CN114605560A - 一种car-nk细胞及其制备方法与应用 - Google Patents
一种car-nk细胞及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及一种CAR‑NK细胞及其制备方法与应用。本发明首先提供了一种靶向BCMA和CD5的双特异性嵌合抗原受体,具有如下结构:S‑BCMA scFv‑CD5scFv‑H‑TM‑CF‑CD3ζ,其中BCMA scFv为BCMA抗原结合域;CD5scFv为CD5抗原结合域;S为信号肽;H为铰链区;TM为跨膜区;CF为共刺激因子;CD3ζ为CD3ζ胞内信号域,该嵌合抗原受体能够同时结合BCMA、CD5两种抗肿瘤靶点,能够显著提高靶向性和有效性;敲除NK细胞中的免疫检查点抑制剂基因,可能给防止肿瘤细胞通过与相关免疫检查点抑制剂位点特异结合而触发免疫逃逸,有实验数据证明选择CTLA4作为敲除免疫检查点,相对于PD‑1、Tim‑3、LAG‑3等其他免疫检查点基因更具有优势。将上述嵌合抗原受体导入NK细胞后制备获得的CAR‑NK细胞,CAR‑NK细胞能够抑制白血病细胞增殖,调解IL‑6、IL‑12、IFN‑γ等细胞因子表达水平,抑制动物模型体内肿瘤生长,发挥协同抗肿瘤作用。
Description
技术领域:
本发明属于肿瘤免疫治疗领域,具体提供了一种CAR-NK细胞及其制备方法与应用。
背景技术:
恶性肿瘤是威胁人类健康的第一大“杀手”,恶性肿瘤的诊治一直是目前国内外探索的热点和难点问题,尽管外科手术、放疗技术和新型化疗药物不断被研发、完善,但不同的恶性肿瘤都难以取得一个长久的预后,这使得抗肿瘤新方法的研究更加迫切和有意义。在已知的恶性肿瘤中,多发性骨髓瘤(multiple myeloma,MM)是一种骨髓浆细胞克隆增殖性疾病,MM发病人数占血液肿瘤患者总数的10%,是仅次于恶性淋巴瘤的第二常见的血液系统恶性肿瘤。骨髓瘤患者血、尿中出现单克隆免疫球蛋白或其片段,造成骨髓造血、肾脏、骨骼等相关靶器官功能损害,临床主要表现为贫血、骨痛和溶骨性破坏、肾功能不全、反复感染等。目前临床上,骨髓瘤治疗以化疗和干细胞移植为主,化学药物治疗副作用较大,严重影响患者生活质量,细胞供者、患者的年龄、移植后相关并发症如移植物抗宿主病、移植后复发等仍然是造血干细胞移植面临的重要问题。因此,迫切需要一种新的治疗方法来改善骨髓瘤患者的预后。
在新型肿瘤治疗方法的研究中,肿瘤免疫治疗越来越多地被人们关注,对抗肿瘤免疫和肿瘤微环境的研究,为肿瘤免疫治疗提供了新的研究基础,肿瘤免疫治疗包括过继免疫治疗和靶向药物治疗。在1988年,美国研究者Rosenberg等首次提出过继免疫治疗的概念,它是指将患者自身T淋巴细胞、自然杀伤细胞(NK细胞)等免疫细胞在体外培养扩增并激活,联合使用生长因子输注回患者体内,使得这些免疫效应细胞发挥杀伤肿瘤细胞的作用,从而达到治疗肿瘤的目标。尽管这种疗法在包括黑色素瘤在内的部分肿瘤治疗中取得了较好的效果,但是对于大多数恶性肿瘤却疗效不佳,主要是因为受到主要组织相容性复合物(Major histocompatibility complex,MHC)的制约,这使得T淋巴细胞直接识别杀伤肿瘤的效果大打折扣。在此背景下,具有高效特异性、持久性和杀伤活性特点的嵌合抗原受体(chimeric antigen receptor,CAR)修饰T淋巴细胞进入了大家的视野。CAR的基本结构包括一个肿瘤相关抗原(tumor-associated antigen,TAA)结合区(通常来源于单克隆抗体抗原结合区域的scFV段),一个胞外铰链区(Hinge area),一个跨膜区(Transmembraneregion)和一个胞内免疫受体酪氨酸活化基序(Immunoreceptor tyrosine-basedactivation motif,ITAM)。这种结构可以突破MHC的制约,且能够通过胞外表达的抗原结合域特异性靶向肿瘤细胞发动攻击,从而发挥高效而持久的抗肿瘤活性。
嵌合抗原受体经历了四代结构,第一代CAR结构简单,无共刺激信号域,导致T细胞无法被完全激活,表现为无法在体内扩增到满足临床需要的程度,疗效不理想;第二代CAR加入了一个共刺激结构域(CD28或4-1BB),显著提高了CAR-T细胞的作用持续时间;第三代CAR则同时添加了两个共刺激结构域,使CAR-T细胞在体内活性更强,但有研究提出三代CAR可能会造成T细胞对刺激做出反应的界限值降低,诱发更重的细胞因子释放综合征;第四代CAR-T细胞又被称为TRUCK(T-cells redirected for universal cytokine killing)-T细胞,含有一个活化的T细胞核因子转录相应元件,可以使CAR-T细胞在肿瘤浸润范围内分泌特定的细胞因子来修饰肿瘤微环境,促进其他的免疫细胞参与免疫反应。目前的临床试验中,CD19 CAR-T细胞在治疗B-ALL患者时可达到80%以上的CR率,在B细胞淋巴瘤中反应率为52%-83%,在CLL的治疗中也有一定的反应率。
然而,CAR-T细胞治疗在带来令人满意的缓解率的同时,产生的相关不良反应也受到了目前临床治疗的关注,CAR-T细胞疗法的毒副反应主要包括:1)插入突变:CAR-T细胞治疗技术是在T细胞中插入一段外源性的DNA片段,有一定的导致第二肿瘤发生的风险;2)脱靶效应:即CAR-T细胞在识别肿瘤特异性抗原、杀伤肿瘤细胞的同时,可能会波及微量表达相同抗原的正常组织,称为脱靶效应;3)炎症反应:CAR-T细胞在抗原刺激下活化,分泌大量炎症因子,形成如细胞因子释放综合征、肿瘤溶解综合征等炎症反应;4)神经毒性;5)B细胞发育不全:是CD19 CAR-T细胞治疗的预期结果,在杀伤肿瘤细胞的同时也杀伤正常的表达CD19的B细胞,从而导致B细胞功能不全甚至B细胞衰竭;6)移植抗宿主反应(graft versus-host disease,GVHD),据报道大约有10%~20%的急性淋巴细胞性白血病(acutelymphoblastic leukemia,ALL)患者对CD19导向的CAR-T19存在原发耐药。上述不良反应中,细胞因子释放综合征(Cytokine release syndrome,CRS)最为常见,据报道CRS总发生率及严重CRS的发生率分别为58%-97%和15%-39%。其发生机制为CAR-T细胞与抗原结合后引起广泛的免疫激活并释放大量的细胞因子从而导致全身炎症反应,也被称为细胞因子风暴,在临床上CRS的首发症状通常为发热,其他反应包括流感样症状、疲乏、头痛和肌痛。也可以影响到各个器官系统,出现恶心呕吐、腹泻、皮疹、缺氧、肺水肿、低血压、既往未见的心律失常、心功能不全、肝功能不全、凝血指标异常等,病情严重时甚至可出现危及生命的休克、毛细血管渗漏、需机械通气纠正的缺氧、恶性心律失常和终末器官功能障碍。
由于CAR-T细胞存在诸多临床应用限制,使得研究人员开始将目光转向另一种免疫细胞——自然杀伤(natural killer,NK)细胞,K细胞属于大颗粒淋巴细胞,约占外周血淋巴细胞总数的10%~15%,NK细胞是天然免疫的重要组成成分,能够介导强大的抗肿瘤和抗病毒反应,NK细胞可释放IFN-γ以及含有穿孔素和颗粒酶的溶酶体,用于杀伤靶细胞,因此NK细胞被认为是细胞毒性CD8+T细胞的先天对应物,NK细胞的细胞毒活性与CD8+T细胞最相似。相比于CAR-T,CAR-NK具有独特的应用优势,包括:1)与T细胞相比,NK细胞具有高度的细胞毒性效应,可以以非抗原特异性方式杀死其靶标,而不会引起GVHD;2)NK细胞克隆扩增的缺乏以及异体NK细胞在数天至数周内的免疫介导排斥反应的缺乏,使得威胁生命的毒CRS的可能性降低;3)NK细胞具备更多的肿瘤杀伤途径,如执行细胞脱粒、激活凋亡途径和介导ADCC功能;4)异体NK细胞来源广泛,包括外周血,脐带血,NK细胞株(NK-92)与诱导多能干细胞(iPSC-NK)等等。由此可见,如何设计并获得适用于NK细胞的嵌合抗原受体结构,进而提供肿瘤治疗的有效性和安全性成为肿瘤治疗领域的热点和重点。
