CN113980130B - 人源化cd37和双特异性cd19-人源化cd37 car-t细胞 - Google Patents
人源化cd37和双特异性cd19-人源化cd37 car-t细胞 Download PDFInfo
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Abstract
本发明涉及含本发明的人源化CD37‑CAR。本发明还涉及双特异性CD19‑人源化CD37CAR,包括:(i)CD19VL,(ii)人源化CD37ScFv,(iii)CD19VH,(iv)跨膜结构域,(v)至少一个共刺激结构域,和(vi)激活结构域。本发明的CAR在血液系统肿瘤的过继免疫基因治疗领域中是有用的。
Description
技术领域
本发明涉及人源化CD37 CAR和双特异性CD19-人源化CD37-CAR和CAR-T细胞,它们在血液系统肿瘤的过继免疫基因治疗领域中是有用的。
背景技术
免疫疗法正在成为一种非常有前途的癌症治疗方法。T细胞或T淋巴细胞是我们免疫系统的武装力量,不断寻找外来抗原并将异常(癌症或经感染细胞)和正常细胞区分开来。利用CAR(嵌合抗原受体)构建体对T细胞进行基因修饰已成为设计肿瘤特异性T细胞最常见的方法。将靶向肿瘤相关抗原(TAA)的CAR-T细胞输入患者体内(称为过继细胞转移或ACT)是一种有效的免疫治疗方法[1,2]。与化疗或抗体相比,CAR-T技术的优点在于经重新编程的工程化T细胞能在患者体内实现增殖和持续存在(“一种活的药物”)[1,3]。
CAR通常由在N-末端部分的单克隆抗体来源的单链可变片段(scFv)、铰链、跨膜结构域和若干胞内共刺激结构域:(i)CD28,(ii)CD137(4-1BB)、CD127或其它共刺激结构域,与CD3-ζ结构域串联组成(图1)[1;2]。CAR的演变经历了从第一代(无共刺激结构域)到第二代(有一个共刺激结构域)再到第三代CAR(有两个共刺激结构域)和第四代(有若干个共刺激结构域)。具有多个共刺激结构域的CAR(所谓的第三代CAR)增强了细胞毒性CAR-T细胞活性,显著改善CAR-T细胞的持久性,从而增强其抗肿瘤活性。
CAR的结构示于图1。左侧:第一代(无共刺激结构域)结构,中间:第二代(一个共刺激结构域CD28或4-1BB),右侧:第三代CAR(两个或若干个共刺激结构域)。该图来自Golubovskaya,Wu,Cancers,2016[3]。
CD19和CD37抗原
CD19是一种已知的在B细胞恶性肿瘤(诸如白血病和淋巴瘤)中过表达的抗原。CD37是跨膜四蛋白(或跨膜4超家族(TM4SF)蛋白)家族蛋白中的成员,该家族蛋白具有四个潜在的跨膜区,CD37在白血病和淋巴瘤患者中也过表达[4]。
发明内容
为了提供新的免疫肿瘤的治疗方法,本发明提供了一种人源化CD37 scFv,其包括具有SEQ ID NO:2的氨基酸序列的VH和具有SEQ ID NO:3的氨基酸序列的VL。
在一些实施方案中,人源化scFv具有SEQ ID NO:1的氨基酸序列。
此外,本发明提供了嵌合抗原受体(CAR),其包括:
(i)权利要求1所述的人源化CD37 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。
在一些实施方案中,嵌合抗原受体具有SEQ ID NO:4的氨基酸序列。
此外,本发明提供了双特异性CAR,其包括:
(i)具有SEQ ID NO:5的氨基酸的CD19 VL,
(ii)权利要求1所述的人源化CD37 ScFv,
(iii)具有SEQ ID NO:6的氨基酸的CD19 VH,
(iv)跨膜结构域,
(v)至少一个共刺激结构域,和
(vi)激活结构域。
在一些实施方案中,双特异性CAR具有SEQ ID NO:7的氨基酸序列。
在一些实施方案中,嵌合抗原受体或双特异性CAR中的所述共刺激结构域是CD28或4-1BB。
在一些实施方案中,嵌合抗原受体或双特异性CAR中的所述激活结构域是CD3ζ。
此外,本发明提供了核酸序列,其编码本发明的嵌合抗原受体或双特异性CAR。
此外,本发明提供了T细胞,其经修饰以表达本发明的嵌合抗原受体或双特异性CAR。
此外,本发明提供了自然杀伤细胞,其经修饰以表达本发明的嵌合抗原受体或双特异性CAR。
本发明的CAR对于血液系统肿瘤的过继免疫基因治疗领域中是有用的。
附图说明
图1、CAR的结构。
图2、构建体结构。A:人源化CD37-CAR构建体的结构;B:双特异性CD19-人源化CD37-CAR构建体的结构。
图3、使用抗小鼠FAB抗体通过FACS检测CAR-阳性细胞。转导后9天抗小鼠(mFAB)或人F(ab)2(hFAB)抗体检测到>40%的CAR-T细胞。
图4、人源化CD37特异性杀伤CHO-CD37靶细胞并分泌高水平的IFN-γ。A:人源化CD37特异性杀伤CHO-CD37靶细胞;B:人源化CD37分泌高水平的IFN-γ。
图5、使用抗小鼠FAB抗体通过FACS检测CAR+细胞。在用PMC930CD19-hCD37 CAR慢病毒转导T细胞后9天,FAB抗体检测到约50%的CAR-阳性细胞。
图6、CD19-CD37-CAR-T细胞特异地杀伤Hela-CD19细胞和CHO-CD37靶细胞。A:使用CD19-hCD37-CAR-T细胞和Hela-CD19靶细胞的杀伤试验;B:使用CD37抗原呈阳性的CHO-CD37的靶细胞杀伤试验。
图7、CD19-hCD37-CAR-T细胞杀伤CD19和CD37阳性的Raji淋巴瘤细胞。
图8、与Hela-CD19、CHO-CD37细胞和Raji细胞一起培养时,CD19-hCD37-CAR-T细胞分泌的IFN-γ。A:与CD19阳性Hela-CD19细胞一起培养时,CD19-hCD37-CAR-T细胞分泌高水平的IFN-γ;B:与CD37-CHO-CD37细胞一起培养时,CD19-hCD37-CAR-T细胞分泌高水平的IFN-γ;C:与CD19+CD37+阳性Raji细胞一起培养时,CD19-hCD37-CAR-T细胞分泌高水平的IFN-γ。
具体实施方式
定义
如本文所使用的,“嵌合抗原受体(CAR)”是一种经过工程改造的受体蛋白,赋予T细胞靶向特定蛋白的新能力。该受体是嵌合的,因为它们将抗原结合功能和T细胞激活功能结合成单一的受体。CAR是一种融合蛋白,包括能够结合抗原的胞外结构域、跨膜结构域,和至少一个胞内结构域。
“嵌合抗原受体(CAR)”有时被称为“嵌合受体”、“T小体”,或“嵌合免疫受体(CIR)”。“能与抗原结合的胞外结构域”指的是能与某一抗原结合的任何寡肽或多肽。“胞内结构域”指的是任何已知作为结构域起作用的寡肽或多肽,该结构域传递信号以激活或抑制细胞内的生物过程。
如本文所使用的,“结构域”指的是多肽中的一个区域,该区域独立于其他区域折叠成特定结构。
如本文所使用的,“人源化抗体”是来自非人物种的抗体,其蛋白质序列已被修饰以增加其与在人类中天然产生的抗体变体的相似性。
如本文所使用的,“单链可变片段(scFv)”指的是来源于保留与抗原结合能力的抗体的单链多肽。scFv的一个示例包括通过重组DNA技术形成的抗体多肽,并且其中免疫球蛋白重链(H链)和轻链(L链)片段的Fv区域通过间隔序列连接。本领域技术人员已知用于工程化scFv的各种方法。
如本文所使用的,“肿瘤抗原”指的是具有抗原性的生物分子,其表达引起癌症。
本发明人已获得了特异性靶向人CD37的小鼠单克隆抗体(PCT/US2020/012385),并将其人源化以制备本发明的人源化抗CD37抗体。发明人随后用这种人源化抗CD37抗体制备了人源化CD37-CAR T细胞,并测试它们在杀伤靶细胞方面是有效的。人源化CD37抗体相对于小鼠CD37抗体的优势包括人源化CD37抗体不会引起针对小鼠CD37序列的免疫应答,并且人源化CD37抗体在人源化hCD37-CAR-T细胞中的耐受性更好。
