CN114907487A - 新型嵌合抗原受体以及包含其的免疫细胞 - Google Patents
新型嵌合抗原受体以及包含其的免疫细胞 Download PDFInfo
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Abstract
本发明为新型嵌合抗原受体以及包含其的免疫细胞,涉及一种能特异性结合肿瘤特异性标识的融合蛋白和能表达该融合蛋白的免疫细胞,例如T细胞或NK细胞。本发明的融合蛋白可以包含嵌合抗原受体(CAR)、白介素12(IL12)和氧依赖性降解区域(ODD)。本发明的CAR包含胞外结构域、跨膜结构域和胞内结构域,所述的胞外结构域能够特异性结合肿瘤特异性抗原,并通过跨膜结构域和胞内结构域激活T或NK细胞。本发明提供的CAR‑T细胞或NK细胞,其以肿瘤特异性标识为靶,利用CAR‑T细胞或NK细胞特异性地杀伤肿瘤细胞,例如骨髓瘤或白血病。本发明的CAR‑T或NK细胞可作为肿瘤类疾病的治疗药物,为肿瘤的预防和治疗提供了新的方法。
Description
技术领域
本发明涉及生物医药领域,具体涉及新型嵌合抗原受体、包含其的免疫细胞及其制备和应用。
背景技术
弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)是恶性淋巴瘤中最常见的一种类型,约占其发病率的30%-40%。DLBCL对传统化疗、放疗的反应均较好,单克隆CD20抗体利妥昔的加入进一步改善了疗效和预后,使半数以上的患者获得长期生存或治愈。现阶段,治疗的挑战是早期复发的难治患者,他们的生存期短,尚没有有效的治疗方法。亟待寻找有效的针对难治性DLBCL 的治疗方法和手段。
CAR-T全称是Chimeric Antigen Receptor T-Cell,基于嵌合抗原受体T细胞的免疫疗法是目前研究的热点。CAR-T治疗基于将肿瘤患者自身免疫T细胞进行分离培养,利用转基因技术将包含特异识别肿瘤细胞表面抗原的分子,例如特异性单链抗体scFv(singlechain antibody fragment)与T细胞共刺激分子的多顺反子蛋白表达于T细胞表面,将经基因改造后的T细胞回输入患者体内,回输后的CAR-T细胞在体内特异性的识别并杀伤肿瘤细胞。
2011年,Carl H June教授发表了一例基于4-1BB共刺激信号、靶向CD19的二代CAR-T治疗案例,适应症为慢性粒细胞性白血病(CLL),并成功治愈身患 CLL的4岁女孩Emily。随后CD19 CAR-T被应用于ALL、CLL、DLBCL等多种血液疾病,其中大部分血液病ALL、CLL缓解率均可达到90%。
相对其他血液病高达90%的缓解率而言,CD19 CAR-T对难治性DLBCL的治愈率不超过50%,究其原因,DLBCL的免疫微环境在一定程度上限制了CD19 CAR-T 的疗效,因此迫切的需要寻找合适的能局部改善DLBLC肿瘤免疫微环境的方法。
白介素12(Interleukin-12,IL-12),最早发现于EBV转化的B细胞中的一种由p35和p40亚基共价连接的异源二聚体复合物。IL-12是具有多种功能的细胞因子,Hsieh et al在1993年发现,原始幼稚CD4+细胞在固有免疫细胞natural killer cell(NK)释放的interferon-γ(IFN-γ)的刺激下诱导表达转录因子STAT1,随后STAT1转录T-bet的表达,T-bet的表达促使幼稚CD4+细胞转化为 CD4+TH1效应细胞,同时T-bet的表达诱发interleukin-12receptorβ2-subunit (IL-12Rβ2)表达于CD4+Th1细胞膜表面,此时IL-12结合于CD4+Th1细胞膜表面的IL-12R,促使CD4+Th1细胞自分泌IFN-γ并和其他炎症因子一起执行效应细胞功能,因此IL-12在固有免疫和适应性细胞免疫中起到了桥梁的连接作用。IL-12 的免疫调节功能并不仅限于固有免疫和适应性免疫的桥梁连接作用,IL-12在促使CD4+TH1细胞自分泌IFN-γ的同时,还可以诱导其他二级和三级促炎症细胞因子的释放,这些促炎症因子的释放对肿瘤细胞同样起到了细胞毒作用,而这些促炎症因子的释放也改变了肿瘤的局部免疫环境,在一定程度上延长了CD8+T细胞的存活,促进了肿瘤杀伤效果。综合从免疫细胞角度来看,IL-12有助于促进 NK、NK-Tcells、CD4+、CD8+T细胞增加其存活率和增强细胞效应功能,特别是其诱导分泌的IFN-γ,也起到了抗肿瘤的作用。从肿瘤微环境角度来看,IFN-γ的分泌可减伤肿瘤细胞分泌血管内皮生长因子(vascular endothelialgrowth factor,VEGF),从而抑制肿瘤的转移。同时经过IL-12刺激的NK、NK-Tcells、CD4+、CD8+T细胞可产生趋化因子IP-10和MIG,IP-10和MIG抑制内皮细胞基质金属蛋白酶(MMP)的表达,减少细胞外基质(ECM)重塑的改变,从而达到减少血管生成和肿瘤侵袭的效果。
发明内容
本发明的发明人发现,将CD19 CAR-T与IL-12连用联合治疗DLBCL,能够提高CD19CAR-T对DLBCL的缓解率。与此同时,IL-12在带来免疫杀伤作用的同时,也带来了一定的细胞毒,尤其是对肝脏的细胞毒损伤,也使得IL-12的抗肿瘤临床应用受到了极大的限制,因此也迫切的需要找到降低IL-12肝毒性的解决办法。
为了克服IL-12和CAR细胞联合使用时的毒负作用,本发明将融合蛋白 (IL-12ODD)与CAR共表达于免疫细胞表面。肿瘤细胞的无氧糖酵解特性使得其能更加适应肿瘤局部的厌氧微环境。本发明设计的CAR或CAR免疫细胞使得氧压调控表达的分泌性IL-12(IL-12ODD)只能在肿瘤局部厌氧微环境下分泌发挥作用,而在正常组织的有氧环境中氧压调控ODD会启动泛素化降解途径使得IL-12 降解,IL-12ODD的应用使得IL-12只有在肿瘤厌氧微环境中高表达发挥抗肿瘤作用,进而减少了在外周血正常组织中IL-12的浓度及其所导致的肝及肺毒性。
另外,本发明发现,基于单链抗体scFv连接抗体重链可变区和轻链可变区的15~20个氨基酸的连接短肽(linker)能提高CAR免疫细胞和IL12联用的治疗效果。具体地,本发明应用了一种新型连接肽Linker218,与传统连接肽(G4S)3相比,Linker218能使单链抗体scFv呈现出更加柔性的空间结构而不会减低亲和力,并增加了对蛋白水解酶***的稳定性。
本发明的发明人通过将包含新型连接肽Linker218的CD19 CAR-T与IL-12通过自剪切肽连接共表达于T细胞表面,在将共表达IL-12的CD19 CAR-T细胞进行回输后,CD19CAR-T细胞归巢***后表达的IL-12,可诱导自身免疫细胞分泌 IFN-γ而改善DLBLC肿瘤免疫微环境及抑制DLBCL进展和转移,同时增加CD19 CAR-T细胞的生存期,延长CD19 CAR-T细胞的杀伤效果,提高CD19 CAR-T免疫疗法对难治性DLBCL的疗效。
本发明的发明人通过体外构建表达包含新型连接肽Linker218的CD19特异性抗原4-1BB、CD28为胞内激活信号的第三代慢病毒质粒,体外利用293T包装合适效价的慢病毒,将CD19特异性抗原及胞内激活信号表达于从外周血分离的 CD3+T细胞,修饰过的T细胞体外杀伤难治性DLBLC系,通过计算生长曲线、计算杀伤效率、体内体外等方法比较CD19 CAR-T与IL12、IL12ODD各组连用的效果。
本发明一方面提供了一种嵌合抗原受体(CAR),其包含(1)胞外抗原结合域;(2)跨膜域;和(3)胞内信号传导域,其特征在于,所述CAR还包含与所述胞内结构域连接并共表达的白介素12(IL12)与氧依赖性降解区域 (ODD)的融合蛋白,任选地,所述胞内结构域与所述融合蛋白通过自剪切蛋白(例如选自由T2A、P2A、E2A、F2A、或其组合组成的组)连接。
在本发明的一个实施方式中,本发明的跨膜域来源于选自由T细胞受体的α、β或ζ链、CD3ε、CD4、CD5、CD8、CD8α、CD9、CD16、CD22、CD28、 CD33、CD37、CD45、CD80、CD86、CD134、CD137、CD152、CD154和ICOS组成的组中的一种或多种的跨膜结构域。
在本发明的一个实施方式中,本发明的胞内信号转导域包含共刺激信号传导域且来自:CD2、CD3ζ、CD3γ、CD3δ、CD3ε、CD4、CD5、CD7、CD22、 CD27、CD28、CD30、CD40、CD66d、CD79a、CD79b、CD83、CD134、CD137、ICOS、 CD154、4-1BB和OX40、LFA-1、LIGHT、NKG2C和B7-H3中的一种或多种。
在本发明的一个实施方式中,本发明的CAR还包含位于所述胞外抗原结合域的C-末端和所述跨膜域的N-末端之间的铰链域,例如来源于CD8α。
在本发明的一个实施方式中,对于本发明的CAR,其中胞外抗原结合域是能结合肿瘤细胞表面抗原(例如CD19,CD20、CD22、CD123、CD30、CD33、 CD38、CD44、CD138、CD276、EGFR、BCMA,HER1、HER2、HER3、EpCAM、间皮素(mesothelin)、FAP(Fibroblast activationprotein)、Glypican-3、CEA、 PSMA、IL13Rα2、CD171、GD2、CEACAM6、CLDN4、CLDN18.2、NKGD2、LAMC2、 CA9、CST1、EPPK1和ANO1中的一种或多种)的分子,例如抗体(Ig、Ig NAR、 Fab片段、Fab’片段、F(ab)’2片段、F(ab)’3片段、Fv、scFv、双-scFv、 (scFv)2、微型抗体、双链抗体、三链抗体、四链抗体、二硫键稳定的Fv蛋白以及单结构域抗体(sdAb,纳米抗体)、双特异性抗体或三特异性抗体)。
对于肿瘤细胞表面抗原中常用的那些,示例性地解释如下。
CD19是表达于B淋巴细胞及滤泡树突状细胞的表面蛋白,属于免疫球蛋白(Ig) 超家族成员,位于16号染色体短臂上(16p11.2),编码556个氨基酸的I型跨膜糖蛋白,分子量95KD。CD19只在正常和恶性B细胞中表达,几乎不在其他组织中表达;其次,CD19在B细胞恶性转化过程中不丢失,难治/复发性病例仍然有效;再者,CD19在造血干细胞和pro-B细胞中不表达,治疗停止后,B细胞可以得到有效地补充。因而近年来靶向CD19的各种白血病治疗策略取得较好的临床效果,包括CD3和CD19的双特异性抗体和靶向CD19的CAR-T等。
CD20抗原是一种B细胞分化抗原,仅表达于前B细胞和成熟B细胞表面,它在95%以上的B细胞性淋巴瘤中表达,而在造血干细胞、血浆细胞和其他正常组织中不表达。靶向CD20的多个单抗(如Rituxan)已经在临床上成功的用于多种淋巴瘤的治疗。
CD38是一个45kDa的单链跨膜糖蛋白,整体结构分为N末端短的胞质尾,单次跨膜域和C端长的胞外区。成年人中,CD38在大多数自然杀伤细胞、T细胞、B细胞,单核细胞/巨噬细胞。血小板和红细胞上也有一定程度的表达。某些靶向CD38的单抗已经被批准用于多发性骨髓瘤的治疗。
BCMA(B细胞成熟抗原)是由185个氨基酸残基组成的III型跨膜蛋白。它属于TNF受体家族成员,与其配体B细胞激活因子BAFF或增殖诱导配体APRIL结合可刺激B细胞增生。BCMA正常表达于成熟的B细胞和浆细胞,在多发性骨髓瘤 (MM)中也有广泛的表达,是多发性骨髓瘤的一个非常理想的免疫治疗靶点。
HER2基因位于人17q21染色体,编码分子量185kD的跨膜蛋白,该蛋白有酪氨酸激酶活性,正常状态下以无活性形式存在,参与调节细胞正常分化,通常只在婴儿期表达,成人只在少数组织中低水平表达。SA 2000;97: 3444-3449.Slamon etal.,Science 1987;235:177-182)。
CEA(癌胚抗原)是大肠癌组织产生的一种糖蛋白,作为抗原可引起患者的免疫反应。其广泛存在于内胚叶起源的消化***癌,也存在于正常胚胎的消化管组织中,在正常人血清中也可有微量存在。癌胚抗原是一个广谱性肿瘤标志物,它能向人们反映出多种肿瘤的存在,对大肠癌、乳腺癌和肺癌的疗效判断、病情发展、监测和预后估计是一个较好的肿瘤标志物。
PSMA是110kDa的II型穿膜蛋白,基因定位于染色体短臂11q上,表达于正常***上皮和***肿瘤细胞中,其中在肿瘤细胞中的表达量上调,有研究认为PSMA参与了***癌发生过程中细胞迁移的调控。在***癌中PSMA的表达和肿瘤的级别及是否存在激素抵抗呈正相关,PSMA的强表达意味着更高的复发率。现认为PSMA是***癌参考依据之一。
更具体地,在本发明CAR中,其中所述IL12具有SEQ ID NO:5的氨基酸序列;所述ODD具有SEQ ID NO:7的氨基酸序列,优选地,所述CAR包含 SEQ ID NO:1和SEQ ID NO:3所示的氨基酸序列。
