CN114249807B - 缺氧触发的人工转录因子、转录控制系统及其应用 - Google Patents
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Abstract
本发明提供了一种缺氧触发的人工转录因子。本发明还提供了一种缺氧触发的转录控制系统,所述转录控制系统包含编码HATF的核酸序列和RE。根据本发明所述的缺氧触发的转录控制系统,其中所述缺氧触发的转录控制系统包括上下游连锁的两套转录控制单元,其中所述上游转录控制单元包含用于控制HATF的缺氧触发的转录反应元件和编码HATF的核酸序列;所述下游转录控制单元包含RE和目的基因。本发明的人工转录因子HATF和识别元件RE联合调控目的基因的放大倍数可达百倍,远优于传统人工转录因子(GAL4)及其反应元件(UAS)的10倍上调。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种缺氧触发的人工转录因子,本发明还涉及包含所述缺氧触发的人工转录因子的缺氧触发的转录控制系统,及其在乏氧性肿瘤治疗中的用途。
背景技术
肿瘤的免疫细胞疗法,例如T细胞受体修饰T细胞(T cell receptor T cells,TCR-T cells)与嵌合抗原受体T细胞(Chimeric antigen receptor T cells,CAR-Tcells)在临床研究中显示出良好的抗肿瘤效果。然而,在临床试验和应用中,细胞疗法的新问题不断。除了难以进入致密的实体瘤之外,常见的不良反应包括由于肿瘤特异性抗原缺乏而导致的脱靶效应,可能致命的神经毒性、过敏反应等副作用,这些都限制了细胞治疗实体瘤的临床应用。因此,有必要进一步开发可调控的精准靶向肿瘤的免疫细胞治疗方法,以降低正常组织的损伤。
研究发现,由于实体瘤内异常血管结构引起的供血不足以及肿瘤细胞的过度增殖,营造了一个相对缺氧的肿瘤微环境,肿瘤组织内的氧水平常低于2%,因此缺氧是多种实体瘤的一个共有特征。针对实体瘤缺氧的微环境,开发通过缺氧信号激活TCR-T细胞、CAR-T细胞或基因工程T细胞的肿瘤杀伤技术,有望提升肿瘤治疗的特异性。
已有研究表明,将缺氧诱导因子-1α(Hypoxia-inducible factors 1-alpha,HIF-1α)的氧依赖降解结构域(Oxygen-dependent degradation domain,ODD)融合至嵌合抗原受体,可使得嵌合抗原受体在常氧环境下降解,而在缺氧环境下富集,从而识别并杀伤肿瘤细胞。然而,融合氧依赖降解结构域的嵌合抗原受体在缺氧坏境下的诱导水平仍处于较低水平,不利于控制抗原异质性较大的肿瘤,特别是肿瘤抗原低表达的实体肿瘤;此外,当前ODD调控的缺氧敏感型CAR-T细胞仍有较高水平的本底泄漏,并能产生一定水平的非缺氧依赖性杀伤,存在安全担忧。此外,缺氧触发启动子驱动的CAR-T细胞虽然具备一定的氧浓度反应能力,但是同样存在较高水平的本底泄漏,从而产生较高水平的非缺氧依赖性杀伤,可能产生靶向非肿瘤细胞引起的毒性反应(On-target off-tumor toxicity)。
因此,有必要进一步开发更为敏感和高效的缺氧触发的人工转录因子,从而研发出更加安全、有效的缺氧敏感性的治疗方法,既能提升细胞治疗安全性,又能有效控制肿瘤的生长。
发明内容
本发明的目的是针对现有技术的不足,提供一种缺氧触发的转录控制系统。本发明提供的缺氧触发的转录控制系统包括上下游连锁的两套转录控制单元。本发明还提供了所述缺氧触发的转录控制系统的用途。本发明提供的转录控制系统由两套连锁的转录控制单元构成,组成上下游两级放大、以达到对缺氧高度敏感的目的,并且该系统可以通过携带不同的目的基因来实现肿瘤治疗药物的制备及精准治疗。与现有技术相比,本发明的缺氧触发的转录控制系统在缺氧下被高效诱导表达,从而提升缺氧触发的严格性与敏感性。并且使用本发明的转录控制系统,使用少量的转录因子即可驱动较高的目的基因的表达,从而进一步放大了其对缺氧的敏感性。
本发明的目的是通过以下技术方案实现的:
一方面,本发明提供了一种缺氧触发的人工转录因子(Hypoxia-regulatedArtificial Transcription Factor,HATF),所述HATF包含:
(1)SEQ ID NO:1所示的序列;
(2)与SEQ ID NO:1所示的序列相比具有一个或几个氨基酸的置换、缺失或添加的序列;或
(3)与SEQ ID NO:1所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。
另一方面,本发明还提供了编码所述HATF的核酸序列。
再一方面,本发明提供了所述HATF的识别元件(Responding Element,RE),所述RE包含选自以下的核心序列:
(1)SEQ ID NO:2所示的序列,或其互补序列;
(2)在严格杂交条件下与SEQ ID NO:2所示的序列杂交的序列;
(3)与SEQ ID NO:2所示的序列具有至少85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98.5%、99%或99.5%序列同一性的序列;或
(4)由通过缺失、取代、插入或增加一个或多个核苷酸而衍生化SEQ ID NO:2所示的序列获得的序列。
优选地,所述RE包含所述核心序列的多个拷贝和最小启动子;更优选地,所述多个拷贝为两个拷贝、三个拷贝、四个拷贝、五个拷贝、六个拷贝、七个拷贝、八个拷贝、九个拷贝或十个拷贝;进一步优选地,所述识别元件RE包含所述核心序列的五个或六个拷贝和最小启动子。
更进一步优选地,所述RE包含选自以下的序列:
(1)SEQ ID NO:3所示的序列,或其互补序列;
(2)在严格杂交条件下与SEQ ID NO:3所示的序列杂交的序列;
(3)与SEQ ID NO:3所示的序列具有至少85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98.5%、99%或99.5%序列同一性的序列;或
(4)由通过缺失、取代、插入或增加一个或多个核苷酸而衍生化SEQ ID NO:3所示的序列获得的序列。
最优选地,所述RE如SEQ ID NO:3所示。
本发明提供的HATF为新型人工转录因子,本发明的发明人发现,使用该HATF与其匹配的RE联合调控目的基因的放大倍数可达百倍以上,远远大于传统人工转录因子及其反应元件的上调倍数。
另一方面,本发明提供了一种缺氧触发的转录控制系统,所述转录控制系统包含编码HATF的核酸序列和RE。
根据本发明所述的缺氧触发的转录控制系统,其中所述缺氧触发的转录控制系统包括上下游连锁的两套转录控制单元,其中所述上游转录控制单元包含用于控制HATF的缺氧触发的转录反应元件(Hypoxia-regulated Transcription Element,HRTE)和编码HATF的核酸序列;所述下游转录控制单元包含RE和目的基因(Gene of Interest,GOI)。
其中,所述HATF在RNA转录层面和蛋白质翻译层面均受缺氧触发,即所述缺氧触发人工转录因子在常氧下不表达或低水平表达,而在缺氧下被高效诱导表达,从而提升缺氧触发的严格性与敏感性。
根据本发明所述的缺氧触发的转录控制系统,其中,所述上下游连锁的转录控制单元非线性串联,位于两个载体;优选地,所述转录控制系统具有如下式中任一项所示的组合形式:
HATF-HRTE和RE-GOI;
HATF-HRTE和GOI-RE;
HRTE-HATF和GOI-RE或
HRTE-HATF和RE-GOI。
或所述上下游连锁的转录控制单元线性串联,位于同一载体;优选地,所述转录控制系统具有如下式中任一项所示的组合形式:
HATF-HRTE-RE-GOI;
HATF-HRTE-GOI-RE;
HRTE-HRTE-GOI;
HRTE-HATF-GOI-RE;
RE-GOI-HATF-HRTE;
RE-GOI-HRTE-HATF;
GOI-RE-HATF-HRTE或
GOI-RE-HRTE-HATF。
根据本发明所述的缺氧触发的转录控制系统,其中,所述HRTE选自血管内皮生长因子基因、红细胞生成素基因、糖酵解酶基因等缺氧诱导基因的侧翼区,其核心序列为5’-(A/G)CGT(G/C)-3’。
根据本发明所述的缺氧触发的转录控制系统,其中所述HRTE包含选自以下的核心序列:
(1)SEQ ID NO:4所示的序列,或其互补序列;
(2)在严格杂交条件下与SEQ ID NO:4所示的序列杂交的序列;
(3)与SEQ ID NO:4所示的序列具有至少85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98.5%、99%或99.5%序列同一性的序列;或
(4)由通过缺失、取代、插入或增加一个或多个核苷酸而衍生化SEQ ID NO:4所示的序列获得的序列。
优选地,所述HRTE包含所述核心序列的多个拷贝和最小启动子;更优选地,所述多个拷贝为两个拷贝、三个拷贝、四个拷贝、五个拷贝、六个拷贝、七个拷贝、八个拷贝、九个拷贝或十个拷贝;进一步优选地,所述HRTE包含所述核心序列的五个或六个拷贝和最小启动子。
更进一步优选地,所述HRTE包含选自以下的序列:
(1)SEQ ID NO:5所示的序列,或其互补序列;
(2)在严格杂交条件下与SEQ ID NO:5所示的序列杂交的序列;
(3)与SEQ ID NO:5所示的序列具有至少85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、98.5%、99%或99.5%序列同一性的序列;或
(4)由通过缺失、取代、插入或增加一个或多个核苷酸而衍生化SEQ ID NO:5所示的序列获得的序列。
最优选地,所述HRTE如SEQ ID NO:5所示。