CD37和CD19蛋白均在生存信号传导中发挥作用。基于CD37和CD19蛋白在B细胞淋巴瘤中的高表达率,这两个靶标均可用于CAR-T细胞治疗。由于导致患者复发的交替剪接的转录物或其他机制[2],CD19表达在淋巴瘤患者中可能下调或丢失,因此双特异性CD19-人源化CD37可用于CAR-T细胞治疗。
本发明人获得了抗人CD19的小鼠单克隆抗体(FMC63,[2])。发明人随后制备了双特异性CD19-人源化CD37 scFv-CAR-T细胞,以靶向过表达CD19和CD37肿瘤抗原的癌细胞。本发明的CD19-hCD37-CAR-T细胞对CHO-CD19和CHO-CD37细胞以及Hela-CD19和Hela-CD37细胞具有高且特异的细胞毒性活性。
双特异性CD19/hCD37 CAR的优势包括双特异性CAR-T细胞靶向淋巴瘤中过表达的CD19和CD37抗原,因此它们更有效。如果一种抗原(CD19或CD37)丢失或下调,双特异性CAR-T细胞仍可靶向另一种抗原。
本发明涉及一种嵌合抗原受体融合蛋白CAR,其从N-末端到C-末端包括:(i)人源化CD37 ScFv;(ii)铰链;(iii)跨膜(TM)结构域;(iv)至少一个共刺激结构域;(v)一个激活结构域。
本发明还涉及一种嵌合抗原受体(CAR)融合蛋白,其从N-末端到C-末端包括:(i)CD19 VL,(ii)CD37 ScFv,(iii)CD19 VH;(iv)铰链;(v)跨膜结构域,(vi)至少一个共刺激结构域,和(vii)激活结构域。
在一个实施方案中,人源化CD37-CAR结构如图2中A所示,并且双特异性CD19-hCD37-CAR如图2中B所示。
图2示出了人源化CD37-CAR和双特异性CD19-人源化CD37-CAR构建体的结构。A、人源化CD37-CAR构建体。信号肽(CD8α信号肽序列);人源化CD37 ScFv(VH-接头-VL);CD8铰链;CD28跨膜结构域;41BB共刺激结构域;CD3激活结构域。B、双特异性CD19-人源化CD37构建体。MNDU3启动子下的第二代慢病毒CAR构建体与4-1BB共刺激结构域一起使用。GM-CSFRα信号肽,CD19 VL;接头;人源化CD37 ScFv;接头;CD19 VH,CD8铰链;CD8跨膜结构域、41BB共刺激结构域和CD3激活结构域。缩写:对CD19-hCD37 CAR说明如下:VL,轻链;L-接头;ScFv-单链可变片段;VH,重链;H,铰链;TM,跨膜结构域;hCD37,人源化CD37ScFv;41BB共刺激和CD3激活结构域。
如图2中A,CAR中的人源化CD37 scFv显示为VH-接头-VL。或者,人源化CD37 scFv可以是VL-接头-VH。
如图2中B,CAR中的双特异性CD19-CD37显示为CD19VL-接头-CD37 ScFv-接头-CD19VH。或者,CAR中的双特异性CD19-CD37可以是CD 19VH-接头-CD37ScFv-接头-CD19VL,或CD 19ScFv-接头-CD37 ScFv,或CD37 ScFv-接头-CD19ScFv。每个ScFv中的VH和VL排列可以是VH-接头-VL或VL-接头-VH。
接头可以是相同的序列或不同的序列。
在一个实施方案中,CAR的共刺激结构域选自由下项组成的组:CD28、4-1BB、GITR、ICOS-1、CD27、OX-40和DAP10。优选的共刺激结构域是CD28或4-1BB。
优选的激活结构域是CD3ζ(CD3Z)
跨膜结构域可以源自天然多肽,或者也可以是人工设计的。源自天然多肽的跨膜结构域能从任何膜结合蛋白或跨膜蛋白中获得。例如,可以使用T细胞受体的α或β链、CD3ζ链、CD28、CD3-ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、ICOS、CD154或GITR的跨膜结构域。人工设计的跨膜结构域是一种主要包括诸如亮氨酸和缬氨酸疏水残基的多肽。优选在合成的跨膜结构域的每一端各发现苯丙氨酸、色氨酸和缬氨酸的三联体。可选地,短寡肽接头或多肽接头(例如长度为2至10个氨基酸的接头),可以布置在跨膜结构域和胞内结构域之间。在一个实施方案中,可以使用具有甘氨酸-丝氨酸连续序列的接头序列。
本发明提供了编码人源化CD37-CAR和双特异性人源化CD37-CD19 CAR的核酸。编码CAR的核酸可以通过常规方法由特定CAR的氨基酸序列而制备。编码氨基酸序列的碱基序列可以从每个结构域氨基酸序列的NCBI RefSeq ID或GenBenk登录号获得,并且本发明的核酸可以使用标准分子生物学和/或化学方法制备。例如,可以基于碱基序列合成核酸,并且本发明的核酸可以通过使用聚合酶链式反应(PCR)将从cDNA文库获得的DNA片段结合来制备。
可以将编码本发明的CAR的核酸插入到载体中,并且可以将载体导入细胞中。例如,可以使用病毒载体,诸如逆转录病毒载体(包括肿瘤逆转录病毒载体、慢病毒载体和假型载体)、腺病毒载体、腺伴随病毒(AAV)载体、猿猴病毒载体、痘苗病毒载体或仙台病毒载体、爱泼斯坦-巴尔病毒(EBV)载体,和单纯疱疹病毒载体。作为病毒载体,优选使用缺乏复制能力从而不能在感染细胞中自我复制的病毒载体。
例如,当使用逆转录病毒载体时,可以通过基于载体所具有的LTR序列和包装信号序列选择合适的包装细胞用于使用该包装细胞制备逆转录病毒颗粒。包装细胞的实例包括PG13(ATCC CRL-10686)、PA317(ATCC CRL-9078)、GP+E-86和GP+envAm-12,以及Psi-Crip。逆转录病毒颗粒也可以用具有高转染效率的293细胞或293T细胞制备。基于逆转录病毒和包装细胞生产的多种逆转录病毒载体可用于包装逆转录病毒载体,这些逆转录病毒载体可从许多公司广泛购得。
CAR-T细胞通过CAR与特定抗原结合,从而将信号传递到细胞中,并且由此激活细胞。表达CAR的细胞的激活根据宿主细胞的种类和CAR的胞内结构域而变化,并且可以基于例如细胞因子的释放、细胞增殖速率的提高、细胞表面分子的变化等作为指标来确认。例如,来自经激活细胞的细胞毒性细胞因子(IFN-γ、肿瘤坏死因子、淋巴毒素等)的释放引起表达抗原的靶细胞的破坏。此外,细胞因子的释放或细胞表面分子的变化刺激其他免疫细胞,例如B细胞、树突细胞、NK细胞,和巨噬细胞。
人源化CD37-CAR-T细胞可用作同种异体CAR-T细胞。
表达CAR的细胞可用作疾病的治疗剂。所述治疗剂包括作为活性成分表达CAR的细胞,并且可以进一步包括合适的赋形剂。
本发明人已经产生了针对过表达CD37的淋巴瘤的血液系统肿瘤细胞的双特异性CD19-hCD37-ScFv-41BB-CD3-CAR-T和hCD37-CAR-T细胞。与未转导T细胞和模拟CAR-T细胞相比,CD19-hCD37-CAR-T细胞对CD19阳性和CD37阳性靶癌细胞的特异性细胞毒性活性更高。
本发明的人源化CD37和双特异性CD19-人源化CD37-CAR-T细胞靶向CHO-CD19和CHO-CD37靶细胞,但不靶向CHO细胞。
使用本发明的CD19和CD37抗体的CD19-hCD37-CAR-T细胞可以有效地用于靶向CD19和CD37阳性淋巴瘤中的CD19和CD37抗原。
CD19-hCD37-CAR-T可与不同疗法联合使用:检查点抑制剂;靶向治疗、小分子抑制剂,和抗体。
CD19-hCD37-CAR-T细胞可在临床上用于CD19和CD37阳性细胞。
共刺激结构域的修饰:CD28、4-1BB和其它共刺激结构域可用于增加其疗效。标签偶联的CD19 ScFv或人源化CD37 ScFv可用于CAR产生。
第三代CAR-T或其他共激活信号结构域可用于CAR内相同的CD19-scFv。
人源化CD19和人源化CD37可用于产生CD19-CD37-CAR-T细胞。
CD19-hCD37 ScFv-CAR与靶向其他肿瘤抗原或肿瘤微环境(VEGFR-1-3)的其他CAR联用,PDL-1、CD80可用于增强单一疗法CD19-CD37-CAR的活性。
