CN115955974A - 靶向cd19和cd20的联合嵌合抗原受体及其应用 - Google Patents
靶向cd19和cd20的联合嵌合抗原受体及其应用 Download PDFInfo
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Abstract
本发明提供靶向CD19和CD20的联合嵌合抗原受体及其应用。具体而言,本发明提供靶向CD19和CD20的联合嵌合抗原受体,其包含靶向CD19的scFv和靶向CD20的scFv、铰链区、跨膜区和胞内信号传导结构域。本发明提供编码嵌合抗原受体的核酸分子和相应的表达载体、CAR‑T细胞及其应用。实验结果显示,本发明提供的嵌合抗原受体显示对肿瘤细胞的极高杀伤能力。本发明的嵌合抗原受体靶向CD19和/或CD20阳性细胞,可用于治疗CD19和/或CD20阳性B细胞淋巴瘤、白血病和其他疾病。
Description
技术领域
本发明涉及生物医学领域,更具体而言,涉及靶向CD19和CD20的联合嵌合抗原受体及其应用。
背景技术
血液系统恶性肿瘤约占人类恶性肿瘤的10%,95%的血液系统恶性肿瘤源自B淋巴细胞。传统的化疗和放疗在血液系统恶性肿瘤的治疗中发挥着重要作用。一些患者疗效显著,但大多数患者难以治愈。新的有效治疗方法一直是此领域的探索热点。
过继T细胞治疗在恶性肿瘤的临床治疗中已经显示出强大的功效和光明的前景。目前,其被誉为最有前途的治疗血液肿瘤的方法之一。CD19在大多数B细胞恶性肿瘤的表面高度表达。多个中心独立使用嵌合抗原受体(CAR)修饰的T细胞靶向表达CD19的B细胞复发难治性恶性肿瘤,取得了前所未有的成功。目前,FDA批准上市的两种CAR-T产品均靶向CD19抗原,其适应症也在扩大,如慢性淋巴细胞白血病。尽管抗CD19 CAR-T的疗效突出,但许多研究表明,CD19嵌合抗原受体(CAR)T细胞治疗也存在许多问题。仍有部分患者的治疗效果不佳,容易复发。其原因包括肿瘤细胞对抗原逃逸的易感性。例如,最近的CD19 CAR细胞治疗实验显示,90%的患者达到完全缓解,但这些患者中的11%最终复发,复发患者主要是CD19阴性肿瘤患者。尤其是在宾夕法尼亚大学医学院开展的一项使用CART19治疗复发性难治性急性B细胞淋巴瘤(R/R B-ALL)的临床试验中,高达94%的患者达到完全缓解。尽管此临床试验的初始反应率很高,但近40%的患者在治疗1个月达到完全缓解后又出现了复发,并且60%以上的复发患者出现CD19阴性肿瘤细胞逃逸。已经在过继转移的表达NY-ESO1的特异性T细胞受体和治疗黑色素瘤的癌症疫苗中发现了抗原逃逸。自发突变和选择性扩增是抗原逃逸的主要原因。
因此,本领域迫切需要开发有效治疗肿瘤和预防抗原逃逸的方法。
发明概述
本发明的一个目的是提供用于有效治疗肿瘤和预防抗原逃逸的方法。
本发明的一个目的是提供靶向CD19和CD20的联合嵌合抗原受体及其制备方法。
具体而言,本发明的一个目的是提供一种靶向CD19和CD20的联合嵌合抗原受体的序列、及其修饰的T细胞(CAR-T19/20)的制备方法和活性鉴定。本发明提供了一种用于治疗CD19和CD20阳性B细胞淋巴瘤的嵌合抗原受体结构。
本公开提供双特异性嵌合抗原受体(CAR)。该双特异性CAR可以包含:(i)抗CD20抗原结合区,其包含分别具有SEQ ID NO:4和SEQ ID NO:3所示氨基酸序列的轻链可变区(VL1)和重链可变区(VH1);和(ii)抗CD19抗原结合区,其包含分别具有SEQ ID NO:5和SEQID NO:6所示氨基酸序列的轻链可变区(VL2)和重链可变区(VH2)。
在某些实施方案中,VL1位于VH1的N端。在某些实施方案中,VH2位于VL2的N端。
所述抗CD20抗原结合区可以是特异性结合CD20的单链可变片段(scFv)。所述抗CD19抗原结合区可以是特异性结合CD19的scFv。在某些实施方案中,特异结合CD20的scFv位于特异结合CD19的scFv的N端。
所述双特异性CAR可以进一步包含:(a)前导序列,(b)铰链区,(c)跨膜结构域,(d)至少一个共刺激信号传导区,(e)胞质信号传导结构域,或(f)其组合。
所述共刺激信号传导区可源自4-1BB(CD137)、CD28、OX40、CD2、CD7、CD27、CD30、CD40、CD70、CD134、PD1、Dap10、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、NKG2D、GITR、TLR2或其组合。
所述胞质信号传导结构域可以源自CD3ζ。
所述铰链区可以源自Ig4、CD8、CD28、CD137或其组合。