在一个具体的实施方案中,根据本发明的人工转录因子HATF具有如SEQ ID NO:1所示的氨基酸序列,其识别元件RE具有如SEQ ID NO:3所示的关键核酸序列,联合调控目的基因(红色荧光蛋白mCherry)的放大倍数可达百倍,远优于传统人工转录因子(GAL4)及其反应元件(UAS)的10倍上调。
根据本发明所述的缺氧触发的转录控制系统,其中,所述目的基因GOI为功能基因;
优选地,所述GOI选自以下的一种或多种:
细胞因子和趋化因子,如GM-CSF、IFN-α/β/γ、IL-2、IL-3、IL-7、IL-12、IL-15、IL-21、IL-33、IL-35、IL-37、CCL4、CCL20、CXCL9、CXCL10、CXCL11、CXCL12、CXCL13、MIP-1α、MIP-1β等;
细胞毒性分子,如TNF-α、针对不同抗原靶标的T细胞衔接子(Bispecific T-cellengager,BiTE)、针对不同抗原靶标的嵌合抗原受体(Chimeric Antigen Receptor,CAR)、凋亡基因、焦亡基因、毒素等;或
针对不同抗原靶标的激动型抗体,如抗CD28抗体、抗4-1BB抗体、抗ICOS抗体、抗GITR抗体、抗OX40抗体和抗CD27抗体,或针对不同抗原靶标的阻断型抗体、CTLA-4抗体、PD-1抗体、PD-L1抗体、LAG-3抗体和Tim3抗体等;
或以上任意的两种或多种的组合。
优选地,所针对的抗原靶标为不同细胞膜上表达的广谱通用型靶标,包括但不限于针对AXL、EGFR、MHC、CD24、CD47、FAP、CD147、HER-2、CD55、CD59、ROR1、ROR2、CD133、CD44v6、CD44v7、CD44v8、CD126、CD171、CEA、EpCAM、TAG72、IL-13Rα、EGFRvIII、GD2、GD3、FRα、PSCA、PSMA、GPC3、CAIX、Claudin18.2、VEGFR2、PD-L1、PD-L2、MSLN、MUC1、c-Met、FOLR1、B7-H3和Trop2等;
优选地,所述GOI的表达框包含SEQ ID NO:6-8中任一项所示的氨基酸序列,包括SEQ ID NO:6所示的红色荧光蛋白mCherry,SEQ ID NO:7所示的结合肿瘤抗原HER2的嵌合抗原受体(CAR)和SEQ ID NO:8所示CD47/CD3的双特异性T细胞衔接子(Bispecific T-cellengager,BiTE)。
本发明还提供了一种核酸序列,其包含本发明所述的缺氧触发的转录控制系统;
优选地,所述核酸序列如SEQ ID NO:9所示。
本发明还提供了一种载体,其包含所述核酸序列;优选地,所述载体选自质粒、逆转录病毒载体、慢病毒载体、腺病毒载体、腺相关病毒载体、痘苗病毒载体、单纯疱疹病毒载体、森林脑炎病毒载体、脊髓灰质炎病毒载体、新城疫病毒载体、转座子或其一种或多种的组合。更优选地,所述载体为慢病毒载体。
本发明还提供了一种宿主细胞,所述宿主细胞包含所述载体或所述宿主细胞的染色体中整合所述核酸分子。
优选地,所述宿主细胞为分离获得的人源细胞,包括胚胎干细胞、脐带血来源干细胞、诱导多能干细胞、造血干细胞、间充质干细胞、脂肪干细胞、T细胞、NK细胞、NKT细胞和巨噬细胞;更优选地,所述人源细胞为基因工程化的免疫细胞;进一步优选地,所述基因工程化的免疫细胞为T细胞、NK细胞、NKT细胞或巨噬细胞;更进一步优选地,所述基因工程化免疫细胞为T细胞。
最优选地,所述基因工程化免疫细胞选自以下的组:
嵌合抗原受体T细胞(CAR-T细胞);
嵌合抗原受体NK细胞(CAR-NK细胞);
嵌合抗原受体NKT细胞(CAR-NKT细胞);
嵌合抗原受体巨噬细胞(CAR-);
T细胞受体T细胞(TCR-T细胞)。
在一个优选的实施方案中,所述基因工程化免疫细胞为CAR-T细胞,所述CAR-T细胞通过所述载体转染或转导引入本发明的缺氧触发的转录控制系统,从而在缺氧环境下诱导表达红色荧光蛋白mCherry、嵌合抗原受体或双特异性T细胞衔接子。
本发明还提供了一种包含所述缺氧触发的转录控制系统的基因工程化细胞的制备方法,其中所述方法包括以下步骤:将包含本发明的缺氧触发的转录控制系统的载体导入宿主细胞内,从而获得所述基因工程化细胞。
在一个优选的实施方案中,所述导入包括同时、先后、或依次导入。
本发明还提供了所述缺氧触发的人工转录因子HATF、所述HATF的识别元件RE、所述缺氧触发的转录控制系统、所述核酸分子、所述载体、所述宿主细胞在制备用于治疗乏氧性疾病、缺血性疾病或癌症的药物或制剂中的用途。
优选地,所述癌症为实体瘤;更优选地,所述实体瘤选自神经母细胞瘤、肺癌、乳腺癌、食管癌、胃癌、肝癌、子宫颈癌、卵巢癌、肾癌、胰腺癌、鼻咽癌、小肠癌、大肠癌、结直肠癌、膀胱癌、骨癌、前列腺癌、甲状腺癌或脑癌中的一种或多种。
一种乏氧性疾病、缺血性疾病或癌症的治疗方法,所述方法包括给予有需要的受试者治疗有效量的缺氧触发的人工转录因子HATF、所述HATF的识别元件RE、所述缺氧触发的转录控制系统、所述核酸分子、所述载体、宿主细胞、载体与细胞的组合、或以上与其他治疗药物与技术的组合,包括但不限于PD-1抗体、PD-L1抗体、CTLA-4抗体、TIGIT抗体、Tim-3抗体、LAG-3抗体。
本发明提供了一种缺氧触发人工调控因子以及包含其的转录控制系统,本发明还提供了其在实体瘤等缺氧性疾病治疗的应用,特别是实体瘤的CAR-T细胞治疗应用。
与现有技术相比,本发明具有以下优点:
1.本发明的人工转录因子HATF和识别元件RE联合调控目的基因的放大倍数可达百倍,远优于传统人工转录因子(GAL4)及其反应元件(UAS)的10倍上调;
2.本发明的人工转录因子HATF在RNA转录与蛋白翻译两个层面上受氧气调控,在常氧环境下高效降解,而在缺氧环境下高效诱导表达,保证了该系统的缺氧触发严格性与敏感性;
3.本发明的人工转录因子HATF可以特异结合其配套的识别元件RE,启动目的基因高效转录和表达,从而实现缺氧环境的靶向递送,避免系统性给药引起的严重毒副作用;
4.本发明所述的缺氧触发的转录控制系统中目的基因的编码蛋白并未作任何的缺氧触发功能域修饰,可以确保目的基因编码蛋白功能不受干扰,发挥出其最大的活性。
应理解,在本发明范围内,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅限制,在此不再一一赘述。
附图说明
以下,结合附图来详细说明本发明的实施方案,其中:
图1示出为携带不受缺氧触发的传统HER2 CAR(图1a)、二单元形式的缺氧触发的转录调控系统(图1b-c)和一单元形式的缺氧转录调控系统(图1d-f)的慢病毒表达质粒图谱。其中,二单元形式的缺氧触发的转录调控系统由两个慢病毒表达质粒提供的HATF和HRTE,以及RE和GOI,而一单元形式的缺氧触发的转录调控系统由一个慢病毒表达质粒提供HATF、HRTE、RE和GOI。GOI分别编码红色荧光蛋白mCherry(图1d)、嵌合抗原受体(CAR)(图1e)或双特异性T细胞衔接子(BiTE)(图1f),其中,mCherry具有指示作用、CAR和BiTE可用于肿瘤免疫治疗。
图2示出为本发明的HATF与其匹配的RE联合调控红色荧光蛋白mCherry的放大倍数可达百倍以上,远远优于传统人工转录因子(GAL4-VP64)载体及其反应元件(GAL4 UAS)的10倍上调。图2a为转染48h目的基因(mCherry)表达流式检测图。图2b和图2c分别显示转染48h后mCherry的表达阳性率和荧光强度均有明显提升,并且本发明的HATF与其匹配的RE元件无论在背景溢漏,还是在目的诱导水平方面,均显著优于传统的人工转录因子及其匹配的反应元件。
图3示出为图1慢病毒表达质粒制备的慢病毒表达载体转导阳性的原代T细胞,在常氧环境下仅能检测到极低水平的mCherry表达,而在缺氧条件下有效诱导mCherry的表达。另外,双病毒载体导入的二单元形式的缺氧触发的转录调控系统的缺氧诱导水平远远低于单病毒载体导入的一单元形式的缺氧触发的转录调控系统。
图4显示了缺氧触发的转录控制系统工程化的T细胞(缺氧敏感HER2CAR-T细胞)和传统HER2 CAR-T细胞在不同氧浓度下的CAR诱导表达水平。流式结果显示,缺氧敏感HER2CAR-T细胞具备良好缺氧诱导特性,生理性缺氧(1%O2)条件下,HER2 CAR表达量显著增加,HRTE2 CAR缺氧诱导表达水平与目前常用的HER2 CAR-T细胞的HER2 CAR表达水平相当。
图5显示了缺氧触发的转录控制系统控制的HER2 CAR-T细胞(缺氧敏感HER2 CAR-T细胞)在缺氧环境下选择性杀伤HER2抗原表达的SKOV3和NCI-H292肿瘤细胞,而传统HER2CAR-T细胞的细胞杀伤则无选择性,在常氧和缺氧环境下的肿瘤细胞杀伤效率并无差异。
图6显示了缺氧出发的转录控制系统控制的HER2 CAR-T细胞(缺氧敏感HER2 CAR-T细胞)在人源HER2靶抗原人源化的小鼠模型上评估其体内安全性。只有对照HER2 CAR-T细胞引起小鼠体重进行性降低,死亡率增加和肝功能受损,且释放大量T细胞活化相关细胞因子入血,而缺氧敏感HER2CAR-T细胞则不会引起上述毒副作用。
图7显示缺氧触发的转录控制系统控制的HER2 CAR-T细胞(缺氧敏感HER2 CAR-T细胞)可以有效控制卵巢癌(SKOV3)和肺癌(NCI-H292)的生长。
图8显示了缺氧触发的转录控制系统调控双特异性T细胞衔接蛋白的表达,即在常氧环境下的缺氧敏感人工转录因子不表达,缺氧环境下诱导表达的人工转录因子可以结合不同拷贝数的人工转录因子识别元件驱动CD47/CD3双特异性T细胞衔接蛋白的表达。
图9显示了缺氧触发的转录控制系统控制的BiTE-T细胞(缺氧敏感BiTE-T细胞)可在缺氧环境下选择性杀伤SKOV3和NCI-H292肿瘤细胞。
图10显示了静脉输注和瘤内注射的缺氧触发的转录控制系统控制的BiTE-T细胞(缺氧敏感BiTE-T细胞)都可以有效地抑制肿瘤的生长。
具体实施方式
以下实施例仅用于说明本发明,但不用来限制本发明的范围。