本发明的CD19-hCD37-CAR可用于产生其他类型可靶向CD19和CD37阳性癌症的细胞,诸如CAR-自然杀伤(NK)细胞、CD19-hCD37-CAR-巨噬细胞、同种异体CAR-T细胞、经基因编辑的T细胞,和其他CD19-HCD 37-CAR造血细胞。本发明提供了用CRISPR或其它方法遗传修饰以下调GVHD(移植物抗宿主病)的不同标志物并表达CD37-CAR的T细胞、或NK细胞、或巨噬细胞、或造血细胞、同种异体现成T细胞。
以下实施例进一步说明了本发明。这些实施例仅仅是为了说明本发明,而不是为了限制本发明。
实施例
本发明人产生了在具有41BB-CD3ζ结构域的慢病毒载体内的人源化CD37和双特异性CD19-hCD37 CAR构建体。这些慢病毒载体具有在MNDU3启动子下的CAR。
如实施例所述,在293T细胞中产生慢病毒,然后使用等剂量的慢病毒转导T细胞。
实施例1A、人源化CD37 CAR序列
全长人源化CD37 CAR(PMC762)如下所示:信号肽、人源化CD37 scFv(VH-接头-VL)、铰链区、跨膜结构域、41BB和CD3结构域。
<CD8α信号肽+Nhe I位点:>(SEQ ID No:8)
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGgctagc
CD8α信号肽标有下划线(+用于克隆的3’端处NheI位点,AS氨基酸)(SEQ ID No:9)
MALPVTALLLPLALLLHAARP AS
<CD37 ScFv>
核苷酸序列(VH加粗,G4S,VL标有下划线)(SEQ ID No:10):
人源化CD37 ScFv氨基酸序列(SEQ ID NO:1)
<人源化CD37 VH>(SEQ ID No:11)
氨基酸序列(人源化CD37 VH,SEQ ID NO:2)
<人源化CD37 VL>(SEQ ID No:12)
氨基酸序列(人源化CD37 VL,SEQ ID NO:3)
AIRMTQSPSSFSASTGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLIYNAKTLPSGVPSRFSGSGSGT
DFTLTISCLQSEDFATYYCQQYWSTPYTFGGGTKLEIR
<Xho位点>
<Ctcgag>
<AAGCCC>
KP
<CD8α铰链>(SEQ ID No:13)
<ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGAGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCAGTGAT>
(SEQ ID No:14)
<TTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFASD>
<CD28跨膜结构域>(SEQ ID No:15)
aagcccttttgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaacagtggcctttattattttctgggtg
(SEQ ID No:16)<KPFWVLVVVGGVLACYSLLVTVAFIIFWV>
<41BB>(SEQ ID No:17)
(SEQ ID No:18)
<CD3>(SEQ ID No:19)
<AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTAA>
(SEQ ID No:20)
<RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR>
<人源化CD37-CAR核酸序列>(SEQ ID No:21):
<人源化CD37 CAR氨基酸序列,SEQ ID NO:4>
MALPVTALLLPLALLLHAARPASEVQLVESGGGLVQPGRSLRLSCTASGFTFSDYWMNWVRQAPGKGLEWVGQIRDKPYNYETFYSDSVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTGSFAYWGAGTTVTVSSGGGGSGGGGSGGGGSAIRMTQSPSSFSASTGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLIYNAKTLPSGVPSRFSGSGSGTDFTLTISCLQSEDFATYYCQQYWSTPYTFGGGTKLEIRLEKPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFASDKPFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
实施例1B、CD19-hCD37 CAR序列
图2示出了双特异性CD19-人源化CD37-CAR构建体的方案。使用慢病毒载体慢EF1a克隆CD19人源化CD37 scFv CAR序列。
以下核苷酸序列显示了本发明的CD19 VL-人源化CD37 ScFv-CD19 VH-CD8铰链-TM8-41BB-CD3ζ。结构包括GM-CSF受体α信号肽、CD19 VL-接头(G4S)-人源化CD37 ScFv(hCD37 VH-接头-hCD 37VL);G4S接头;CD19 VH;CD8铰链,CD8跨膜;41BB共刺激结构域;CD3ζ激活结构域(图2)。
<GM-CSF受体α信号肽>(SEQ ID No:22)
atgctgctgctcgtgacaagcctgctgctgtgcgagctgccccaccctgcctttctgctgatcccc
(SEQ ID No:23)MLLLVTSLLLCELPHPAFLLIP
<CD19 VL>(SEQ ID No:24)
氨基酸,CD19 VL,SEQ ID NO:5
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIT
<G4S接头>(SEQ ID No:25)
GGC GGA GGA GGG AGT
<hCD37 ScFv>=hCD37 VH-接头-hCD37 VL(与实施例1A相同)
<接头G4S>
核苷酸(SEQ ID No:26):
氨基酸(SEQ ID No:27)
GGGGS
<CD19VH>
核苷酸(SEQ ID No:28):
氨基酸,CD19 VH,SEQ ID NO:6
<GS两个氨基酸间隔子>
<AGC GGG>
<CD8铰链>(SEQ ID No:29)
accacgacgcccgcccctagacccccgacgcccgctccgactatagcgagccaacctctcagcctgaggcctgaagcatgtcgaccagcagcaggaggggcagtacacaccaggggcctggattttgcctgtgat
氨基酸(SEQ ID No:30)
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD
<CD8跨膜结构域>
参见实施例1B
<41BB共刺激结构域>
参见实施例1B
<CD3ζ>
参见实施例1B
全长CD19-人源化-CD37 CAR(PMC930)如下所示:GM-CSF受体α信号肽标有下划线;CD19 VL以粗体显示;G4S接头以斜体带下划线显示;人源化CD37 ScFv(VH-接头-VL);接头G4S以斜体带下划线显示;CD19 VH以粗体、斜体显示;SG-氨基酸;然后CD8铰链以粗体带下划线显示;CD8α跨膜区以常规字体带下划线显示;然后4-1BB结构域以粗体显示;CD3激活域以常规字体显示。
双特异性CD19-人源化CD37-CAR(PMC930)核苷酸序列(SEQ ID No:31):
/>