所述跨膜结构域可以源自CD8、CD28、CD3ε、CD45、CD4、CD5、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154或其组合。
在某些实施方案中,所述双特异性CAR可以具有SEQ ID NO:16所示的氨基酸序列。
本公开提供表达本发明双特异性CAR的免疫细胞。该免疫细胞可以是T细胞或自然杀伤(NK)细胞。该免疫细胞可以是同种异体的或自体的。
本公开还包括编码本发明双特异性CAR的核酸。
本公开还提供包含本发明核酸的载体。
本公开提供治疗癌症的方法。该方法可以包括对有需要的个体施用所述的免疫细胞。
所述癌症可以是血液癌症。所述癌症可以是B细胞恶性肿瘤。所述癌症可以是霍奇金淋巴瘤、非霍奇金淋巴瘤、白血病和/或多发性骨髓瘤。所述癌症可以是急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、慢性髓细胞性白血病、急性成淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)或其组合。
在本发明的第一方面,提供了嵌合抗原受体(CAR),其中该嵌合抗原受体的结构如下式I所示:
L-scFv1-I-scFv2-H-TM-C-CD3ζ(I)
其中,
每个“-”独立地是连接肽或肽键;
L是任选的信号肽序列;
I是柔性接头;
H是任选的铰链区;
TM是跨膜结构域;
C是共刺激信号分子;
CD3ζ是源自CD3ζ的胞质信号传导序列;
scFv1和scFv2两者之一是靶向CD19的抗原结合结构域,且另一者是靶向CD20的抗原结合结构域。
在另一个优选实施方案中,scFv1是靶向CD20的抗原结合结构域,而scFv2是靶向CD19的抗原结合结构域。
在另一个优选实施方案中,靶向CD20的抗原结合结构域的结构如下式A或式B所示:
VH1-VL1(A);VL1-VH1(B)
其中VH1是抗CD20抗体重链可变区;VL1是抗CD20抗体轻链可变区;“-”是连接肽或肽键。
在另一个优选实施方案中,靶向CD20的抗原结合结构域的结构如式B所示。
在另一个优选实施方案中,所述VH1的氨基酸序列如SEQ ID NO:1所示,且所述VL1的氨基酸序列如SEQ ID NO:2所示;或
所述VH1的氨基酸序列如SEQ ID NO:3所示,且所述VL1的氨基酸序列如SEQ ID NO:4所示。
在另一个优选实施方案中,所述VH1和VL1通过柔性接头(或连接肽)连接,并且该柔性接头(或连接肽)是1-4个、优选2-4个、更优选3-4个连续的如SEQ ID NO:7(GGGGS)所示的序列。
在另一个优选实施方案中,所述VL1和VH1通过如SEQ ID NO:19所示的柔性接头连接。
在另一个优选实施方案中,靶向CD19的抗原结合结构域的结构如下式C或式D所示:
VL2-VH2(C);VH2-VL2(D)
其中VL2是抗CD19抗体轻链可变区;VH2是抗CD19抗体重链可变区;“-”是连接肽或肽键。
在另一个优选实施方案中,靶向CD19的抗原结合结构域的结构如式D所示。
在另一个优选实施方案中,所述VL2的氨基酸序列如SEQ ID NO:5所示,所述VH2的氨基酸序列如SEQ ID NO:6所示。
在另一个优选实施方案中,所述VH2和VL2通过柔性接头(或连接肽)连接,并且该柔性接头(或连接肽)是1-4个、优选2-4个、更优选3-4个连续的如SEQ ID NO:7(GGGS)所示的序列。
在另一个优选实施方案中,所述VH2和VL1通过如SEQ ID NO:20所示的柔性接头连接。
在另一个优选实施方案中,所述scFv1和/或scFv2是鼠源的、人源的、人源和鼠源嵌合的或全人源化的单链抗体可变区片段。
在另一个优选实施方案中,所述嵌合抗原受体的结构如下式II所示:
L-VL1-VH1-I-VH2-VL2-H-TM-C-CD3ζ(II)
其中每个元件如上文所述。
在另一个优选实施方案中,柔性接头I的序列包含2-6个、优选3-4个连续的如SEQID NO:7(GGGS)所示的序列。
在另一个优选实施方案中,柔性接头I的序列如SEQ ID NO:7所示。
在另一个优选实施方案中,L是选自下组的蛋白的信号肽:CD8、CD28、GM-CSF、CD4、CD137及其组合。
在另一个优选实施方案中,L是源自CD8的信号肽。
在另一个优选实施方案中,L的氨基酸序列如SEQ ID NO:8所示。
在另一个优选实施方案中,H是选自下组蛋白的铰链区:CD8、CD28、CD137、Ig4及其组合。
在另一个优选实施方案中,H是源自Ig4的铰链区。
在另一个优选实施方案中,H的氨基酸序列如SEQ ID NO:9所示。