以下实施例的实验方法,如无特殊说明,均为本领域的常规实验方法。以下实施例中所使用的实验材料,若无特殊说明,均为自常规生化试剂销售公司购买所得,其中:
DMEM培养基、RPMI1640培养基均购自Corning公司;淋巴细胞培养基X-VIVO 15购自Lonza公司。
T细胞生长培养基的配制方法参考中国发明专利CN201910163391.1,由基础培养基和细胞因子组成,基础培养基为淋巴细胞培养基X-VIVO 15,额外添加细胞因子5ng/mLIL-7、10ng/mL IL-15和30ng/mL IL-21。其中,细胞因子IL-7和IL-15购自R&D公司,IL-21则购自近岸蛋白质科技有限公司。
胎牛血清购自BI公司。
TurboFect转染试剂盒购自Thermo Fisher Scientific公司。
Lenti-X慢病毒浓缩试剂购自Takara公司。
基因合成购自上海捷瑞生物工程有限公司。
空白慢病毒表达质粒(pXW-EF1α-MCS-P2A-EGFP和pXW-EF1α-MCS)中的包装质粒psPAX2和包膜质粒PMD2.G购自Addgene公司;pSV1.0-EGFP-ATR-RE、pSV1.0-EGFP-GAL4UAS、pSV1.0-HATF、pSV1.0-Tat和pSV1.0-GAL4-VP64均购自上海鑫湾生物科技有限公司。
Stable 3化学感受态细胞购自上海唯地生物技术有限公司。
无内毒素质粒小提试剂盒和无内毒素质粒中提试剂盒分别购自OMEGA公司和Macherey Nagel公司。
荧光素酶底物购自普洛麦格生物技术有限公司。
HEK293T细胞、A549肺癌细胞、SKOV3卵巢癌细胞和NCI-H292肺癌细胞购自美国ATCC。稳定整合萤火虫荧光素酶基因的SKOV3-luc和NCI-H292-luc由本司改造而来。
重症联合免疫缺陷小鼠(B-NDG)购自百奥赛图江苏基因生物技术有限公司。
荷载人源HER2基因和萤火虫荧光素酶的复制缺陷型5型腺病毒(HER2-Luc-Ad)购自吉凯基因。
实施例1慢病毒表达质粒的构建
由上海捷瑞生物工程有限公司合成SEQ ID NO:2-5和9所示的核酸序列,并克隆至空白慢病毒表达质粒(pXW-EF1α-MCS-P2A-EGFP和pXW-EF1α-MCS),获得下述重组慢病毒表达质粒:
pXW-EF1α-HER2 CAR-P2A-EGFP、
pXW-EF1α-BFP-HATF-HRTE、
pXW-EF1α-GFP-RE-mCherry、
pXW-EF1α-GFP-HATF-HRTE-RE-mCherry、
pXW-EF1α-GFP-HATF-HRTE-RE-CAR、
pXW-EF1α-GFP-HATF-HRTE-RE-BiTE,质粒图谱如图1所示。
实施例2慢病毒的包装、浓缩和滴度测定
2.1慢病毒的包装
HEK293T细胞处理:转染前24小时,收集处于对数生长期的HEK293T细胞,将其接种于10cm细胞培养皿中(6×106~8×106个细胞),细胞在含有10mL的完全DMEM培养基中生长,置于37℃,5%CO2细胞培养箱中培养18-24小时,细胞密度达到70-90%即可进行质粒转染。
HEK293T细胞转染:在15mL离心管中加入1mL基础DMEM培养基,按照质量比为慢病毒表达质粒:包装质粒:包膜质粒=1:3:1配制转染混合液,质粒总量合计15μg/皿。以质粒量(μg):转染试剂(μL)=1:2的比例加入TurboFect转染试剂30μL,室温孵育15-20min后加至铺有HEK293T细胞的培养皿中,置于37℃,5%CO2细胞培养箱中继续培养48小时后收集病毒上清,1000×g,4℃离心10min,弃去管底沉淀并收集病毒上清。
2.2慢病毒的浓缩
使用0.45μm滤器进一步过滤离心收集的病毒上清,加入1/3病毒上清体积的Lenti-X慢病毒浓缩试剂,颠倒混匀数次,4℃孵育过夜,2000×g,4℃离心45min,离心管底部可见白色沉淀,即为浓缩后的病毒颗粒。小心弃除上清,以原病毒上清的1/50-1/100体积的空白RPMI1640培养基重悬白色沉淀,分装并于-80℃冻存备用。
2.3慢病毒滴度测定
将Jurkat T细胞按照1×105个/孔接种于96孔U底板上,将所收集的慢病毒浓缩液按10倍递增稀释。将100μL的病毒稀释液加入到相应孔中,加入促感染试剂硫酸鱼精蛋白并调整浓度至10μg/mL,1000×g,32℃离心感染90min,过夜培养后更换新鲜RPMI1640完全培养基,继续培养48h,流式细胞仪检测荧光阳性细胞比例。采用下面的公式计算病毒滴度:
病毒滴度(TU/mL)=1×105×荧光阳性细胞比例/100×1000×相应的稀释倍数。
实施例3基因工程化T细胞的制备
分别将浓缩获得的慢病毒载体,如下所述:
LV-EF1α-HER2 CAR-P2A-EGFP、
LV-EF1α-BFP-HATF-HRTE、
LV-EF1α-GFP-RE-mCherry、
LV-EF1α-GFP-HATF-HRTE-RE-mCherry、
LV-EF1α-GFP-HATF-HRTE-RE-CAR、
LV-EF1α-GFP-HATF-HRTE-RE-BiTE,以MOI=3的比例加至铺有1×106个预先活化的外周血单个核细胞的48孔平底板中,添加促感染试剂硫酸鱼精蛋白并将工作浓度调至10μg/mL,1000×g,32℃离心感染90min,过夜培养后,更换新鲜的T细胞生长培养基继续培养。每2-3天添加新鲜的T细胞生长培养基,并调整细胞密度至0.5×106~2×106个细胞/mL。感染后6-7天,移除活化T细胞的免疫磁珠,继续培养、扩增基因工程化的T细胞,待细胞静息后(磁珠去除后9-14天)方可进行后续的功能实验。
实施例4基因工程化A549细胞的制备
分别将浓缩获得的含有2-6个拷贝数RE的慢病毒载体LV-EF1α-GFP-HATF-HRTE-RE-BiTE(MOI=3)加至隔天铺有3×105个A549细胞的6孔平底板中,添加促感染试剂聚凝胺,并将工作浓度调至10μg/mL,过夜培养后,更换新鲜的完全培养基R10(RPMI1640+10%FBS+1%PS)继续培养。待细胞长至覆盖度80%后进行扩大培养备用。
实施例5本发明的缺氧触发的人工转录因子的转录诱导水平
为了验证本发明的HATF较传统GAL4-VP64人工转录因子有更好的诱导外源基因表达的能力,在HEK293T细胞做了质粒转染实验。将HEK293T细胞按5×104个/孔铺到48孔板内,待第二天细胞贴壁后进行转染。单转染组只转染0.25μg反应元件质粒pSV1.0-EGFP-ATR-RE或pSV1.0-EGFP-GAL4UAS,实验组转染0.25μg的pSV1.0-EGFP-RE质粒和pSV1.0-HATF或pSV1.0-Tat,或0.25μg的pSV1.0-EGFP-GAL4UAS质粒和pSV1.0-GAL4-VP64,以质粒量(μg):转染试剂(μL)=1:2的比例加入TurboFect转染试剂,室温孵育15-20min后加至细胞培养板中,置于37℃,5%CO2细胞培养箱中培养48h后流式检测目的基因mCherry的表达情况。
结果图2所示,RE转染组的目的基因mCherry表达阳性率仅为3.90%,HATF诱导后mCherry阳性率高达93.3%,进一步添加Tat的阳性率高达96.9%,而GAL4UAS转染组目的基因mCherry表达阳性率为11.4%,GAL4-VP64诱导后mCherry阳性率为70.9%(图2a)。HATF诱导阳性率为反应元件对照组的22.7倍(图2b),荧光强度则为反应元件对照组的110倍(图2c),Tat加入则进一步提升了诱导水平,阳性率和荧光强度的诱导倍数分别提高到23.6倍和347倍,而传统GAL4-VP64诱导阳性率为反应元件对照组的5.7倍(图2b),荧光强度仅为反应元件对照组的15倍(图2c),说明本发明中构建的HATF人工转录因子无论在背景泄漏水平,还是目的基因的诱导能力,均优于传统的GAL4-VP64人工转录因子。
实施例6缺氧敏感转录控制系统调控荧光蛋白的表达
采用实施例1的慢病毒表达质粒、实施例2的慢病毒载体制备方法和实施例3所述的方法制备整合EF1α-GFP-RE-mCherry、EF1α-BFP-HATF-HRTE和EF1α-GFP-RE-mCherry以及EF1α-GFP-HATF-HRTE-RE-mCherry基因的三种不同T细胞,分别为RE-mCherry反应元件、二单元形式的缺氧敏感转录控制系统(双载体共感染)和一单元形式的缺氧敏感转录控制系统(单载体感染)。将以上三种基因工程化T细胞置于常氧条件(21%O2)和缺氧条件(1%O2)下培养24h,培养结束后收集细胞并用FACS buffer(2%FBS的1×PBS)洗脱1遍,500×g离心5min,结束后用300μL FACS buffer重悬混匀,再使用流式细胞仪检测红色荧光蛋白mCherry的表达。
结果如图3所示:图3流式检测结果显示,本发明的一单元形式的缺氧敏感转录控制系统在常氧环境下的背景泄漏低至3.05%,缺氧环境下诱导表达高水平的红色荧光蛋白mCherry,阳性率增加至91.4%,平均荧光强度(Mean fluorescence intensity,MFI)高达1480。有趣的是,双病毒载体共感染获得的二单元形式的缺氧敏感转录控制系统的缺氧诱导水平远远低于单病毒载体感染获得的一单元形式的缺氧敏感转录控制系统,mCherry阳性率和荧光强度仅为31.8%和86.6,仅为一单元形式缺氧诱导阳性率和平均荧光强度的34.8%和5.85%,提示携带一单元形式的缺氧敏感转录控制系统单载体的缺氧诱导效果最优,本底泄漏和缺氧诱导水平均显著优于目前报道的双载体的二元转录放大系统。
实施例7缺氧敏感转录控制系统调控嵌合抗原受体的表达
