CN111484563B - 一种抗cd38嵌合抗原受体及其应用 - Google Patents
一种抗cd38嵌合抗原受体及其应用 Download PDFInfo
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Abstract
本发明涉及一种抗CD38嵌合抗原受体(CD38‑CAR)及其应用，抗CD38嵌合抗原受体包括抗原结合结构域(scfv)和信号传导结构域，其中所述抗原结合结构域(CD38scFv)为抗人CD38抗体，其信号转导结构域由人CD8a分子铰链区与跨膜区CD8TM(CD8a‑CD8TM)、人CD28分子胞内区CD28(CD28)、人4‑1BB分子胞内区(4‑1BB)、人CD3ζ分子胞内区(CD3ζ)依次串联构成。CD38scFv包含特定序列的重链可变区和轻链可变区。本发明的嵌合抗原受体有更高的特异性和安全性，能够有效作用于CD38阳性的肿瘤。
Description
技术领域
本发明涉及肿瘤免疫治疗技术领域，提供了治疗人肿瘤的方法和组合物。本发明通过基因工程技术获得编码高亲和性hCD38单链抗体(scFv)、人CD8a分子铰链区(CD8Hinge)与跨膜区(CD8TM)、人CD28分子胞内区(CD28)、人4-1BB分子胞内区(4-1BB)、人CD3ζ分子胞内区(CD3ζ)融合基因，将该融合基因插入表达载体中，并转导入人T淋巴细胞中，使T细胞表达该融合基因。本发明还涉及前述融合基因表达的多肽、载体，以及用于免疫治疗的在其表面表达所述CAR的免疫细胞。本发明所涉及的修饰的T细胞能靶向并特异性杀伤CD38阳性的肿瘤细胞。
背景技术
CD38是一种45kDa大小的单链跨膜糖蛋白，整体结构可以分为N末端的胞内区，单次跨膜结构和C端的胞外区。它的胞外区能够催化环腺苷二磷酸核糖(cADPR,cyclic ADP-ribose)的合成和降解。cADPR是核苷酸的代谢产物，通过作用于ryanodine受体(RyRs)参与细胞内钙库的钙动员。在成年人中，CD38在大多数NK细胞，T细胞，B细胞，巨噬细胞中表达。胰腺、脑、肾脏和肌肉中也有少量的CD38表达。
CD38在多种肿瘤表面高表达，包括多发性骨髓瘤，弥漫性大B细胞淋巴癌(DLBCL)，慢性淋巴细胞白血病(CLL)，急性淋巴细胞白血病(ALL)，浆细胞性白血病(PCL)，急性髓性白血病(AML)，滤泡性淋巴瘤(FL)，套细胞淋巴瘤(MCL)和肺癌等。
抗CD38-CAR技术有别于抗体药物、ADC和重组蛋白等传统生物药物，它具有活的药物的特性。如，抗体药物需要介导免疫细胞杀伤肿瘤细胞，而CAR-T细胞识别后，可以直接激活T细胞，进而直接杀死肿瘤细胞。CAR-T是活的药物，在对病人的治疗过程中可以在体内大量扩增，相对于传统的抗体药物疗法，起效迅速，缓解率高，而且缓解时间更长。
发明内容
本发明的发明目的之一在于提供一种针对现有技术的不足，提供特异性更好、安全性更高、疗效更加显著的嵌合抗原受体及其应用。
本发明的发明目的之二在于提供编码该嵌合抗原受体的核酸及其应用。
本发明的发明目的之三在于提供含有该嵌合抗原受体的细胞及其应用。
本发明的发明目的之四在于提供一种针对CD38阳性肿瘤的人源化抗体。
为了解决上述技术问题，本发明采用的技术方案详述如下：