在另一个优选实施方案中,TM是选自下组蛋白的跨膜区:CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154及其组合。
在另一个优选实施方案中,TM是源自CD8或CD28的跨膜区。
在另一个优选实施方案中,TM的序列如SEQ ID NO:10或11所示。
在另一个优选实施方案中,C是选自下组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及其组合。
在另一个优选实施方案中,C是源自4-1BB或CD28的共刺激信号分子。
在另一个优选实施方案中,C的氨基酸序列如SEQ ID NO:12或13所示。
在另一个优选实施方案中,CD3ζ的氨基酸序列如SEQ ID NO:14所示。
在另一个优选实施方案中,CAR的氨基酸序列如SEQ ID NO:15或16所示。
在某些实施方案中,抗CD20抗原结合区包含重链可变区,该重链可变区包含与SEQID NO:3或SEQ ID NO:1所示的氨基酸序列具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的氨基酸序列。
在某些实施方案中,抗CD20抗原结合区包含轻链可变区,该轻链可变区包含与SEQID NO:4或SEQ ID NO:2所示的氨基酸序列具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的氨基酸序列。
在某些实施方案中,抗CD19抗原结合区包含重链可变区,该重链可变区包含与SEQID NO:6所示的氨基酸序列具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的氨基酸序列。
在某些实施方案中,抗CD19抗原结合区包含轻链可变区,该轻链可变区包含与SEQID NO:5所示的氨基酸序列具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的氨基酸序列。
抗CD20抗原结合区的重链可变区可以包含与奥法木单抗(Ofatumumab)重链可变区CDR(分别如SEQ ID NO:3的位置30-35、位置50-66、位置99-111所示的CDR1、CDR2和CDR3)或Leu16抗体重链可变区CDR(分别如SEQ ID NO:1的位置31-35、位置50-66、位置99-111所示的CDR1、CDR2、CDR3)具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、或约99%、或约100%同一性的一个、两个或三个互补决定区(CDR)。
抗CD20抗原结合区的轻链可变区可以包含与奥法木单抗轻链可变区CDR(分别如SEQ ID NO:4的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)或Leu16抗体轻链可变区CDR(分别如SEQ ID NO:2的位置24-33、位置49-55、位置88-96所示的CDR1、CDR2、CDR3)具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的一个、两个或三个互补决定区(CDR)。
抗CD20抗原结合区的重链可变区可以包含与奥法木单抗重链可变区CDR(分别如SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42所示的CDR1、CDR2和CDR3)或Leu16抗体重链可变区CDR(分别如SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:51所示的CDR1、CDR2、CDR3)具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的一个、两个或三个互补决定区(CDR)。
抗CD20抗原结合区的轻链可变区可以包含与奥法木单抗轻链可变区CDR(分别如SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45所示的CDR1、CDR2和CDR3)或Leu16抗体轻链可变区CDR(分别如SEQ ID NO:54、SEQ ID NO:56、SEQ ID NO:58所示的CDR1、CDR2、CDR3)具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的一个、两个或三个互补决定区(CDR)。
