CN113166253A - 具有在CDR1区突变的人源化CD19 scFv的CAR-T细胞 - Google Patents
具有在CDR1区突变的人源化CD19 scFv的CAR-T细胞 Download PDFInfo
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Abstract
本发明涉及一种在CDR1中具有缬氨酸到甘氨酸突变的人源化CD19单链可变片段(scFv),其包含具有SEQ ID NO:6所示氨基酸序列的人源化VH和具有SEQ ID NO:5所示氨基酸序列的人源化VL。本发明还涉及CD19嵌合抗原受体融合蛋白,其从N末端到C末端包含:(i)本发明的单链可变片段(scFv),(ii)跨膜结构域,(iii)至少一个共刺激结构域,和(iv)激活结构域。对于体内和体外的CAR‑T细胞,这种人源化的CD19‑CAR‑T细胞分泌细胞因子IFN‑γ,具有特异性杀伤活性。
Description
技术领域
本发明涉及人源化CD19-CAR-T细胞,其包含的CD19 scFv在CD19 scFv VH CDR1区有突变(克隆11)。本发明的人源化CD19-CAR-T细胞特异性地降低白血病细胞的生长,并且可用于白血病和淋巴瘤患者的细胞治疗。
背景技术
免疫疗法正在成为一种非常有前景的癌症治疗方法。T细胞或T淋巴细胞是免疫系统的有效武器,它们能够持续性地搜寻正常细胞中的外来抗原或非正常细胞(如癌细胞或被感染细胞)。基因修饰的具有CAR(嵌合抗原受体)构建物的 T细胞是设计肿瘤特异性T细胞的最常见方案。靶向肿瘤相关抗原(TAA)的CAR- T细胞可以被输入患者(称为过继细胞转移或ACT),这代表了一种有效的免疫治疗方法[1,2]。与化疗或抗体技术相比,CAR-T技术的优点在于重编程的工程化T细胞可以在患者体内增殖并持续存在(“活的药物”)[1,3,4]。
通常,CAR包括位于N端的单克隆抗体衍生的单链可变片段(scFv)、铰链区、跨膜结构域和若干个胞内共刺激结构域((i)CD28、(i i)CD137(4-1BB)、 CD27或其他共刺激域),以及串联的CD3-zeta激活结构域(图1)[1,2]。CAR的发展从第一代(没有共刺激域)到第二代(具有一个共刺激域)到第三代CAR(具有多个共刺激域)。生成的具有两个共刺激结构域的CAR(即所谓的第三代CAR) 会使CAR-T细胞的细胞毒性增强,并改善CAR-T细胞的持续性,从而增强其抗肿瘤活性。CAR的结构如图1所示。左栏是第一代CAR(没有共刺激结构域)的结构,中间是第二代CAR(一个共刺激结构域CD28或者4-BB),右栏是第三代CAR(两个或多个共刺激结构域)。该图来自Golubovskayaa,Wu,癌症,2016[6]。
本领域需要一种改进的疗效改善且毒性降低的过继性T细胞免疫疗法。
具体实施方式
本发明的目的是提供具有突变的CD19 scFv的人源化CD19-CAR-T细胞。
在本发明的第一方面,提供了一种人源化CD19的单链可变片段(scFv),其包含具有SEQ ID NO:6所示氨基酸序列的VH和具有SEQ ID NO:5所示氨基酸序列的VL。
在另一优选例中,所述的scFv包含VH和VL之间的接头。
在另一优选例中,所述的scFv具有SEQ ID NO:7所示的氨基酸序列。
在另一优选例中,所述的scFv具有SEQ ID NO:4所示的氨基酸序列。
在本发明的第二方面,提供了一种嵌合抗原受体(CAR)融合蛋白:其从N末端到C末端包含:
(i)本发明第一方面所述的scFv,
(ii)跨膜结构域,
(iii)至少一个共刺激结构域,和
(iv)激活结构域。
在另一优选例中,所述的嵌合抗原受体融合蛋白具有下式I结构:
L-scFv-H-TM-C-CD3ζ (I)
式中,
各“-”独立地为连接肽或肽键;
L为任选的信号肽序列;
scFv为本发明第二方面所述的scFv;
H为任选的铰链区;
TM为跨膜结构域;
C为共刺激信号分子;
CD3ζ为源于CD3ζ的胞浆信号传导序列。
在另一优选例中,所述的L为选自下组蛋白的信号肽:CD8、GM-CSF、 CD4、CD137、或其组合。
在另一优选例中,所述的L为CD8来源的信号肽。
在另一优选例中,所述的H为选自下组蛋白的铰链区:CD8、CD28、 CD137、或其组合。
在另一优选例中,所述的H为CD8来源的铰链区。
在另一优选例中,所述的TM为选自下组的蛋白的跨膜区:CD28、CD3 epsilon、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、 CD80、CD86、CD134、CD137、CD154、或其组合。
在另一优选例中,所述的TM包括CD8来源的跨膜区,和/或CD28来源的跨膜区。
在另一优选例中,所述的C为选自下组的蛋白的共刺激信号分子:OX40、 CD2、CD7、CD27、CD28、CD30、CD40、CD70、CD134、4-1BB(CD137)、PD1、 Dap10、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、NKG2D、GITR、 TLR2、或其组合。
在另一优选例中,C包括4-1BB来源的共刺激信号分子,和/或CD28来源的共刺激信号分子。
在另一优选例中,所述的CAR融合蛋白具有SEQ ID NO:14所示的氨基酸序列。
在本发明的第三方面,提供了一种抗人CD19的抗体,其包含具有SEQ ID NO:6所示氨基酸序列的VH和具有SEQ ID NO:5所示氨基酸序列的VL。
在另一优选例中,所述抗体结合于人CD19蛋白。
在另一优选例中,所述的抗体选自:动物源抗体、嵌合抗体、人源化抗体、或其组合。
在另一优选例中,所述的抗体为双链抗体或单链抗体。
在另一优选例中,所述的抗体为单克隆抗体。
在本发明的第四方面,提供了一种重组蛋白,所述的重组蛋白具有:
(I)如本发明第一方面所述的scFv、或本发明第三方面所述的抗体;以及
(II)任选的协助表达和/或纯化的标签序列。
在另一优选例中,所述的标签序列包括6His标签。
在另一优选例中,所述的重组蛋白(或多肽)包括融合蛋白。
在另一优选例中,所述的重组蛋白为单体、二聚体、或多聚体。
本发明的第五方面,提供了一种抗体药物偶联物,所述的抗体药物偶联物含有:
(a)如本发明第一方面所述的scFv、或本发明第三方面所述的抗体;以及