一种嵌合抗原受体(CAR)，其包括：抗原结合结构域(CD38scfv)和信号传导结构域，其中所述抗原结合结构域(CD38scFv)，为抗人CD38抗体，其信号转导结构域由人CD8a分子铰链区与跨膜区CD8TM(CD8a-CD8TM)、人CD28分子胞内区CD28(CD28)、人4-1BB分子胞内区(4-1BB)、人CD3ζ分子胞内区(CD3ζ)依次串联构成。本发明嵌合抗原受体CD38-CAR结构为CD38scFv-CD8a-CD8TM-CD28-4-1BB-CD3ζ。
本发明中嵌合抗原受体中的抗人CD38scfv氨基酸序列如SEQ ID NO.1所示，或与SEQ ID NO.1所示氨基酸序列具有85％-99％同一性的多肽；其核苷酸编码序列SEQ IDNO.2所示，或与SEQ ID NO.2所示具有85％-99％同一性的核苷酸序列。
抗人CD38抗体，所述抗体重链序列如SEQ ID NO.17所示，或与SEQ ID NO.17所示氨基酸序列具有85％-99％同一性的多肽；其编码序列如SEQ ID NO.18所示，或与SEQ IDNO.18具有85％-99％同一性的核苷酸序列。所述抗体轻链如SEQ ID NO.19或与SEQ IDNO.19所示氨基酸序列具有85％-99％同一性的多肽；其编码序列如SEQ ID NO.20所示，或与SEQ ID NO.20具有85％-99％同一性的核苷酸序列。
抗人CD38抗体，所述抗体的重链可变区HCDR1的序列如SEQ ID NO.11所示、HCDR2的序列如SEQ ID NO.12所示、HCDR3的序列如SEQ ID NO.13所示；所述抗体的轻链可变区LCDR1的序列如SEQ ID NO.14所示、LCDR2的序列如SEQ ID NO.15所示、LCDR3的序列如SEQID NO.16所示。
本发明中的嵌合抗原受体中的人CD8a分子铰链区与跨膜区CD8TM的氨基酸序列如SEQ ID NO.3所示，或与SEQ ID NO.3所示氨基酸序列具有85％-99％同一性的多肽；其编码序列为SEQ ID NO.4，或与SEQ ID NO.4所示核苷酸序列具有85％-99％同一性的序列。
本发明中的人CD28分子胞内区CD28的氨基酸序列如SEQ ID NO.5所示，或与SEQID NO.5所示氨基酸序列具有85％-99％同一性的多肽；其编码序列为SEQ ID NO.6，或与SEQ ID NO.6所示核苷酸序列具有85％-99％同一性的序列。
本发明中的人4-1BB分子胞内区的氨基酸序列如SEQ ID NO.7所示，或与SEQ IDNO.7所示氨基酸序列具有85％-99％同一性的多肽；其编码序列为SEQ ID NO.8，或与SEQID NO.8所示核苷酸序列具有85％-99％同一性的序列。
本发明中的人CD3ζ分子胞内区的氨基酸序列如SEQ ID NO.9所示，或与SEQ IDNO.9所示氨基酸序列具有85％-99％同一性的多肽；其编码序列为SEQ ID NO.10，或与SEQID NO.10所示核苷酸序列具有85％-99％同一性的序列。
一种重组表达载体，其特征在于所述重组表达载体包含抗人CD38抗体HCDR1、HCDR2、HCDR3的编码基因；抗人CD38抗体LCDR1、LCDR2、LCDR3的编码基因。
一种重组表达载体，其特征在于所述重组表达载体包含抗人CD38抗体的重链和轻链编码基因。
一种重组表达载体，其特征在于所述重组表达载体包含抗原结合结构域(CD38scFv)。
一种重组表达载体，其特征在于所述的重组表达载体包含本发明的抗原受体CD38-CAR。
一种表达抗人CD38抗体HCDR1、HCDR2、HCDR3；抗人CD38抗体LCDR1、LCDR2、LCDR3的细胞，该细胞优选免疫细胞；进一步优选T淋巴细胞、NK细胞、NKT细胞、巨噬细胞、间充质干细胞、造血干细胞、多能干细胞或胚胎干细胞培养分化的免疫细胞。