本发明所提高的CAR任选地还包含标签序列(例如Poly-His、 Hemagglutinin、c-Myc、GST、Flag-tag等)或IgG1-Fc蛋白序列。
本发明的另一方面还提供编码CAR的核苷酸,优选地,所述核苷酸序列包含SEQ IDNO:2所示的核苷酸序列或包含由SEQ ID NO:2-SEQ ID NO:10- SEQ ID NO:4依次组成的核苷酸序列。
本发明的第三方面提供了分离的CAR-T细胞或CAR-NK细胞或或单核巨噬细胞,其中所述细胞能够表达CAR或包含本发明的多核苷酸。
本发明的第四方面提供了一种载体,其包含上述的多核苷酸。
在一个具体的实施方式中,本发明的载体是表达载体,例如病毒载体,优选为逆转录病毒载体,例如慢病毒载体,优选为选自人免疫缺陷病毒 1(HIV-1)、人免疫缺陷病毒2(HIV-2)、维斯纳-梅迪病毒(VMV)病毒、山羊关节炎-脑炎病毒(CAEV)、马传染性贫血病毒(EIAV)、猫免疫缺陷病毒(FIV)、牛免疫缺陷病毒(BIV)、猿猴免疫缺陷病毒(SIV)、腺病毒和痘病毒。
本发明的第五方面提供了一种药物组合物,其包含权利要求本发明所提供的嵌合抗原受体,或包含本发明所提供的CAR-T细胞或CAR-NK细胞或或单核巨噬细胞,以及任选地,药学上可接受的载体。
本发明的第五方面提供了制备权利要求本发明所提供的CAR-T细胞或 CAR-NK细胞或或单核巨噬细胞的方法,其包括将本发明所提供的载体引入至 T淋巴细胞或自然杀伤细胞或或单核巨噬细胞。
本发明的第五方面提供了一种用途。具体而言,所述用途是指本发明所提供的CAR,或本发明所提供的CAR-T细胞或CAR-NK细胞在制备治疗和/或预防癌症的药物中的用途,示例性地,所述癌症为骨髓瘤和白血病。
本发明还提供了一种制备本发明所述的CAR-T细胞或CAR-NK细胞或或单核巨噬细胞,或制备本发明所述的免疫效应细胞的方法,其包括将本发明所述的载体引入至所述细胞。
示例性地,本发明的CAR-T细胞的制备方法包括如下步骤:
(1)合成和扩增CAR-自剪切蛋白-IL12-ODD蛋白基因,将所述蛋白基因克隆到慢病毒表达载体上;
(2)利用慢病毒包装质粒和步骤(1)得到的慢病毒表达载体质粒感染293T 细胞,包装和制备慢病毒;和
(3)利用步骤(2)得到的慢病毒感染T细胞,得到CAR-T细胞。
本发明还提供了如下项目的材料在制备治疗和/或预防癌症的药物中的用途:
(a)本发明所述的CAR;或
(b)本发明所述的CAR-T细胞或CAR-NK细胞。
示例性地,所述癌症为高表达肿瘤特异性标识的肿瘤及相关疾病,例如骨髓瘤和白血病。
本发明还提供了治疗和/或预防癌症的方法,其包括将有效量的(a)本发明所述的CAR;或(b)本发明所述的CAR-T细胞或CAR-NK细胞或或单核巨噬细胞施用至受试者。
对于本发明所述的融合蛋白、CAR等,本发明也考虑了其变体,例如其同一性序列或人源化序列等。示例性地,所述同一性序列是指与原序列或参考序列的同一性约约70%或以上、71%或以上、72%或以上、73%或以上、74%或以上、75%或以上、76%或以上、77%或以上、78%或以上、79%或以上、80%或以上、81%或以上、82%或以上、83%或以上、84%或以上、85%或以上、86%或以上、87%或以上、88%或以上、89%或以上、90%或以上、91%或以上、92%或以上、93%或以上、 94%或以上、95%或以上、96%或以上、97%或以上、98%或以上、99%或以上、99.1 或以上、99.2或以上、99.3%或以上、99.4%或以上、99.5%或以上、99.6%或以上、99.7%或以上、99.8%或以上、或99.9%或以上。
对于本发明的多核苷酸,本发明还考虑了其简并序列或互补序列。示例性地,所述简并序列与原序列或参考序列的同源性约60%或以上、约70%或以上、71%或以上、72%或以上、73%或以上、74%或以上、75%或以上、76%或以上、77%或以上、78%或以上、79%或以上、80%或以上、81%或以上、82%或以上、83%或以上、84%或以上、85%或以上、86%或以上、87%或以上、88%或以上、89%或以上、 90%或以上、91%或以上、92%或以上、93%或以上、94%或以上、95%或以上、96%或以上、97%或以上、98%或以上、99%或以上、99.1或以上、99.2或以上、99.3%或以上、99.4%或以上、99.5%或以上、99.6%或以上、99.7%或以上、99.8%或以上、或99.9%或以上。
本发明提供的CAR能够特异性结合肿瘤特异性抗原肿瘤特异性标识,并通过跨膜结构域和共刺激信号传导区激活该T细胞。该CAR-T细胞能够表达以肿瘤特异性标识为靶抗原的融合蛋白,因此能够特异性地杀伤肿瘤细胞,用于***类疾病,例如用于肿瘤特异性标识高表达的肿瘤的治疗。
附图说明
图1是***CD19CARIL12ODD构建体的pEF质粒结构示意图。
图2是ELISA检测CAR19IL12ODD分别在正常氧(17%)和低氧(1%)条件下分泌IL12水平。
图3,其中:图3A:LDH检测CAR19对弥漫大B细胞淋巴瘤细胞系Ly3体外杀伤效率;图3B:CAR19对弥漫大B细胞淋巴瘤细胞系Ly3体内杀伤曲线。
图4,其中:图4A:ELISA检测CAR19对弥漫大B细胞淋巴瘤细胞系Ly3体内杀伤后外周血中IL12浓度;图4B:流失检测CAR19对弥漫大B细胞淋巴瘤细胞系Ly3体内杀伤后外周血中CAR-T细胞存活比例。
具体实施方式
本发明的CART或NK细胞可以靶向肿瘤特异性标识(例如CD19),进而可以用于治疗例如与CD19相关的癌症。
本发明的CAR的高亲合力使得CAR-T或NK细胞能够a)识别具有高、中和低肿瘤标识表面表达的肿瘤靶细胞,具有低的脱靶反应性,b)针对所述肿瘤靶细胞而被活化,和c)杀伤所述肿瘤靶细胞。因此,本发明的CAR-T可以用于治疗多种癌症,例如淋巴瘤,多发性骨髓瘤肿瘤细胞和急性髓细胞性白血病和B-NHL,例如滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤和慢性淋巴细胞白血病等。
在体外共培养***中,本发明的CAR-T或NK细胞能够对弥漫大B细胞淋巴瘤(DLBCL)具有显著的疗效或抑制作用。
通过动物实验证实,本发明的CAR-T或NK细胞能够显著杀死弥漫大B细胞淋巴瘤(DLBCL),且促进对肿瘤的浸润。
同时,通过实验也正是了含有本发明抗体的融合蛋白CD19-PE24对RPMI 8226细胞的体外杀伤作用。
嵌合抗原受体:
CAR包含衍生自抗体的细胞外胞外域和包含衍生自T细胞信号传导蛋白的信号传导模块的胞内域。在一种实施方式中,胞外域可以包含来自免疫球蛋白的重链可变区,或包含重链和轻链的可变区,例如被构建为单链可变片段(scFv),优选为仅有重链可变区的单域抗体(sdAb)。sdAb连接到铰链区,该铰链区提供灵活性并通过跨膜结构域将信号转导至胞内信号传导域。跨膜域优选源自CD8α。在第一代CAR中(术语“代”是针对胞内信号传导域结构域而言),胞内信号传导域由TCR复合物的ζ链组成。第二代CAR被设计成含有源自CD28或4-1BB的单一共刺激域。第三代CAR包括两个共刺激域,例如4-1BB-CD3ζ。本发明优选涉及第二代或第三代CAR。
本发明示例性提供了将免疫效应细胞的细胞毒性重定向至癌细胞的基因工程受体。这些基因工程受体在本文中称为嵌合抗原受体(CAR)。CAR是基于靶向抗原(例如CD19)的抗体特异性与活化T细胞受体或NK细胞受体的胞内域组合,具有特异性抗例如CD19细胞免疫活性的嵌合蛋白分子。在本文中,术语“嵌合”是指由不同来源的不同蛋白质或DNA组成。
本发明的CAR包括结合例如CD19的胞外域(也称为结合域或抗原结合域)、跨膜域、和胞内域或胞内信号传导域。示例性地,CAR的抗CD19抗原结合域与靶细胞表面上的CD19的结合导致CAR的聚集并向含有CAR的细胞递送活化刺激。CAR能够特异性地重定向免疫效应细胞,从而引发增殖、细胞因子产生、吞噬作用或靶抗原表达细胞的细胞杀死。
在本发明的一些实施方式中,CAR包含如下结构域:人源化的特异性结合癌细胞特异性表面抗原的胞外结合域;跨膜域;一个或多个胞内信号传导域。在一些实施方式中,CAR顺序性地包含人源化的CD19抗原结合片段的胞外结合域;一个或多个间隔区域;跨膜域;一个或多个胞内信号传导域;以及与信号转导域通过自剪切蛋白连接的IL12-ODD融合蛋白。
“胞外抗原结合域”或“胞外结合域”可互换使用,并为CAR提供特异性结合感兴趣的靶抗原(例如CD19)的能力。结合域可以衍生自天然、合成、半合成或重组来源。优选的是重组来源的sdAb。
“特异性结合”应如本领域技术人员所理解的那样,本领域技术人员清楚地知道可用于测试结合和结合特异性的各种实验方法或手段。确定平衡缔合或平衡解离常数的方法是本领域已知的。在许多蛋白质间相互作用中,可能会出现一些交叉反应或背景结合,但这并不损害CAR和表位之间结合的“特异性”。例如,“特异性结合”描述了抗-CD19抗体或其抗原结合片段 (也包含它们的CAR)与CD19的结合,其结合亲和力高于背景结合。
“抗原(Ag)”是指可以在动物中刺激抗体产生或T细胞应答的化合物、组合物或物质。在本发明的一些实施方式中,靶抗原是CD19多肽的表位。“表位”是指与结合剂结合的抗原区域。表位可以由连续氨基酸形成,或者导致蛋白质的三级结构的非连续氨基酸形成。
“单链Fv”或“scFv”抗体片段包含抗体的VH域和VL域,其中这些结构域以单一多肽链且以任一方向存在(例如,VL-VH或VH-VL)。通常,scFv多肽还包含VH域和VL域之间的多肽接头,该多肽接头使得scFv能够形成用于抗原结合的所需结构。在优选的实施方式中,本发明的CAR包含抗原特异性结合域,该抗原特异性结合域是scFv并且可以是鼠、人或人源化scFv。可以从对希望的靶标有特异性的杂交瘤的V区基因克隆单链抗体。在特别的实施方式中,抗原特异性结合域是结合人CD19多肽的人源化scFv。
抗体和抗体片段:
CAR包含胞外抗原结合域,其包含结合肿瘤特异性标识(例如CD19)多肽的抗体或抗体片段。因此,本发明的抗体或抗体片段包括但不限于多克隆、单克隆、双特异性、人、人源化或嵌合的抗体、单链片段(scFv)、单可变片段(ssFv)、单结构域抗体(例如来自纳米抗体的VHH片段)、Fab片段、F(ab′)2片段、由Fab表达文库产生的片段、抗独特型抗体和表位结合片段或任何上述的组合,条件是它们具有本发明所述CAR的相似结合特性,优选包含如本文所述的相应的CDR、或VH和VL区。微小抗体和多价抗体如双价抗体、三价抗体、四价抗体和五价抗体也可用于本发明的方法中。本发明的免疫球蛋白分子可以是免疫球蛋白分子的任何类别(即IgG、IgE、IgM、IgD和IgA)或亚类。因此,如本文所用,术语抗体还包括由本发明的CAR包含的抗体和抗体片段,其通过修饰完整抗体产生或使用重组DNA方法重新合成。
如本文所用,“抗体”通常是指由基本上由免疫球蛋白基因或免疫球蛋白基因片段编码的一种或多种多肽组成的蛋白质。当使用术语“抗体”时,也可以认为是指“抗体片段”。任选地,抗体或抗体片段可以与其他蛋白或其他蛋白的融合蛋白化学缀合成或表达为带有其他蛋白的融合蛋白。在一些实施方案中,本发明的抗体或抗原结合片段包含于多特异性抗体上,例如双特异性抗体。这样的多特异性抗体可通过已知的方法产生,例如交联两种或更多种相同类型或不同类型的抗体、抗原结合片段(例如scFv)。制备多特异性抗体的示例性方法包括在PCT专利公开文本第WO2013/163427号中描述的那些,通过引用将其整体并入本文。
本发明的结合域多肽和抗体或抗体片段或CAR蛋白的亲和力可以使用常规技术容易地确定,例如通过竞争性ELISA(酶联免疫吸附测定)、或使用表面等离子共振装置(如Biacore)。
可以使用本领域已知的方法制备人源化抗体,该人源化抗体包含本发明抗体或抗体片段的一个或多个CDR或包含衍生自所述抗体或抗体片段的一个或多个CDR。例如,一般可以使用四个步骤来使单克隆抗体人源化:(1)确定起始抗体轻链和重链可变域的核苷酸和预测的氨基酸序列;(2)设计人源化抗体,即决定在人源化过程中使用哪个抗体框架区;(3)开展人源化方法/技术;和(4)人源化抗体的转染和表达。例如,参见,美国专利第6,180,370号。
术语人源化抗体意指免疫球蛋白的至少一部分框架区和任选的CDR区的一部分或其他参与结合的区域来源于或调整为人免疫球蛋白序列。小鼠单克隆抗体的人源化、嵌合或部分人源化形式可以例如通过重组DNA技术制备。通过重组DNA技术将非人抗体的CDR区与人恒定区连接,可以产生人源化形式的小鼠抗体(Queen等人,1989;WO 90/07861)。可供选择地,用于本发明方法的单克隆抗体可以是人单克隆抗体。人抗体可以例如使用噬菌体展示法来获得(WO 91/17271;WO 92/01047)。