(b)与所述抗体部分偶联的偶联部分,所述偶联部分选自下组:可检测标记物、药物、毒素、细胞因子、放射性核素、酶、或其组合。
在另一优选例中,所述的抗体部分与所述的偶联部分通过化学键或接头进行偶联。
在本发明的第六方面,提供了一种核酸分子,所述的核酸分子编码本发明第一方面所述的scFv、或本发明第二方面所述的CAR融合蛋白、或本发明第三方面所述的抗体。
在另一优选例中,所述核酸分子编码本发明第一方面所述的scFv,且具有SEQ IDNO.:1所示的编码VL的核酸序列和SEQ ID NO.:2所示的编码VH的核酸序列。
在本发明的第七方面,提供了一种载体,所述载体含有本发明第六方面所述的核酸分子。
在另一优选例中,所述的载体选自下组:DNA、RNA、质粒、慢病毒载体、腺病毒载体、逆转录病毒载体、转座子、或其组合。
在另一优选例中,所述载体为慢病毒载体。
在本发明的第八方面,提供了一种宿主细胞,所述的宿主细胞含有本发明的第七方面所述的载体、或染色体中整合有外源的本发明第六方面所述的核酸分子、或表达本发明第一方面所述的scFv、或表达本发明第二方面所述的CAR融合蛋白、或表达本发明第三方面所述的抗体。
在另一优选例中,所述细胞为分离的细胞,和/或所述细胞为基因工程化的细胞。
在另一优选例中,所述细胞为哺乳动物细胞。
在另一优选例中,所述细胞为T细胞。
在另一优选例中,所述的宿主细胞为工程化的免疫细胞。
在另一优选例中,所述的工程化的免疫细胞包括T细胞或NK细胞,较佳地为(i)嵌合抗原受体T细胞(CAR-T细胞);或(ii)嵌合抗原受体NK细胞(CAR- NK细胞)。
在本发明的第九方面,提供了一种制备工程化免疫细胞的方法,所述的工程化免疫细胞表达本发明第二方面所述的CAR融合蛋白,包括以下步骤:将本发明第六方面所述的核酸分子或本发明第七方面所述的载体转导入T细胞或NK细胞内,从而获得所述工程化免疫细胞。
在另一优选例中,所述的方法还包括对获得的工程化免疫细胞进行功能和有效性检测的步骤。
在本发明的第十方面,提供了一种制剂,所述制剂含有本发明第一方面所述的scFv、或本发明第二方面所述的CAR融合蛋白、或本发明第七方面所述的载体、或本发明第八方面所述的细胞,以及药学上可接受的载体、稀释剂或赋形剂。
在本发明的第十一方面,提供了一种用途,将本发明第一方面所述的 scFv、本发明第二方面的CAR融合蛋白、本发明第三方面所述的抗体、本发明第四方面所述的重组蛋白、或本发明第五方面所述的抗体药物偶联物、或本发明第八方面所述的细胞,用于制备预防和/或治疗癌症或肿瘤的药物或制剂。
在另一优选例中,所述肿瘤选自下组:血液肿瘤、实体瘤、或其组合。
在另一优选例中,所述血液肿瘤选自下组:急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性淋巴白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、或其组合。
在另一优选例中,所述实体瘤选自下组:胃癌、胃癌腹膜转移、肝癌、肾癌、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、宫颈癌、卵巢癌、淋巴癌、鼻咽癌、肾上腺肿瘤、膀胱肿瘤、非小细胞肺癌 (NSCLC)、脑胶质瘤、子宫内膜癌、睾丸癌、结直肠癌、尿路肿瘤、甲状腺癌、或其组合。
在另一优选例中,所述实体瘤选自下组:卵巢癌、间皮瘤、肺癌、胰腺癌、乳腺癌、肝癌、子宫内膜癌、或其组合。
在本发明的第十二方面,提供了一种用于制备本发明第八方面所述细胞的试剂盒,所述试剂盒含有容器,以及位于所述容器内的本发明第六方面所述的核酸分子、或本发明第七方面所述的载体。
在本发明的第十三方面,提供了一种如本发明第八方面所述细胞、或本发明第十方面所述的制剂的用途,用于预防和/或治疗癌症或肿瘤。
在本发明的第十四方面,提供了一种治疗疾病的方法,包括给需要治疗的对象施用适量的本发明第八方面所述的细胞、或本发明第十方面所述的制剂。
在另一优选例中,所述疾病为癌症或肿瘤。
应理解,在本发明范围内中,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,在此不再一一累述。
附图说明
图1显示了CAR的结构。
图2人源化CD19-CAR构建物的结构。
图3显示了在CDR1区有突变(V27G)的人源化CD19模型。
图4显示了FACS检测的人源化CD19-CAR构建物,用人源化FAB抗体和流式细胞仪进行。
图5显示了人源化CD19-CAR-T细胞杀伤Hela-CD19细胞,但不杀伤Hela细胞。
图6显示了人源化CD19-CAR-T细胞针对HeLa-CD19阳性细胞分泌IFN-γ。*, p<0.05,人源化CAR-T细胞与小鼠CD19-CAR-T细胞、T细胞和模拟CAR-T(Mock CAR-T)细胞相比,针对Hela-CD19细胞分泌的IFN-γ。
图7显示了人源化CD19-CAR-T细胞显著降低小鼠异种移植瘤的生长。
图8显示了人源化CD19-CAR-T细胞显著降低NSG小鼠体内Raji-荧光素酶异种移植瘤的总通量(成像信号)。P<0.05,CD19-CAR-T细胞与模拟(Mock)、1 ×PBS处理的小鼠。
图9显示了人源化CD19-CAR-T细胞显著延长Raji异种移植模型小鼠的存活时间。Kaplan-Meier生存曲线显示,与鼠源CD19-CAR-T细胞和模拟CAR-T细胞相比,VH CDR1区突变(V27G)的人源化CD19-CAR-T细胞显著延长小鼠的存活时间。以每只小鼠1×107个细胞,静脉注射CAR-T细胞。*p<0.05,hCD19-41BB-CD3 CAR-T细胞与模拟CAR-T细胞相比;**p<0.05,mCD19-41BB-CD3 CAR-T细胞与模拟CAR-T细胞相比。
图10显示了与用未突变的人源化CD19 CAR-T细胞处理的小鼠相比,在VH CDR1中具有V27G突变的人源化CD19 CAR延长小鼠的存活时间。
图11显示了小鼠体内注射后用人FAB检测的人源化CD19-CAR-T细胞。抗 FMC63兔抗体检测鼠源CD19-CAR-T细胞;人抗-(Fab'2)抗体检测人源化CD19- CAR-T细胞。
定义