BCMA(B cell maturation antigen,B细胞成熟抗原)是肿瘤坏死因子受体(TNF-receptor)超家族成员,又名CD269,位于人16号染色体的短臂上(16p13.13),由3个外显子和2个内含子组成,BCMA是一种184个氨基酸和20.2-kDa的III型反式膜糖蛋白,具有含有6个半胱氨酸保守基序的末端。BCMA在幼稚的B细胞中检测不到,在造血干细胞和正常血液系统中也罕有表达,但是几乎在所有的多发性骨髓瘤(Multiple myeloma,MM)细胞均被识别出有BCMA表达,这使得BCMA成为了多发性骨髓瘤疾病活动性和预后的重要生物标志物。目前国内外研究中针对BCMA靶点开发出了多种抗体药物和嵌合抗原受体免疫细胞,为提高肿瘤治疗的选择性,研究人员开始关注靶向BCMA的双特异抗体或嵌合抗原受体研究,例如WO2019067677A1公开了靶向CD307E和BCMA的双特异嵌合抗原受体,CN109485734A公开了靶向BCMA和CD19的双特异性嵌合抗原受体,HK40050871A公开了靶向BCMA和CD3的双特异性抗体。将靶向BCMA的嵌合抗原受体应用于NK细胞也见少量报道,如US20210277136A1、WO2021146147A1等公开了构建CAR-NK细胞,用于治疗肿瘤相关疾病。
虽然上述产品和疗法取得了一定的治疗效果,但是靶向性和有效性仍有待强化,如何筛选获得靶向BCMA的嵌合抗原受体,以及所述抗原结合域可与其他哪种已知和/或未知抗肿瘤抗原识别分子构成强而有效的双特异性抗肿瘤结构,进而提供安全有效的肿瘤治疗手段,成为了肿瘤免疫治疗领域的研究热点和重点之一。此外,随着肿瘤免疫逃逸现象的揭示,如何避免肿瘤免疫逃逸的发生,如何在嵌合抗原受体免疫细胞中关闭免疫检查点抑制剂通路,也越来越受到业内的重视。此外,嵌合抗原受体在T细胞中的应用较多,但是在NK细胞仅有少量尝试,如何选择适合于NK细胞的嵌合抗原受体结构,以及如何与免疫检查点抗肿瘤机制想配合仍有待于证实和挖掘。
发明内容
为解决上述技术问题,本发明中提供了一种双特异性嵌合抗原受体,所述嵌合抗原受体包括如下结构:S-BCMA scFv-CD5 scFv-H-TM-C-CD3ζ,其中“-”为连接肽或肽键;S为信号肽;H为铰链区;TM为跨膜结构域;C为共刺激信号分子;CD3ζ为胞内信号传导序列;BCMAscFv包括如SEQ ID NO:1-3所示重链CDR区和SEQ ID NO:4-6所示轻链CDR区;CD5 scFv包括如SEQ ID NO:7-9所示重链CDR区和SEQ ID NO:10-12所示轻链CDR区。
现有技术中已经报道了多种可与BCMA形成双特异性抗体或嵌合抗原受体的潜在抗肿瘤靶点,包括但不限于CD19、CD20、CD3、PD-1/PD-L1等等,但是究竟BCMA与何种抗肿瘤靶点配合的效果更好,在制备嵌合抗原受体免疫细胞方面更具有优势,仍然莫衷一是,难以得出较为明确的结论。因此,本发明中筛选并获得了具有全新结构的靶向BCMA抗原结合域,将其与其他不同的靶向抗肿瘤靶点的抗原结合分子构成双特异性嵌合抗原受体结构,分别验证了其对于多发性骨髓瘤的抑制效果,发现靶向BCMA和CD5的双特异性嵌合抗原受体抗肿瘤活性最高,适用于构建CAR-NK细胞,从而为基于BCMA抗原的抗肿瘤药物的开发提供了新的研究途径和思路。
进一步的,BCMA scFv包括如SEQ ID NO:13所示重链可变区和SEQ ID NO:14所示轻链可变区;所述scFv序列中的重链可变区或轻链可变区也可以是与上述氨基酸序列保持高度同一性且具有相同功能的分子,所述同一性包括80-99%,优选85%、90%、95%、98%、99%。
进一步的,所述CD5 scFv包括如SEQ ID NO:15所示重链可变区和SEQ ID NO:16所示轻链可变区;所述scFv序列中的重链可变区或轻链可变区也可以是与上述氨基酸序列保持高度同一性且具有相同功能的分子,所述同一性包括80-99%,优选85%、90%、95%、98%、99%。
进一步的,所述共刺激信号分子选自CD27、CD28、4-1BB、CD11c、ITGB1、OX40、CD30、CD40、ICOS、CD11b、ITGAX中的一种或多种,优选为CD28和/或4-1BB,更优选为CD28。
进一步的,所述嵌合抗原受体的氨基酸序列如SEQ ID NO:17所示;所述嵌合抗原受体氨基酸序列也可以是与上述氨基酸序列保持高度同一性且具有相同功能的分子,所述同一性包括80-99%,优选85%、90%、95%、98%、99%。
提供了一种核酸分子,核酸分子编码上述的双特异性嵌合抗原受体。
进一步的,所述核酸分子的核苷酸序列如SEQ ID NO:18所示;也可以是与SEQ IDNO:18保持高度同一性且具有相同功能的分子,所述同一性包括80-99%,优选85%、90%、95%、98%、99%。
提供了一种NK细胞,所述的NK细胞表达上述的双特异性嵌合抗原受体。
进一步的,所述NK细胞为敲除CTLA4基因的T细胞。
免疫检查点及其作用机制的发现,对于抗肿瘤药物的开发具有里程碑式的意义。在人体的免疫过程中,正常组织利用T细胞上的免疫检查点避免被自身的免疫细胞攻击,从而避免正常组织的损伤和破坏,然而肿瘤细胞利用该机制可躲避免疫细胞的攻击而造成免疫逃逸。阻断免疫检查点可恢复T细胞对肿瘤细胞的识别、杀伤能力,免疫检查点抑制剂已显示出对多种肿瘤有效,目前研究最多的免疫检查点是程序性细胞死亡受体1及其配体(pro-grammed cell death 1/programmed cell death 1ligand,PD-1/PD-L1),但是从临床应用情况来看,仍有部分患者对PD-1/PD-L1抑制剂响应不足,因此有必要尝试基于其他免疫检查点靶标开发药物,例如细胞毒性T淋巴细胞抗原4(cytotoxic Tlymphocyteantigen 4,CTLA4)、T细胞免疫球蛋白和黏蛋白3(T cell immunoglobulin and mucin-3,Tim-3)、淋巴细胞激活基因3(lymphocyte activating gene 3,LAG-3)等等。本发明经过实验验证,发现在CAR-NK细胞中阻断CTLA4基因,似乎更有利于对抗多发性骨髓瘤,可大幅度提升肿瘤细胞杀伤能力。
提供了一种双特异性嵌合抗原受体或相应的CAR-NK细胞在制备肿瘤药物中的应用。所述肿瘤包括但不限于:淋巴瘤、白血病、多发性骨髓瘤、慢性淋巴细胞白血病、慢性骨髓性白血病、急性淋巴细胞白血病、急性骨髓性白血病、霍奇金氏淋巴瘤;优选多发性骨髓瘤。
有益效果
本发明中提供了一种新型靶向BCMA和CD5双特异性嵌合抗原受体,能够显著提高对骨髓瘤细胞的杀伤作用,丰富了基于BCMA靶点的双特异或多特异抗体或嵌合抗原受体的研究,为了组合靶点的筛选提供了新的研究基础和应用基础;进一步的,敲除了NK细胞中的免疫检查点CTLA4基因,可解除肿瘤免疫逃逸,提高对骨髓瘤细胞的杀伤效果;在体内实验中,可显著抑制肿瘤生长速度,促进抗肿瘤免疫因子表达,引发机体免疫抗肿瘤机制,发挥协同抗肿瘤效果。