一种表达抗人CD38抗体的重链和轻链的细胞，该细胞优选免疫细胞；进一步优选T淋巴细胞、NK细胞、NKT细胞、巨噬细胞、间充质干细胞、造血干细胞、多能干细胞或胚胎干细胞培养分化的免疫细胞。
一种表达CD38scFv的细胞，该细胞优选免疫细胞；进一步优选T淋巴细胞、NK细胞、NKT细胞、巨噬细胞、间充质干细胞、造血干细胞、多能干细胞或胚胎干细胞培养分化的免疫细胞。
一种表达嵌合抗原受体CD38-CAR的细胞，该细胞优选免疫细胞；进一步优选T淋巴细胞、NK细胞、NKT细胞、巨噬细胞、间充质干细胞、造血干细胞、多能干细胞或胚胎干细胞培养分化的免疫细胞。
一种制备新型嵌合抗原受体CD38-CAR修饰的T细胞的方法，该方法包括分离和激活待修饰的T细胞，然后以前述表达载体转导该T细胞。
含有所述新型嵌合抗原受体、表达载体、所述细胞在制备治疗肿瘤的药物中的用途。所述肿瘤为CD38呈阳性的肿瘤，优选骨髓瘤、淋巴瘤。
附图说明
图1表示采用电转的转染方式将质粒pMD19-T-CD38-CAR转入T细胞中，得到表达CD38-CAR基因的T淋巴细胞的阳性率。
图2表示表达CD38-CAR基因的T淋巴细胞与RPMI8226细胞共孵育24小时和48小时后显示的杀伤作用，其中T-156是本发明中表达CD38-CAR基因的T淋巴细胞的缩写，效应细胞：靶细胞(E﹕T)＝4﹕1或1﹕1。
图3表示表达CD38-CAR基因的T淋巴细胞与人多发性骨髓瘤细胞、白血病细胞共孵育72小时，上清中分泌的IFN-γ，其中156-CAR T是本发明中表达CD38-CAR基因的T淋巴细胞的缩写。
图4表示表达CD38-CAR基因的T淋巴细胞与人多发性骨髓瘤细胞、白血病细胞共孵育72小时，上清中分泌的GM CSF。其中156-CAR T是本发明中表达CD38-CAR基因的T淋巴细胞的缩写。
图5表示表达CD38-CAR基因的T淋巴细胞与人多发性骨髓瘤细胞、白血病细胞共孵育72小时，上清中分泌的IL-2。其中156-CAR T是本发明中表达CD38-CAR基因的T淋巴细胞的缩写。
图6表示表达CD38-CAR基因的T淋巴细胞与Raji细胞分别共孵育24小时和48小时后显示的杀伤作用，其中T-156是本发明中表达CD38-CAR基因的T淋巴细胞的缩写，效应细胞：靶细胞(E﹕T)＝4﹕1或1﹕1。
图7表示表达CD38-CAR基因的T淋巴细胞与Daudi细胞分别共孵育24小时和48小时后显示的杀伤作用，其中T-156是本发明中表达CD38-CAR基因的T淋巴细胞的缩写，效应细胞﹕靶细胞(E﹕T)＝4﹕1或1﹕1。
图8表示表达CD38-CAR基因的T淋巴细胞与THP-1细胞分别共孵育24小时和48小时后显示的杀伤作用，其中T-156是本发明中CD38-CAR基因的T淋巴细胞的缩写，效应细胞﹕靶细胞(E﹕T)＝4﹕1或1﹕1。
具体实施方式
本发明提供了一种靶向CD38的嵌合抗原受体、免疫效应细胞及其在临床治疗肿瘤中的应用，下面结合具体实施例，进一步阐述本发明。
本发明所用的术语氨基酸序列的“同一性”(identity)可以与“相似性”互换使用，指的是氨基酸序列之间通过序列比对软件例如BLAST确定的相似程度。氨基酸序列比对的方法和软件对于本领域技术人员是公知的。可以通过对已知氨基酸序列进行一个或几个(例如1-15个，例如2、3、5、8、10或12个)氨基酸残基的取代、缺失和/或添加而获得经改造的氨基酸序列。例如，通过常规蛋白质工程手段(例如氨基酸保守取代等)，对本发明SEQ IDNO.1所示的CD38抗原结合结构域进行改造，可以获得与SEQ ID NO.1具有至少85％(例如85％～99％或90％～99％或95％～99％)序列同一性，并且具有基本相同的抗原结合结构域的变体序列。