如本文所用,“嵌合抗原受体(CAR)”是一种融合蛋白,其包含能够结合抗原的胞外结构域、与胞外结构域衍生自不同多肽的跨膜结构域,以及至少一个胞内结构域。“嵌合抗原受体(CAR)”有时也称为“嵌合受体”、“T-body”或“嵌合免疫受体(CIR)”。“能够结合抗原的胞外结构域”是指能够结合某一抗原的任何寡肽或多肽。“胞内结构域”是指已知的作为传递信号以激活或抑制细胞内生物过程的结构域起作用的任何寡肽或多肽。
“CDR”是抗体VH或VL链的互补决定区,其对与抗原的结合至关重要。
如本文所用,“人源化抗体”是来自非人种的抗体,其蛋白质序列被修饰以增加其与在人体内自然产生的抗体变体的相似性。
如本文所用,“结构域”是指多肽中独立于其它区域且折叠成特定结构的区域。
如本文所用,“单链可变区片段(scFv)”是指源自抗体的单链多肽,其保留了结合抗原的能力。scFv的实例包括通过重组DNA技术形成的抗体多肽,其中免疫球蛋白重链(H链)和轻链(L链)片段的Fv区经由间隔序列连接。工程化scFv的各种方法是本领域技术人员熟知的。
如本文所用,“肿瘤抗原”是指具有抗原性的生物分子,其表达导致癌症。
CD19
CD19是一种B细胞型淋巴细胞抗原,在所有的B细胞恶性肿瘤中均有表达,包括急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)和非霍奇金淋巴瘤。这种在白血病和淋巴瘤中的普遍表达使得该抗原成为CAR-T细胞靶向的诱人靶点[3]。
CD19结构与信号传导
人CD19蛋白是一种95kDa的跨膜糖蛋白,由556个氨基酸组成:20-291位为胞外结构域;292-313位为跨膜结构域;314-556位为胞浆结构域,如下所示(胞外结构域用下划线标记)。它属于免疫球蛋白超家族蛋白,介导B细胞受体(BCR) 依赖的和非依赖的信号转导。CD19与BCR和其它细胞表面蛋白结合,通过结合其它激酶和结合配体来调节细胞内信号传导。CD19信号与Src家族激酶、PI3K激酶、 Abl、AKT依赖的信号通路有关。CD19是B细胞介导生存信号传导和免疫应答的生物标志物。
本发明的突变的CD19 scFv
本发明人产生了包含VH CDR区突变(V27G)的人源化CD19 scFv,并基于该包含突变的人源化CD19 scFv序列产生了特异性靶向CD19的CAR-T细胞。本发明人制备了人源化CD19-CAR-T细胞以靶向过表达CD19抗原的癌细胞。本发明的人源化CD19-CAR-T细胞针对白血病癌细胞分泌高水平IFN-γ并杀伤HeLa-CD19阳性靶细胞,但不杀伤对照Hela细胞。
本发明涉及来源小鼠克隆FMC63的人源化抗人CD19抗体,其包含具有SEQ ID NO:6所示氨基酸序列的人源化VH和具有SEQ ID NO:5所示氨基酸序列的人源化 VL。在一种实施方式中,人源化抗人CD19抗体是单链可变片段(scFv)。
本发明还涉及嵌合抗原受体融合蛋白,其从N末端到C末端包含:(i)抗CD19 的单链可变片段(scFv)(本发明)、(ii)跨膜结构域、(iii)至少一个共刺激结构域,和(iv)激活结构域。
图2显示了人源化CD19 CAR构建物的结构。显示了在VH的CDR1区含有突变 V27G的人源化CD19 scFv(克隆11)。采用了第二代CD19-CAR。
本发明人制备了在CD19 scFv的CDR1区具有突变V27G的人源化CD19-scFv,并将该人源化CD19-scFv用于CAR的制备,以产生针对白血病细胞的CD19-41BB- CD3-CAR-T(hCD19-CAR-T)细胞。本发明的人源化CD19-CAR-T细胞分泌高水平的 IFN-γ,在与Hela-CD19细胞的细胞毒性试验中呈阳性,但与Hela细胞不呈阳性,这表明CAR-T细胞对CD19过表达的靶癌细胞具有特异性杀伤活性。
本发明的人源化CD19-scFv与小鼠CD19-scFv相比的优点包括:由于人源化 CD19scFv的对人的较低的免疫原性。因此,人源化CD19-CAR-T细胞在许多临床应用中作为治疗剂是有利的。
与未突变的人源化CD19-scFv相比,本发明在VH CDR1中包含突变(VH中的 V27G)的人源化CD19-scFv的优点包括:延长用突变的人源化CD19-CAR T细胞治疗的小鼠的存活时间。
本发明的人源化CD19 scFv可用于免疫治疗应用:毒素/药物偶联抗体、单克隆治疗抗体和CAR-T细胞免疫治疗。
使用本发明的人源化CD19 scFv的人源化CD19-CAR-T细胞有效地靶向CD19 阳性癌细胞系中的CD19抗原。
人源化CD19-CAR-T细胞可与不同的化疗联合使用:检查点抑制剂、靶向疗法、小分子抑制剂和抗体。
人源化CD19-CAR-T细胞可用于CD19阳性癌细胞的临床应用。
共刺激结构域的修饰:CD28、4-1BB等可用于增加其疗效。偶联标签的人源化CD19scFv可用于CAR的产生。
人源化CD19-CAR-T细胞可以与不同的安全开关一起使用:t-EGFR、RQR(利妥昔单抗-CD34-利妥昔单抗)、诱导型半胱天冬酶9(caspase-9)等。
第三代CAR-T或其他共刺激信号转导结构域可用于CAR内的相同人源化 CD19-scFv。
人源化CD19 CAR可与靶向其它肿瘤抗原或肿瘤微环境的CAR组合,例如 VEGFR-1-3、PDL-1,还可以制备靶向CD19和CD3或其它抗原的双特异性抗体用于治疗。
人源化的CD19-CAR-T细胞可用于对抗癌症干细胞或肿瘤起始细胞,二者对化疗最具抗性并可形成侵袭性肿瘤。
载体
本发明还提供了编码本发明CAR序列的DNA构建物。
编码期望分子的核酸序列可利用在本领域中已知的重组方法获得,诸如例如通过从表达基因的细胞中筛选文库,通过从已知包括该基因的载体中得到该基因,或通过利用标准的技术,从包含该基因的细胞和组织中直接分离。可选地,感兴趣的基因可被合成生产。
本发明也提供了其中插入本发明的表达盒的载体。源于逆转录病毒诸如慢病毒的载体是实现长期基因转移的合适工具,因为它们允许转基因长期、稳定的整合并且其在子细胞中增殖。慢病毒载体具有超过源自致癌逆转录病毒诸如鼠科白血病病毒的载体的优点,因为它们可转导非增殖的细胞,诸如肝细胞。它们也具有低免疫原性的优点。
简单概括,通常可操作地连接本发明的表达盒或核酸序列至启动子,并将其并入表达载体。该载体适合于复制和整合真核细胞。典型的克隆载体包含可用于调节期望核酸序列表达的转录和翻译终止子、初始序列和启动子。