如本文所用,人源化抗体还指非人(例如鼠、骆驼、美洲驼、鲨)抗体的形式,其是含有衍生自非人免疫球蛋白的最小序列的特异性嵌合免疫球蛋白、免疫球蛋白链或其片段(例如Fv、Fab、Fab′、F(ab′)2或抗体的其他抗原结合亚序列,例如VHH。
如本文所用,人或人源化抗体或抗体片段是指具有与人产生的抗体的氨基酸序列相对应的氨基酸序列的抗体,且可使用本领域已知的制备抗体的任何技术制备。可以通过竞争性结合实验或其他方式选择人抗体或其片段,以确定其具有与特定小鼠抗体相同的表位结合特异性。
嵌合抗原受体的进一步说明
在某些实施方式中,本发明的CAR可以包含为了分子的适当间隔和构象而添加的在各个域之间的接头残基,例如包含氨基酸序列的接头,其连接VH域和VL域并提供与两个亚结合域的相互作用相容的间隔区功能,使得所得多肽保持对靶分子的特异性结合亲和力。本发明的CAR可包含一个、两个、三个、四个或五个或更多个接头。在特别的实施方式中,接头的长度为约1至约25个氨基酸、约5至约20个氨基酸、或约10至约20个氨基酸、或任何适当长度的氨基酸。
接头的示例性实例包括甘氨酸聚合物;甘氨酸-丝氨酸聚合物;甘氨酸- 丙氨酸聚合物;丙氨酸-丝氨酸聚合物;本领域已知的其他柔性接头,例如惠特洛接头。甘氨酸和甘氨酸-丝氨酸聚合物是相对非结构化的,因此可以作为融合蛋白的各域或其中一些域(例如本文所述的CAR)之间的连接。
在特别的实施方式中,CAR的结合域之后是一个或多个“间隔区”或“间隔区多肽”,相当于连接子,其在将抗原结合域远离效应细胞表面,以使得细胞与细胞之间能够适当接触、抗原结合和活化。在某些实施方式中,间隔区域是免疫球蛋白的一部分,包括但不限于一个或多个重链恒定区,例如CH2和CH3。间隔区域可包括天然存在的免疫球蛋白铰链区或改变的免疫球蛋白铰链区的氨基酸序列。在一种实施方式中,间隔区域包括IgG1或IgG4 的CH2和CH3结构域。
在一些实施方式中,CAR的结合域之后可以是一个或多个“铰链域”,其在将抗原结合域远离效应细胞表面,以使得细胞与细胞之间能够适当接触、抗原结合和活化。CAR可以在结合域和跨膜域(TM)之间包含一个或多个铰链域。铰链域可以为天然、合成、半合成或重组来源。铰链域可包括天然存在的免疫球蛋白铰链区或改变的免疫球蛋白铰链区的氨基酸序列。适用于本文所述CAR的示例性铰链域包括衍生自1型膜蛋白(例如CD8α、CD4、CD28、PD1、CD152和CD7)的胞外区的铰链区,它们可以是来自这些分子的野生型铰链区,或可以是改变的。在另一种实施方式中,铰链域包含PD1、CD152或 CD8α铰链区。
“跨膜域”是CAR的一部分,其融合胞外结合部分和胞内信号传导域并将CAR锚定在免疫效应细胞的质膜上。TM域可以衍生自天然、合成、半合成或重组来源。TM域可以衍生自T细胞受体的α、β或ζ链、CD3ε、CD3ζ、 CD4、CD5、CD8α、CD9、CD16、CD22、CD27、CD28、CD33、CD37、CD45、CD64、 CD80、CD86、CD134、CD137、CD152、CD154和PD1。在一种实施方式中,本发明的CAR包含衍生自CD8α或CD28的TM结构域。
在特别的实施方式中,本发明的CAR包含胞内信号传导域。“胞内信号传导域”是指参与将有效的抗CD19CAR与人CD19多肽结合的信息转导到免疫效应细胞内部以引发效应细胞功能(例如活化、产生细胞因子、增殖和细胞毒活性,所述细胞毒活性包括向CAR所结合的靶细胞释放细胞毒性因子)或由抗原结合胞外CAR域引发的其他细胞反应。术语“效应功能”是指免疫效应细胞的特化功能。例如,T细胞的效应功能可以是细胞溶解活性或包括细胞因子分泌在内的帮助或活性。术语“胞内信号传导域”是指蛋白质中转导效应功能信号并指导细胞执行特化功能的部分。
本发明的CAR包含一个或多个共刺激信号传导域,以增强表达CAR受体的T细胞或NK细胞的功效、扩增和/或记忆形成。如本文所用,术语“共刺激信号传导域”是指CAR分子的胞内信号传导域,提供在与抗原结合后T淋巴细胞或NK细胞的有效活化和功能所需的第二信号。
蛋白
“蛋白”、“多肽片段”和“多肽”可互换使用,除非有相反的说明,并且根据常规含义,即作为氨基酸序列使用。蛋白不限于特定长度,例如,它们可以包含全长蛋白质序列或全长蛋白质的片段,并且可以包括多肽的翻译后修饰(例如糖基化、乙酰化、磷酸化等)以及包括天然存在的和非天然存在的本领域已知的其他修饰。
在各种实施方式中,本发明的CAR多肽或蛋白包含在蛋白质N末端的能在翻译时或翻译后指导蛋白质转移的信号(或前导区)序列。可以使用各种熟知的重组和/或合成技术制备多肽。本发明的多肽具体包括本公开的CAR,或具有对本文公开的CAR的一个或多个(例如1-20个,1-10个或1-5个)氨基酸缺失、添加和/或替换的序列。
核酸
如本文所用,术语“多核苷酸”是指mRNA、RNA、基因组RNA(gRNA)、正链RNA(RNA(+))、负链RNA(RNA(-))、基因组DNA(gDNA)、互补DNA(cDNA)或重组DNA。多核苷酸包括单链和双链多核苷酸。优选地,本发明的多核苷酸包括与本文所述的任何参考序列具有至少约70%,71%,72%,73%,74%, 75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%, 86%,87%,88%,89%,90%,91%,92%,94%,95%,96%,97%, 98%,99%,99.5%,99.9%或100%的序列同一性的多核苷酸或变体,通常其中变体保持参考序列的至少一种生物学活性。
示例性地,本发明所述的编码CD19结合域-CD8α hinge-CD8TM-4-1BB-CD3ζ-P2A-IL12-ODD融合蛋白的多核苷酸的序列是任何能够编码该融合蛋白的任何DNA序列,优选地,该序列为SEQ ID NO:2、或SEQ ID NO:2-SEQ ID NO:10-SEQ ID NO:4依次组成的核苷酸序列,或其互补序列。另一方面,本发明所述的编码CD19结合域-CD8α hinge-CD8TM-4-1BB-CD3ζ-P2A-IL12-ODD融合蛋白的多核苷酸的序列可为在严紧条件下与由SEQ ID NO:2的多核苷酸序列或由SEQ ID NO:2-SEQ ID NO:10- SEQ ID NO:4依次组成的核苷酸序列进行杂交、且编码该融合蛋白的多核苷酸或其互补序列;
本文所述的“严紧条件”,可以为低严紧条件、中严紧条件、高严紧条件中的任一种,优选为高严紧条件。示例性地,“低严紧条件”可为30℃、5×SSC、 5×Denhardt液、0.5%SDS、52%甲酰胺的条件;“中严紧条件”可为40℃、5×SSC、 5×Denhardt液、0.5%SDS、52%甲酰胺的条件;“高严紧条件”可为50℃、5×SSC、 5×Denhardt液、0.5%SDS、52%甲酰胺的条件。本领域技术人员应当理解温度越高越能得到高同源性的多多核苷酸。另外,本领域技术人员可以选择影响杂交的严紧度的温度、探针浓度、探针长度、离子强度、时间、盐浓度等多个因素形成的综合结果来实现相应的严紧度。
除此之外可杂交的多核苷酸还示例性地可以为,通过FASTA、BLAST等同一检索软件用***设定的默认参数进行计算时,与SEQ ID NO:2或由SEQ ID NO:2- SEQ ID NO:10-SEQ ID NO:4依次组成的核苷酸序列的多核苷酸具有约70%或以上、71%或以上、72%或以上、73%或以上、74%或以上、75%或以上、76%或以上、77%或以上、78%或以上、79%或以上、80%或以上、81%或以上、82%或以上、 83%或以上、84%或以上、85%或以上、86%或以上、87%或以上、88%或以上、89%或以上、90%或以上、91%或以上、92%或以上、93%或以上、94%或以上、95%或以上、96%或以上、97%或以上、98%或以上、99%或以上、99.1或以上、99.2或以上、99.3%或以上、99.4%或以上、99.5%或以上、99.6%或以上、99.7%或以上、 99.8%或以上、或99.9%或以上同一性的多核苷酸。
核苷酸序列的同一性,可以使用Karlin及Altschul的算法规则BLAST(Proc.Natl.Acad.Sci.USA 87:2264-2268,1990;Proc.Natl.Acad.Sci.USA 90:5873,1993)来确定。基于BLAST算法规则的程序BLASTN、BLASTX已被开发 (AltschulSF,etal:JMol Biol 215:403,1990)。使用BLASTN分析碱基序列时,如使参数为score=100、wordlength=12;此外使用BLASTX分析氨基酸序列时,如使参数为score=50、wordlength=3;使用BLAST和Gapped BLAST程序时,采用各程序的***可设定默认参数值。
可以使用本领域已知和可获得的各种成熟技术中的任何一种来制备、操作和/或表达多核苷酸。为了表达所希望的多肽或蛋白,可以将编码多肽的核苷酸序列***合适的载体中。载体的实例是质粒、自主复制序列和转座元件。另外的示例性载体包括但不限于质粒、噬菌粒、粘粒、人工染色体(例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1衍生的人工染色体(PAC))、噬菌体(例如λ噬菌体或M13噬菌体)和动物病毒。动物病毒载体的实例包括但不限于逆转录病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(例如单纯疱疹病毒)、痘病毒、杆状病毒、***瘤病毒和乳多空病毒(例如SV40)。表达载体的实例是用于在哺乳动物细胞中表达的pClneo载体(Promega);用于在哺乳动物细胞中进行慢病毒介导的基因转移和表达的Lenti4/V5-DESTTM、 pLenti6/V5-DESTTM和pLenti6.2/V5-GW/lacZ(Invitrogen)。在特别的实施方式中,本文公开的嵌合蛋白的编码序列可以连接到用于在哺乳动物细胞中表达嵌合蛋白的这类表达载体中。存在于表达载体中的“控制元件”或“调节序列”是载体的非翻译区(例如复制起点、启动子、增强子、翻译起始信号 (SD序列或Kozak序列)内含子、多腺苷酸化序列、5′和3′非翻译区),其与宿主细胞蛋白相互作用以进行转录和翻译。这类元件或序列的强度和特异性可以不同。取决于所用的载体***和宿主,可以使用任何数量的合适的转录和翻译元件或序列,包括广泛表达型启动子和诱导型启动子。
载体
在特别的实施方式中,用编码CAR的逆转录病毒载体(例如慢病毒载体) 转导细胞(例如,免疫效应细胞,例如T细胞)。例如,用编码CAR的载体转导免疫效应细胞,所述载体包含结合CD19多肽的人源化抗CD19抗体或抗原结合片段,所述人源化抗CD19抗体或抗原结合片段具有跨膜域和胞内信号传导域,使得这些经转导的细胞可以引发CAR介导的细胞毒性反应。
逆转录病毒是基因传递的常用工具。在特别的实施方式中,逆转录病毒用于将编码嵌合抗原受体(CAR)的多核苷酸递送至细胞。如本文所用,术语“逆转录病毒”是指一种RNA病毒,其逆转录其基因组RNA为线性双链DNA 拷贝,随后将其基因组DNA共价整合到宿主基因组中。一旦病毒被整合到宿主基因组中,它就被称为“原病毒”。原病毒作为RNA聚合酶II的模板,并指导RNA分子的表达,所述RNA分子编码产生新病毒颗粒所需的结构蛋白和酶。
适用于特别的实施方式的示例性逆转录病毒包括但不限于:莫洛尼鼠白血病病毒(M-MuLV)、莫洛尼鼠肉瘤病毒(MoMSV)、哈维鼠肉瘤病毒(HaMuSV)、鼠乳腺肿瘤病毒(MuMTV)、长臂猿白血病病毒(GaLV)、猫白血病病毒(FLV)、鼠干细胞病毒(MSCV)和劳斯氏肉瘤病毒(RSV))和慢病毒。
如本文所用,术语“慢病毒”是指包含很多逆转录病毒的组(或属)。示例性慢病毒包括但不限于:HIV(人免疫缺陷病毒;包括HIV 1型和HIV 2型);维斯那-梅迪病毒(visna-maedivirus,VMV)病毒;山羊关节炎-脑炎病毒
(CAEV);马传染性贫血病毒(EIAV);猫免疫缺陷病毒(FIV);牛免疫缺陷病毒(BIV);和猿猴免疫缺陷病毒(SIV)。在一种实施方式中,基于HIV的载体骨架(即HIV顺式作用序列元件)是优选的。在特别的实施方式中,慢病毒用于将包含CAR的多核苷酸递送至细胞。
术语“载体”在本文中用于指能够转移或转运另一种核酸分子的核酸分子。转移的核酸通常与载体核酸分子连接,例如***载体核酸分子中。载体可以包括指导细胞中自主复制的序列,或者可以包括足以允许整合到宿主细胞DNA中的序列。有用的载体包括,例如,质粒(例如DNA质粒或RNA质粒)、转座子、粘粒、细菌人工染色体和病毒载体。有用的病毒载体包括例如复制缺陷型逆转录病毒和慢病毒。
对于本领域技术人员显而易见的是,术语“病毒载体”广泛用于指核酸分子(例如转移质粒)或介导核酸转移的病毒颗粒,核酸分子包括病毒衍生的通常促进核酸分子转移或整合到细胞基因组中的核酸元件。病毒颗粒通常包括各种病毒组件,有时还包括除核酸外的宿主细胞组件。