双特异性CD19-CD37 CAR的氨基酸序列(SEQ ID NO:7):
MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSEVQLVESGGGLVQPGRSLRLSCTASGFTFSDYWMNWVRQAPGKGLEWVGQIRDKPYNYETFYSDSVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTGSFAYWGAGTTVTVSSGGGGSGGGGSGGGGSAIRMTQSPSSFSASTGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLIYNAKTLPSGVPSRFSGSGSGTDFTLTISCLQSEDFATYYCQQYWSTPYTFGGGTKLEIRGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSSGTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
实施例2、CAR慢病毒制备
如[5]中所述,使用293细胞通过标准程序制备慢病毒。
实施例3、从全血中分离外周血单个核细胞(PBMC)
在10mL Heparin vacutainers(Becton Dickinson)中从个体或混合献血者(取决于所需血液量)采集全血(Stanford Hospital Blood Center,Stanford,CA)。取约10ml的抗凝全血与无菌磷酸盐缓冲盐水(PBS)缓冲液在50ml锥形离心管中混合,总体积为20ml(PBS,pH 7.4,无Ca2+/Mg2+)。非常小心地移除经稀释血浆/Ficoll界面处的含外周血单个核细胞的细胞层(PBMC),避免任何Ficoll,用PBS洗涤两次,并在200×g下室温离心10min。用血细胞计数器计数细胞。使用CAR-T培养基(AIM V-AlbuMAX(BSA)(Life Technologies),具有5%AB血清和1.25ug/mL两性霉素B(Gemini Bioproducts,Woodland,CA)、100U/mL青霉素和100ug/mL链霉素)洗涤PBMC一次,并用于实验或于-80℃冷冻。
实施例4、来自PBMC的T细胞激活
经分离的细胞(用无Ca2+/Mg2+的1×PBS(ph 7.4)洗涤)以5×105细胞/mL的浓度在不含人白细胞介素-2(huIL-2)(Invitrogen)的CAR-T培养基(AIM V-AlbuMAX(BSA)(LifeTechnologies),具有5%AB血清和1.25μg/mL两性霉素B(Gemini Bioproducts,Woodland,CA)、100U/mL青霉素和100μg/mL链霉素)中洗涤一次。将细胞以最终浓度为5×105细胞/mL重新悬浮在具有300U/mL huIL-2的CAR-T培养基中。以1:1激活PBMC(CD3-CD28珠与细胞的比例)。
实施例5、T细胞的转导和扩增
PBMC激活后,细胞在37℃、5%CO2条件下孵育24小时。向每个1×106细胞的孔中加入5×106慢病毒和2μL/mL的Transplus培养基(Alstem,Richmond,CA)(最终稀释为1:500)。在重复添加病毒之前,将细胞额外孵育24小时。然后,在持续存在300U/ml IL-2的含IL-2的新鲜培养基的情况下培养细胞12-14天(总培养时间取决于所需CAR-T细胞的最终数量)。每2-3天分析一次细胞浓度,同时加入培养基,将细胞悬液稀释至1×106个细胞/ml。
实施例6、FACS用于CAR阳性细胞检测
洗涤细胞并将其悬浮在FACS缓冲液(磷酸盐缓冲液(PBS)+0.1%叠氮化钠和0.4%BSA)中。将细胞分成1x106等分试样。
在冰上用常规山羊IgG(LifeTechnologies)封闭Fc受体10min。
使用生物素标记的多克隆山羊抗小鼠F(ab)2抗体(Life Technologies)检测CD19和CD37scFv。
同型生物素标记的常规多克隆山羊IgG抗体(Life Technologies)用作同型对照。(1:200稀释,反应体积100μl)。将细胞在4℃孵育25分钟,并用FACS缓冲液洗涤一次。
将细胞悬浮在FACS缓冲液中,并通过向每个试管中加入100μl 1:1000稀释的常规小鼠lgG,用常规小鼠IgG(Invitrogen)封闭,并在冰上孵育10分钟。细胞用流式细胞仪缓冲液洗涤,并重悬于100μl FACS缓冲液中。然后用藻红蛋白(PE)标记的链霉亲和素(BDPharmingen,San Diego,CA)和别藻蓝蛋白(APC)标记的CD3(eBiocience,San Diego,CA)对细胞进行染色。向试管2和3中各加入1.0μl PE和APC。
实施例7、细胞毒性试验(实时细胞毒性试验)。
根据如[5]描述的制造商的方案,使用ACEA机进行细胞毒性检测。
实施例8、人源化CD37-CAR-T细胞。
将人源化CD37(PMC762)CAR转导至PBMC,并用抗小鼠和抗人F(ab)2抗体通过FACS分析人源化CD37-CAR-T细胞是否表达人源化scFv(图3)。两种抗F(ab)2抗体均识别CD37scFv(图3),这证实CAR表达良好。
图3示出了使用抗小鼠FAB抗体通过FACS检测到CAR阳性细胞。转导后9天抗小鼠(mFAB)或人F(ab)2(hFAB)抗体检测到>40%的CAR-T细胞。
使用CD37阳性靶细胞通过实时细胞毒性试验(RTCA)分析人源化CD37-CAR-T细胞。人源化CD37-CAR-T细胞(PMC762)特异性杀伤CHO-CD37细胞并分泌IFN-γ,而T细胞、模拟CAR-T细胞(无scFv)或其他两种具有相同的VH和不同的VL序列的人源化CD37-CAR-T细胞:PMC769,和PMC770-CAR-T细胞不能特异性杀伤CHO-CD37细胞并分泌IFN-γ(图4中A、B)。
图4示出了人源化CD37(PMC 762)特异性杀伤CHO-CD37靶细胞,并分泌高水平的IFN-γ。A、用PMC762 hCD37-CAR-T细胞和靶CHO-CD37细胞进行RTCA杀伤分析。阴性对照是:模拟、PMC769和PMC770 CAR-T细胞(具有相同VH和不同VL的其他hCD37CAR-T细胞)。B、RTCA后分析上清液的IFN-γ分泌。与CHO-CD37细胞一起时,人源化CD37(PMC762)CAR-T细胞分泌高水平的IFN-γ。
实施例9、CD19人源化CD37-CAR-T细胞(PMC930)表达CAR+ScFv细胞
如图2所示,在CAR内插入具有41BB共刺激结构域和CD3ζ结构域的双特异性CD19-hCD37 scFv序列,并将CAR慢病毒转导至T细胞。CD19-hCD37-CAR细胞在体外有效扩增(未显示)。生成了不含scFv和TF标签的模拟对照,并将其用作细胞毒性和细胞因子分析中的阴性对照。使用抗小鼠-F(ab)2和抗人F(ab)2抗体通过FACS检测CD19-hCD37-CAR T细胞(图5)。
图5示出了使用抗小鼠FAB抗体通过FACS检测到CAR+细胞。在用PMC930CD19-hCD37CAR慢病毒转导T细胞后9天,FAB抗体检测到约50%的CAR阳性细胞。
实施例10、CD19-hCD37-CAR-T细胞杀伤CHO-CD37、Hela-CD19和Raji细胞
CD19-hCD37 CAR-T细胞与CHO-CD37稳定细胞系(用CD37抗原稳定转导)和Hela-CD19(CD19-阳性)共孵育,并使用基于阻抗的XCelligence系统进行实时细胞毒性试验(RTCA)。CD19-hCD37-CAR-T细胞杀伤Hela-CD19细胞,而T细胞、模拟CAR-T细胞和hCD37-CAR-T细胞不杀伤Hela-CD19细胞(图6中A)。CD19-hCD37-CAR-T细胞也能杀伤CHO-CD37靶细胞(图6中B),杀伤效果与单个CD37 CAR-T细胞相同。