本发明的表达构建体也可利用标准的基因传递方案,用于核酸免疫和基因疗法。基因传递的方法在本领域中是已知的。见例如美国专利号5,399,346、 5,580,859、5,589,466,在此通过引用全文并入。在另一个实施方式中,本发明提供了基因疗法载体。
该核酸可被克隆入许多类型的载体。例如,该核酸可被克隆入如此载体,其包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。特定的感兴趣载体包括表达载体、复制载体、探针产生载体和测序载体。
进一步地,表达载体可以以病毒载体形式提供给细胞。病毒载体技术在本领域中是公知的并在例如Sambrook等(2001,分子克隆:实验室手册,冷泉港实验室,纽约)和其他病毒学和分子生物学手册中进行了描述。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺伴随病毒、疱疹病毒和慢病毒。通常,合适的载体包含在至少一种有机体中起作用的复制起点、启动子序列、方便的限制酶位点和一个或多个可选择的标记(例如,WO01/96584;WO01/29058;和美国专利号6,326,193)。
已经开发许多基于病毒的系统,用于将基因转移入哺乳动物细胞。例如,逆转录病毒提供了用于基因传递系统的方便的平台。可利用在本领域中已知的技术将选择的基因插入载体并包装入逆转录病毒颗粒。该重组病毒可随后被分离和传递至体内或离体的对象细胞。许多逆转录病毒系统在本领域中是已知的。在一些实施方式中,使用腺病毒载体。许多腺病毒载体在本领域中是已知的。在一个实施方式中,使用慢病毒载体。
额外的启动子元件,例如增强子,可以调节转录开始的频率。通常地,这些位于起始位点上游的30-110bp区域中,尽管最近已经显示许多启动子也包含起始位点下游的功能元件。启动子元件之间的间隔经常是柔性的,以便当元件相对于另一个被倒置或移动时,保持启动子功能。在胸苷激酶(tk)启动子中,启动子元件之间的间隔可被增加隔开50bp,活性才开始下降。取决于启动子,表现出单个元件可合作或独立地起作用,以起动转录。
合适的启动子的一个例子为即时早期巨细胞病毒(CMV)启动子序列。该启动子序列为能够驱动可操作地连接至其上的任何多核苷酸序列高水平表达的强组成型启动子序列。合适的启动子的另一个例子为延伸生长因子-1α(EF- 1α)。然而,也可使用其他组成型启动子序列,包括但不限于类人猿病毒 40(SV40)早期启动子、小鼠乳癌病毒(MMTV)、人免疫缺陷病毒(HIV)长末端重复 (LTR)启动子、MoMuLV启动子、鸟类白血病病毒启动子、艾伯斯坦-巴尔 (Epstein-Barr)病毒即时早期启动子、鲁斯氏肉瘤病毒启动子、以及人基因启动子,诸如但不限于肌动蛋白启动子、肌球蛋白启动子、血红素启动子和肌酸激酶启动子。进一步地,本发明不应被限于组成型启动子的应用。诱导型启动子也被考虑为本发明的一部分。诱导型启动子的使用提供了分子开关,其能够当这样的表达是期望的时,打开可操作地连接诱导型启动子的多核苷酸序列的表达,或当表达是不期望的时关闭表达。诱导型启动子的例子包括但不限于金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
为了评估CAR多肽或其部分的表达,被引入细胞的表达载体也可包含可选择的标记基因或报道基因中的任一个或两者,以便于从通过病毒载体寻求被转染或感染的细胞群中鉴定和选择表达细胞。在其他方面,可选择的标记可被携带在单独一段DNA上并用于共转染程序。可选择的标记和报道基因两者的侧翼都可具有适当的调节序列,以便能够在宿主细胞中表达。有用的可选择标记包括例如抗生素抗性基因,诸如neo等等。
报道基因用于鉴定潜在转染的细胞并用于评价调节序列的功能性。通常地,报道基因为以下基因:其不存在于受体有机体或组织或由受体有机体或组织进行表达,并且其编码多肽,该多肽的表达由一些可容易检测的性质例如酶活性清楚表示。在DNA已经被引入受体细胞后,报道基因的表达在合适的时间下进行测定。合适的报道基因可包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌型碱性磷酸酶或绿色萤光蛋白的基因(例如,Ui-Tei等,2000FEBS Letters479:79-82)。合适的表达系统是公知的并可利用已知技术制备或从商业上获得。通常,显示最高水平的报道基因表达的具有最少5个侧翼区的构建体被鉴定为启动子。这样的启动子区可被连接至报道基因并用于评价试剂调节启动子-驱动转录的能力。
将基因引入细胞和将基因表达入细胞的方法在本领域中是已知的。在表达载体的内容中,载体可通过在本领域中的任何方法容易地引入宿主细胞,例如,哺乳动物、细菌、酵母或昆虫细胞。例如,表达载体可通过物理、化学或生物学手段转移入宿主细胞。
将多核苷酸引入宿主细胞的物理方法包括磷酸钙沉淀、脂质转染法、粒子轰击、微注射、电穿孔等等。生产包括载体和/或外源核酸的细胞的方法在本领域中是公知的。见例如Sambrook等(2001,Molecular Cloning:A Laboratory Manual,Cold Spring HarborLaboratory,New York)。将多核苷酸引入宿主细胞的优选方法为磷酸钙转染。
将感兴趣的多核苷酸引入宿主细胞的生物学方法包括使用DNA和RNA载体。病毒载体,特别是逆转录病毒载体,已经成为最广泛使用的将基因插入哺乳动物例如人细胞的方法。其他病毒载体可源自慢病毒、痘病毒、单纯疱疹病毒I、腺病毒和腺伴随病毒等等。见例如美国专利号5,350,674和5,585,362。
将多核苷酸引入宿主细胞的化学手段包括胶体分散系统,诸如大分子复合物、纳米胶囊、微球、珠;和基于脂质的系统,包括水包油乳剂、胶束、混合胶束和脂质体。用作体外和体内传递工具(delivery vehicle)的示例性胶体系统为脂质体(例如,人造膜囊)。
在使用非病毒传递系统的情况下,示例性传递工具为脂质体。考虑使用脂质制剂,以将核酸引入宿主细胞(体外、离体(ex vivo)或体内)。在另一方面,该核酸可与脂质相关联。与脂质相关联的核酸可被封装入脂质体的水性内部中,散布在脂质体的脂双层内,经与脂质体和寡核苷酸两者都相关联的连接分子附接至脂质体,陷入脂质体,与脂质体复合,分散在包含脂质的溶液中,与脂质混合,与脂质联合,作为悬浮液包含在脂质中,包含在胶束中或与胶束复合,或以其他方式与脂质相关联。与组合物相关联的脂质、脂质/DNA或脂质/表达载体不限于溶液中的任何具体结构。例如,它们可存在于双分子层结构中,作为胶束或具有“坍缩的(collapsed)”结构。它们也可简单地被散布在溶液中,可能形成大小或形状不均一的聚集体。脂质为脂肪物质,其可为天然发生或合成的脂质。例如,脂质包括脂肪小滴,其天然发生在细胞质以及包含长链脂肪族烃和它们的衍生物诸如脂肪酸、醇类、胺类、氨基醇类和醛类的该类化合物中。