术语病毒载体可以指能够将核酸转移到细胞中的病毒或病毒颗粒,或被转移的核酸本身。病毒载体和转移质粒含有主要衍生自病毒的结构和/或功能遗传元件。术语“逆转录病毒载体”是指主要来源于逆转录病毒的含有结构和功能遗传元件或其部分的病毒载体或质粒。术语“慢病毒”指的是逆转录病毒科的属,其能够有效感染非周期性和有丝***后的细胞;它们可传递显著量的遗传信息进入宿主细胞的DNA,以便它们是基因传递载体的最有效的方法之一。
因此,在优选实施方式中,本发明涉及用编码CAR的表达载体转染细胞的方法。例如,在一些实施方式中,载体包含额外的序列,例如促进CAR表达的序列,例如启动子、增强子、poly-A信号和/或一个或多个内含子。在优选的实施方式中,CAR编码序列的侧翼是转座子序列,使得存在转座酶以允许编码序列整合到转染细胞的基因组中。
在一些实施方式中,用转座酶进一步转染遗传转化的细胞,所述转座酶促进CAR编码序列整合到转染细胞的基因组中。在一些实施方式中,转座酶作为DNA表达载体提供。然而,在优选的实施方式中,转座酶作为可表达的 RNA或蛋白质提供,使得转座酶不在转基因细胞中发生长期表达。例如,在一些实施方式中,转座酶作为mRNA提供(例如,包含帽和poly-A尾的mRNA)。可以根据本发明的实施方式使用任何转座酶***。然而,在一些实施方式中,转座酶是鲑鱼型Tel样转座酶(SB)。在一些实施方式中,转座酶是具有增加的酶活性的工程化酶。转座酶的一些具体实例包括但不限于SB 10、SB 11 或SB 100X转座酶(参见,例如,Mates等人,2009,Nat Genet.41(6):753-61 或US9228180,其通过引用并入本文)。例如,方法可以包括对具有编码SB 10、 SB 11或SB 100X转座酶的mRNA的细胞进行电穿孔。
序列变体:
所要求保护的核酸、蛋白质、抗体、抗体片段和/或CAR的序列变体(例如由百分比序列同一性限定的那些)也包括在本发明的范围内,其维持本发明的类似结合特性。这些变体显示了替代序列,但保持基本相同的结合特性例如靶特异性,因为所提供的特定序列已知是功能类似物或功能上的类似物。序列同一性涉及进行序列比对时相同核苷酸或氨基酸的百分比。
本文所用的叙述“序列同一性”是指在比较窗口上基于核苷酸-核苷酸或基于氨基酸-氨基酸的序列相同的程度。因此,可以通过以下来计算“序列同一性的百分比”:在比较窗口上比较两个最佳比对序列,确定两个序列上存在相同核酸碱基(例如A、T、C、G、I)或相同氨基酸残基(例如,Ala、Pro、 Ser、Thr、Gly、Val、Leu、He、Phe、Tyr、Trp、Lys、Arg、His、Asp、Glu、 Asn、Gln、Cys和Met)的位置的数量来产生匹配位置的数量,将匹配位置的数量除以比较窗口中位置的总数量(即窗口大小),以及将结果乘以100以得到序列同一性的百分比。包括了具有与本文所述的任何参考序列至少约 50%,55%,60%,65%,70%,75%,80%,85%,90%,95%,96%,97%,98%,99%或100%的序列同一性的核苷酸或多肽,通常其中多肽变体保持参考多肽的至少一种生物学活性。
本领域普通技术人员将理解,由于遗传密码的简并性,存在许多编码如本文所述的多肽或蛋白的核苷酸序列。这些多核苷酸中的一些与任何天然基因的核苷酸序列具有最小的同源性或序列同一性。尽管如此,本发明特别考虑了由于密码子使用的差异而变化的多核苷酸。落入所述序列同一性的序列中的缺失、替换和其他变化也包括在本发明中。
可通过替换发生的蛋白质序列修饰也包括在本发明的范围内。如本文所定义的替换是对蛋白质的氨基酸序列进行的修饰,借此,一个或多个氨基酸被相同数量的(不同的)氨基酸替换,从而产生含有与初级蛋白质不同的氨基酸序列的蛋白质。可以进行替换,其优选不显著改变蛋白质的功能。与添加一样,替换可以是天然的或人工的。本领域熟知的是,可以在不显著改变蛋白质功能的情况下进行氨基酸替换。当修饰涉及用一种氨基酸替换另一种具有相似性质的氨基酸的“保守性”氨基酸替换时,尤其如此。这类“保守性的”氨基酸可以是天然或合成的氨基酸,其由于大小、电荷、极性和构象而可被替换但不会显著影响蛋白质的结构和功能。通常,许多氨基酸可被保守性氨基酸替换而不会有害地影响蛋白质的功能。
一般来说,非极性氨基酸Gly、Ala、Val、Ile和Leu;非极性芳香族氨基酸Phe、Trp和Tyr;中性极性氨基酸Ser、Thr、Cys、Gln、Asn和Met;带正电荷的氨基酸Lys、Arg和His;带负电荷的氨基酸Asp和Glu代表保守性氨基酸组。这份清单并非穷举。例如,熟知的是,Ala、Gly、Ser和有时 Cys可以相互替代,即使它们属于不同的组。
替代变体在抗体分子中除去至少一个氨基酸残基,并在其位置上***不同的残基。对于替代诱变的发生,最感兴趣的位置包括高变区,但也考虑了 FR改变。如果这样的替代导致生物活性的变化,则可以引入更大量的改变,并筛选产物。
组合物和制剂
本发明的组合物可包含如本文所考虑的一种或多种多肽、多核苷酸、包含该多核苷酸的载体、经遗传修饰的免疫效应细胞等。组合物包括但不限于药物组合物。“药物组合物”是指在药学上可接受的或生理学上可接受的溶液中配制的组合物,其单独或与一种或多种其他治疗方式组合施用于细胞或动物。还应理解,如果需要,本发明的组合物也可以与其他药剂组合施用,例如细胞因子、生长因子、激素、小分子、化学治疗剂、前药、药物、抗体或其他各种药物活性剂。对组合物中还可包含的其它组分实际上没有限制,条件是额外的组分不会不利地影响组合物递送预期疗法的能力。
术语“药学上可接受的”在本文中用于指在合理的医学判断范围内适合用于与人类和动物的组织接触而没有过量毒性、刺激、过敏反应或其他问题或并发症并且与合理的利益/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用,“药学上可接受的载体、稀释剂或赋形剂”包括但不限于已经由美国食品和药品管理局或中国食品药品监督管理局批准可用于人或家畜的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/ 着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂、表面活性剂或乳化剂。示例性的药学上可接受的载体包括但不限于糖,例如乳糖、葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;黄芪胶;麦芽;明胶;滑石;可可脂,蜡,动植物油脂,石蜡,有机硅,膨润土,硅酸,氧化锌;油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和豆油;二醇,例如丙二醇;多元醇,例如甘油、山梨糖醇、甘露醇和聚乙二醇;酯类,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;海藻酸;无热原水;等渗盐水;林格氏溶液;乙醇;磷酸盐缓冲液;以及药物制剂中使用的任何其他相容性物质。
在特别的实施方式中,本发明的组合物包含一定量的本发明的表达CAR 的免疫效应细胞。如本文所用,术语“量”是指实现有益或所希望的预防或治疗结果(包括临床结果)的经遗传修饰的治疗细胞(例如T细胞)的“有效量”。
“预防有效量”是指有效实现所希望的预防结果的经遗传修饰的治疗细胞的量。通常但不是必须的,因为预防剂量在受试者中用于疾病之前或疾病的早期阶段,所以预防有效量小于治疗有效量。术语预防不一定是指完全禁止或防止特定的医学病症。术语预防还指降低某种医学病症发生或症状恶化的风险。
经遗传修饰的治疗细胞的“治疗有效量”可以根据各种因素而变化,所述因素例如疾病状态、年龄、性别和个体体重,以及干细胞和祖细胞在个体中引发所希望的反应的能力。治疗有效量也是这样的量,即,治疗有益效果超过病毒或转导的治疗细胞的任何毒性或有害作用。术语“治疗有效量”包括有效“治疗”受试者(例如患者)的量。当指示治疗量时,可以由医生在考虑年龄、体重、肿瘤大小、感染或转移的程度和患者(受试者)状况的个体差异的情况下确定待施用的本发明组合物的精确量。可以通常规定的是,包含本文所述T细胞的药物组合物可以以102至1010个细胞/kg体重,优选105至 106个细胞/kg体重的剂量(包括在这些范围内的所有整数值)来施用。细胞的数量将取决于组合物的最终用途以及其中包含的细胞类型。对于本文提供的用途,细胞通常为1L或更少的体积,可以为500mL或更少,甚至250mL或 100mL或更少。因此,所希望细胞的密度通常大于106个细胞/ml,通常大于 107个细胞/ml,通常为108个细胞/ml或更高。免疫细胞的临床相关数量可以分配成多次输注,该多次输注累积等于或超过105、106、107、108、109、1010、 1011或1012个细胞。在本发明的一些实施方式中,特别是因为所有输注的细胞将被重定向至特定的靶抗原,可以施用较低数量的细胞。表达CAR的细胞组合物可以在这些范围内的剂量下多次施用。对于接受治疗的患者,细胞可以是同种异体的、同基因的、异基因的或自体的。
通常,包含如本文所述活化和扩增的细胞的组合物可用于治疗和防止免疫受损个体中出现的疾病。特别地,包含本发明的经CAR修饰的T细胞的组合物用于治疗B细胞恶性肿瘤。本发明的经CAR修饰的T细胞可以单独施用,或作为药物组合物与载体、稀释剂、赋形剂和/或与其他组分或其他细胞因子或细胞群组合施用。在特别的实施方式中,本发明的药物组合物包含一定量的经遗传修饰的T细胞,以及一种或多种药学上或生理学上可接受的载体、稀释剂或赋形剂。
包含表达CAR的免疫效应细胞群(例如T细胞)的本发明药物组合物可包含:缓冲液,例如中性缓冲盐水、磷酸盐缓冲盐水等;碳水化合物,例如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸(例如甘氨酸);抗氧化剂;螯合剂(例如EDTA)或谷胱甘肽;佐剂,例如氢氧化铝;和防腐剂。优选配制本发明的组合物用于肠胃外施用,例如血管内(静脉内或动脉内)、腹膜内或肌肉内施用。
液体药物组合物无论是溶液、悬浮液或其他类似形式,可包括以下中的一种或多种:无菌稀释剂(例如注射用水)、盐水溶液(优选生理盐水、林格氏溶液、等渗氯化钠)、固定油(例如可用作溶剂或悬浮介质的合成单甘油酯或甘油二酯)、聚乙二醇、甘油、丙二醇或其它溶剂;抗菌剂,例如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;和缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐,和调节渗透压的试剂,例如氯化钠或葡萄糖。肠胃外制剂可以封装在由玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。可注射药物组合物优选是无菌的。
在特别的实施方式中,本发明的组合物包含单独的有效量的表达CAR的免疫效应细胞,或其与一种或多种治疗剂的组合。因此,表达CAR的免疫效应细胞组合物可以单独施用或与其他已知的癌症治疗组合施用,所述其他已知的癌症治疗例如放射疗法、化学疗法、移植、免疫疗法、激素疗法、光动力疗法等。组合物也可以与抗生素组合施用。本领域可接受这类治疗剂作为如本文所述的特定疾病状态(例如特定癌症)的标准治疗。考虑的示例性治疗剂包括细胞因子、生长因子、类固醇、NSAID、DMARD、抗炎剂、化学治疗剂、放射治疗剂、治疗性抗体或其他活性和辅助性药剂。
治疗方法
本发明的经遗传修饰的免疫效应细胞提供用于治疗癌症的过继免疫疗法的改进方法,所述癌症包括但不限于急性骨髓性白血病、慢性骨髓性白血病、鼻咽癌、神经胶质瘤、结肠癌、胃癌、***癌、肾细胞癌、***和卵巢癌,肺癌(SCLC和NSCLC)、胃癌、胆囊癌、以及和癌相关的恶病体质、疲劳、乏力、恶病体质和血钙过多的副肿瘤性综合症。
在本发明的另一个方面,提供了如本文所述的根据本发明的CAR和CAR-T 或NK用于治疗疾病的方法,其中所述方法包括向所述患者施用治疗有效量的如本文所述的CAR或CAR-T或NK,示例地,所述疾病选自:急性骨髓性白血病、慢性骨髓性白血病、鼻咽癌、神经胶质瘤、结肠癌、胃癌、***癌、肾细胞癌、***和卵巢癌,肺癌(SCLC和NSCLC)、胃癌、胆囊癌、以及和癌相关的恶病体质、疲劳、乏力、恶病体质和血钙过多的副肿瘤性综合症。
如本文所用,术语“个体”和“受试者”通常可互换使用,并且是指可以用本文别处公开的基因治疗载体、基于细胞的治疗剂和方法治疗的表现出疾病、病症或病况的症状的任何动物。在优选的实施方式中,受试者包括可以用本文别处公开的基因治疗载体、基于细胞的治疗剂和方法治疗的表现出造血***的疾病、病症或病况的症状的任何动物。典型的受试者包括实验动物(例如小鼠、大鼠、兔或豚鼠)、农场动物和家畜或宠物(例如猫或狗)。包括非人灵长类动物,优选包括人类患者。