采用实施例1的慢病毒表达质粒、实施例2的慢病毒载体制备方法和实施例3所述的方法制备携带EF1α-HER2 CAR-P2A-EGFP和EF1α-GFP-HATF-HRTE-RE-CAR基因的两种工程化T细胞,分别命名为HER2 CAR-T细胞(阳性对照)和缺氧敏感HER2 CAR-T细胞。将以上两种基因工程化T细胞分别置于常氧条件(21%O2)或缺氧条件(1%O2)下培养24h,结束后收集细胞并用FACS buffer洗脱1遍,加入2μg/mL流式抗体PE-anti-DYKDDDDK,室温避光孵育20min,结束后用FACS buffer洗脱2遍,300μL FACS buffer重悬混匀,然后使用流式细胞仪检测HER2 CAR分子的表达。
结果如图4所示:流式检测结果显示,常氧和缺氧条件下HER2 CAR-T细胞(阳性对照)均高表达HER2 CAR分子,而缺氧敏感HER2 CAR-T细胞于常氧条件下低表达HER2 CAR分子(10.8%),而在缺氧条件下上调HER2 CAR分子的表达(62.6%),CAR阳性率和平均荧光强度分别提升6倍和235倍,远远优于目前报道的缺氧敏感CAR-T细胞的诱导效果(JuilleratA,Marechal A,Filhol JM,et al.An oxygen sensitive self-decision makingengineered CAR T-cell[J].Sci Rep.2017,7:39833;Liao Q,He H,Mao Y,etal.Engineering T cells with hypoxia-inducible chimeric antigen receptor(HiCAR)for selective tumor killing.Biomark Res.2020,8(1):56)。
实施例8缺氧敏感转录控制系统调控嵌合抗原受体T细胞的肿瘤细胞杀伤
肿瘤细胞杀伤效率由基于荧光素酶的细胞杀伤检测方法(Luciferase-basedcytotoxicity assay)进行评估。首先,将1×104个SKOV3-Luc(萤火虫荧光素酶基因修饰的人卵巢癌细胞)或NCI-H292-Luc(萤火虫荧光素酶基因修饰的人肺癌细胞)接种于96孔平底黑板上,每孔100μL培养基,置于37℃,5%CO2细胞培养箱中培养18h。第二天,以效应细胞:靶细胞为1:2、1:1和2:1的比例加入实施例6的基因工程化T细胞及同期培养的未转导T细胞至含有靶细胞的孔中,分别置于常氧条件(21%O2)或缺氧条件(1%O2)下培养24h,共培养结束后使用96微孔板发光检测仪检测靶细胞的荧光素酶活力值。
细胞杀伤率的计算公式如下所示,
细胞杀伤率(%)=(未转导T细胞组荧光素酶活力值-实验组荧光素酶活力值)/未转导T细胞组荧光素酶活力值×100
结果如图5所示:HER2 CAR-T细胞(阳性对照)在常氧或缺氧条件下均能有效杀伤SKOV3和NCI-H292肿瘤细胞,并无选择性杀伤特性。缺氧敏感HER2 CAR-T细胞在常氧条件下的肿瘤杀伤活性较低,效应细胞:靶细胞为2:1时的杀伤率为10.33%(SKOV3)和13.33%(NCI-H292),缺氧环境下则能选择性高效杀伤SKOV3肿瘤细胞(67.67%)和NCI-H292肿瘤细胞(93.33%),肿瘤细胞杀伤活性提升了6倍。
实施例9缺氧敏感CAR-T细胞的体内安全性
用1×PBS稀释重组腺病毒(HER2-Ad)至目标剂量8×109TU/mL;
用1mL注射器腹腔注射125μL HER2-Ad,7天后进行小动物活体成像仪检测荧光素酶的表达,选取阳性小鼠后随机分组,除了HER2 CAR-T细胞输注组13只小鼠,其余每组4只小鼠,用于后续实验;
静脉回输5×106个HER2 CAR-T细胞、缺氧敏感HER2 CAR-T细胞和对照细胞,每隔2-3天称量小鼠体重、眼眶静脉采血检测血清细胞因子和观察小鼠的健康状况。
结果如图6所示:对照HER2 CAR-T细胞引起小鼠体重进行性降低(图6a),死亡率增加(图6b)和肝功能受损引起大量谷丙转氨酶(ALT)入血(图6c),且释放大量的T细胞活化相关细胞因子入血(图6d),而缺氧敏感HER2 CAR-T细胞则不会引起上述毒副作用,提示其不会引起靶向非肿瘤细胞引起的毒性(On-target off-tumor toxicity)。
实施例10缺氧敏感CAR-T细胞的体内抗肿瘤作用
提前一天对无菌隔离器饲养的B-NDG小鼠进行背部局部脱毛,脱毛可以使用脱毛膏或动物剃毛器,使其暴露出肿瘤细胞接种部位的皮肤即可;
左手固定小鼠,即左手同时抓紧小鼠的头部、颈部和背部皮肤,使其背部朝左翻,充分暴露背部右侧剃毛部位后,右手用酒精棉球对其进行消毒处理。1mL胰岛素注射器吹打混匀预先准备好的SKOV3或NCI-H292肿瘤细胞后吸取125μL细胞悬液(5×106个肿瘤细胞),将针头以针尖与皮肤呈30°-40°角度斜着刺入小鼠皮下,缓慢推注细胞悬液,避免细胞溢漏。待125μL细胞悬液注射完毕,留针2-3秒后迅速拔出,可见注射部位的皮下鼓起一个清晰可见的小包;
细胞接种后每隔2-3天观察小鼠的成瘤情况和健康状态,成瘤后用游标卡尺测量基线肿瘤体积并进行后续实验。
静脉回输5×106个缺氧敏感HER2 CAR-T细胞和对照细胞,每隔2-3天测量肿瘤大小,用游标卡尺分别测量肿瘤的长径和短径,肿瘤体积的计算公式如下:体积=(长径×短径2)/2。
结果如图7所示:缺氧敏感转录控制系统控制的HER2 CAR-T细胞(缺氧敏感HER2CAR-T细胞)可以有效抑制SKOV3(卵巢癌)和NCI-H292(肺癌)的生长,细胞回输35天的肿瘤抑制率高达100%和78.5%。
实施例11缺氧触发的CD47/CD3双特异性T细胞衔接蛋白的表达
实施例4的基因工程化A549细胞提前一天铺在12孔平底板中,每孔3×105个细胞,总体积为1mL;
第二天将平板放在常氧条件(21%O2)或缺氧条件(1%O2)下培养24h,结束后收集细胞,用1×BS重悬,加入4×SDS Loading Buffer稀释成1×后充分吹打混匀,将样品放在锅中并用电磁炉加热煮沸10min,使蛋白充分变性;
根据目标蛋白缺氧敏感人工转录因子分子量(72.5kD)和BiTE分子量(54.7kD),配制浓度为10%的上、下层SDS-PAGE胶,让样品在SDS-PAGE胶中进行电泳分离2h,接着采用湿转法将样品从凝胶中转移到预先经过甲醇活化的PVDF膜上;
根据蛋白Marker的指示,剪下含有目标蛋白和内参蛋白的PVDF膜置于5%脱脂奶粉封闭液中,摇床上室温孵育封闭至少1h;
将封闭好的PVDF膜取出,置于小鼠抗His标签一抗稀释液中,一抗稀释比例为1:1000,摇床上4℃过夜;
回收一抗稀释液,-20℃冻存备用。将PVDF膜取出并用PBST在摇床上振荡洗脱3次,每次8min,洗脱结束后加入相应的山羊抗小鼠IgG-HRP二抗稀释液,二抗稀释比例为1:3000,摇床上室温孵育1h;
将PVDF膜取出后再用PBST洗脱3次,显色后曝光。
结果如图8所示:图8为蛋白质免疫印迹检测曝光结果,常氧条件下几乎不表达缺氧敏感人工转录因子和下游目的基因CD47/CD3-BiTE,缺氧环境下则能诱导表达缺氧敏感人工转录因子和启动下游目的基因CD47/CD3-BiTE的表达。另外,2-6个拷贝的核心序列串联重复并不影响缺氧敏感转录控制系统的调控活性,均能实现常氧环境下的降解,缺氧环境下的目的蛋白高效诱导表达。
实施例12缺氧敏感转录控制系统调控CD47/CD3-BiTE-T细胞的肿瘤细胞杀伤
肿瘤细胞杀伤效率检测方法和杀伤效率计算同实施例7。首先,将1×104个SKOV3-Luc(荧光素酶基因修饰的人卵巢癌细胞)或NCI-H292-Luc(荧光素酶基因修饰的人肺癌细胞)接种于96孔平底黑板上,每孔100μL培养基,置于37℃,5%CO2细胞培养箱中培养18h。第二天,以效应细胞:靶细胞=1:2、1:、2:1的比例加入实施例8的缺氧敏感CD47/CD3-BiTE-T细胞及同期培养的未转导T细胞至含有靶细胞的孔中,分别置于常氧条件(21%O2)或缺氧条件(1%O2)下培养20小时,共培养结束后使用96微孔板发光检测仪检测靶细胞的荧光素酶活力值。
结果如图9所示:缺氧敏感CD47/CD3-BiTE-T细胞在常氧条件下的肿瘤杀伤活性较低,效应细胞:靶细胞=2:1分别为2.67%(SKOV3)和3.33%(NCI-H292),缺氧环境下则能选择性杀伤SKOV3细胞(78.67%)和NCI-H292细胞(97.67%),杀伤活性增加近30倍。
实施例13缺氧敏感CD47/CD3-BiTE-T细胞的体内抗肿瘤作用
首先,将5×106个NCI-H292-Luc(萤火虫荧光素酶基因修饰的人肺癌细胞)接种于B-NDG小鼠背部右侧皮下,每只注射125μL肿瘤细胞悬液,于肿瘤接种后6天静脉或瘤内注射实施例3制备的缺氧敏感BiTE-T细胞及同期培养的未转导T细胞,每只荷瘤小鼠回输5×106个阳性细胞。自肿瘤细胞接种后,则采用游标卡尺量取肿瘤的长径和短径并计算肿瘤体积,肿瘤体积的计算公式如下所示,肿瘤体积=(长径×短径2)/2。
结果如图10所示:静脉回输和瘤内注射缺氧敏感CD47/CD3-BiTE-T细胞均能有效控制肺癌的生长,相对于未转导T细胞治疗组,细胞回输后一个月的肿瘤抑制率分别为52.35%(静脉回输)和78.69%(瘤内注射)。
上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
序列表
<110> 上海鑫湾生物科技有限公司
<120> 缺氧触发的人工转录因子、转录控制系统及其应用
<130> DIC21110057R
<150> 2021109302685
<151> 2021-08-13
<160> 9
<170> SIPOSequenceListing 1.0
<210> 1
<211> 661
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Met His His His His His His Pro Lys Lys Lys Arg Lys Val Ser Asn
1 5 10 15