在使用非病毒递送系统的情况下,示例性地使用基因组编辑技术来完成本发明,例如CRISPR-Cas9、ZFN或TALEN。
在本发明的一个优选地实施方式中,所述载体为慢病毒载体。
DNA构建物进一步包含信号肽编码序列。优选地,该信号肽序列连接在抗原结合结构域的核酸序列上游。
治疗性应用
本发明包括用编码本发明表达盒的慢病毒载体(LV)转导的细胞。转导的T 细胞可以诱导CAR介导的T细胞反应。
因此,本发明也提供了刺激对哺乳动物的靶细胞群或组织的T细胞-介导的免疫应答的方法,其包括以下步骤:给哺乳动物施用本发明的CAR-T细胞。
在一个实施方式中,本发明包括一类细胞疗法,其中T细胞经基因修饰以表达本发明的CAR,并且将CAR-T细胞输注给需要的受体。输注的细胞能够杀死受体体内的肿瘤细胞。与抗体疗法不同,CAR-T细胞能够体内复制,产生可导致持续肿瘤控制的长期持久性。
在一个实施方式中,本发明的CAR-T细胞可经历稳固的体内T细胞扩展并可持续延长的时间量。另外,CAR介导的免疫应答可为过继免疫疗法步骤的一部分,其中CAR-修饰T细胞诱导对CAR中的抗原结合结构域特异性的免疫应答。例如,抗CD19的CAR-T细胞引起抗CD19阳性的细胞的特异性免疫应答。
尽管本文公开的数据具体公开了包括抗CD19 scFv、铰链和跨膜区、和4- 1BB和CD3ζ信号传导结构域的慢病毒载体,但本发明应被解释为包括对构建体组成部分中的每一个的任何数量的变化。
可被治疗的适应疾病包括CD19阳性肿瘤和B细胞过多引起的疾病。CD19阳性肿瘤可以包括CD19阳性非实体肿瘤(诸如血液学肿瘤,例如白血病和淋巴瘤) 或实体瘤。用本发明的CAR治疗的癌症类型包括但不限于癌、胚细胞瘤和肉瘤,和某些白血病或淋巴恶性肿瘤、良性和恶性肿瘤、和恶性瘤,例如肉瘤、癌和黑素瘤。也包括成人肿瘤/癌症和儿童肿瘤/癌症。
血液学癌症为血液或骨髓的癌症。血液学(或血原性)癌症的例子包括白血病,包括急性白血病(诸如急性淋巴细胞白血病、急性髓细胞白血病、急性骨髓性白血病和成髓细胞性、前髓细胞性、粒-单核细胞型、单核细胞性和红白血病)、慢性白血病(诸如慢性髓细胞(粒细胞性)白血病、慢性骨髓性白血病和慢性淋巴细胞白血病)、真性红细胞增多症、淋巴瘤、霍奇金氏疾病、非霍奇金氏淋巴瘤(无痛和高等级形式)、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症、重链疾病、骨髓增生异常综合征、多毛细胞白血病和脊髓发育不良。
实体瘤为通常不包含囊肿或液体区的组织的异常肿块。实体瘤可为良性或恶性的。不同类型的实体瘤以形成它们的细胞类型命名(诸如肉瘤、癌和淋巴瘤)。实体瘤诸如肉瘤和癌的例子包括纤维肉瘤、粘液肉瘤、脂肪肉瘤间皮瘤、淋巴恶性肿瘤、胰腺癌卵巢癌、。
本发明的CAR-修饰T细胞也可用作对哺乳动物离体免疫和/或体内疗法的疫苗类型。优选地,哺乳动物为人。
对于离体免疫,以下中的至少一项在将细胞施用进入哺乳动物前在体外发生:i)扩增细胞,ii)将编码CAR的核酸引入细胞,和/或iii)冷冻保存细胞。
离体程序在本领域中是公知的,并在以下更完全地进行讨论。简单地说,细胞从哺乳动物(优选人)中分离并用表达本文公开的CAR的载体进行基因修饰 (即,体外转导或转染)。CAR-修饰的细胞可被施用给哺乳动物接受者,以提供治疗益处。哺乳动物接受者可为人,和CAR-修饰的细胞可相对于接受者为自体的。可选地,细胞可相对于接受者为同种异基因的、同基因的(syngeneic)或异种的。
除了就离体免疫而言使用基于细胞的疫苗之外,本发明也提供了体内免疫以引起针对患者中抗原的免疫应答的组合物和方法。
通常,如本文所述的激活和扩增的细胞可用于治疗和预防在免疫受损的个体中产生的疾病。特别地,本发明的CAR修饰的T细胞用于CCL的治疗。在某些实施方案中,本发明的细胞用于治疗有患CCL风险的患者。因此,本发明提供治疗或预防CCL的方法,包括向需要的受试者施用治疗有效量的本发明的CAR修饰的 T细胞。
本发明的CAR-修饰的T细胞可被单独施用或作为药物组合物与稀释剂和/ 或与其他组分诸如IL-2、IL-17或其他细胞因子或细胞群结合施用。简单地说,本发明的药物组合物可包括如本文所述的靶细胞群,与一种或多种药学或生理学上可接受载体、稀释剂或赋形剂结合。这样的组合物可包括缓冲液诸如中性缓冲盐水、硫酸盐缓冲盐水等等;碳水化合物诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸诸如甘氨酸;抗氧化剂;螯合剂诸如EDTA 或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。本发明的组合物优选配制用于静脉内施用。
本发明的药物组合物可以以适于待治疗(或预防)的疾病的方式施用。施用的数量和频率将由这样的因素确定,如患者的病症、和患者疾病的类型和严重度——尽管适当的剂量可由临床试验确定。
当指出“免疫学上有效量”、“抗肿瘤有效量”、“肿瘤-抑制有效量”或“治疗量”时,待施用的本发明组合物的精确量可由医师确定,其考虑患者(对象)的年龄、重量、肿瘤大小、感染或转移程度和病症的个体差异。可通常指出:包括本文描述的T细胞的药物组合物可以以104至109个细胞/kg体重的剂量,优选105至106个细胞/kg体重的剂量(包括那些范围内的所有整数值)施用。T细胞组合物也可以以这些剂量多次施用。细胞可通过使用免疫疗法中公知的注入技术(见例如Rosenberg等,NewEng.J.of Med.319:1676,1988)施用。对于具体患者的最佳剂量和治疗方案可通过监测患者的疾病迹象并因此调节治疗由医学领域技术人员容易地确定。
对象组合物的施用可以以任何方便的方式进行,包括通过喷雾法、注射、吞咽、输液、植入或移植。本文描述的组合物可被皮下、皮内、瘤内、结内、脊髓内、肌肉内、通过静脉内(i.v.)注射或腹膜内施用给患者。在一个实施方式中,本发明的T细胞组合物通过皮内或皮下注射被施用给患者。在另一个实施方式中,本发明的T细胞组合物优选通过i.v.注射施用。T细胞的组合物可被直接注入肿瘤,淋巴结或感染位置。