对靶Raji Burkitt淋巴瘤细胞(CD37和CD19阳性)进行了同样的试验,PMC930CD19-hCD37 CAR-T细胞比单纯CD37细胞杀伤更多的Raji Burkitt淋巴瘤细胞(图7)。
图6示出了CD19-CD37-CAR-T细胞特异地杀伤Hela-CD37细胞和CHO-CD37靶细胞。A、使用CD19-hCD37-CAR-T细胞和Hela-CD19靶细胞的杀伤试验。B、使用CD37抗原呈阳性的CHO-CD37靶细胞杀伤试验。
图7示出了CD19-hCD37-CAR-T细胞杀伤CD19和CD37阳性的Raji淋巴瘤细胞。
实施例11、CD19-hCD37-CAR-T细胞针对CD19和CD37阳性靶细胞分泌高水平的IFN-γ
在CD19-hCD37-CAR-T细胞与靶细胞一起孵育后,我们收集了上清液,并根据Fisher的方案用它们的试剂盒进行ELISA。CD19-hCD37-CAR-T针对CD19阳性Hela-CD19靶细胞(图8中A)和CD37阳性靶CHO-CD37(图8中B)分泌的IFN-γ水平显著高于模拟CAR-T细胞和T细胞。在Raji细胞中观察到了相同的高水平(图8中C)。双特异性Cd19-hCD37-CAR-T细胞分泌的IFN-γ水平高于单纯的hCD37-CAR-T细胞。结果显示CD19-hCD37-CAR-T细胞具有高度特异性,可特异性靶向CD37和CD19阳性细胞。
PMC930在体内对Raji肿瘤生长也有抑制作用(未显示)。因此,双特异性CD19-人源化CD37在临床上可作为抗淋巴瘤的良好细胞治疗剂。
图8示出了与Hela-CD19、CHO-CD37细胞和Raji细胞一起时,CD19-hCD37-CAR-T细胞分泌的IFN-γ。与CD19阳性Hela-CD19细胞(A)、CD37-CHO-CD37细胞(B)和CD19+CD37+阳性Raji细胞(C)一起时,CD19-hCD37-CAR-T细胞分泌高水平的IFN-γ。
参考文献
[1]M.V.Maus,A.R.Haas,G.L.Beatty,S.M.Albelda,B.L.Levine,X.Liu,Y.Zhao,M.Kalos,and C.H.June,T cells expressing chimeric antigen receptors can causeanaphylaxis in humans.Cancer Immunol Res 1(2013)26-31.
[2]M.V.Maus,S.A.Grupp,D.L.Porter,and C.H.June,Antibody-modified Tcells:CARs take the front seat for hematologic malignancies.Blood 123(2014)2625-35.
[3]V.Golubovskaya,and L.Wu,Different Subsets of T Cells,Memory,Effector Functions,and CAR-T Immunotherapy.Cancers(Basel)8(2016).
[4]F.Kroschinsky,J.M.Middeke,M.Janz,G.Lenz,M.Witzens-Harig,R.Bouabdallah,P.La Rosee,A.Viardot,G.Salles,S.J.Kim,T.M.Kim,O.Ottmann,J.Chromik,A.M.Quinson,U.von Wangenheim,U.Burkard,A.Berk,and N.Schmitz,Phase Idose escalation study of BI 836826(CD37 antibody)in patients with relapsed orrefractory B-cell non-Hodgkin lymphoma.Invest New Drugs(2020).
[5]Vita Golubovskaya,Hua Zhou,Feng Li,et al.Novel CD37,Humanized CD37and Bi-Specific Humanized CD37-CD19 CAR-T Cells Specifically Target Lymphoma[J].Cancers,2021,13(5):981.
序列表
<110> 普瑞迈博生物技术有限公司
湖南远泰生物技术有限公司
<120> 人源化CD37和双特异性CD19-人源化CD37 CAR-T细胞
<150> US63/056,899
<151> 2020-07-27
<160> 31
<170> SIPOSequenceListing 1.0
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Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
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Arg
<210> 8
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<212> DNA
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20
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<213> 人工序列
<220>
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cccggtaaag gcctggaatg ggtgggacaa attcgcgata agccgtataa ttacgaaaca 180
ttctacagcg actctgtcaa gggtagattc acaatctccc gggatgacag taaatccatt 240
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ttcagtgcat caacaggaga cagagtaacg ataacgtgcc gggcaagcgg taacatccat 480
aattaccttg cgtggtacca acagaaacct ggtaaagcgc cgaaacttct catttacaat 540
gctaagaccc ttccctccgg agttccctct aggtttagtg gctcaggtag cgggaccgac 600
tttaccttga caatcagttg cctgcaatca gaagactttg caacttacta ctgccaacag 660
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<212> DNA
<213> 人工序列
<220>
<223> 人源化CD37 VH
<400> 11
gaagtacaac tcgtcgagtc cggcggggga ctggtacagc ccggacggtc cctgagactt 60
agttgtacgg cttctggttt cacgttttcc gactattgga tgaattgggt gaggcaagcg 120
cccggtaaag gcctggaatg ggtgggacaa attcgcgata agccgtataa ttacgaaaca 180
ttctacagcg actctgtcaa gggtagattc acaatctccc gggatgacag taaatccatt 240
gcatacctcc agatgaactc tctcaaaacc gaggatacag ctgtatatta ttgcactggg 300