Leu Leu Thr Val His Gln Asn Leu Pro Ala Leu Pro Val Asp Ala Thr
20 25 30
Ser Asp Glu Val Arg Lys Asn Leu Met Asp Met Phe Arg Asp Arg Gln
35 40 45
Ala Phe Ser Glu His Thr Trp Lys Met Leu Leu Ser Val Cys Arg Ser
50 55 60
Trp Ala Ala Trp Cys Lys Leu Asn Asn Arg Lys Trp Phe Pro Ala Glu
65 70 75 80
Pro Glu Asp Val Arg Asp Tyr Leu Leu Tyr Leu Gln Ala Arg Gly Leu
85 90 95
Ala Val Lys Thr Ile Gln Gln His Leu Gly Gln Leu Asn Met Leu His
100 105 110
Arg Arg Ser Gly Leu Pro Arg Pro Ser Asp Ser Asn Ala Val Ser Leu
115 120 125
Val Met Arg Arg Ile Arg Lys Glu Asn Val Asp Ala Gly Glu Arg Ala
130 135 140
Lys Gln Ala Leu Ala Phe Glu Arg Thr Asp Phe Asp Gln Val Arg Ser
145 150 155 160
Leu Met Glu Asn Ser Asp Arg Cys Gln Asp Ile Arg Asn Leu Ala Phe
165 170 175
Leu Gly Ile Ala Tyr Asn Thr Leu Leu Arg Ile Ala Glu Ile Ala Arg
180 185 190
Ile Arg Val Lys Asp Ile Ser Arg Thr Asp Gly Gly Arg Met Leu Ile
195 200 205
His Ile Gly Arg Thr Lys Thr Leu Val Ser Thr Ala Gly Val Glu Lys
210 215 220
Ala Leu Ser Leu Gly Val Thr Lys Leu Val Glu Arg Trp Ile Ser Val
225 230 235 240
Ser Gly Val Ala Asp Asp Pro Asn Asn Tyr Leu Phe Cys Arg Val Arg
245 250 255
Lys Asn Gly Val Ala Ala Pro Ser Ala Thr Ser Gln Leu Ser Thr Arg
260 265 270
Ala Leu Glu Gly Ile Phe Glu Ala Thr His Arg Leu Ile Tyr Gly Ala
275 280 285
Lys Asp Asp Ser Gly Gln Arg Tyr Leu Ala Trp Ser Gly His Ser Ala
290 295 300
Arg Val Gly Ala Ala Arg Asp Met Ala Arg Ala Gly Val Ser Ile Pro
305 310 315 320
Glu Ile Met Gln Ala Gly Gly Trp Thr Asn Val Asn Ile Val Met Asn
325 330 335
Phe Ile Arg Asn Leu Asp Ser Glu Thr Gly Ala Met Val Arg Leu Leu
340 345 350
Glu Asp Gly Asp Ser Arg Ala Ala Ala Gly Gly Ser Gly Gly Ser Gly
355 360 365
Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp
370 375 380
Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp
385 390 395 400
Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp
405 410 415
Leu Asp Met Leu Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
420 425 430
Gly Gly Gly Gly Ser Ser Glu Asp Thr Ser Ser Leu Phe Asp Lys Leu
435 440 445
Lys Lys Glu Pro Asp Ala Leu Thr Leu Leu Ala Pro Ala Ala Gly Asp
450 455 460
Thr Ile Ile Ser Leu Asp Phe Gly Ser Asn Asp Thr Glu Thr Asp Asp
465 470 475 480
Gln Gln Leu Glu Glu Val Pro Leu Tyr Asn Asp Val Met Leu Pro Ser
485 490 495
Pro Asn Glu Lys Leu Gln Asn Ile Asn Leu Ala Met Ser Pro Leu Pro
500 505 510
Thr Ala Glu Thr Pro Lys Pro Leu Arg Ser Ser Ala Asp Pro Ala Leu
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Asn Gln Glu Val Ala Leu Lys Leu Glu Pro Asn Pro Glu Ser Leu Glu
530 535 540
Leu Ser Phe Thr Met Pro Gln Ile Gln Asp Gln Thr Pro Ser Pro Ser
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Asp Gly Ser Thr Arg Gln Ser Ser Pro Glu Pro Asn Ser Pro Ser Glu
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Tyr Cys Phe Tyr Val Asp Ser Asp Met Val Asn Glu Phe Lys Leu Glu
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Leu Val Glu Lys Leu Phe Ala Glu Asp Thr Glu Ala Lys Asn Pro Phe
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Ser Thr Gln Asp Thr Asp Leu Asp Leu Glu Met Leu Ala Pro Tyr Ile
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Pro Met Asp Asp Asp Phe Gln Leu Arg Ser Phe Asp Gln Leu Ser Pro
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Leu Glu Ser Ser Ser Ala Ser Pro Glu Ser Ala Ser Pro Gln Ser Thr
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Val Thr Val Phe Gln
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<210> 2
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<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
ataacttcgt ataatgtatg ctatacgaag ttat 34
<210> 3
<211> 269
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
taacttcgta taatgtatgc tatacgaagt tatataactt cgtataatgt atgctatacg 60
aagttatata acttcgtata atgtatgcta tacgaagtta taaagtgaaa gtcgagctcg 120
gtacccgggt cgactgcata taagcagctg ctctgcatat aagcagctgc tttttgcctg 180
tactgggtct ctctggttag accagatctg agcctgggag ctctctggct aactagggaa 240
cccactgctt aagcctcaat aaagcttgc 269
<210> 4
<211> 35
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
ccacagtgca tacgtgggct ccaacaggtc ctctt 35
<210> 5
<211> 175
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
ccacagtgca tacgtgggct ccaacaggtc ctcttccaca gtgcatacgt gggctccaac 60