本文所用的术语“抗原结合结构域”是包括具有功能的抗体部分，优选抗原结合和/或完整抗体的可变区。抗体片段包括Fab、Fab′、F(ab′)2、Fv fragments、单链抗体scFv单域抗体VHH及多特异性抗体。
本发明附图中的T-156/156-CAR T是本发明中表达CD38-CAR基因的T淋巴细胞的缩写，两者指同一种T细胞。
下面将结合附图，对本发明的优选实施例进行详细的描述。实施例中未注明具体条件的实验方法，通常按照常规条件，例如《分子克隆实验指南》(第三版，J.萨姆布鲁克等著)中所述的条件或按照制造厂商所建议的条件。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
实施例1 CAR序列合成及载体构建
嵌合抗原受体由江苏金斯瑞合成，获得的antiCD38-CAR结构的DNA序列通过酶切连接插入到pMD19-T质粒中，构建非病毒的电转表达质粒pMD19-T-CD38-CAR。
实施例2电转表达质粒提取
将带有pMD19-T-CD38-CAR基因的电转质粒转入大肠杆菌中，使带有pMD19-T-CD38-CAR基因的pMD19-T-CD38-CAR在大肠杆菌中大量扩增。然后采用无内毒素质粒大抽试剂盒提取大肠杆菌的质粒DNA。
将构建好的带有pMD19-T-CD38-CAR基因的质粒42℃水浴热击90秒，转化到大肠杆菌Top10感受态中，使用LB培养基37℃，200rpm/min过夜培养14-16h，使带有pMD19-T-CD38-CAR基因的质粒在大肠杆菌中大量扩增。第二天将过夜培养的菌液4000rpm离心15min后，去掉上清，然后使用无内毒素质粒大抽试剂盒(Endo-Free Plasmid Maxi Kit，Omega，货号：D6926)提取大肠杆菌中的pMD19-T-CD38-CAR质粒。
实施例3 T细胞转染与纯化
从人血清中分离淋巴细胞，并加入T淋巴细胞培养液(CTSTM AIM VTM SFM(RUO)，Thermo，货号：A3021002)，OKT-3，hIL-2和无内毒素的质粒DNA进行扩展培养，采用电转的转染方式将质粒pMD19-T-CD38-CAR转入T细胞中，得到带有CD38-CAR基因的T淋巴细胞(CD38-CAR-T)。
取外周血做抗凝素处理，室温放置15min，室温350*g离心5min，取出血浆待用，加入等体积的1*PBS稀释。加入等体积的Ficoll溶液于上层缓缓加入。室温离心25min，离心后从上至下依次分为血小板层，白细胞层，Ficoll层及红细胞层。将白细胞层小心吸出，转移到新的离心管中，使用PBS清洗2次后，将沉淀细胞计数，并且重悬至密度2*107/ml，并使用10％DMSO的血清冻存细胞。将分离好的PBMC直接用于培养，并加入含10％FBS的T淋巴细胞培养液(CTSTM AIM VTM SFM(RUO)，Thermo，货号：A3021002)，温度为37℃，湿度为5％，二氧化碳浓度为5％的过夜培养。