附图说明
图1:嵌合抗原受体结构示意图
图2:不同CAR-NK细胞对骨髓瘤细胞存活率的影响;
图3:免疫检查点抑制剂基因敲除对CAR-NK细胞抗肿瘤活性的影响;
图4:肿瘤体积变化图;
图5:IL-6表达水平变化图;
图6:IL-12表达水平变化图;
图7:IFN-γ表达水平变化图;
具体实施方式
以下非限制性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何形式限制本发明。凡基于本发明上述内容所实现的技术均应当属于本申请要求保护的范围之中。
以下实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂生物材料、检测试剂盒,如无特殊说明,均可从商业途径获得。
实施例1:嵌合抗原受体设计
本实施例构建了包括抗BCMA靶点的双特异性抗体,序列示意图如图1所示,其结构为S-BCMA scFv-CDx scFv-H-TM-C-CD3ζ,其中BCMA scFv为靶向BCMA的抗原结合域;CDxscFv为靶向CDx的抗原结合域,具体包括CD3 scFv、CD5 scFv、CD7 scFv、CD19 scFv、CD20scFv;“-”为连接肽或肽键;S为信号肽;H为铰链区;TM为跨膜结构域;C为共刺激信号分子;CD3ζ为胞内信号传导序列。
各个靶点的抗原结合域序列为发明人在前期研究中获得,以靶向BCMA和CD5的双特异性嵌合抗原受体为例,其中BCMA scFv包括如SEQ ID NO:1-3所示重链CDR区和SEQ IDNO:4-6所示轻链CDR区;CD5 scFv包括如SEQ ID NO:7-9所示重链CDR区和SEQ ID NO:10-12所示轻链CDR区;BCMA scFv包括如SEQ ID NO:13所示重链可变区和SEQ ID NO:14所示轻链可变区;CD5 scFv包括如SEQ ID NO:15所示重链可变区和SEQ ID NO:16所示轻链可变区。BCMA-CD5嵌合抗原受体的氨基酸序列如SEQ ID NO:17所示,其核苷酸序列如SEQ ID NO:18所示。
实施例2:NK细胞制备
本实施例中采用密度梯度离心法获得患者外周血单个核细胞(Peripheral BloodMononuclear Cell,PBMC)。具体步骤包括:
用加有抗凝剂的采血管抽取20mL人外周血至离心管中,2000rpm离心10min;收集上层血浆,剩余血细胞沉淀中,加入等体积预温的生理盐水重悬,充分混匀;另取一支离心管,将混匀的血细胞沉淀按1:1体积轻轻地加到淋巴细胞分离液表面,18000rpm离心25min;小心吸取白色淋巴细胞层;将白膜层转移至新的离心管中,用PBS补至45mL,1500rpm离心5min,洗涤两次;加入适量的RPMI1640(含10%FBS)完全培养基重悬细胞并计数。
使用NK细胞分选试剂盒(购自biolegend公司)分选出NK细胞,使用RPMI1640(含10%FBS)进行扩大培养,并加入细胞因子IL-18(100U/mL)和IL-15(100U/mL)进行激活。
实施例3:NK细胞免疫检查点基因敲除
根据人PD-1、CTLA4、LAG-3和Tim-3基因的序列结构,并参考相关CRISPR基因编辑工具的现有研究内容,设计各自的sgRNA序列,其中为PD-1基因的sgRNA为如SEQ ID NO.19所示的核苷酸序列,CTLA4基因的sgRNA为如SEQ ID NO.20所示的核苷酸序列,LAG-3基因的sgRNA为如SEQ ID NO.21所示的核苷酸序列,Tim-3基因的sgRNA为如SEQ ID NO.22所示的核苷酸序列。将上述sgRNA核酸序列委托生工生物工程(上海)有限公司合成并分别插入标准载体连接至CRISPR/CAS9表达载体pX330A得到pX330A-TIGIT载体和pX330A-PD-1、pX330A-CTLA4、pX330A-LAG-3、pX330A-Tim-3载体。
将上述载体电转染NK细胞,具体步骤包括:取1×107个NK细胞,加入500μL电转缓冲液重悬细胞,并上下吹打均匀;细胞悬液中加入上述载体质粒(10ug),上下吹打均匀,并转入无菌洁净的电转杯中,预定条件设置参数:300V,10ms,进行2次电击操作;电击完成后,将电转杯置于冰上孵育10min,以使核酸充分进入细胞;将电击杯从冰上取出,将细胞从电转杯中转移出来,过滤后计数,按照一定的细胞密度接种于新鲜的DMEM培养基中,置于37℃、5%CO2培养箱培养。
电转后第2~3天通过流式细胞术检测NK细胞的目标表达情况,目标基因敲除效率=(对照组表达量-实验组表达量)/对照组表达量×100%,结果显示NK细胞的PD-1、CTLA4、LAG-3和Tim-3基因的敲除效率分别为98.5%、98.7%、99.2%和97.2%。
实施例4:CAR-NK细胞制备
将本发明中所提供的嵌合抗原受体基因片段导入psb1576载体中,再将上述载体导入感受态细胞中,采用质粒提取试剂盒(购自Axygen公司)提取质粒,测序鉴定目标基因序列是否正确。将阳性克隆质粒交由博生吉安科细胞技术有限公司分别合成慢病毒载体。
将实施例2中制备的NK细胞和实施例3中制备的基因敲除NK细胞分别激活,加入新鲜培养基中,在37℃,5%CO2的环境下培养10天后,离心收集细胞;用新鲜培养基重悬细胞,调整细胞密度至1×106cells/mL,按MOI=10分别加入各种慢病毒于24孔培养板中,混匀后放置于37℃、5%CO2培养箱培养,培养48h-96h后更换新鲜培养基;应用PCR法测定CAR-NK细胞的转导效率,阳性率达95%以上,符合实验要求。
实施例5:CAR-NK细胞对肿瘤细胞的杀伤作用
为验证CAR-NK细胞的肿瘤杀伤效果,本发明中选用人多发性骨髓瘤细胞系RPMI8226(购自美国ATCC公司)作为研究对象。
5.1肿瘤细胞培养
从液氮中取出并复苏RPMI 8226细胞,以1×106个/mL接种于RPMI 1640完全培养基(含10%FBS),37℃、5%CO2细胞培养箱中无菌培养。每隔36-72h计数并传代1次,观察细胞状态,当细胞存活率达到80%以上时,进行后续实验。
5.2 CAR-NK细胞共培养
分别收获CAR-NK细胞与上述肿瘤细胞,使用无菌PBS洗涤3次,然后按1:1比例混合CAR-NK细胞与肿瘤细胞,调整细胞密度至1×106个/mL,接种于96孔板中,置于37℃,5%CO2培养箱中共培养24h。以无菌PBS溶液作为阴性对照。
5.3 MTT法检测不同CAR-NK细胞的肿瘤杀伤效率
CAR-NK细胞与肿瘤细胞共培养48h天后,离心取上清,每孔加入20μLMTT处理4h,之后弃掉MTT后加入150μL DMSO,摇床震荡10min;同时设置空白对照孔。以空白对照孔调零,通过酶标仪检测490nm波长处的吸光度(OD值)。计算细胞的相对存活率(cell viability):cell viability(%)=(实验组OD-空白组OD)/(对照组OD-空白组OD)×100%。
结果如图2所示,本发明中所提供的双特异性CAR-NK细胞能够有效杀死骨髓瘤细胞,但令人惊奇的是,与较多报道的BCMA靶点与CD3、CD19、CD20组合相比,本发明中所提供的靶向BCMA抗原结合域与CD5组合更能有效杀伤骨髓瘤细胞,在与靶向BCMA和CD5双特异性CAR-NK细胞孵育中,RPMI 8226细胞的存活率最低,其次为BCMA与CD20的组合,而BCMA与CD3、CD19和CD7的组合效果更次之。这提示了,BCMA与CD5的组合更能发挥协同抗肿瘤效果。