在某些实施方案中,抗CD20抗原结合区的重链可变区包含与奥法木单抗重链可变区CDR(如SEQ ID NO:3的位置30-35、位置50-66、位置99-111所示的CDR1、CDR2和CDR3)相同的三个CDR,且抗CD20抗原结合区的轻链可变区包含与奥法木单抗轻链可变区CDR(分别如SEQ ID NO:4的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)相同的三个CDR。
在某些实施方案中,抗CD20抗原结合区的重链可变区包含与奥法木单抗重链可变区CDR(分别如SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42所示的CDR1、CDR2和CDR3)相同的三个CDR,且抗CD20抗原结合区的轻链可变区包含与奥法木单抗轻链可变区CDR(分别如SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45所示的CDR1、CDR2和CDR3)相同的三个CDR。
在某些实施方案中,抗CD20抗原结合区的重链可变区包含与Leu16抗体重链可变区CDR(分别如SEQ ID NO:1的位置31-35、位置50-66、位置99-111所示的CDR1、CDR2、CDR3)相同的三个CDR,且抗CD20抗原结合区的轻链可变区包含与Leu16抗体轻链可变区CDR(分别如SEQ ID NO:2的位置24-33、位置49-55、位置88-96所示的CDR1、CDR2、CDR3)相同的三个CDR。
在某些实施方案中,抗CD20抗原结合区的重链可变区包含与Leu16抗体重链可变区CDR(分别如SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:51所示的CDR1、CDR2、CDR3)相同的三个CDR,且抗CD20抗原结合区的轻链可变区包含与Leu16抗体轻链可变区CDR(分别如SEQID NO:54、SEQ ID NO:56、SEQ ID NO:58所示的CDR1、CDR2、CDR3)相同的三个CDR。
抗CD19抗原结合区的重链可变区可以包含与FMC63抗体重链可变区CDR(分别如SEQ ID NO:6的位置31-35、位置50-65、位置98-109所示的CDR1、CDR2和CDR3)具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的一个、两个或三个互补决定区(CDR)。
抗CD19抗原结合区的轻链可变区可以包含与FMC63抗体轻链可变区CDR(分别如SEQ ID NO:5的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的一个、两个或三个互补决定区(CDR)。
抗CD19抗原结合区的重链可变区可以包含与FMC63抗体重链可变区CDR(分别如SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62所示的CDR1、CDR2和CDR3)具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的一个、两个或三个互补决定区(CDR)。
抗CD19抗原结合区的轻链可变区可以包含与FMC63抗体轻链可变区CDR(分别如SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:39所示的CDR1、CDR2和CDR3)具有至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一性的一个、两个或三个互补决定区(CDR)。
在某些实施方案中,抗CD19抗原结合区的重链可变区包含与FMC63抗体重链可变区CDR(分别如SEQ ID NO:6的位置31-35、位置50-65、位置98-109所示的CDR1、CDR2和CDR3)相同的三个CDR,且抗CD19抗原结合区的轻链可变区包含与FMC63抗体轻链可变区CDR(分别如SEQ ID NO:5的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)相同的三个CDR。
在某些实施方案中,抗CD19抗原结合区的重链可变区包含与FMC63抗体重链可变区CDR(分别如SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62所示的CDR1、CDR2和CDR3)相同的三个CDR,且抗CD19抗原结合区的轻链可变区包含与FMC63抗体轻链可变区CDR(分别如SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:39所示的CDR1、CDR2和CDR3)相同的三个CDR。
在本发明的第二方面,提供编码本发明第一方面的嵌合抗原受体的核酸分子。