如本文所用,“治疗”包括对疾病或病理状况的症状或病理学的任何有益或期望的作用,并且可包括所治疗的疾病或病症的一种或多种可测量标记物的甚至最小的减少。治疗可任选地涉及疾病或病症的症状的减轻或改善,或疾病或病症的进展的延迟。“治疗”不一定表示完全根除或治愈疾病或病症或其相关症状。
如本文所用,“预防”表示防止、抑制或降低疾病或病症发生或复发的可能性的方法。它还指延迟疾病或病症的发作或复发,或延迟疾病或病症的症状的发生或复发。如本文所用,“防止”和类似词语还包括在疾病或病症发作或复发之前降低疾病或病症的强度、影响、症状和/或负担。
在一种实施方式中,在有此需要的受试者中治疗癌症的方法包括施用有效量、例如治疗有效量的包含本发明的经遗传修饰的免疫效应细胞的组合物。施用的数量和频率将由诸如患者的状况以及患者的疾病的类型和严重性等因素确定,尽管适当的剂量可以通过临床试验确定。
本发明的组合物的施用可以以任何方便的方式进行,包括通过气溶胶吸入、注射、摄取、输血、植入或移植进行。在优选的实施方式中,肠胃外施用组合物。本文所用的短语“肠胃外施用”是指除肠内和局部施用以外的施用方式,通常通过注射,包括但不限于血管内、静脉内、肌肉内、动脉内、鞘内、囊内、眶内、瘤内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、包膜下、蛛网膜下腔、脊柱内和胸骨内注射和输注。在一种实施方式中,通过直接注射到肿瘤、***或感染部位而将本发明的组合物施用于受试者。
本文中出现的英文名称不区分大小写;CD19 CAR-T表示能表达CD19特异性结合域的CAR-T细胞;CD8TM表示跨膜结构域。
相对NK细胞(包括CAR-NK)而言,本发明对T细胞(包括CAR-T细胞)进行了更详尽的描述,但是一般情况下对于T细胞的这些描述也是适用于NK细胞的。在此,将对T细胞描述的内容中出现“T细胞”或其同义词替换为“NK细胞”或其同义词的描述纳入此处。这从叙述简洁的角度考虑是十分必要的。如果根据现有技术判断在某些情况下这种替换是不合适的,则不进行该替换。
本文已采用的术语和表述用作描述性而不是限制性术语,并且在此种术语和表述的使用中不预期排除所示和所述特征或其部分的任何等价物,但应认识到各种修饰在请求保护的本发明的范围内是可能的。
因此,应当理解尽管本发明已通过优选实施方案和任选特征具体公开,但本领域技术人员可以采用本文公开的概念的修饰和变化,并且此类修饰和变化被视为在如由附加权利要求定义的本发明的范围内。
为更清楚地说明本发明,现结合如下实施例进行详细说明,但这些实施例仅是对本发明的示例性描述,并不能解释为对本申请的限制。
实施例1:慢病毒载体的制备
1)基因合成慢病毒表达质粒;2)基因合成Kozal-CD8a signal-CD19 SCFV-CD8aTM-4-1BB-CD3zeta融合基因序列(其氨基酸序列如SEQ ID NO:1所示,其DNA序列如SEQID NO:2所示,其结构示意图见图1);3)基因合成核苷酸序列,该核苷酸序列为:自剪切蛋白P2A基因(其氨基酸序列如SEQ ID NO:9 所示,其DNA序列如SEQ ID NO:10所示)-IL12ODD融合基因序列(其氨基酸序列如SEQ ID NO:3所示,其DNA序列如SEQ ID NO:4所示);4)使用多片段同源重组的方法将以上基因合成片段***慢病毒表达质粒,将重组载体转化至大肠杆菌菌株Stbl3,经过卡那霉素筛选和单克隆测序,获得目的重组质粒;然后扩大培养含目的重组质粒的宿主菌,使用去内毒素试剂盒获得无菌无内毒素质粒,即含CD19CARIL12ODD基因片段的质粒载体,其结构见图1;5)同时将慢病毒包装辅助质粒pMDLgpRRE、pRRE、pCMV-VSV-G分别转化大肠杆菌菌株Stbl3,氨苄青霉素筛选,使用去内毒素试剂盒获得无菌无内毒素质粒。
实施例2:CAR19IL12ODD慢病毒的制备
1)接种5x106的293T细胞于含有10mlDMEM+10%FBS培养基的10cm培养皿中;2)24小时后,更换10ml新鲜的DMEM+10%FBS培养基,将病毒质粒 (CAR19IL12ODD:25μg、pMDLgpRRE:7.5ug、pRRE:6ug、pCMV-VSV-G:6ug)与 250ul无血清DMEM混合,制备质粒悬液;将45ul1ug/ml的转染试剂(Linear Polyethylenimine,PEI)与250ul无血清DMEM混合,制备PEI悬液;室温放置 5分钟后将250ul质粒悬液与PEI悬液混合,30分钟后将其加入到293T细胞中,轻轻混匀;3)8小时后,更换20ml新鲜DMEM+10%FBS培养基;4)60小时后收取培养基上清,离心除去细胞碎片,上清用0.45μm滤器过滤;然后利用Amicon Ultra-15 CentrifugalFilter Unit with Ultracel-30 membrane(Merckmillipore,货号UFC903096),4℃、1500g条件下离心30分钟,将病毒上清浓缩10倍,获得病毒液,利用梯度稀释法对病毒进行效价,分装后放于-80℃保存。
实施例3:CAR19IL12ODD CAR-T细胞的制备及功能验证
1)外周血淋巴细胞的分离:采集外周血,加入与血液样本等量的外周血淋巴细胞分离液,800g离心20min,收集白膜层淋巴细胞,PBS洗两次;2)外周血淋巴细胞中CD3T细胞的分离:重悬1X107淋巴细胞在5ml含5%FBS的X-VIVO TM 15培养基于6孔板中,CD3和CD8的抗体检测外周淋巴细胞中CD3T细胞的比例,利用Human T-Expander CD3/CD28(Gibco,货号11141D)分离并刺激 CD3T细胞;3)将2X105CD3T细胞与5X105IU病毒混合于24孔板,30℃、1500g 离心90min,4h后,补加1ml含5%FBS的X-VIVOTM 15培养基培养基,轻轻吹打混匀,放回培养箱培养,24小时后,更换1ml新鲜5%FBS的X-VIVOTM 15培养基;
4)48小时后,调节T细胞浓度至5×105/ml,全部更换新鲜培养基;5)72小时后,调节T细胞浓度至5×105/ml,WB验证CAR19IL12ODD蛋白的表达;用流式细胞仪检测和确认CAR-T细胞中CAR表达情况;分别将CAR19IL12ODD CAR-T 细胞置于正常氧气浓度及缺氧浓度条件下培养,利用ELESA检测细胞培养上清中IL12的分泌浓度(图2),结果显示CAR19IL12ODD在正常氧气浓度条件(17%) 下检测到低剂量的IL12分泌表达,而厌氧条件下(1%)则分泌出高达26pg/ml 的IL12分泌。
以上结果显示,本发明的CAR19IL12ODD均能在CD3T细胞中表达,且ODD 结构域能有效控制IL12的分泌表达。
实施例4:LDH实验
检测CAR19IL12ODD CAR-T细胞对DLBCL细胞系Ly3的体外杀伤作用 (CytoToxNon-RadioactiveCytotoxicity Assay,Promega,货号G1780):1) 取CAR19IL12ODD CAR-T效应细胞和靶细胞Ly3,PBS洗二遍,台盼蓝染色计数; 2)U型96孔板中每孔加1x104的靶细胞于50ul 5%FBS的1640培养基中;3)设置梯度效靶比实验组:按效靶比10:1、5:1、2.5:1、1.25:1、0.6:1、0.3: 1、以及0.15:1加入相应数量的效应细胞,每孔加入效应细胞的体积是50ul; 4)设置下列对照组别:空白组(100ul 5%FBS的1640培养基)、效应细胞自发组(50ul效应细胞+50ul 5%FBS的1640培养基)、和靶细胞自发组(50ul靶细胞+50ul 5%FBS的1640培养基)、靶细胞最大释放组(50ul靶细胞+50ul 5%FBS的1640培养基),于37℃、5%CO2培养箱中培养;5)4h后,取出板子,250g离心5min(此步骤前1h,靶细胞最大释放组加10ul 10x裂解液);6)取50ul上清到新的平底96孔板,每孔加50ul Cytoto x底物,锡箔纸包被,室温反应30min;7) 每孔加50ul终止液终止反应,酶标仪492nm处测其吸光值;8)计算杀伤效率,杀伤效率=(实验组-效应细胞自发组-靶细胞自发组)/(靶细胞最大释放组-靶细胞自发组)X100;实验结果如图3A,从本发明的CAR-T可以对弥漫大B细胞淋巴瘤(DLBCL)具有显著的疗效或抑制作用。
实施例5:动物试验检测CAR19IL12ODD CAR-T细胞对DLBCL细胞系Ly3的体内杀伤作用及功能验证
选取4-6周龄的重度免疫缺陷型叙利亚仓鼠,适应饲养环境一周后于前肢侧翼皮下接种1×107/只的Ly3弥漫大B细胞淋巴瘤肿瘤细胞。观察测量肿瘤大小,2-4周后,肿瘤生长至250mm3时,把叙利亚仓鼠随机分为5只一组,腹腔注射体外培养7-8天的CAR-T细胞,给药量均为1×107/只。在回输CAR19IL12ODD CAR-T细胞后的3、6、9、12天即肿瘤接种后的17、20、23、26天取外周血检测IL12浓度及CAR-T细胞流式检测表明(图4A和图4B),IL12明显增加了CAR-T 细胞在体内的存活时间;继续观察测量肿瘤大小,当对照组肿瘤长至伦理极限时,按伦理要求处死实验动物,取肿瘤组织进行免疫组化染色,利用以下公式计算肿瘤大小变化并绘制肿瘤生长曲线,肿瘤大小=(1/2)*长径*短径的平方;从图3B可以看出,本申请实施例中所制备的CAR-T对人弥漫大B细胞淋巴瘤 (DLBCL)有显著的抑制作用;免疫组化结果(未示出)显示,IL12明显促进了 CAR-T的肿瘤浸润,CAR-T细胞中IL12的表达在打破DLBLC的肿瘤免疫微环境中发挥了作用。以上结果表明,本申请实施例中所制备的CAR19IL12ODD CAR-T 细胞通过打破免疫微环境对人弥漫大B细胞淋巴瘤(DLBCL)起到了显著疗效或抑制作用。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换等,均应包含在本发明的保护范围之内。
序列表
<110> 郑州大学
<120> 新型嵌合抗原受体以及包含其的免疫细胞
<130> 21SG1F7645
<160> 10
<170> PatentIn version 3.5
<210> 1
<211> 522
<212> PRT
<213> 人工序列
<220>
<223> CAR氨基酸序列
<400> 1
Ala Thr Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu
1 5 10 15
Leu Leu His Ala Ala Arg Pro Ala Ala Ala Asp Ile Gln Met Thr Gln
20 25 30
Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser
35 40 45
Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln
50 55 60
Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu
65 70 75 80
His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr
100 105 110
Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser
130 135 140
Gly Glu Gly Ser Thr Lys Gly Glu Val Lys Leu Gln Glu Ser Gly Pro
145 150 155 160
Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser
165 170 175
Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro
180 185 190
Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr
195 200 205
Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn
210 215 220
Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp
225 230 235 240
Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr
245 250 255
Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala
260 265 270