5.4 MTT法检测免疫检查点基因敲除CAR-NK细胞的肿瘤杀伤效率
为了进一步提高抗肿瘤效果,抑制肿瘤免疫逃逸现象,本实施例中将靶点BCMA与CD5嵌合抗原受体构建入PD-1、CTLA4、LAG-3和Tim-3基因敲除NK细胞中,获得△PD-1-BCMA-CD5 CAR-NK细胞、△CTLA4-BCMA-CD5CAR-NK细胞、△LAG-3-BCMA-CD5 CAR-NK细胞、△Tim-3-BCMA-CD5CAR-NK细胞、(构建方法同实施例4)。将上述CAR-NK细胞分别与人多发性骨髓瘤细胞系RPMI 8226共培养,采用MTT法检测细胞存活率(方法同5.1-5.3节)。
结果如图3所示,敲除免疫检查点基因后,CAR-NK细胞的抗肿瘤活性得到了不同程度的进一步增强,但是在敲除PD-1基因和LAG-3基因的NK细胞中,促进效果不显著,与未敲除细胞相比不具有显著差异;CTLA4和Tim-3基因敲除后,抗肿瘤活性得到显著强化,且CTLA4敲除的效果更加明显。
实施例6 CAR-NK细胞对体内肿瘤的抑制作用
6.1动物模型制备及给药
复苏并培养RPMI 8226细胞,方法同5.1节。取6-8周体重相近的健康BALB/c裸鼠,将多发性骨髓瘤RPMI 8226稀释至1×106个/mL,取300μL上述细胞溶液注射至裸鼠腋下,待其瘤体积增至100mm3左右,表明造模成功。将实验动物随机分为三组,分别注射1×106个△CTLA4 BCMA-CD5 CAR-NK细胞和BCMA-CD5 CAR-NK细胞,以等体积的生理盐水作为对照组。
6.2肿瘤体积检测
首次给药时间记为第0周,每周检测肿瘤体积,具体方法为:使用游标卡尺测量肿瘤长径(L)和短径(W),按公式V=(W2×L)/2计算肿瘤体积,共检测3周。
如图4所示,本发明中所提供的CAR-NK细胞能够显著抑制骨髓瘤肿瘤体积的增加,抑制肿瘤的生长过程,与生理盐水对照组相比,使用CAR-NK细胞治疗3周后,肿瘤体积减小约一半,而使用CTLA4基因敲除的CAR-NK细胞肿瘤抑制效果更加明显,说明这种免疫检查点基因修饰的CAR-NK细胞在体内实验中可以激活机体内的免疫系统,发挥持久而高效的肿瘤抑制作用。
6.4检测血液中IL-6、IL-12、IFN-γ含量
前期CAR-T细胞的研究中发现,在细胞因子调节方面,靶向BCMA的CAR-T细胞对于白介素类因子的影响更加明显,而对于TGF-β、TNFα的影响较小,因此本发明中集中考察CAR-NK细胞对于白介素(如IL-6,IL-12)的影响。此外,NK细胞具有较强的IFN-γ调节能力,所以本发明中也对该因子进行考察,以便揭示CAR-NK细胞免疫调节机制。
给药3周后,裸鼠眼眶静脉取血后置于离心机以3000r/min离心15min,去上层血清置于离心管,保存于-80℃冰箱备用。按ELISA试剂盒(购自武汉博士德生物工程有限公司公司)说明书步骤分别测量裸鼠血清中IL-6、IL-12、IFN-γ的含量。
白介素-6(inlerleukin-6,IL-6)是由T细胞、B细胞、单核细胞、巨噬细胞、成纤维细胞、血管内皮细胞以及部分肿瘤细胞分泌产生的一种多功能、多效应及多向性的细胞因子。IL-6是一种典型的促成瘤细胞因子,在体内通过激活Janus蛋白酪氨酸蛋白激酶2(Janus kinase 2,JAK2)、信号转导和转录激活因子3(signal transduction andactivator of transcription 3,STAT3)、磷脂酰肌醇3-激酶(phosphatidylinositol3kinase,PI3K)、蛋白激酶B(protein kinase B,AKT)及Ras蛋白/细胞外信号调节激酶(extracellular regulatedprotein kinases,ERK)等信号通路,影响肿瘤细胞的增殖、存活、分化、迁移、侵袭、转移、血管生成、炎症和新陈代谢,有文献研究表明,IL-6在包括皮肤癌、乳腺癌、肺癌、食道癌、肝癌、胰腺癌、胃癌、结肠直肠癌、前列腺癌、肾癌、膀胱癌和血液癌在内的多种癌症中表达升高或异常。在本实施例中,如图5所示,在肿瘤模型中IL-6高水平表达,使用BCMA-CD5 CAR-NK细胞治疗后,IL-6表达量开始下降,在△CTLA4 BCMA-CD5CAR-NK细胞治疗组中,这一趋势得到了进一步强化,说明本发明所提供的CAR-NK细胞可有效抑制IL-6的分泌,进而抑制肿瘤的增殖、存活、分化、迁移、侵袭、转移等过程。
白介素-12(inlerleukin-12,IL-12)是一种具有广泛生物学活性的细胞因子,主要由激活的炎性细胞产生,它能通过调节固有免疫、获得性免疫及抑制肿瘤血管生成发挥抗肿瘤作用。IL-12参与抗肿瘤过程的主要方式包括:(1)IL-12能提高CD8+NK细胞、自然杀伤细胞(natural killer cell,NK)等细胞毒性淋巴细胞的肿瘤杀伤作用;(2)IL-12刺激免疫细胞产生IFN-γ和其他二级和三级促炎性细胞因子,可对肿瘤细胞产生直接毒性,和/或能通过抑制肿瘤血管生成抑制肿瘤生长;(3)IL-12可通过诱导或增加Th1细胞和细胞毒性T淋巴细胞(CTL)的反应能力,增强机体肿瘤抗原特异性免疫;(4)IL-12还能通过刺激Th1反应增加调理型和补体结合型IgG抗体的产生,增强抗肿瘤活性。在本实施例中,如图6所示,使用CAR-NK细胞治疗后,裸鼠体内IL-12水平显著提升,但BCMA-CD5 CAR-NK细胞和△CTLA4BCMA-CD5 CAR-NK细胞中却未见显著差异,说明本发明所提供的CAR-NK细胞可有效上调IL-12的表达水平,但这一现象与CTLA4基因表达并未见明显关联。
干扰素γ(interferon-γ,IFN-γ)属于II型干扰素,是水溶性二聚体细胞因子,由Th1型细胞(主要是活化T细胞和NK细胞)分泌,可以通过活化巨噬细胞来提升抗原提呈能力,刺激机体固有免疫系统,使内皮细胞与淋巴细胞相互作用,调控细胞因子谱表达与细胞凋亡。IFN-γ可激活NK细胞和巨噬细胞发挥细胞毒作用,促进巨噬细胞产生IL-12和IL-18,通过抗原提呈机制发挥机体适应性免疫反应,目前重组IFN-γ蛋白已被用于膀胱瘤、黑色素瘤、淋巴瘤、卵巢癌、神经胶质瘤、结肠癌等多种肿瘤的治疗中,并且取得了不错的效果。在本发明中,如图7所示,经过CAR-NK细胞治疗后,裸鼠体内的IFN-γ分泌被调节至高水平,且使用CTLA4基因突变的CAR-NK细胞效果更强,更能够通过IFN-γ及其相关通路抑制肿瘤生长过程。
综上所述,本发明中提供了一种新型靶向BCMA和CD5的嵌合抗原受体,将其导入NK细胞构建为CAR-NK细胞后,能够有效杀伤多发性骨髓瘤细胞,这种杀伤作用在敲除CTLA4基因后更加有效;在体内实验中可显著抑制肿瘤生长,并通过调节IL-6、IL-12、IFN-γ表达水平,激活体内其他免疫调节机制,发挥协同抗肿瘤作用,为相关抗肿瘤药物或疗法的开发提供了新的思路。
虽然本发明参考其示例性的实施例已经进行了具体显示和描述,本领域的技术人员应当理解的是,在不偏离由所附权利要求书所涵盖的本发明的范围的情况下,可以在其中做出在形式和细节方面的多种改变。
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Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