在另一个优选实施方案中,所述核酸分子是分离的。
在另一个优选实施方案中,所述核酸分子的核苷酸序列如SEQ ID NO:17或18所示。
在本发明的第三方面,提供包含本发明第二方面的核酸分子的载体。
在另一个优选实施方案中,所述载体包含DNA、RNA。
在另一个优选实施方案中,所述载体选自质粒、病毒载体、转座子及其组合。
在另一个优选实施方案中,所述载体包括DNA病毒和逆转录病毒载体。
在另一个优选实施方案中,所述载体选自慢病毒载体、腺病毒载体、腺相关病毒载体及其组合。
在另一个优选实施方案中,所述载体是慢病毒载体。
在本发明的第四方面,提供宿主细胞,该宿主细胞包含本发明第三方面的载体、或具有整合到其基因组中的本发明第二方面的外源核酸分子、或表达本发明第一方面的嵌合抗原受体。
在另一个优选实施方案中,所述细胞是分离的细胞。
在另一个优选实施方案中,所述细胞是遗传改造的细胞。
在另一个优选实施方案中,所述细胞是哺乳动物细胞。
在另一个优选实施方案中,所述细胞是CAR-T细胞和/或CAR-NK细胞。
在另一个优选实施方案中,所述细胞靶向CD19和CD20二者。
在本发明的第五方面,提供用于制备表达本发明第一方面的嵌合抗原受体的CAR-T细胞的方法,其中该方法包括以下步骤:将本发明第二方面的核酸分子或本发明第三方面的载体转导入T细胞,从而获得CAR-T细胞。
在另一个优选实施方案中,该方法进一步包括检测所获得的CAR-T细胞的功能和有效性的步骤。
在本发明的第六方面,提供制剂,其包含本发明第一方面的嵌合抗原受体、本发明第二方面的核酸分子、本发明三方面的载体或本发明第四方面的宿主细胞,以及可药用载体、稀释剂或赋形剂。
在另一个优选实施方案中,所述制剂为液体制剂。
在另一个优选实施方案中,所述制剂的剂型是注射剂。
在另一个优选实施方案中,所述制剂包含本发明第四方面的宿主细胞,且所述宿主细胞的浓度为1×103-1×108细胞/ml,优选1×104-1×107细胞/ml。
在本发明的第七方面,提供本发明第一方面的嵌合抗原受体、本发明第二方面的核酸分子、本发明三方面的载体或本发明第四方面的宿主细胞在制备用于预防和/或治疗肿瘤或癌症的药物或制剂中的用途。
在另一个优选实施方案中,所述肿瘤选自血液肿瘤、实体瘤及其组合;优选地,所述肿瘤是血液肿瘤。
在另一个优选实施方案中,所述血液肿瘤选自急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性成淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)及其组合。
在另一个优选实施方案中,所述实体瘤选自胃癌、胃癌腹膜转移、肝癌、白血病、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、淋巴瘤、鼻咽癌、肾上腺肿瘤、膀胱肿瘤、非小细胞肺癌(NSCLC)、胶质瘤、子宫内膜癌及其组合。
在本发明的第八方面,提供用于制备本发明第四方面的细胞的试剂盒,其中该试剂盒包含容器以及位于该容器中的本发明第二方面的核酸分子或本发明第三方面的载体。
在本发明的第九方面,提供本发明第四方面的细胞或本发明第六方面的制剂在预防和/或治疗癌症或肿瘤中的用途。
在本发明的第十方面,提供治疗疾病的方法,其包括对需要治疗的个体施用适量的本发明第四方面的细胞或本发明第六方面的制剂。
在另一个优选实施方案中,所述疾病是癌症或肿瘤。
本公开提供双特异性嵌合抗原受体(CAR)。该双特异性CAR可以包含:(i)含有轻链可变区(VL1)和重链可变区(VH1)的抗CD20抗原结合区;以及(ii)含有轻链变区(VL2)和重链可变区(VH2)的抗CD19抗原结合区。VL1可以包含三个互补决定区(CDR),即CDR1、CDR2和CDR3,其分别具有与SEQ ID NO:43、SEQ ID NO:44和SEQ ID NO:45所示的氨基酸序列约80%至约100%、约85%至约100%、约90%至约100%或约95%至约100%同一性的氨基酸序列。VH1可以包含三个CDR,即CDR1、CDR2和CDR3,其分别具有与SEQ ID NO:40、SEQ ID NO:41、SEQ ID:42所示的氨基酸序列约80%至约100%、约85%至约100%、约90%至约100%或约95%至约100%同一性的氨基酸序列。VL2可以包含三个互补决定区(CDR),即CDR1、CDR2和CDR3,其分别具有与SEQ ID NO:63、SEQ ID NO:64和SEQ ID NO:39所示的氨基酸序列约80%至约100%、约85%至约100%、约90%至约100%或约95%至约100%同一性的氨基酸序列。VH2可以包含三个CDR,即CDR1、CDR2和CDR3,其分别具有与SEQ ID NO:60、SEQ ID NO:61、SEQ ID:62所示的氨基酸序列约80%至约100%、约85%至约100%、约90%至约100%或约95%至约100%同一性的氨基酸序列。