Ala Ala Arg Ser Phe Ser His Phe Val Pro Val Phe Leu Pro Ala Lys
275 280 285
Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
290 295 300
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
305 310 315 320
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
325 330 335
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
340 345 350
Val Ile Thr Leu Tyr Cys Asn His Arg Asn His Met Gly Gly Thr Ser
355 360 365
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
370 375 380
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
385 390 395 400
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
405 410 415
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
420 425 430
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
435 440 445
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
450 455 460
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
465 470 475 480
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
485 490 495
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
500 505 510
Ala Leu His Met Gln Ala Leu Pro Pro Arg
515 520
<210> 2
<211> 1566
<212> DNA
<213> 人工序列
<220>
<223> CAR核苷酸序列
<400> 2
gccaccatgg ccttaccagt gaccgccttg ctcctgccgc tggccttgct gctccacgcc 60
gccaggccgg cggccgctga catccagatg acacagacta catcctccct gtctgcctct 120
ctgggagaca gagtcaccat cagttgcagg gcaagtcagg acattagtaa atatttaaat 180
tggtatcagc agaaaccaga tggaactgtt aaactcctga tctaccatac atcaagatta 240
cactcaggag tcccatcaag gttcagtggc agtgggtctg gaacagatta ttctctcacc 300
attagcaacc tggagcaaga agatattgcc acttactttt gccaacaggg taatacgctt 360
ccgtacacgt tcggaggggg gactaagttg gaaataacag gctccacctc tggatccggc 420
aagcccggat ctggcgaggg atccaccaag ggcgaggtga aactgcagga gtcaggacct 480
ggcctggtgg cgccctcaca gagcctgtcc gtcacatgca ctgtctcagg ggtctcatta 540
cccgactatg gtgtaagctg gattcgccag cctccacgaa agggtctgga gtggctggga 600
gtaatatggg gtagtgaaac cacatactat aattcagctc tcaaatccag actgaccatc 660
atcaaggaca actccaagag ccaagttttc ttaaaaatga acagtctgca aactgatgac 720
acagccattt actactgtgc caaacattat tactacggtg gtagctatgc tatggactac 780
tggggtcaag gaacctcagt caccgtctcc tcagcggccg caagatcttt cagccacttc 840
gtgccggtct tcctgccagc gaagcccacc acgacgccag cgccgcgacc accaacaccg 900
gcgcccacca tcgcgtcgca gcccctgtcc ctgcgcccag aggcgtgccg gccagcggcg 960
gggggcgcag tgcacacgag ggggctggac ttcgcctgtg atatctacat ctgggcgccc 1020
ttggccggga cttgtggggt ccttctcctg tcactggtta tcacccttta ctgcaaccac 1080
aggaaccata tgggaggaac tagtaaacgg ggcagaaaga aactcctgta tatattcaaa 1140
caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1200
ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1260
cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1320
gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1380
aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1440
tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1500
cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1560
cctcgc 1566
<210> 3
<211> 841
<212> PRT
<213> 人工序列
<220>
<223> IL12ODD融合蛋白氨基酸序列
<400> 3
Met Gly His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu
1 5 10 15
Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser Val Pro Gly Val Gly Val Pro Gly
325 330 335
Val Gly Ala Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe
340 345 350
Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met
355 360 365
Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu
370 375 380
Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu
385 390 395 400
Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser
405 410 415
Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys
420 425 430
Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu
435 440 445
Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met
450 455 460
Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile
465 470 475 480
Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln
485 490 495
Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu
500 505 510
Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg
515 520 525
Val Met Ser Tyr Leu Asn Ala Ser Val Asp Gln Gln Thr Glu Cys Val
530 535 540
Leu Lys Pro Val Glu Ser Ser Asp Met Lys Met Thr Gln Leu Phe Thr
545 550 555 560
Lys Val Glu Ser Glu Asp Thr Ser Ser Leu Phe Asp Lys Leu Lys Lys
565 570 575
Glu Pro Asp Ala Leu Thr Leu Leu Ala Pro Ala Ala Gly Asp Thr Ile
580 585 590
Ile Ser Leu Asp Phe Gly Ser Asn Asp Thr Glu Thr Asp Asp Gln Gln
595 600 605
Leu Glu Glu Val Pro Leu Tyr Asn Asp Val Met Leu Pro Ser Pro Asn
610 615 620
Glu Lys Leu Gln Asn Ile Asn Leu Ala Met Ser Pro Leu Pro Thr Ala
625 630 635 640
Glu Thr Pro Lys Pro Leu Arg Ser Ser Ala Asp Pro Ala Leu Asn Gln
645 650 655
Glu Val Ala Leu Lys Leu Glu Pro Asn Pro Glu Ser Leu Glu Leu Ser
660 665 670
Phe Thr Met Pro Gln Ile Gln Asp Gln Thr Pro Ser Pro Ser Asp Gly
675 680 685
Ser Thr Arg Gln Ser Ser Pro Glu Pro Asn Ser Pro Ser Glu Tyr Cys
690 695 700
Phe Tyr Val Asp Ser Asp Met Val Asn Glu Phe Lys Leu Glu Leu Val
705 710 715 720
Glu Lys Leu Phe Ala Glu Asp Thr Glu Ala Lys Asn Pro Phe Ser Thr
725 730 735
Gln Asp Thr Asp Leu Asp Leu Glu Met Leu Ala Pro Tyr Ile Pro Met
740 745 750
Asp Asp Asp Phe Gln Leu Arg Ser Phe Asp Gln Leu Ser Pro Leu Glu
755 760 765
Ser Ser Ser Ala Ser Pro Glu Ser Ala Ser Pro Gln Ser Thr Val Thr
770 775 780
Val Phe Gln Gln Thr Gln Ile Gln Glu Pro Thr Ala Asn Ala Thr Thr
785 790 795 800
Thr Thr Ala Thr Thr Asp Glu Leu Lys Thr Val Thr Lys Asp Arg Met
805 810 815
Glu Asp Ile Lys Ile Leu Ile Ala Ser Pro Ser Pro Thr His Ile His
820 825 830
Lys Glu Thr Thr Ser Ala Thr Ser Ser
835 840
<210> 4