aggtcctctt ccacagtgca tacgtgggct ccaacaggtc ctcttccaca gtgcatacgt 120
gggctccaac aggtcctctt ccacagtgca tacgtgggct ccaacaggtc ctctt 175
<210> 6
<211> 236
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Met Val Ser Lys Gly Glu Glu Asp Asn Met Ala Ile Ile Lys Glu Phe
1 5 10 15
Met Arg Phe Lys Val His Met Glu Gly Ser Val Asn Gly His Glu Phe
20 25 30
Glu Ile Glu Gly Glu Gly Glu Gly Arg Pro Tyr Glu Gly Thr Gln Thr
35 40 45
Thr Lys Leu Lys Val Thr Lys Gly Gly Pro Leu Pro Phe Ala Trp Asp
50 55 60
Ile Leu Ser Pro Gln Phe Met Tyr Gly Ser Lys Ala Tyr Val Lys His
65 70 75 80
Pro Ala Asp Ile Pro Asp Tyr Leu Lys Leu Ser Phe Pro Glu Gly Phe
85 90 95
Lys Trp Glu Arg Val Met Asn Phe Glu Asp Gly Gly Val Val Thr Val
100 105 110
Thr Gln Asp Ser Ser Leu Gln Asp Gly Glu Phe Ile Tyr Lys Val Lys
115 120 125
Leu Arg Gly Thr Asn Phe Pro Ser Asp Gly Pro Val Met Gln Lys Lys
130 135 140
Thr Met Gly Trp Glu Ala Ser Ser Glu Arg Met Tyr Pro Glu Asp Gly
145 150 155 160
Ala Leu Lys Gly Glu Ile Lys Gln Arg Leu Lys Leu Lys Asp Gly Gly
165 170 175
His Tyr Asp Ala Glu Val Lys Thr Thr Tyr Lys Ala Lys Lys Pro Val
180 185 190
Gln Leu Pro Gly Ala Tyr Asn Val Asn Ile Lys Leu Asp Ile Thr Ser
195 200 205
His Asn Glu Asp Tyr Thr Ile Val Glu Gln Tyr Glu Arg Ala Glu Gly
210 215 220
Arg His Ser Thr Gly Gly Met Asp Glu Leu Tyr Lys
225 230 235
<210> 7
<211> 498
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Tyr Lys Asp Asp Asp Asp Lys Asp Ile Gln
20 25 30
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
35 40 45
Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala Trp
50 55 60
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala
65 70 75 80
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser
85 90 95
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
100 105 110
Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly
115 120 125
Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Gly Ser Thr Ser Gly Ser
130 135 140
Gly Lys Pro Gly Ser Gly Glu Gly Ser Glu Val Gln Leu Val Glu Ser
145 150 155 160
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
165 170 175
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln
180 185 190
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn
195 200 205
Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
210 215 220
Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg
225 230 235 240
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly
245 250 255
Phe Tyr Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser
260 265 270
Ser Thr Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
275 280 285
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
290 295 300
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
305 310 315 320
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
325 330 335
Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu
340 345 350
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
355 360 365
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
370 375 380
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
385 390 395 400
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
405 410 415
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
420 425 430
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
435 440 445
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
450 455 460
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
465 470 475 480
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
485 490 495
Pro Arg
<210> 8
<211> 520
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
20 25 30
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Ser Asp Tyr
35 40 45
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
50 55 60
Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
65 70 75 80
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
85 90 95
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Gly His Gly Phe Pro Arg
100 105 110
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln
130 135 140
Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys
145 150 155 160
Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg
165 170 175
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Ser
180 185 190
Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile
195 200 205
Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu
210 215 220
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp
225 230 235 240
His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
245 250 255
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
260 265 270
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser
275 280 285
Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser
290 295 300
Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu
305 310 315 320
Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
325 330 335
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu
340 345 350
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro
355 360 365
Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
385 390 395 400
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
405 410 415
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr Gly Met Ser Trp
420 425 430
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Thr Ile Thr
435 440 445
Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe
450 455 460
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn
465 470 475 480
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu
485 490 495
Ala Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
500 505 510
Ser Ser His His His His His His
515 520
<210> 9
<211> 2539
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
tcactggaac acggtcacgg ttgactgtgg tgaagcgctc tcaggacttg cgctagaaga 60
ttcgagaggg gacagctgat caaatgaccg cagctgaaag tcatcgtcca taggaatgta 120
aggtgcgagc atttctaagt ccaggtcggt gtcctgtgtt gaaaatgggt tctttgcctc 180
agtatcctct gcgaacagct tctcgactaa ctccagctta aactcattca ccatgtcgct 240
atcgacgtag aagcagtact cggatgggga attgggctca ggggaagact gcctagttga 300
tccgtcggat ggagatggag tctgatcctg aatctgtggc atagtaaatg aaagctccag 360
agactctggg tttggctcta gcttcagggc cacctcctgg ttcagagcgg gatcggcgct 420
agacctgagt ggcttaggtg tctcggcggt aggcagtggt gacatagcca gattaatatt 480
ttgcagcttc tcattaggag aaggcagcat gacatcattg tacagaggca cctcctccag 540
ctgctggtcg tcggtctctg tatcgttaga cccaaagtcc aggctaataa ttgtatcgcc 600
ggcggcgggt gcgaggagtg tgagtgcgtc gggctccttc ttgagcttgt caaacagtga 660
tgaggtatcc tcgctggacc ctccgccgcc ggagcccccg cccccggacc cgcctccgcc 720
tgatccgagc atgtccaggt caaagtcatc cagtgcatct gatcccaaca tgtcgagatc 780
gaaatcgtcc agagcgtcag atcccagcat gtccagatca aaatcatcca gggcgtcgct 840
gcccagcata tccaggtcga agtcgtccag ggcatcagat ccgccagagc ctccgcttcc 900
gcctgcggca gctctagaat cgccgtcctc gagcaggcgc accatagccc cggtctcaga 960
atcgaggttt ctgatgaagt tcatcacaat attcacattg gtccatcccc ctgcctgcat 1020
aatctctggg atagagaccc cggctctagc catatcgcgg gcggctccca ctctagctga 1080
gtggccggac caagccaggt accgctgccc gctatcgtcc ttggccccgt aaatgagtct 1140
gtgggttgcc tcgaaaattc cctccagtgc cctagtagac agctgtgaag ttgcagaagg 1200
ggcagcgacg ccgttcttcc gcactctaca aaacaggtaa ttattagggt cgtcggcgac 1260
gccggacacg ctaatccacc gctcgaccag ctttgtcact cccagtgaca gagccttctc 1320
gacgccagca gtagacacga gtgtctttgt gcgtccgatg tggatgagca tgcgccctcc 1380
gtcagtgcgt gaaatatcct tgactctgat cctagcgatc tctgcaatgc gcaggagggt 1440
gttgtatgca attcccagaa aggcgagatt ccgaatgtcc tggcaccgat cagagttctc 1500
catgagggat ctcacctgat caaagtcggt ccgctcaaag gcgagggcct gcttagcgcg 1560
ctcgccagcg tcgacgttct cctttctaat gcgtctcatg acgagtgaca cggcattgga 1620
atcagatggt ctagggaggc cggaccggcg gtggagcatg ttcagctggc cgaggtgctg 1680
ctgaatagtc ttgactgcca gtcccctagc ctggaggtac agcaggtagt cgcgcacatc 1740
ctcgggctcg gctgggaacc acttgcggtt attgagctta caccaagcgg cccaagacct 1800
acacacggac aggagcatct tccaagtgtg ctcgctaaaa gcctgtctat cgcgaaacat 1860
atccatgaga ttcttccgca cctcatcgga agttgcatcc acggggagag cgggcagatt 1920
ctggtggact gtcaggagat tagagacctt gcgcttcttc ttagggtggt ggtggtggtg 1980
gtgcatctgc agaccggtgg atcccagcac agtctccagg cgatctgacg gttcactaaa 2040
cgagctctgc ttatataggc ctcccaccgt acacgccacc tcgacatacc acagtgcata 2100
cgtgggctcc aacaggtcct cttccacagt gcatacgtgg gctccaacag gtcctcttcc 2160
acagtgcata cgtgggctcc aacaggtcct cttccacagt gcatacgtgg gctccaacag 2220
gtcctcttcc acagtgcata cgtgggctcc aacaggtcct cttatgcata taacttcgta 2280
taatgtatgc tatacgaagt tatataactt cgtataatgt atgctatacg aagttatata 2340
acttcgtata atgtatgcta tacgaagtta taaagtgaaa gtcgagctcg gtacccgggt 2400
cgactgcata taagcagctg ctctgcatat aagcagctgc tttttgcctg tactgggtct 2460