在本发明的某些实施方式中,利用本文描述的方法或本领域已知的其他将 T细胞扩展至治疗性水平的方法活化和扩展的细胞,与任何数量的有关治疗形式结合(例如,之前、同时或之后)施用给患者,所述治疗形式包括但不限于用以下试剂进行治疗:所述试剂诸如抗病毒疗法、西多福韦和白细胞介素-2、阿糖胞苷(也已知为ARA-C)或对MS患者的那他珠单抗治疗或对牛皮癣患者的厄法珠单抗治疗或对PML患者的其他治疗。在进一步的实施方式中,本发明的T细胞可与以下结合使用:化疗、辐射、免疫抑制剂,诸如,环孢菌素、硫唑嘌呤、甲氨喋呤、麦考酚酯和FK506,抗体或其他免疫治疗剂。在进一步的实施方式中,本发明的细胞组合物与骨髓移植、利用化疗剂诸如氟达拉滨、外部光束放射疗法(XRT)、环磷酰胺结合(例如,之前、同时或之后)而施用给患者。例如,在一个实施方式中,对象可经历高剂量化疗的标准治疗,之后进行外周血干细胞移植。在一些实施方式中,在移植后,对象接受本发明的扩展的免疫细胞的注入。在一个额外的实施方式中,扩展的细胞在外科手术前或外科手术后施用。
施用给患者的以上治疗的剂量将随着治疗病症的精确属性和治疗的接受者而变化。人施用的剂量比例可根据本领域接受的实践实施。通常,每次治疗或每个疗程,可将1×106个至1×1010个本发明经修饰的T细胞(如,CAR-T 19细胞),通过例如静脉回输的方式,施用于患者。
以下实施例进一步说明本发明。下述实施例只是为了说明本发明,而不应被解释为是限制性的。
实施例
发明人将人源化CD19-scFv-CAR构建物克隆至慢病毒载体的Xba I和EcoR I 位点中。pCD510-FMC63-28z慢病毒CAR构建物,其在Xba I和Eco RI克隆位点之间包含人源化CD19 scFv-41BB-CD3zeta插入物。
在293T细胞中产生慢病毒,用RT-PCR方法测定滴度。随后,用等剂量的慢病毒转导T细胞。
实施例1人源化CD19抗体:VH和VL及scFv序列
发明人对来自小鼠CD19 FMC63 scFv克隆的CD19 scFv进行人源化,并基于体内疗效数据选择了在CDR1中具有突变的人源化scFv(克隆11)。人源化CD19 scFv的结构为:VL-连接肽-VH。连接肽为G S T S G S G K P G S G E G S T K G(SEQ ID NO:7)。
用粗体突出显示了人源化CD19 VL的核苷酸序列(SEQ ID NO:1);常规字体突出显示了VH的核苷酸序列(SEQ ID NO:2,粗体标记突变(ggc)编码G);中间(斜体,较小字体)是编码连接肽(G S T S G S G K P G S G E G S T K G(SEQ ID NO:7))的核苷酸序列(SEQID NO:3)
人源化CD19 scFv(SEQ ID NO:4):粗体VL,常规字体VH,CDR区用下划线标记,突变位于VH的第27位氨基酸(SEQ ID NO:6),显示为较大斜体G(VH的 V27G),
蛋白中,粗体突出显示了VL的氨基酸序列(SEQ ID NO:5);常规非斜体突出显示了VH的氨基序列(SEQ ID NO:6);之间的斜体化的较小字体是连接肽的氨基酸序列(SEQ IDNO:7)。
通过三维建模和结合实验,发明人发现,人源化CD19抗体中的VH CDR1区突变可改善抗体与CD19抗原的结合。图3显示了克隆11的突变,VH CDR1 V27G。
实施例2人源化CD19-CAR序列
人源化CD19-CAR构建物的设计方案如图2所示。利用带有EF1a启动子的慢病毒载体克隆人源化scFv CAR序列。
以下核苷酸序列显示了本发明的CD8前导-人源化CD19 scFv-CD8铰链-TM8-41BB-CD3 zeta。CAR结构包括人CD8信号肽、人源化CD19 scFv(VL-连接肽-VH)、 CD8铰链、CD8跨膜、41BB共刺激和CD3 zeta激活结构域(图2)。
CD8前导序列-CD19 scFv(VL-连接肽-VH)-CD8铰链-CD8 TM-41BB-CD3 Zeta:
<CD8前导>
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCG (SEQID NO:8)
<人源化CD19(VL-连接肽-VH),克隆11scFv>(编码V27G的突变ggc以粗体显示)
<CD8铰链>
ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCC CTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCT GTGAT(SEQ IDNO:9)
<CD8 TM>
ATCTACATCTGGGCGCCCCTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGC(SEQ ID NO:10)
<4-1BB共刺激结构域>
AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACT ACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG(SEQ ID NO:11)
<CD3 zeta>
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTAT AACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTG AGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAA GATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGC CTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCC CTCGCTAATAG(SEQ ID NO:12)
<EcoRI限制酶切位点>
gaattc(SEQ ID NO:13)
翻译的人源化CD19-4-1BB-CD3-CAR蛋白的氨基酸序列(构建物结构见图3),VHCDR1突变以粗体下划线显示:
实施例3人源化CD19-CAR-T细胞杀伤白血病细胞并针对CD19阳性癌细胞分泌IFN-γ
我们用人源化CD19-CAR构建物设计人源化CD19-CAR-T细胞,如图2所示。我们用模拟scFv(无关scFv)产生模拟CAR-T细胞,作为阴性对照。用FACS检测人源化CD19-CAR-T细胞表达的CD19 scFv。
结果如图4所示。用人FAB抗体对人源化CD19-CAR构建物进行FACS检测。人源化CD19-CAR慢病毒转导至T细胞后,对人源化CD19-CAR阳性细胞进行检测。 CD3Z显示CD3zeta激活结构域。
实施例4人源化CD19-CAR-T细胞杀伤Hela-CD19细胞但不杀伤Hela细胞
我们将本发明的人源化效应CD19-CAR-T细胞与靶Hela-CD19靶细胞以及 Hela(CD19-阴性)对照细胞孵育,并进行实时细胞毒性测定(RTCA,如[4]所述)。
结果如图5所示。人源化CD19-CAR-T细胞特异性地杀伤Hela-CD19细胞,与 T细胞和模拟CAR-T细胞相比,CAR-T细胞处理的靶细胞数(细胞指数)显著减少 (图5,上栏)。人源化CD19-CAR-T细胞不杀伤CD19阴性Hela细胞,T细胞、模拟和CAR-T细胞在杀伤CD19阴性Hela细胞方面没有显著差异(图5,下栏)。这表明人源化CD19-CAR-T细胞对CD19抗原的靶向具有高特异性,仅杀伤CD19阳性细胞而不杀伤CD19阴性Hela细胞(图5)。
利用xCELLigence实时细胞毒性分析检测人源化CD19-CAR-T和鼠源CD19- 41BB-CD3 CAR-T细胞的细胞毒性,如[4]所述。Y轴显示了归一化细胞指数,X轴显示了以小时为单位的时间。右侧自上而下表示,仅靶细胞;随后是加入靶细胞的以下效应细胞:T细胞;模拟CAR-T细胞;鼠源CD19-CAR-T细胞;人源化CD19 CAR-T细胞。
实施例5人源化CD19 CAR-T细胞针对靶Hela-CD19细胞分泌IFN-γ
我们收集了人源化CD19-CAR-T细胞和靶Hela-CD19共孵育后的上清液,并进行IFN-γ测定,如[5]所述。
结果如图6所示。人源化CD19-CAR-T细胞针对Hela-CD19分泌的IFN-γ明显高于T细胞和模拟CAR-T细胞。人源化CD19-CAR-T细胞分泌IFN-γ水平显著高于鼠源CD19-CAR-T细胞(P<0.05),提示人源化CD19-CAR-T细胞对抗CD19阳性靶细胞的活性更高。
实施例6人源化CD19-CAR-T细胞抑制Raji异种移植瘤的体内生长
我们将Raji-荧光素酶阳性细胞静脉注射到NSG小鼠中,然后第二天注射1 ×107个人源化CD19-CAR-T细胞,如[4]所述。我们使用IVIS系统通过成像检测 Raji异种移植瘤细胞的生长情况。
结果如图7所示。与对照、未处理和模拟CAR-T细胞相比,人源化CD19-CAR- T细胞显著降低Raji异种移植瘤的生长。人源化CAR-T细胞比鼠源CD19-CAR-T细胞对Raji肿瘤生长的抑制更明显。
第14天成像的量化结果如图8所示,其显示鼠源和人源化CD19-CAR-T细胞均显著降低成像信号(以光子/秒为单位的总通量)。
实施例7相比于CD19-CAR-T细胞处理的小鼠,人源化CD19-CAR-T细胞显著延长Raji异种移植模型小鼠的存活时间
Kaplan-Meier生存曲线显示,与鼠源CD19-CAR-T细胞或对照模拟CAR-T细胞相比,向小鼠注射人源化CD19-CAR-T细胞后,小鼠的生存时间显著增加(图 9)。这表明与鼠源CD19-CAR-T细胞相比,人源化CD19-CAR-T细胞具有优势和提高的疗效。
实施例8与用未突变的人源化CD19 CAR-T细胞处理的小鼠相比,在VH CDR1中具有V27G突变的人源化CD19 CAR延长小鼠的存活时间
我们比较了VH CDR1中具有V27G突变(克隆11)的人源化CD19-CAR和没有突变的人源化CD19-CAR。图10所示的“无突变huCD19”是来自小鼠克隆FMC63的人源化抗体,在CDR区无突变。“无突变huCD19”与克隆11具有相同的VL序列,但 VH的框架区不同。一般来说,抗原结合活性受CDR区的影响,而不受框架区的影响。
图10中的结果显示,用VH中具有V27G突变的人源化CD19-CAR治疗的小鼠比用没有突变的人源化CD19-CAR-T细胞治疗的小鼠的存活时间延长。
实施例9小鼠体内注射CD19-CAR-T细胞后,用CD19或FAB抗体以及FACS进行检测
在向具有Raji异种移植瘤细胞的小鼠注射CAR-T细胞后的第7天收集小鼠血液以检测体内的CAR-T细胞。
结果如图11所示。在7天后,用兔抗-FMC63 scFv抗体(Promab)检测鼠源 CD19-CAR-T细胞,或用人FAB检测人源化CD19-CAR-T细胞,均容易在小鼠体内检测到CD19-CAR-T细胞。这表明CAR-T细胞在体内持续存在,这与Raji异种移植瘤的生长被显著抑制相一致。
参考文献
1.Maus,M.V.;Haas,A.R.;Beatty,G.L.;Albelda,S.M.;Levine, B.L.;Liu,X.;Zhao,Y.;Kalos,M.;June,C.H.表达嵌合抗原受体的T细胞可以引起人类过敏反应.CancerImmunol Res 2013,1,26-31.
2.Maus,M.V.;Grupp,S.A.;Porter,D.L.;June,C.H.抗体修饰的T 细胞:CAR在血液系统恶性肿瘤的占首要位置.血液2014,123,2625-2635.
3.Eshhar,Z.;Waks,T.;Gross,G.T-体/CAR T细胞的出现.Cancer J 2014,20,123-126.
4.Berahovich,R.;Xu,S.;Zhou,H.;Harto,H.;Xu,Q.;Garcia, A.;Liu,F.;Golubovskaya,V.M.;Wu,L.Flag标记的CD19特异性的CAR-T 细胞可以在体内和体外清除携带CD19的实体肿瘤细胞.Front Biosci (Landmark Ed)2017,22,1644-1654.
5.Golubovskaya,V.;Berahovich,R.;Zhou,H.;Xu,S.;Harto,H.; Li,L.;Chao,C.C.;Mao,M.M.;Wu,L.CD47-CAR-T细胞有效杀伤靶癌细胞并阻断胰腺肿瘤的生长.癌症(Basel)2017,9.