<211> 2523
<212> DNA
<213> 人工序列
<220>
<223> IL12ODD融合蛋白核苷酸序列
<400> 4
atgggtcacc agcagttggt catctcttgg ttttccctgg tttttctggc atctcccctc 60
gtggccatat gggaactgaa gaaagatgtt tatgtcgtag aattggattg gtatccggat 120
gcccctggag aaatggtggt cctcacctgt gacacccctg aagaagatgg tatcacctgg 180
accttggacc agagcagtga ggtcttaggc tctggcaaaa ccctgaccat ccaagtcaaa 240
gagtttggag atgctggcca gtacacctgt cacaaaggag gcgaggttct aagccattcg 300
ctcctgctgc ttcacaaaaa ggaagatgga atttggtcca ctgatatttt aaaggaccag 360
aaagaaccca aaaataagac ctttctaaga tgcgaggcca agaattattc tggacgtttc 420
acctgctggt ggctgacgac aatcagtact gatttgacat tcagtgtcaa aagcagcaga 480
ggctcttctg acccccaagg ggtgacgtgc ggagctgcta cactctctgc agagagagtc 540
agaggggaca acaaggagta tgagtactca gtggagtgcc aggaggacag tgcctgccca 600
gctgctgagg agagtctgcc cattgaggtc atggtggatg ccgttcacaa gctcaagtat 660
gaaaactaca ccagcagctt cttcatcagg gacatcatca aacctgaccc acccaagaac 720
ttgcagctga agccattaaa gaattctcgg caggtggagg tcagctggga gtaccctgac 780
acctggagta ctccacattc ctacttctcc ctgacattct gcgttcaggt ccagggcaag 840
agcaagagag aaaagaaaga tagagtcttc acggacaaga cctcagccac ggtcatctgc 900
cgcaaaaatg ccagcattag cgtgcgggcc caggaccgct actatagctc atcttggagc 960
gaatgggcat ctgtgccctg cagtgttcct ggagtagggg tacctggggt gggcgccaga 1020
aacctccccg tggccactcc agacccagga atgttcccat gccttcacca ctcccaaaac 1080
ctgctgaggg ccgtcagcaa catgctccag aaggccagac aaactctaga attttaccct 1140
tgcacttctg aagagattga tcatgaagat atcacaaaag ataaaaccag cacagtggag 1200
gcctgtttac cattggaatt aaccaagaat gagagttgcc taaattccag agagacctct 1260
ttcataacta atgggagttg cctggcctcc agaaagacct cttttatgat ggccctgtgc 1320
cttagtagta tttatgaaga cttgaagatg taccaggtgg agttcaagac catgaatgca 1380
aagctgctga tggatcctaa gaggcagatc tttctagatc aaaacatgct ggcagttatt 1440
gatgagctga tgcaggccct gaatttcaac agtgagactg tgccacaaaa atcctccctt 1500
gaagaaccgg atttttataa aactaaaatc aagctctgca tacttcttca tgctttcaga 1560
attcgggcag tgactattga tagagtgatg agctatctga atgcttccgt cgaccaacaa 1620
acagaatgtg tccttaaacc ggttgaatct tcagatatga aaatgactca gctattcacc 1680
aaagttgaat cagaagatac aagtagcctc tttgacaaac ttaagaagga acctgatgct 1740
ttaactttgc tggccccagc cgctggagac acaatcatat ctttagattt tggcagcaac 1800
gacacagaaa ctgatgacca gcaacttgag gaagtaccat tatataatga tgtaatgctc 1860
ccctcaccca acgaaaaatt acagaatata aatttggcaa tgtctccatt acccaccgct 1920
gaaacgccaa agccacttcg aagtagtgct gaccctgcac tcaatcaaga agttgcatta 1980
aaattagaac caaatccaga gtcactggaa ctttctttta ccatgcccca gattcaggat 2040
cagacaccta gtccttccga tggaagcact agacaaagtt cacctgagcc taatagtccc 2100
agtgaatatt gtttttatgt ggatagtgat atggtcaatg aattcaagtt ggaattggta 2160
gaaaaacttt ttgctgaaga cacagaagca aagaacccat tttctactca ggacacagat 2220
ttagacttgg agatgttagc tccctatatc ccaatggatg atgacttcca gttacgttcc 2280
ttcgatcagt tgtcaccatt agaaagcagt tccgcaagcc ctgaaagcgc aagtcctcaa 2340
agcacagtta cagtattcca gcagactcaa atacaagaac ctactgctaa tgccaccact 2400
accactgcca ccactgatga attaaaaaca gtgacaaaag accgtatgga agacattaaa 2460
atattgattg catctccatc tcctacccac atacataaag aaactactag tgccacatca 2520
tca 2523
<210> 5
<211> 536
<212> PRT
<213> 人工序列
<220>
<223> IL12蛋白氨基酸序列
<400> 5
Met Gly His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu
1 5 10 15
Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser Val Pro Gly Val Gly Val Pro Gly
325 330 335
Val Gly Ala Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe
340 345 350
Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met
355 360 365
Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu
370 375 380
Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu
385 390 395 400
Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser
405 410 415
Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys
420 425 430
Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu
435 440 445
Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met
450 455 460
Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile
465 470 475 480
Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln
485 490 495
Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu
500 505 510
Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg
515 520 525
Val Met Ser Tyr Leu Asn Ala Ser
530 535
<210> 6
<211> 1608
<212> DNA
<213> 人工序列
<220>
<223> IL12蛋白核苷酸序列
<400> 6
atgggtcacc agcagttggt catctcttgg ttttccctgg tttttctggc atctcccctc 60
gtggccatat gggaactgaa gaaagatgtt tatgtcgtag aattggattg gtatccggat 120
gcccctggag aaatggtggt cctcacctgt gacacccctg aagaagatgg tatcacctgg 180
accttggacc agagcagtga ggtcttaggc tctggcaaaa ccctgaccat ccaagtcaaa 240
gagtttggag atgctggcca gtacacctgt cacaaaggag gcgaggttct aagccattcg 300
ctcctgctgc ttcacaaaaa ggaagatgga atttggtcca ctgatatttt aaaggaccag 360
aaagaaccca aaaataagac ctttctaaga tgcgaggcca agaattattc tggacgtttc 420
acctgctggt ggctgacgac aatcagtact gatttgacat tcagtgtcaa aagcagcaga 480
ggctcttctg acccccaagg ggtgacgtgc ggagctgcta cactctctgc agagagagtc 540
agaggggaca acaaggagta tgagtactca gtggagtgcc aggaggacag tgcctgccca 600
gctgctgagg agagtctgcc cattgaggtc atggtggatg ccgttcacaa gctcaagtat 660
gaaaactaca ccagcagctt cttcatcagg gacatcatca aacctgaccc acccaagaac 720
ttgcagctga agccattaaa gaattctcgg caggtggagg tcagctggga gtaccctgac 780
acctggagta ctccacattc ctacttctcc ctgacattct gcgttcaggt ccagggcaag 840
agcaagagag aaaagaaaga tagagtcttc acggacaaga cctcagccac ggtcatctgc 900
cgcaaaaatg ccagcattag cgtgcgggcc caggaccgct actatagctc atcttggagc 960
gaatgggcat ctgtgccctg cagtgttcct ggagtagggg tacctggggt gggcgccaga 1020
aacctccccg tggccactcc agacccagga atgttcccat gccttcacca ctcccaaaac 1080
