Gly Asn Lys Val Ala Val Lys Cys
850 855 860
Ile Lys Asn Asp Ala Thr Ala Gln Ala Phe Leu Ala Glu Ala Ser Val
865 870 875 880
Met Thr Gln Leu Arg His Ser Asn Leu Val Gln Leu Leu Gly Val Ile
885 890 895
Val Glu Glu Lys Gly Gly Leu Tyr Ile Val Thr Glu Tyr Met Ala Lys
900 905 910
Gly Ser Leu Val Asp Tyr Leu Arg Ser Arg Gly Arg Ser Val Leu Gly
915 920 925
Gly Asp Cys Leu Leu Lys Phe Ser Leu Asp Val Cys Glu Ala Met Glu
930 935 940
Tyr Leu Glu Gly Asn Asn Phe Val His Arg Asp Leu Ala Ala Arg Asn
945 950 955 960
Val Leu Val Ser Glu Asp Asn Val Ala Lys Val Ser Asp Phe Gly Leu
965 970 975
Thr Lys Glu Ala Ser Ser Thr Gln Asp Thr Gly Lys Leu Pro Val Lys
980 985 990
Trp Thr Ala Pro Glu Ala Leu Arg Glu Lys Lys Phe Ser Thr Lys Ser
995 1000 1005
Asp Val Trp Ser Phe Gly Ile Leu Leu Trp Glu Ile Tyr Ser Phe
1010 1015 1020
Gly Arg Val Pro Tyr Pro Arg Ile Pro Leu Lys Asp Val Val Pro
1025 1030 1035
Arg Val Glu Lys Gly Tyr Lys Met Asp Ala Pro Asp Gly Cys Pro
1040 1045 1050
Pro Ala Val Tyr Glu Val Met Lys Asn Cys Trp His Leu Asp Ala
1055 1060 1065
Ala Met Arg Pro Ser Phe Leu Gln Leu Arg Glu Gln Leu Glu His
1070 1075 1080
Ile Lys Thr His Glu Leu His Leu Gly Ser Gly Ala Thr Asn Phe
1085 1090 1095
Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
1100 1105 1110
Gly Gly Arg Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu
1115 1120 1125
Ala Leu Leu Leu His Ala Ala Arg Pro Asp Tyr Lys Asp Asp Asp
1130 1135 1140
Asp Lys Glu Val Gln Leu Leu Glu Gln Ser Gly Ala Glu Leu Ala
1145 1150 1155
Arg Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr
1160 1165 1170
Thr Phe Thr Asn Tyr Gly Leu Ser Trp Val Lys Gln Arg Pro Gly
1175 1180 1185
Gln Val Leu Glu Trp Ile Gly Glu Val Tyr Pro Arg Ile Gly Asn
1190 1195 1200
Ala Tyr Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala
1205 1210 1215
Asp Lys Ser Ser Ser Thr Ala Ser Met Glu Leu Arg Ser Leu Thr
1220 1225 1230
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Arg Gly Ser Tyr
1235 1240 1245
Asp Thr Asn Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr
1250 1255 1260
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1265 1270 1275
Ser Gly Gly Gly Gly Ser Glu Leu Val Met Thr Gln Thr Pro Leu
1280 1285 1290
Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg
1295 1300 1305
Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1310 1315 1320
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1325 1330 1335
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
1340 1345 1350
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
1355 1360 1365
Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser Thr His Val
1370 1375 1380
Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Thr Thr
1385 1390 1395
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser
1400 1405 1410
Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
1415 1420 1425
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp
1430 1435 1440
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu
1445 1450 1455
Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser
1460 1465 1470
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
1475 1480 1485
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
1490 1495 1500
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
1505 1510 1515
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
1520 1525 1530
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
1535 1540 1545
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
1550 1555 1560
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
1565 1570 1575
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
1580 1585 1590
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
1595 1600 1605
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
1610 1615 1620
Ala Leu Pro Pro Arg
1625
Claims (4)
1.一种双靶点系统,其特征在于,其包含有抑制性的合成Notch以及嵌合抗原受体;
所述合成Notch包含有Notch1序列与CSK激酶结合的融合蛋白;
所述抑制性的合成Notch还包含有与抗原靶点X相结合的scFv,与抗原靶点X相结合的scFv以及Notch1序列、CSK激酶依次连接;
所述抑制性的合成Notch还包含有CD8α信号肽,所述CD8α信号肽、与抗原靶点X相结合的scFv以及Notch1序列、CSK激酶依次连接;
所述Notch1序列具有负调节域和跨膜区,所述CD8α信号肽、与抗原靶点X相结合的scFv以及负调节域、跨膜区、CSK激酶依次连接;
所述抑制性的合成Notch和所述嵌合抗原受体通过P2A多肽连接;所述嵌合抗原受体包括依次连接的CD8α信号肽、与抗原靶点Y相结合的scFv以及CD8铰链区、CD28跨膜区、4-1BB、CD3ζ。
2.一种权利要求1所述的双靶点系统的制备方法,其特征在于,包括:
A、设计抑制性的合成Notch和所述嵌合抗原受体的双靶点系统,确定其结构元件和氨基酸序列;
B、合成双靶点系统的DNA序列,对编码氨基酸的密码子进行人源化优化,将基因序列连接至pWPT-GFP质粒载体,测序验证;
C、采用双靶点系统pWPT-GFP表达质粒、psPAX2和pMD2.G三质粒共转染293T细胞,包装慢病毒,48小时后收集含慢病毒的培养基上清,浓缩慢病毒;
D、慢病毒转导Jurkat T细胞,筛选和分离表达抑制性synNotch和CAR的双靶点系统的Jurkat T单克隆细胞株。
3.权利要求1所述的双靶点系统在用于制备改造免疫细胞并调节免疫细胞活性的药物、药物组合物、试剂和/或试剂盒中的应用。
4.权利要求1所述的双靶点系统在用于制备预防和/或治疗肿瘤的药物、药物组合物、试剂和/或试剂盒中的应用。
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