使用第二步提取的质粒进行核转染，产生抗CD38T细胞(CD38-CAR-T)，该载体编码包括CD38 scFv，CD28跨膜区，人4-1BB，人CD 3ζ，嘌呤霉素，然后选择0.5-2μg/ml嘌呤霉素。对于一次核转染，将2x107个PBMC细胞用10μg抗CD38-CARpiggyBac转座子载体和5μgSuperpiggy Bac转座酶质粒重悬于人T细胞Nucleofector试剂盒(Lonza，Cat.#VPA-1002)的100μl缓冲液中。并使用NucleofectorTMII/2b装置(Lonza)T细胞电转程序，进行电穿孔。核转染后一天，添加50ng/ml的抗CD3抗体(Miltenyi，Cat.#130-093-387)，外周血单核细胞(PBMC)和300IU/ml的人IL-2。到T细胞进行扩增至一定数量后，细胞培养物补充有50ng/ml抗CD3纯抗体和300IU/mL IL-2，用于第二轮刺激和扩增。
实施例4 T细胞CAR表达效率
T细胞转染20天后，利用流式细胞术对T细胞表面CAR的表达情况进行检测。结果如图1所示。图1显示CAR表达阳性率到达100％，证明CAR表达质粒构建及电转质粒的成功。
T细胞转染20天后，利用流式细胞术对T细胞表面CAR的表达情况进行检测。取出3*105T细胞，室温300g离心5min，使用anti-myc-PE荧光抗体(Muc-Tag(9B11)Mouse mAb PEconjugate，cell signaling，货号：3739S)进行室温孵育1h后,进行流式检测。结果如图1所示。图1显示myc-PE阳性率到达100％，证明CAR表达质粒构建及电转质粒的成功。
实施例5 CAR-T细胞对CD38阳性的RPMI-8226肿瘤细胞的长效杀伤作用
为了确定CD38-CAR-T细胞具有更好的持续杀伤能力，实验使用了携带有Luciference荧光信号的靶细胞进行杀伤试验。按照效靶比(效应细胞：靶细胞，E：T)4：1和1：1的比例，将T细胞(效应细胞)分别与CD38阳性靶细胞(RPMI-8226-Fluc)或CD38阴性靶细胞(K562-Fluc)共孵育24小时，48小时(如图2所示)。共孵育结束后，添加Luciference荧光信号的底物(Perkinelmer,货号：122799)，然后通过酶标仪分析靶细胞凋亡情况。结果显示，CD38-CAR-T细胞对过表达CD38的肿瘤细胞具有很强的杀伤能力，而对CD38阴性细胞的影响很小，说明该CAR-T细胞具有很强的特异性杀伤能力。
将上述构建好的未转导质粒的T细胞，和CD38-CAR-T细胞分别与荧光素酶报告基因转染的细胞，按照效靶比(效应细胞：靶细胞，E：T)4：1和1：1的比例，将T细胞分别与CD38阳性靶细胞(RPMI-8226-Fluc)或CD38阴性靶细胞(K562-Fluc)共孵育。使用96孔白色微孔板和使用含10％FBS的完全RPMI 1640培养基，在37℃，湿度为5％，二氧化碳浓度为5％的培养箱中，分别进行24小时，48小时的共孵育培养，并且每个样本做3个重复。同时，将1x104CD38靶细胞作为对照，在96孔白色微孔板中的完全RPMI 1640培养基中分别培养24小时，48小时。到达实验时间后，加入0.75mg/ml D-荧光素K+盐(Perkinelmer,货号：122799)，并使用EnSpire多模式读板仪(PerkinElmer)立即读取信号分析靶细胞凋亡情况。结果显示(图2)，我们构建的CD38-CAR-T细胞对过表达CD38的肿瘤细胞具有很强的杀伤能力，而对CD38阴性细胞的影响很小，说明该CD38-CAR-T细胞具有很强的特异性杀伤能力。对CD38阴性细胞的影响很小，说明该CAR-T细胞具有很强的特异性杀伤能力。