210 215 220
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
225 230 235 240
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Thr Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
340 345 350
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
405 410 415
Asp Ser Asp Gly Ser Phe Leu Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
450 455 460
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
485 490 495
Thr Val Thr Leu Thr Cys Ser Val Glu Ala Met Pro Ser Trp Val Gln
500 505 510
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Thr Cys Thr Gln
515 520 525
Leu Met Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Thr Gly
530 535 540
Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala
545 550 555 560
Glu Tyr Tyr Cys Tyr Ser Asn Ala Met Trp Ser Ser Pro Lys Ala Ala
565 570 575
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala
580 585 590
Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn
595 600 605
Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val
610 615 620
Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu
625 630 635 640
Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser
645 650 655
Tyr Leu Ser Leu Thr Thr Glu Gln Trp Lys Ser His Arg Ser Tyr Ser
660 665 670
Cys Gln Val Thr His Glu Gln Ser Thr Val Glu Lys Thr Val Ala Pro
675 680 685
Thr Glu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
690 695 700
Gly Gly Ser Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
705 710 715 720
Pro Ser Glu Thr Leu Ser Leu Thr Leu Val Lys Ser Lys Leu Ser Ser
725 730 735
Gly Ser Tyr Phe Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
740 745 750
Glu Trp Ile Gly Asp Thr Ala Pro Pro Gly Trp Asp Met Glu Pro Ala
755 760 765
Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Glu Asp Thr Ser
770 775 780
Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr
785 790 795 800
Ala Val Tyr Tyr Cys Ala Arg Trp Gly Gln Pro Ser Gly Thr Leu Val
805 810 815
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
820 825 830
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
835 840 845
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
850 855 860
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
865 870 875 880
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
885 890 895
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
900 905 910
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
915 920 925
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
930 935 940
Pro Lys Pro Lys Asp Thr Leu Gln Ile Ser Arg Thr Pro Glu Val Thr
945 950 955 960
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
965 970 975
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
980 985 990
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
995 1000 1005
Leu His Gln Asp Trp Leu Asn Pro Lys Glu Tyr Lys Cys Lys Val Ser
1010 1015 1020
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
1025 1030 1035 1040
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
1045 1050 1055
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
1060 1065 1070
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Met Pro Glu
1075 1080 1085