agtttcgcct actggggagc tgggacgacg gtaacggtat cctca 345
<210> 12
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 人源化CD37 VL
<400> 12
gccattagga tgactcagag ccccagttct ttcagtgcat caacaggaga cagagtaacg 60
ataacgtgcc gggcaagcgg taacatccat aattaccttg cgtggtacca acagaaacct 120
ggtaaagcgc cgaaacttct catttacaat gctaagaccc ttccctccgg agttccctct 180
aggtttagtg gctcaggtag cgggaccgac tttaccttga caatcagttg cctgcaatca 240
gaagactttg caacttacta ctgccaacag tattggagca ccccctatac gtttggcggc 300
ggtactaaac tggaaatccg c 321
<210> 13
<211> 135
<212> DNA
<213> 人工序列
<220>
<223> CD8α铰链
<400> 13
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgag ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcca gtgat 135
<210> 14
<211> 45
<212> PRT
<213> 人工序列
<220>
<223> CD8α铰链
<400> 14
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Ser Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Ser Asp
35 40 45
<210> 15
<211> 87
<212> DNA
<213> 人工序列
<220>
<223> CD28跨膜结构域
<400> 15
aagccctttt gggtgctggt ggtggttggt ggagtcctgg cttgctatag cttgctagta 60
acagtggcct ttattatttt ctgggtg 87
<210> 16
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> CD28跨膜结构域
<400> 16
Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr
1 5 10 15
Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 17
<211> 126
<212> DNA
<213> 人工序列
<220>
<223> 41BB
<400> 17
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactg 126
<210> 18
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 41BB
<400> 18
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 19
<211> 342
<212> DNA
<213> 人工序列
<220>
<223> CD3
<400> 19
agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
cgggaccctg agatgggggg aaagccgcag agaaggaaga accctcagga aggcctgtac 180
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300
acctacgacg cccttcacat gcaggccctg ccccctcgct aa 342
<210> 20
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> CD3
<400> 20
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 21
<211> 1482
<212> DNA
<213> 人工序列
<220>
<223> 人源化CD37-CAR核酸序列
<400> 21
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggctagcg aagtacaact cgtcgagtcc ggcgggggac tggtacagcc cggacggtcc 120
ctgagactta gttgtacggc ttctggtttc acgttttccg actattggat gaattgggtg 180
aggcaagcgc ccggtaaagg cctggaatgg gtgggacaaa ttcgcgataa gccgtataat 240
tacgaaacat tctacagcga ctctgtcaag ggtagattca caatctcccg ggatgacagt 300
aaatccattg catacctcca gatgaactct ctcaaaaccg aggatacagc tgtatattat 360
tgcactggga gtttcgccta ctggggagct gggacgacgg taacggtatc ctcaggtggc 420
ggtggaagcg gtggtggagg tagtggaggg ggtgggagtg ccattaggat gactcagagc 480
cccagttctt tcagtgcatc aacaggagac agagtaacga taacgtgccg ggcaagcggt 540
aacatccata attaccttgc gtggtaccaa cagaaacctg gtaaagcgcc gaaacttctc 600
atttacaatg ctaagaccct tccctccgga gttccctcta ggtttagtgg ctcaggtagc 660
gggaccgact ttaccttgac aatcagttgc ctgcaatcag aagactttgc aacttactac 720
tgccaacagt attggagcac cccctatacg tttggcggcg gtactaaact ggaaatccgc 780
ctcgagaagc ccaccacgac gccagcgccg cgaccaccaa caccggcgcc caccatcgcg 840
tcgcagcccc tgtccctgcg cccagaggcg agccggccag cggcgggggg cgcagtgcac 900
acgagggggc tggacttcgc cagtgataag cccttttggg tgctggtggt ggttggtgga 960
gtcctggctt gctatagctt gctagtaaca gtggccttta ttattttctg ggtgaaacgg 1020
ggcagaaaga aactcctgta tatattcaaa caaccattta tgagaccagt acaaactact 1080
caagaggaag atggctgtag ctgccgattt ccagaagaag aagaaggagg atgtgaactg 1140
agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 1200
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 1260
cgggaccctg agatgggggg aaagccgcag agaaggaaga accctcagga aggcctgtac 1320
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 1380
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 1440
acctacgacg cccttcacat gcaggccctg ccccctcgct aa 1482
<210> 22
<211> 66
<212> DNA
<213> 人工序列
<220>
<223> GM-CSF受体α信号肽
<400> 22
atgctgctgc tcgtgacaag cctgctgctg tgcgagctgc cccaccctgc ctttctgctg 60
atcccc 66
<210> 23
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> GM-CSF受体α信号肽
<400> 23
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro
20
<210> 24
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> CD19 VL
<400> 24
gacatccaga tgacccagac caccagcagc ctgagcgcca gcctgggcga tagagtgacc 60
atcagctgca gagccagcca ggacatcagc aagtacctga actggtatca gcagaaaccc 120
gacggcaccg tgaagctgct gatctaccac accagcagac tgcacagcgg cgtgcccagc 180
agattttctg gcagcggctc cggcaccgac tacagcctga ccatctccaa cctggaacag 240
gaagatatcg ctacgtactt ttgtcagcag ggaaacacgc ttccatacac cttcggcggc 300
ggtacgaagt tggagatcac g 321
<210> 25
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> G4S接头
<400> 25
ggcggaggag ggagt 15
<210> 26
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 接头G4S
<400> 26
ggtggtggag ggagc 15
<210> 27
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头G4S
<400> 27
Gly Gly Gly Gly Ser
1 5
<210> 28
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> CD19VH
<400> 28
gaggtcaaac tgcaggaatc cggaccaggg cttgtagccc cctcacaaag cctcagcgtg 60
acttgtacag tgagcggcgt tagtctgccg gactatggag tttcttggat tcggcaaccg 120
cccagaaaag ggctggaatg gcttggtgtt atatggggct cagaaactac ctattacaac 180
agtgctctca aaagccggct cacaataata aaggataata gcaaatctca agttttcctg 240
aaaatgaact ctctgcaaac agatgacacg gcgatctact actgcgcgaa acactactat 300
tacggcggca gctacgccat ggactattgg gggcagggga cgtcagtgac agtgtctagc 360
<210> 29
<211> 135
<212> DNA
<213> 人工序列
<220>
<223> CD8铰链
<400> 29
accacgacgc ccgcccctag acccccgacg cccgctccga ctatagcgag ccaacctctc 60
agcctgaggc ctgaagcatg tcgaccagca gcaggagggg cagtacacac caggggcctg 120
gattttgcct gtgat 135
<210> 30
<211> 45
<212> PRT
<213> 人工序列
<220>
<223> CD8铰链
<400> 30
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 31
<211> 2166
<212> DNA
<213> 人工序列
<220>
<223> 双特异性CD19-人源化CD37-CAR(PMC930)核苷酸序列
<400> 31
atgctgctgc tcgtgacaag cctgctgctg tgcgagctgc cccaccctgc ctttctgctg 60
atccccgaca tccagatgac ccagaccacc agcagcctga gcgccagcct gggcgataga 120
gtgaccatca gctgcagagc cagccaggac atcagcaagt acctgaactg gtatcagcag 180
aaacccgacg gcaccgtgaa gctgctgatc taccacacca gcagactgca cagcggcgtg 240
cccagcagat tttctggcag cggctccggc accgactaca gcctgaccat ctccaacctg 300
gaacaggaag atatcgctac gtacttttgt cagcagggaa acacgcttcc atacaccttc 360
ggcggcggta cgaagttgga gatcacgggc ggaggaggga gtgaagtaca actcgtcgag 420
tccggcgggg gactggtaca gcccggacgg tccctgagac ttagttgtac ggcttctggt 480
ttcacgtttt ccgactattg gatgaattgg gtgaggcaag cgcccggtaa aggcctggaa 540
tgggtgggac aaattcgcga taagccgtat aattacgaaa cattctacag cgactctgtc 600
aagggtagat tcacaatctc ccgggatgac agtaaatcca ttgcatacct ccagatgaac 660
tctctcaaaa ccgaggatac agctgtatat tattgcactg ggagtttcgc ctactgggga 720
gctgggacga cggtaacggt atcctcaggt ggcggtggaa gcggtggtgg aggtagtgga 780
gggggtggga gtgccattag gatgactcag agccccagtt ctttcagtgc atcaacagga 840
gacagagtaa cgataacgtg ccgggcaagc ggtaacatcc ataattacct tgcgtggtac 900