实施例7 CART细胞引起RPMI-8226肿瘤细胞相关细胞因子分泌
将CD38-CAR-T细胞(效应细胞)分别与CD38阳性靶细胞(RPMI-8226-Fluc)或CD38阴性靶细胞(K562-Fluc)共孵育72小时(如图3所示)。共孵育结束后，检测上清中分泌的GMCSF，IFN-r和IL-2。在96孔板中，将4x105未转染质粒的T细胞或CD38-CAR-T细胞分别与1x105K562(CD38阴性靶细胞)，RPMI8226(CD38阳性细胞)，共培养于200μl的新鲜的含10％FBS的1640培养基中。72小时后，收集上清液，并使用来自PerkinElmer的AlphaLISA试剂盒来检测包括干扰素(IFN-γ)，肿瘤坏死因子(TNF-α)，粒细胞-巨噬细胞集落刺激因子(GM-CSF)和白细胞介素-2(IL-2)等细胞因子的表达量(如图3-5所示)。
实施例8 CD38-CAR-T细胞对CD38阳性的THP-1肿瘤细胞的长效杀伤作用
将上述构建好的未转导质粒的T细胞，和CD38-CAR-T细胞分别与荧光素酶报告基因转染的细胞，按照效靶比(效应细胞：靶细胞，E：T)4：1和1：1的比例，将T细胞分别与CD38阳性靶细胞(THP-1-Fluc)或CD38阴性靶细胞(K562-Fluc)共孵育。使用96孔白色微孔板和使用含10％FBS的完全RPMI 1640培养基，在37℃，湿度为5％，二氧化碳浓度为5％的培养箱中，分别进行24小时，48小时的共孵育培养，并且每个样本做3个重复。同时，将1x 104 CD38靶细胞作为对照，在96孔白色微孔板中的完全RPMI 1640培养基中分别培养24小时，48小时。到达实验时间后，加入0.75mg/ml D-荧光素K+盐(Perkinelmer,货号：122799)，并使用EnSpire多模式读板仪(PerkinElmer)立即读取信号分析靶细胞凋亡情况。结果显示(图8)，我们构建的CD38-CAR-T细胞对过表达CD38的肿瘤细胞具有很强的杀伤能力，而对CD38阴性细胞的影响很小，说明该CAR-T细胞具有很强的特异性杀伤能力。
实施例9 CD38-CAR-T细胞对CD38阳性的Daudi肿瘤细胞的长效杀伤作用
将上述构建好的未转导质粒的T细胞，和CD38-CAR-T细胞分别与荧光素酶报告基因转染的细胞，按照效靶比(效应细胞：靶细胞，E：T)4：1和1：1的比例，将T细胞分别与CD38阳性靶细胞(Daudi-Fluc)或CD38阴性靶细胞(K562-Fluc)共孵育。使用96孔白色微孔板和使用含10％FBS的完全RPMI 1640培养基，在37℃，湿度为5％，二氧化碳浓度为5％的培养箱中，分别进行24小时，48小时的共孵育培养，并且每个样本做3个重复。同时，将1x 104 CD38靶细胞作为对照，在96孔白色微孔板中的完全RPMI 1640培养基中分别培养24小时，48小时。到达实验时间后，加入0.75mg/ml D-荧光素K+盐(Perkinelmer,货号：122799)，并使用EnSpire多模式读板仪(PerkinElmer)立即读取信号分析靶细胞凋亡情况。结果显示(图7)，我们构建的CD38-CAR-T细胞对过表达CD38的肿瘤细胞具有很强的杀伤能力，而对CD38阴性细胞的影响很小，说明该CAR-T细胞具有很强的特异性杀伤能力。
实施例10 CD38-CAR-T细胞对CD38阳性的Raji肿瘤细胞的长效杀伤作用