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
1090 1095 1100
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
1105 1110 1115 1120
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
1125 1130 1135
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Gly Gly Gly Gly Ser
1140 1145 1150
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Val Leu Thr Gln
1155 1160 1165
Pro Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys
1170 1175 1180
Gly Gly Asn Asn Ile Gly Ser Lys Gln Pro Pro Ile Tyr Tyr Gly Gln
1185 1190 1195 1200
Ala Pro Val Val Asn Pro Ser Lys Leu Val Ser Ser Gly Ile Pro Glu
1205 1210 1215
Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser
1220 1225 1230
Arg Val Glu Ala Gly Asp Glu Gly Ala Thr Ala Thr Thr Ser Pro Trp
1235 1240 1245
Met Glu Phe Asp Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro
1250 1255 1260
Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys
1265 1270 1275 1280
Ala Thr Leu Val Cys Leu Ile Trp Asp Phe Tyr Pro Gly Ala Val Thr
1285 1290 1295
Val Ala Trp Lys Gly Asp Ser Ser Pro Val Lys Ala Gly Val Glu Thr
1300 1305 1310
Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr
1315 1320 1325
Leu Ser Leu Thr Pro Glu Gln His Lys Ser His Arg Ser Tyr Ser Cys
1330 1335 1340
Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Thr Ala Pro Thr
1345 1350 1355 1360
Glu Cys Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
1365 1370 1375
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
1380 1385 1390
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
1395 1400 1405
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1410 1415 1420
Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu
1425 1430 1435 1440
His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg
1445 1450 1455
Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg
1460 1465 1470
Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1475 1480 1485
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
1490 1495 1500
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
1505 1510 1515 1520
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
1525 1530 1535
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
1540 1545 1550
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
1555 1560 1565
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
1570 1575 1580
Arg
1585
<210> 18
<211> 4755
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
atggcgctgc cggtgaccgc gctgctgctg ccgctggcgc tgctgctgca tgcggcgcgc 60
ccggaagtgc agctggtgga aagcggcggc ggcctggtgc agccgccggg cagcctgcgc 120
ctgagctgcg cggcgagcgg ctttaccttt aacctgacca ccgaaccgtt ttgggtgcgc 180
caggcgccgg gcaaaggcct ggaatgggtg gcgcgcattg tgaccgcgga atgcagctgg 240
atggaacgct ttaccattag ccgcgatgat agcaaaaaca gcctgtatct gcagatgaac 300
agcctgaaaa ccgaagatac cgcggtgtat tattgcgcgc gcgaagaact ggatagcagc 360
aactataaac tgcagtggcc gtggggccag ggcaccctgg tgaccgtgag cagcgcgagc 420
accaaaggcc cgagcgtgtt tccgctggcg ccgtgcagcc gcagcaccag cgaaagcacc 480
gcggcgctgg gctgcctggt gaaagattat tttccggaac cggtgaccgt gagctggaac 540
agcggcgcgc tgaccagcgg cgtgcatacc tttccggcgg tgctgcagag cagcggcctg 600
tatagcctga gcagcgtggt gaccgtgccg agcagcagcc tgggcaccaa aacctatacc 660