序列表
<110> 浙江瑞加美生物科技有限公司
<120> 具有在CDR1区突变的人源化CD19 scFv的CAR-T细胞
<130> P2021-1080
<150> US62/773,112
<151> 2018-11-29
<160> 16
<170> PatentIn version 3.5
<210> 1
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD19 VL
<400> 1
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgcc gcgcgagcca ggatattagc aaatatctga actggtatca gcagaaaccg 120
ggcaaagcgc cgaaactgct gatttatcat accagccgcc tgcatagcgg cgtgccgagc 180
cgctttagcg gcagcggcag cggcaccgat tttaccctga ccattagcag cctgcagccg 240
gaagattttg cgacctatta ttgccagcag ggcaacaccc tgccgtatac ctttggcggc 300
ggcaccaaag tggaaattaa a 321
<210> 2
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD19 VH
<400> 2
caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60
acctgcaccg tgagcggcgg cagcctgccg gattatggcg tgagctggat tcgccagccg 120
ccgggcaaag gcctggaatg gattggcgtg atttggggca gcgaaaccac ctattataac 180
agcgcgctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240
aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgaa acattattat 300
tatggcggca gctatgcgat ggattattgg ggccagggca ccctggtgac cgtgagcagc 360
<210> 3
<211> 54
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 3
ggctccacct ctggatccgg caagcccgga tctggcgagg gatccaccaa gggc 54
<210> 4
<211> 245
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CD19 scFv
<400> 4
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1 5 10 15
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Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
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Leu Thr Cys Thr Val Ser Gly Gly Ser Leu Pro Asp Tyr Gly Val Ser
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Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile
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Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Val
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Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser
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Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Tyr
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Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
225 230 235 240
Val Thr Val Ser Ser
245
<210> 5
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CD19 VL
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
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Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
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<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
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<213> 人工序列(Artificial Sequence)
<220>
<223> CD8前导
<400> 8
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 9
<211> 135
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD8铰链
<400> 9
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 10
<211> 72
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD8跨膜结构域
<400> 10
atctacatct gggcgcccct ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gc 72
<210> 11
<211> 126
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 11
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactg 126
<210> 12
<211> 342
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD3 zeta
<400> 12
agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc 60
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180
gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240
cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300
tacgacgccc ttcacatgca ggccctgccc cctcgctaat ag 342
<210> 13
<211> 6
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> EcoRI限制性酶切位点
<400> 13
gaattc 10
<210> 14
<211> 489
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CD19-4-1BB-CD3-CAR
<400> 14
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 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
20 25 30
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala
50 55 60
Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
115 120 125
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
130 135 140
Lys Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro
145 150 155 160
Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Leu Pro
165 170 175
Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
180 185 190
Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala
195 200 205
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
210 215 220
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
225 230 235 240
Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp
245 250 255
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro
260 265 270
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
275 280 285
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
290 295 300
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
305 310 315 320
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
325 330 335
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
340 345 350
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
355 360 365
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
370 375 380
Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu
385 390 395 400
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
405 410 415
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
420 425 430
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
435 440 445
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
450 455 460
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
465 470 475 480
Leu His Met Gln Ala Leu Pro Pro Arg
485
<210> 15
<211> 735
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD19 scFv
<400> 15
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgcc gcgcgagcca ggatattagc aaatatctga actggtatca gcagaaaccg 120
ggcaaagcgc cgaaactgct gatttatcat accagccgcc tgcatagcgg cgtgccgagc 180
cgctttagcg gcagcggcag cggcaccgat tttaccctga ccattagcag cctgcagccg 240
gaagattttg cgacctatta ttgccagcag ggcaacaccc tgccgtatac ctttggcggc 300
ggcaccaaag tggaaattaa aggctccacc tctggatccg gcaagcccgg atctggcgag 360
ggatccacca agggccaggt gcagctgcag gaaagcggcc cgggcctggt gaaaccgagc 420
gaaaccctga gcctgacctg caccgtgagc ggcggcagcc tgccggatta tggcgtgagc 480
tggattcgcc agccgccggg caaaggcctg gaatggattg gcgtgatttg gggcagcgaa 540
accacctatt ataacagcgc gctgaaaagc cgcgtgacca ttagcgtgga taccagcaaa 600
aaccagttta gcctgaaact gagcagcgtg accgcggcgg ataccgcggt gtattattgc 660
gcgaaacatt attattatgg cggcagctat gcgatggatt attggggcca gggcaccctg 720
gtgaccgtga gcagc 735
<210> 16
<211> 556
<212> PRT
<213> 智人(Homo sapiens)
<400> 16
Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met
1 5 10 15
Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp
20 25 30
Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln
35 40 45
Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu
50 55 60
Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile
65 70 75 80
Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu
85 90 95
Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr
100 105 110
Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp
115 120 125
Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro
130 135 140
Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala
145 150 155 160
Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Leu Pro Pro
165 170 175
Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro
180 185 190
Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser
195 200 205
Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser
210 215 220
Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp
225 230 235 240
Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala
245 250 255
Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu
260 265 270
Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly
275 280 285
Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu
290 295 300
Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg
305 310 315 320
Arg Lys Arg Lys Arg Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val
325 330 335
Thr Pro Pro Pro Gly Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu
340 345 350
Ser Leu Pro Thr Pro Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala
355 360 365
Ala Gly Leu Gly Gly Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp
370 375 380
Val Gln Ala Asp Gly Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly
385 390 395 400
Pro Glu Glu Glu Glu Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu
405 410 415
Asp Ser Glu Phe Tyr Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu
420 425 430
Ser Gln Asp Gly Ser Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly
435 440 445
Pro Glu Asp Glu Asp Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu
450 455 460
Asp Glu Glu Leu Thr Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser
465 470 475 480
Pro His Gly Ser Ala Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Gly
485 490 495
Ser Gln Ser Tyr Glu Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro Gln
500 505 510
Leu Arg Ser Ile Arg Gly Gln Pro Gly Pro Asn His Glu Glu Asp Ala
515 520 525
Asp Ser Tyr Glu Asn Met Asp Asn Pro Asp Gly Pro Asp Pro Ala Trp
530 535 540
Gly Gly Gly Gly Arg Met Gly Thr Trp Ser Thr Arg
545 550 555
Claims (10)
1.一种人源化CD19的单链可变片段(scFv),其特征在于,包含具有SEQ ID NO:6所示氨基酸序列的VH和具有SEQ ID NO:5所示氨基酸序列的VL。
2.根据权利要求1所述的scFv,其特征在于,还包含VH和VL之间的接头。
3.根据权利要求2所述的scFv,其特征在于,具有SEQ ID NO:7所示的氨基酸序列。
4.一种嵌合抗原受体(CAR)融合蛋白,其特征在于,其从N末端到C末端包含:
(i)权利要求1所述的scFv,
(ii)跨膜结构域,
(iii)至少一个共刺激结构域,和
(iv)激活结构域。
5.根据权利要求4所述的CAR融合蛋白,其特征在于,具有SEQ ID NO:14所示的氨基酸序列。
6.一种抗人CD19的抗体,其特征在于,所述抗体包含具有SEQ ID NO:6所示氨基酸序列的VH和具有SEQ ID NO:5所示氨基酸序列的VL。
7.一种核酸分子,其特征在于,所述的核酸分子编码权利要求1所述的scFv、或权利要求4所述的CAR融合蛋白、或权利要求6所述的抗体。
8.一种载体,其特征在于,所述载体含有权利要求7所述的核酸分子。
9.一种宿主细胞,其特征在于,所述的宿主细胞含有权利要求8所述的载体或以外源染色体整合的权利要求7所述的核酸分子、染色体中整合有外源的权利要求7所述的核酸分子、或表达权利要求1所述的scFv、或权利要求4所述的CAR融合蛋白、或权利要求6所述的抗体。
10.一种制剂,其特征在于,所述制剂含有权利要求1所述的scFv、或权利要求4所述的CAR融合蛋白、或权利要求8所述的载体、或权利要求9所述的细胞,以及药学上可接受的载体、稀释剂或赋形剂。
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US62/773,112 | 2018-11-29 | ||
PCT/CN2019/109633 WO2020108090A1 (en) | 2018-11-29 | 2019-09-30 | Car-t cells with humanized cd19 scfv with mutation in cdr 1 region |
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