ctgctgaggg ccgtcagcaa catgctccag aaggccagac aaactctaga attttaccct 1140
tgcacttctg aagagattga tcatgaagat atcacaaaag ataaaaccag cacagtggag 1200
gcctgtttac cattggaatt aaccaagaat gagagttgcc taaattccag agagacctct 1260
ttcataacta atgggagttg cctggcctcc agaaagacct cttttatgat ggccctgtgc 1320
cttagtagta tttatgaaga cttgaagatg taccaggtgg agttcaagac catgaatgca 1380
aagctgctga tggatcctaa gaggcagatc tttctagatc aaaacatgct ggcagttatt 1440
gatgagctga tgcaggccct gaatttcaac agtgagactg tgccacaaaa atcctccctt 1500
gaagaaccgg atttttataa aactaaaatc aagctctgca tacttcttca tgctttcaga 1560
attcgggcag tgactattga tagagtgatg agctatctga atgcttcc 1608
<210> 7
<211> 305
<212> PRT
<213> 人工序列
<220>
<223> ODD蛋白氨基酸序列
<400> 7
Val Asp Gln Gln Thr Glu Cys Val Leu Lys Pro Val Glu Ser Ser Asp
1 5 10 15
Met Lys Met Thr Gln Leu Phe Thr Lys Val Glu Ser Glu Asp Thr Ser
20 25 30
Ser Leu Phe Asp Lys Leu Lys Lys Glu Pro Asp Ala Leu Thr Leu Leu
35 40 45
Ala Pro Ala Ala Gly Asp Thr Ile Ile Ser Leu Asp Phe Gly Ser Asn
50 55 60
Asp Thr Glu Thr Asp Asp Gln Gln Leu Glu Glu Val Pro Leu Tyr Asn
65 70 75 80
Asp Val Met Leu Pro Ser Pro Asn Glu Lys Leu Gln Asn Ile Asn Leu
85 90 95
Ala Met Ser Pro Leu Pro Thr Ala Glu Thr Pro Lys Pro Leu Arg Ser
100 105 110
Ser Ala Asp Pro Ala Leu Asn Gln Glu Val Ala Leu Lys Leu Glu Pro
115 120 125
Asn Pro Glu Ser Leu Glu Leu Ser Phe Thr Met Pro Gln Ile Gln Asp
130 135 140
Gln Thr Pro Ser Pro Ser Asp Gly Ser Thr Arg Gln Ser Ser Pro Glu
145 150 155 160
Pro Asn Ser Pro Ser Glu Tyr Cys Phe Tyr Val Asp Ser Asp Met Val
165 170 175
Asn Glu Phe Lys Leu Glu Leu Val Glu Lys Leu Phe Ala Glu Asp Thr
180 185 190
Glu Ala Lys Asn Pro Phe Ser Thr Gln Asp Thr Asp Leu Asp Leu Glu
195 200 205
Met Leu Ala Pro Tyr Ile Pro Met Asp Asp Asp Phe Gln Leu Arg Ser
210 215 220
Phe Asp Gln Leu Ser Pro Leu Glu Ser Ser Ser Ala Ser Pro Glu Ser
225 230 235 240
Ala Ser Pro Gln Ser Thr Val Thr Val Phe Gln Gln Thr Gln Ile Gln
245 250 255
Glu Pro Thr Ala Asn Ala Thr Thr Thr Thr Ala Thr Thr Asp Glu Leu
260 265 270
Lys Thr Val Thr Lys Asp Arg Met Glu Asp Ile Lys Ile Leu Ile Ala
275 280 285
Ser Pro Ser Pro Thr His Ile His Lys Glu Thr Thr Ser Ala Thr Ser
290 295 300
Ser
305
<210> 8
<211> 915
<212> DNA
<213> 人工序列
<220>
<223> ODD蛋白的核苷酸序列
<400> 8
gtcgaccaac aaacagaatg tgtccttaaa ccggttgaat cttcagatat gaaaatgact 60
cagctattca ccaaagttga atcagaagat acaagtagcc tctttgacaa acttaagaag 120
gaacctgatg ctttaacttt gctggcccca gccgctggag acacaatcat atctttagat 180
tttggcagca acgacacaga aactgatgac cagcaacttg aggaagtacc attatataat 240
gatgtaatgc tcccctcacc caacgaaaaa ttacagaata taaatttggc aatgtctcca 300
ttacccaccg ctgaaacgcc aaagccactt cgaagtagtg ctgaccctgc actcaatcaa 360
gaagttgcat taaaattaga accaaatcca gagtcactgg aactttcttt taccatgccc 420
cagattcagg atcagacacc tagtccttcc gatggaagca ctagacaaag ttcacctgag 480
cctaatagtc ccagtgaata ttgtttttat gtggatagtg atatggtcaa tgaattcaag 540
ttggaattgg tagaaaaact ttttgctgaa gacacagaag caaagaaccc attttctact 600
caggacacag atttagactt ggagatgtta gctccctata tcccaatgga tgatgacttc 660
cagttacgtt ccttcgatca gttgtcacca ttagaaagca gttccgcaag ccctgaaagc 720
gcaagtcctc aaagcacagt tacagtattc cagcagactc aaatacaaga acctactgct 780
aatgccacca ctaccactgc caccactgat gaattaaaaa cagtgacaaa agaccgtatg 840
gaagacatta aaatattgat tgcatctcca tctcctaccc acatacataa agaaactact 900
agtgccacat catca 915
<210> 9
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 自剪切蛋白P2A氨基酸序列
<400> 9
Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn
1 5 10 15
Pro Gly Pro
<210> 10
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 自剪切蛋白P2A核苷酸序列
<400> 10
gccacgaact tctctctgtt aaagcaagca ggagatgttg aagaaaaccc cgggcct 57
Claims (15)
1.一种嵌合抗原受体(CAR),其包含(1)胞外抗原结合域;(2)跨膜域;和(3)胞内信号传导域,其特征在于,所述CAR还包含与所述胞内结构域连接并共表达的白介素12(IL12)与氧依赖性降解区域(ODD)的融合蛋白,任选地,所述胞内结构域与所述融合蛋白通过自剪切蛋白(例如选自由T2A、P2A、E2A、F2A、或其组合组成的组)连接。
2.根据权利要求1所述的CAR,其中所述跨膜域来源于选自由T细胞受体的α、β或ζ链、CD3ε、CD4、CD5、CD8、CD8α、CD9、CD16、CD22、CD28、CD33、CD37、CD45、CD80、CD86、CD134、CD137、CD152、CD154和ICOS组成的组中的一种或多种的跨膜结构域。
3.根据权利要求1所述的CAR,所述胞内信号转导域包含共刺激信号传导域且来自:CD2、CD3ζ、CD3γ、CD3δ、CD3ε、CD4、CD5、CD7、CD22、CD27、CD28、CD30、CD40、CD66d、CD79a、CD79b、CD83、CD134、CD137、ICOS、CD154、4-1BB和OX40、LFA-1、LIGHT、NKG2C和B7-H3中的一种或多种。
4.如权利要求1-3中任一项所述的CAR,还包含位于所述胞外抗原结合域的C-末端和所述跨膜域的N-末端之间的铰链域。
5.如权利要求4所述的CAR,其中所述铰链域来源于CD8α。
6.如权利要求1所述的CAR,其中胞外抗原结合域是能结合肿瘤细胞表面抗原(例如CD19,CD20、CD22、CD123、CD30、CD33、CD38、CD44、CD138、CD276、EGFR、BCMA,HER1、HER2、HER3、EpCAM、间皮素(mesothelin)、FAP(Fibroblast activation protein)、Glypican-3、CEA、PSMA、IL13Rα2、CD171、GD2、CEACAM6、CLDN4、CLDN18.2、NKGD2、LAMC2、CA9、CST1、EPPK1和ANO1中的一种或多种)的分子,例如抗体(Ig、Ig NAR、Fab片段、Fab’片段、F(ab)’2片段、F(ab)’3片段、Fv、scFv、双-scFv、(scFv)2、微型抗体、双链抗体、三链抗体、四链抗体、二硫键稳定的Fv蛋白以及单结构域抗体(sdAb,纳米抗体)、双特异性抗体或三特异性抗体)。
7.如权利要求1所述的CAR,其中所述IL12具有SEQ ID NO:5的氨基酸序列;所述ODD具有SEQ ID NO:7的氨基酸序列,优选地,所述CAR包含SEQ ID NO:1和SEQ ID NO:3所示的氨基酸序列。
8.如权利要求1所述的融合蛋白,其还包含标签序列(例如Poly-His、
Hemagglutinin、c-Myc、GST、Flag-tag等)或IgG1-Fc蛋白序列。
9.核苷酸,其编码权利要求1-8中任一项所述的CAR,优选地,所述核苷酸序列包含SEQID NO:2所示的核苷酸序列,或包含SEQ ID NO:2-SEQ ID NO:10-SEQ ID NO:4依次连接的核苷酸序列。
10.分离的CAR-T细胞或CAR-NK细胞或单核巨噬细胞,其特征在于,所述CAR-T细胞或CAR-NK细胞或单核巨噬细胞能够表达权利要求1-8中任一项所述的CAR;所述CAR-T细胞或CAR-NK细胞或单核巨噬细胞包含权利要求9中所述的多核苷酸。
11.载体,其包含根据权利要求9所述的多核苷酸。
12.如权利要求11所述的载体,其中所述载体是表达载体,例如病毒载体,优选为逆转录病毒载体或溶瘤病毒,例如慢病毒载体,优选为选自人免疫缺陷病毒1(HIV-1)、人免疫缺陷病毒2(HIV-2)、维斯纳-梅迪病毒(VMV)病毒、山羊关节炎-脑炎病毒(CAEV)、马传染性贫血病毒(EIAV)、猫免疫缺陷病毒(FIV)、牛免疫缺陷病毒(BIV)、猿猴免疫缺陷病毒(SIV)、腺病毒和痘病毒。
13.药物组合物,其包含权利要求1-8中任一项所述的嵌合抗原受体,包含如权利要求10所述的细胞,以及任选地,药学上可接受的载体。
14.制备权利要求10所述的细胞的方法,其包括将权利要求11或12的载体引入至T淋巴细胞或自然杀伤细胞或单核巨噬细胞。
15.权利要求1-8中任一项所述的细胞在制备治疗和/或预防癌症的药物中的用途,示例性地,所述癌症为骨髓瘤和白血病。
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