tgcaacgtgg atcataaacc gagcaacacc aaagtggata aacgcgtgga aagcaaatat 720
ggcccgccgt gcccgccgtg cccggcgccg gaagcggcgg gcggcccgag cgtgtttctg 780
tttccgccga aaccgaaaga taccctgatg attagccgca ccccggaagt gacctgcgtg 840
gtggtggatg tgagccagga agatccggaa gtgcagttta actggtatgt ggatggcgtg 900
gaagtgcata acgcgaaaac caaaccgcgc gaagaacagt ttaacagcac ctatcgcgtg 960
gtgagcgtgc tgaccgtgct gcatcaggat tggctgaacg gcaccgaata taaatgcaaa 1020
gtgagcaaca aaggcctgcc gagcagcatt gaaaaaacca ttagcaaagc gaaaggccag 1080
ccgcgcgaac cgcaggtgta taccctgccg ccgagccagg aagaaatgac caaaaaccag 1140
gtgagcctga cctgcctggt gaaaggcttt tatccgagcg atattgcggt ggaatgggaa 1200
agcaacggcc agccggaaaa caactataaa accaccccgc cggtgctgga tagcgatggc 1260
agctttctgc tgtatagcaa actgaccgtg gataaaagcc gctggcagga aggcaacgtg 1320
tttagctgca gcgtgatgca tgaagcgctg cataaccatt atacccagaa aagcctgagc 1380
ctgagcctgg gcaaaggcgg cggcggcagc ggcggcggcg gcagcggcgg cggcggcagc 1440
cagaccgtgg tgacccagga accgagcctg accgtgagcc cgggcggcac cgtgaccctg 1500
acctgcagcg tggaagcgat gccgagctgg gtgcagcaga aaccgggcca ggcgccgcgc 1560
ggcctgattg gcacctgcac ccagctgatg gcgccgggca ccccggcgcg ctttagcggc 1620
agcctgaccg gcggcaaagc ggcgctgacc ctgagcggcg tgcagccgga agatgaagcg 1680
gaatattatt gctatagcaa cgcgatgtgg agcagcccga aagcggcgtt tggcggcggc 1740
accaaactga ccgtgctggg ccagccgaaa gcggcgccga gcgtgaccct gtttccgccg 1800
agcagcgaag aactgcaggc gaacaaagcg accctggtgt gcctgattag cgatttttat 1860
ccgggcgcgg tgaccgtggc gtggaaagcg gatagcagcc cggtgaaagc gggcgtggaa 1920
accaccaccc cgagcaaaca gagcaacaac aaatatgcgg cgagcagcta tctgagcctg 1980
accaccgaac agtggaaaag ccatcgcagc tatagctgcc aggtgaccca tgaacagagc 2040
accgtggaaa aaaccgtggc gccgaccgaa tgcagcggcg gcggcggcag cggcggcggc 2100
ggcagcggcg gcggcggcag ccagctgcag ctgcaggaaa gcggcccggg cctggtgaaa 2160
ccgagcgaaa ccctgagcct gaccctggtg aaaagcaaac tgagcagcgg cagctatttt 2220
tggggctgga ttcgccagcc gccgggcaaa ggcctggaat ggattggcga taccgcgccg 2280
ccgggctggg atatggaacc ggcgtataac ccgagcctga aaagccgcgt gaccattagc 2340
gaagatacca gcaaaaacca gtttagcctg aaactgagca gcgtgaccgc ggcggatacc 2400
gcggtgtatt attgcgcgcg ctggggccag ccgagcggca ccctggtgac cgtgagcagc 2460
gcgagcacca aaggcccgag cgtgtttccg ctggcgccgt gcagccgcag caccagcgaa 2520
agcaccgcgg cgctgggctg cctggtgaaa gattattttc cggaaccggt gaccgtgagc 2580
tggaacagcg gcgcgctgac cagcggcgtg catacctttc cggcggtgct gcagagcagc 2640
ggcctgtata gcctgagcag cgtggtgacc gtgccgagca gcagcctggg caccaaaacc 2700
tatacctgca acgtggatca taaaccgagc aacaccaaag tggataaacg cgtggaaagc 2760
aaatatggcc cgccgtgccc gccgtgcccg gcgccggaag cggcgggcgg cccgagcgtg 2820
tttctgtttc cgccgaaacc gaaagatacc ctgcagatta gccgcacccc ggaagtgacc 2880
tgcgtggtgg tggatgtgag ccaggaagat ccggaagtgc agtttaactg gtatgtggat 2940
ggcgtggaag tgcataacgc gaaaaccaaa ccgcgcgaag aacagtttaa cagcacctat 3000
cgcgtggtga gcgtgctgac cgtgctgcat caggattggc tgaacccgaa agaatataaa 3060
tgcaaagtga gcaacaaagg cctgccgagc agcattgaaa aaaccattag caaagcgaaa 3120
ggccagccgc gcgaaccgca ggtgtatacc ctgccgccga gccaggaaga aatgaccaaa 3180
aaccaggtga gcctgacctg cctggtgaaa ggcttttatc cgagcgatat tgcggtggaa 3240
tgggaaagca acggcatgcc ggaaaacaac tataaaacca ccccgccggt gctggatagc 3300
gatggcagct tttttctgta tagccgcctg accgtggata aaagccgctg gcaggaaggc 3360