caacagaaac ctggtaaagc gccgaaactt ctcatttaca atgctaagac ccttccctcc 960
ggagttccct ctaggtttag tggctcaggt agcgggaccg actttacctt gacaatcagt 1020
tgcctgcaat cagaagactt tgcaacttac tactgccaac agtattggag caccccctat 1080
acgtttggcg gcggtactaa actggaaatc cgcggtggtg gagggagcga ggtcaaactg 1140
caggaatccg gaccagggct tgtagccccc tcacaaagcc tcagcgtgac ttgtacagtg 1200
agcggcgtta gtctgccgga ctatggagtt tcttggattc ggcaaccgcc cagaaaaggg 1260
ctggaatggc ttggtgttat atggggctca gaaactacct attacaacag tgctctcaaa 1320
agccggctca caataataaa ggataatagc aaatctcaag ttttcctgaa aatgaactct 1380
ctgcaaacag atgacacggc gatctactac tgcgcgaaac actactatta cggcggcagc 1440
tacgccatgg actattgggg gcaggggacg tcagtgacag tgtctagcag cgggaccacg 1500
acgcccgccc ctagaccccc gacgcccgct ccgactatag cgagccaacc tctcagcctg 1560
aggcctgaag catgtcgacc agcagcagga ggggcagtac acaccagggg cctggatttt 1620
gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 1680
ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 1740
ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1800
gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1860
gcgtacaagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1920
tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1980
aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 2040
agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 2100
ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 2160
cgctaa 2166
Claims (11)
1.人源化CD37 scFv,其包括具有SEQ ID NO:2的氨基酸序列的VH和具有SEQ ID NO:3的氨基酸序列的VL。
2.权利要求1所述的人源化scFv,其具有SEQ ID NO:1的氨基酸序列。
3.嵌合抗原受体(CAR),其包括:
(i)权利要求1所述的人源化CD37 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。
4.权利要求3所述的嵌合抗原受体,其具有SEQ ID NO:4的氨基酸序列。
5.双特异性CAR,其包括:
(i)具有SEQ ID NO:5的氨基酸的CD19 VL,
(ii)权利要求1所述的人源化CD37 ScFv,
(iii)具有SEQ ID NO:6的氨基酸的CD19 VH,
(iv)跨膜结构域,
(v)至少一个共刺激结构域,和
(vi)激活结构域。
6.权利要求5所述的双特异性CAR,其具有SEQ ID NO:7的氨基酸序列。
7.权利要求3所述的嵌合抗原受体或权利要求5所述的双特异性CAR,其中,所述共刺激结构域是CD28或4-1BB。
8.权利要求3所述的嵌合抗原受体或权利要求5所述的双特异性CAR,其中,所述激活结构域是CD3ζ。
9.编码权利要求3所述的嵌合抗原受体或权利要求5所述的双特异性CAR的核酸序列。
10.经修饰以表达权利要求3所述的嵌合抗原受体或权利要求5所述的双特异性CAR的T细胞。
11.经修饰以表达权利要求3所述的嵌合抗原受体或权利要求5所述的双特异性CAR的自然杀伤细胞。
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CN101282745A (zh) * | 2005-07-25 | 2008-10-08 | 特鲁比昂药品公司 | 用cd37-特异性和cd20-特异性结合分子减少b-细胞 |
CN109789164A (zh) * | 2016-08-30 | 2019-05-21 | 亘喜生物科技(上海)有限公司 | 具有gitr胞内结构域作为共刺激结构域的嵌合抗原受体 |
CN110300603A (zh) * | 2017-02-14 | 2019-10-01 | 亘喜生物科技(上海)有限公司 | Cd47-car-t细胞 |
CN110505882A (zh) * | 2017-03-31 | 2019-11-26 | 默沙东公司 | 用pd-1的拮抗剂和抗ctla4抗体的组合治疗癌症的组合物和方法 |
WO2020146267A1 (en) * | 2019-01-11 | 2020-07-16 | Promab Biotechnologies, Inc. | Cd37-antibody and cd37-car-t cells |
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WO2014099671A1 (en) * | 2012-12-20 | 2014-06-26 | Bluebird Bio, Inc. | Chimeric antigen receptors and immune cells targeting b cell malignancies |
CN105296433B (zh) * | 2014-08-01 | 2018-02-09 | 中山康方生物医药有限公司 | 一种ctla4抗体、其药物组合物及其用途 |
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CN101282745A (zh) * | 2005-07-25 | 2008-10-08 | 特鲁比昂药品公司 | 用cd37-特异性和cd20-特异性结合分子减少b-细胞 |
CN109789164A (zh) * | 2016-08-30 | 2019-05-21 | 亘喜生物科技(上海)有限公司 | 具有gitr胞内结构域作为共刺激结构域的嵌合抗原受体 |
CN110300603A (zh) * | 2017-02-14 | 2019-10-01 | 亘喜生物科技(上海)有限公司 | Cd47-car-t细胞 |
CN110505882A (zh) * | 2017-03-31 | 2019-11-26 | 默沙东公司 | 用pd-1的拮抗剂和抗ctla4抗体的组合治疗癌症的组合物和方法 |
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