将上述构建好的未转导质粒的T细胞，和CD38-CAR-T细胞分别与荧光素酶报告基因转染的细胞，按照效靶比(效应细胞：靶细胞，E：T)4：1和1：1的比例，将T细胞分别与CD38阳性靶细胞(Raji-Fluc)或CD38阴性靶细胞(K562-Fluc)共孵育。使用96孔白色微孔板和使用含10％FBS的完全RPMI 1640培养基，在37℃，湿度为5％，二氧化碳浓度为5％的培养箱中，分别进行24小时，48小时的共孵育培养，并且每个样本做3个重复。同时，将1x 104 CD38靶细胞作为对照，在96孔白色微孔板中的完全RPMI 1640培养基中分别培养24小时，48小时。到达实验时间后，加入0.75mg/ml D-荧光素K+盐(Perkinelmer,货号：122799)，并使用EnSpire多模式读板仪(PerkinElmer)立即读取信号分析靶细胞凋亡情况。结果显示(图6)，我们构建的CD38-CAR-T细胞对过表达CD38的肿瘤细胞具有很强的杀伤能力，而对CD38阴性细胞的影响很小，说明该CAR-T细胞具有很强的特异性杀伤能力。
SEQUENCE LISTING
<110> 徐州医科大学附属医院
<120> 一种抗CD38嵌合抗原受体及其应用
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Claims (9)
1.一种抗CD38嵌合抗原受体，其特征在于，所述嵌合抗原受体由抗人CD38单链抗体scFv、人CD8a分子铰链区与跨膜区CD8TM、人CD28分子胞内区CD28、人4-1BB分子胞内区、人CD3ζ分子胞内区依次串联构成；所述抗人CD38单链抗体scFv的氨基酸序列如SEQ ID NO.1所示，人CD8a分子铰链区与跨膜区CD8TM的氨基酸序列如SEQ ID NO.3所示，人CD28分子胞内区CD28的氨基酸序列如SEQ ID NO.5所示，人4-1BB分子胞内区的氨基酸序列如SEQ IDNO.7所示，人CD3ζ分子胞内区的氨基酸序列如SEQ ID NO.9所示。
2.一种抗CD38抗体，其特征在于，所述抗体序列如SEQ ID NO.1所示。
3.权利要求2所述的抗CD38抗体的编码基因，其核苷酸序列如SEQ ID NO.2所示。
4.一种抗CD38抗体，其特征在于所述抗体的重链的三个CDR区序列分别为如SEQ IDNO.11所示的CDR1、如SEQ ID NO.12所示的CDR2、如SEQ ID NO.13所示的CDR3，轻链的三个CDR区序列分别为如SEQ ID NO.14所示的CDR1、如SEQ ID NO.15所示的CDR2、如SEQ IDNO.16所示的CDR3。
5.一种抗CD38抗体，其特征在于,抗体重链序列如SEQ ID NO.17所示，抗体轻链序列如SEQ ID NO.19所示。
6.编码权利要求5所述抗体的基因，其由编码所述抗体重链和轻链的核苷酸序列组成，其中，重链的编码序列如SEQ ID NO.18所示，轻链的编码序列如SEQ ID NO.20所示。
7.一种重组表达载体，其特征在于，所述重组表达载体包含权利要求1所述的嵌合抗原受体的编码基因；或所述重组表达载体包含权利要求2，4或5所述的抗CD38抗体的编码基因。
8.一种免疫细胞，其特征在于，所述免疫细胞包含权利要求1所述的嵌合抗原受体，或所述免疫细胞包含权利要求2，4或5所述的抗CD38抗体，所述免疫细胞为T淋巴细胞。
9.权利要求8所述的免疫细胞在制备治疗肿瘤药物中的应用，其特征在于，所述肿瘤为CD38阳性的骨髓瘤、淋巴瘤或白血病。
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