ctctggttag accagatctg agcctgggag ctctctggct aactagggaa cccactgctt 2520
aagcctcaat aaagcttgc 2539
Claims (44)
1.一种缺氧触发的转录控制系统,其中,所述缺氧触发的转录控制系统包括上下游连锁的两套转录控制单元,所述上下游连锁的转录控制单元非线性串联,位于两个载体;或所述上下游连锁的转录控制单元线性串联,位于同一载体;
其中,所述上游转录控制单元包含用于控制人工转录因子HATF的缺氧触发的转录反应元件HRTE和编码人工转录因子HATF的核酸序列;所述下游转录控制单元包含人工转录因子HATF的识别元件RE和目的基因GOI,
其中,所述人工转录因子HATF包含如SEQ ID NO:1所示的序列;所述人工转录因子HATF的识别元件RE包含如SEQ ID NO:2所示的核心序列;
其中,所述HRTE的核心序列为5’-(A/G)CGT(G/C)-3’;
其中,所述GOI选自以下的一种或多种:
细胞因子和趋化因子;
细胞毒性分子;
针对不同抗原靶标的激动型抗体;
或针对不同抗原靶标的阻断型抗体;
或以上任意的两种或多种的组合。
2.根据权利要求1所述的缺氧触发的转录控制系统,其中,所述RE包含所述核心序列的多个拷贝和最小启动子。
3.根据权利要求2所述的缺氧触发的转录控制系统,其中,所述多个拷贝为两个拷贝、三个拷贝、四个拷贝、五个拷贝、六个拷贝、七个拷贝、八个拷贝、九个拷贝或十个拷贝。
4.根据权利要求3所述的缺氧触发的转录控制系统,其中,所述识别元件RE包含所述核心序列的五个或六个拷贝和最小启动子。
5.根据权利要求1至4中任一项所述的缺氧触发的转录控制系统,其中,所述RE的序列如SEQ ID NO:3所示。
6.根据权利要求1至4中任一项所述的缺氧触发的转录控制系统,其中,所述转录控制系统具有如下式中任一项所示的组合形式:
HATF-HRTE和RE-GOI;
HATF-HRTE和GOI-RE;
HRTE-HATF和GOI-RE或
HRTE-HATF和RE-GOI;
或所述转录控制系统具有如下式中任一项所示的组合形式:
HATF-HRTE-RE-GOI;
HATF-HRTE-GOI-RE;
HRTE-HRE-GOI;
HRTE-HATF-GOI-RE;
RE-GOI-HATF-HRTE;
RE-GOI-HRTE-HATF;
GOI-RE-HATF-HRTE或
GOI-RE-HRTE-HATF。
7.根据权利要求1至4中任一项所述的缺氧触发的转录控制系统,其中,所述HRTE包含如SEQ ID NO:4所示的序列。
8.根据权利要求7所述的缺氧触发的转录控制系统,其中,所述HRTE包含所述核心序列的多个拷贝和最小启动子。
9.根据权利要求8所述的缺氧触发的转录控制系统,其中,所述多个拷贝为两个拷贝、三个拷贝、四个拷贝、五个拷贝、六个拷贝、七个拷贝、八个拷贝、九个拷贝或十个拷贝。
10.根据权利要求9所述的缺氧触发的转录控制系统,其中,所述HRTE包含所述核心序列的五个或六个拷贝和最小启动子。
11.根据权利要求7所述的缺氧触发的转录控制系统,其中,所述HRTE的序列如SEQ IDNO:5所示。
12.根据权利要求1所述的缺氧触发的转录控制系统,其中,所述细胞因子和趋化因子选自GM-CSF、IFN-α/β/γ、IL-2、IL-3、IL-7、IL-12、IL-15、IL-21、IL-33、IL-35、IL-37、CCL4、CCL20、CXCL9、CXCL10、CXCL11、CXCL12、CXCL13、MIP-1α或MIP-1β。
13.根据权利要求1所述的缺氧触发的转录控制系统,其中,所述细胞毒性分子选自TNF-α、针对不同抗原靶标的T细胞衔接子、针对不同抗原靶标的嵌合抗原受体、凋亡基因、焦亡基因或毒素。
14.根据权利要求1所述的缺氧触发的转录控制系统,其中,所述激动型抗体选自抗CD28抗体、抗4-1BB抗体、抗ICOS抗体、抗GITR抗体、抗OX40抗体或抗CD27抗体。
15.根据权利要求1所述的缺氧触发的转录控制系统,其中,所述阻断型抗体选自CTLA-4抗体、PD-1抗体、PD-L1抗体、LAG-3抗体或Tim3抗体。
16.根据权利要求1所述的缺氧触发的转录控制系统,其中,所针对的抗原靶标选自AXL、EGFR、MHC、CD24、CD47、FAP、CD147、HER-2、CD55、CD59、ROR1、ROR2、CD133、CD44v6、CD44v7、CD44v8、CD126、CD171、CEA、EpCAM、TAG72、IL-13Rα、EGFRvIII、GD2、GD3、FRα、PSCA、PSMA、GPC3、CAIX、Claudin18.2、VEGFR2、PD-L1、PD-L2、MSLN、MUC1、c-Met、FOLR1、B7-H3和Trop2的一种或多种。
17.一种核酸序列,其包含权利要求1至16中任一项所述的缺氧触发的转录控制系统。
18.根据权利要求17所述的核酸序列,其中,所述核酸序列包含如SEQID NO:9所示的核酸序列和目的基因GOI的核酸序列。
19.一种载体,其包含如权利要求17或18所述的核酸序列。
20.根据权利要求19所述的载体,其中,所述载体选自质粒、逆转录病毒载体、慢病毒载体、腺病毒载体、腺相关病毒载体、痘苗病毒载体、单纯疱疹病毒载体、森林脑炎病毒载体、脊髓灰质炎病毒载体、新城疫病毒载体、转座子或其一种或多种的组合。
21.根据权利要求20所述的载体,其中,所述载体为慢病毒载体。
22.一种宿主细胞,所述宿主细胞包含所述如权利要求19至21中任一项所述的载体或所述宿主细胞的染色体中整合如权利要求17或18所述的核酸序列。
23.根据权利要求22所述的宿主细胞,其中,所述宿主细胞为分离获得的人源细胞。
24.根据权利要求22所述的宿主细胞,其中,所述宿主细胞选自胚胎干细胞、脐带血来源干细胞、诱导多能干细胞、造血干细胞、间充质干细胞、脂肪干细胞、T细胞、NK细胞、NKT细胞或巨噬细胞。
25.根据权利要求23所述的宿主细胞,其中,所述人源细胞为基因工程化的免疫细胞。
26.根据权利要求25所述的宿主细胞,其中,所述基因工程化的免疫细胞为T细胞、NK细胞、NKT细胞或巨噬细胞。
27.根据权利要求26所述的宿主细胞,其中,所述基因工程化免疫细胞为T细胞。
28.根据权利要求25所述的宿主细胞,其中,所述基因工程化免疫细胞选自以下的组:
嵌合抗原受体T细胞;
嵌合抗原受体NK细胞;
嵌合抗原受体NKT细胞;
嵌合抗原受体巨噬细胞;
T细胞受体T细胞。
29.如权利要求1至16中任一项所述的缺氧触发的转录控制系统、如权利要求17或18所述的核酸序列、如权利要求19至21中任一项所述的载体或如权利要求22至28中任一项所述的宿主细胞在制备用于治疗癌症的药物或制剂中的用途,所述癌症为实体瘤。
30.根据权利要求29所述的用途,其中,所述实体瘤选自神经母细胞瘤、肺癌、乳腺癌、食管癌、胃癌、肝癌、子宫颈癌、卵巢癌、肾癌、胰腺癌、鼻咽癌、小肠癌、大肠癌、结直肠癌、膀胱癌、骨癌、前列腺癌、甲状腺癌或脑癌中的一种或多种。
31.一种缺氧触发的转录控制系统,其中,所述缺氧触发的转录控制系统包括上下游连锁的两套转录控制单元,所述上下游连锁的转录控制单元非线性串联,位于两个载体;或所述上下游连锁的转录控制单元线性串联,位于同一载体;
其中,所述上游转录控制单元包含用于控制人工转录因子HATF的缺氧触发的转录反应元件HRTE和编码人工转录因子HATF的核酸序列;所述下游转录控制单元包含人工转录因子HATF的识别元件RE和目的基因GOI,
其中,所述人工转录因子HATF包含如SEQ ID NO:1所示的序列;所述人工转录因子HATF的识别元件RE包含如SEQ ID NO:2所示的核心序列;
其中,所述HRTE的核心序列为5’-(A/G)CGT(G/C)-3’;
其中,所述GOI的表达框包含SEQ ID NO:7或8所示的氨基酸序列。
32.一种核酸序列,其包含权利要求31所述的缺氧触发的转录控制系统。
33.根据权利要求32所述的核酸序列,其中,所述核酸序列包含如SEQID NO:9所示的核酸序列和目的基因GOI的核酸序列。
34.一种载体,其包含如权利要求32或33所述的核酸序列。
35.根据权利要求34所述的载体,其中,所述载体选自质粒、逆转录病毒载体、慢病毒载体、腺病毒载体、腺相关病毒载体、痘苗病毒载体、单纯疱疹病毒载体、森林脑炎病毒载体、脊髓灰质炎病毒载体、新城疫病毒载体、转座子或其一种或多种的组合。
36.根据权利要求35所述的载体,其中,所述载体为慢病毒载体。
37.一种宿主细胞,所述宿主细胞包含所述如权利要求34至36中任一项所述的载体或所述宿主细胞的染色体中整合如权利要求32或33所述的核酸序列。
38.根据权利要求37所述的宿主细胞,其中,所述宿主细胞为分离获得的人源细胞。
39.根据权利要求37所述的宿主细胞,其中,所述宿主细胞选自胚胎干细胞、脐带血来源干细胞、诱导多能干细胞、造血干细胞、间充质干细胞、脂肪干细胞、T细胞、NK细胞、NKT细胞或巨噬细胞。
40.根据权利要求38所述的宿主细胞,其中,所述人源细胞为基因工程化的免疫细胞。
41.根据权利要求40所述的宿主细胞,其中,所述基因工程化的免疫细胞为T细胞、NK细胞、NKT细胞或巨噬细胞。
42.根据权利要求41所述的宿主细胞,其中,所述基因工程化免疫细胞为T细胞。
43.根据权利要求40所述的宿主细胞,其中,所述基因工程化免疫细胞选自以下的组:
嵌合抗原受体T细胞;
嵌合抗原受体NK细胞;
嵌合抗原受体NKT细胞;
嵌合抗原受体巨噬细胞;
T细胞受体T细胞。
44.如权利要求31所述的缺氧触发的转录控制系统、如权利要求32或33所述的核酸序列、如权利要求34至36中任一项所述的载体或如权利要求37至43中任一项所述的宿主细胞在制备用于治疗癌症的药物或制剂中的用途,所述癌症为肺癌或卵巢癌。
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