aacgtgttta gctgcagcgt gatgcatgaa gcgctgcata accattatac ccagaaaagc 3420
ctgagcctga gcctgggcaa aggcggcggc ggcagcggcg gcggcggcag cggcggcggc 3480
ggcagcagct atgtgctgac ccagccgccg agcgtgagcg tggcgccggg ccagaccgcg 3540
cgcattacct gcggcggcaa caacattggc agcaaacagc cgccgattta ttatggccag 3600
gcgccggtgg tgaacccgag caaactggtg agcagcggca ttccggaacg ctttagcggc 3660
agcaacagcg gcaacaccgc gaccctgacc attagccgcg tggaagcggg cgatgaaggc 3720
gcgaccgcga ccaccagccc gtggatggaa tttgataaac tgaccgtgct gggccagccg 3780
aaagcggcgc cgagcgtgac cctgtttccg ccgagcagcg aagaactgca ggcgaacaaa 3840
gcgaccctgg tgtgcctgat ttgggatttt tatccgggcg cggtgaccgt ggcgtggaaa 3900
ggcgatagca gcccggtgaa agcgggcgtg gaaaccacca ccccgagcaa acagagcaac 3960
aacaaatatg cggcgagcag ctatctgagc ctgaccccgg aacagcataa aagccatcgc 4020
agctatagct gccaggtgac ccatgaaggc agcaccgtgg aaaaaaccac cgcgccgacc 4080
gaatgcagca ccaccacccc ggcgccgcgc ccgccgaccc cggcgccgac cattgcgagc 4140
cagccgctga gcctgcgccc ggaagcgtgc cgcccggcgg cgggcggcgc ggtgcatacc 4200
cgcggcctgg attttgcgtg cgatatttat atttgggcgc cgctggcggg cacctgcggc 4260
gtgctgctgc tgagcctggt gattaccctg tattgccgca gcaaacgcag ccgcctgctg 4320
catagcgatt atatgaacat gaccccgcgc cgcccgggcc cgacccgcaa acattatcag 4380
ccgtatgcgc cgccgcgcga ttttgcggcg tatcgcagcc gcgtgaaatt tagccgcagc 4440
gcggatgcgc cggcgtatca gcagggccag aaccagctgt ataacgaact gaacctgggc 4500
cgccgcgaag aatatgatgt gctggataaa cgccgcggcc gcgatccgga aatgggcggc 4560
aaaccgcgcc gcaaaaaccc gcaggaaggc ctgtataacg aactgcagaa agataaaatg 4620
gcggaagcgt atagcgaaat tggcatgaaa ggcgaacgcc gccgcggcaa aggccatgat 4680
ggcctgtatc agggcctgag caccgcgacc aaagatacct atgatgcgct gcatatgcag 4740
gcgctgccgc cgcgc 4755
<210> 19
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
gaggaccgca gccagcc 17
<210> 20
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
ctgcaaagca atgcacg 17
<210> 21
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
ggtgtgggcc caggagg 17
<210> 22
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 22
ggtcatcaaa ccagcca 17
Claims (10)
1.一种靶向BCMA和CD5的双特异性嵌合抗原受体,其特征在于,所述嵌合抗原受体包括如下结构:S-BCMA scFv-CD5 scFv-H-TM-C-CD3ζ,其中BCMA scFv为靶向BCMA的抗原结合域;CD5 scFv为靶向CD5的抗原结合域;“-”为连接肽或肽键;S为信号肽;H为铰链区;TM为跨膜结构域;C为共刺激信号分子;CD3ζ为胞内信号传导序列;BCMA scFv包括如SEQ ID NO:1-3所示重链CDR区和SEQ ID NO:4-6所示轻链CDR区;CD5 scFv包括如SEQ ID NO:7-9所示重链CDR区和SEQ ID NO:10-12所示轻链CDR区。
2.根据权利要求1所述的双特异性嵌合抗原受体,其特征在于,所述BCMA scFv包括如SEQ ID NO:13所示重链可变区和SEQ ID NO:14所示轻链可变区。
3.根据权利要求1所述的双特异性嵌合抗原受体,其特征在于,所述CD5 scFv包括如SEQ ID NO:15所示重链可变区和SEQ ID NO:16所示轻链可变区。
4.根据权利要求1所述的双特异性嵌合抗原受体,其特征在于,所述共刺激信号分子选自CD27、CD28、4-1BB、CD11c、ITGB1、OX40、CD30、CD40、ICOS、CD11b、ITGAX中的一种或多种。
5.根据权利要求1所述的双特异性嵌合抗原受体,其特征在于,所述嵌合抗原受体的氨基酸序列如SEQ ID NO:17所示。
6.一种核酸分子,其特征在于,所述核酸分子编码权利要求1-5任一项所述的双特异性嵌合抗原受体。
7.根据权利要求6所述的核酸分子,其特征在于,所述核酸分子的核苷酸序列如SEQ IDNO:18所示。
8.一种NK细胞,其特征在于,所述的NK细胞表达有权利要求1-5任一项所述的双特异性嵌合抗原受体。
9.根据权利要求8所述的免疫细胞,其特征在于,所述NK细胞为敲除CTLA4基因的NK细胞。
10.权利要求1-5所述的双特异性嵌合抗原受体或权利要求6-7所述的核酸分子或权利要求8-9所述的NK细胞在制备肿瘤药物中的应用。
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CN115925974A (zh) * | 2022-07-27 | 2023-04-07 | 再少年(北京)生物科技有限公司 | 一种针对实体瘤的通用性的ips来源的car-nk细胞的制备方法 |
CN115925974B (zh) * | 2022-07-27 | 2023-06-16 | 再少年(北京)生物科技有限公司 | 一种针对实体瘤的通用性的ips来源的car-nk细胞的制备方法 |
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