在某些实施方案中,VL1位于VH1的N端。
在某些实施方案中,VH2位于VL2的N端。
在某些实施方案中,VL1和VH1分别具有与SEQ ID NO:4和SEQ ID NO:3所示的氨基酸序列约80%至约100%同一性的氨基酸序列。
在某些实施方案中,VL2和VH2分别具有与SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列约80%至约100%同一性的氨基酸序列。
在某些实施方案中,抗CD20抗原结合区是特异性结合CD20的单链可变片段(scFv)。在某些实施方案中,抗CD19抗原结合区是特异性结合CD19的scFv。
所述双特异性CAR可以进一步包含以下之一或多个元件:(a)信号肽,(b)铰链区,(c)跨膜结构域,(d)共刺激区,和(e)胞质信号传导结构域。
所述共刺激区可以包含选自下组蛋白的共刺激区:4-1BB(CD137)、CD28、OX40、CD2、CD7、CD27、CD30、CD40、CD70、CD134、PD1、Dap10、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、NKG2D、GITR、TLR2或其组合。
所述胞质信号传导结构域可以包含CD3ζ的胞质信号传导结构域。
所述铰链区可以包含选自下组蛋白(野生型和突变体)的铰链区:Ig4、CD8、CD28、CD137或其组合。
所述跨膜结构域可以包括选自下组蛋白的跨膜结构域:CD8、CD28、CD3ε、CD45、CD4、CD5、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154或其组合。
在某些实施方案中,所述双特异性CAR包含与SEQ ID NO.16所示的氨基酸序列约80%至约100%、约85%至约100%、约90%至约100%或约95%至约100%同一性的氨基酸序列。
本公开提供表达本发明双特异性CAR的免疫细胞。该免疫细胞可以是T细胞或自然杀伤(NK)细胞。
本公开还包括编码本发明双特异性CAR的核酸。
本公开提供包含本发明核酸的载体。
本公开还提供治疗癌症的方法。该方法可以包括对有需要的个体施用本发明的免疫细胞。
所述免疫细胞可以是同种异体的或自体的。
所述癌症可以是血液癌症。该癌症可以是B细胞恶性肿瘤。该癌症可以是霍奇金淋巴瘤、非霍奇金淋巴瘤、白血病和/或多发性骨髓瘤。该癌症可以是急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、慢性髓细胞性白血病、急性成淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)或其组合。
在某些实施方案中,在对个体施用所述双特异性CAR后约28天中,该双特异性CAR可以在个体血液中产生约0.5e+06拷贝/μg基因组DNA(拷贝/gDNA)至约4e+06拷贝/gDNA、约0.5e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.5e+06拷贝/gDNA、约1e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.5e+06拷贝/gDNA、约1.2e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.2e+06拷贝/gDNA、约0.8e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.2e+06拷贝/gDNA、约1.6e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.2e+06拷贝/gDNA、约1e+06拷贝/μg基因组DNA(拷贝/gDNA)至约2e+06拷贝/gDNA、约0.6e+06拷贝/μg基因组DNA(拷贝/gDNA)至约1.8e+06拷贝/gDNA、约3e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.2e+06拷贝/gDNA、约0.5e+06拷贝/μg基因组DNA(拷贝/gDNA)至约1.7e+06拷贝/gDNA、约2e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.2e+06拷贝/gDNA、约1.5e+06拷贝/μg基因组DNA(拷贝/gDNA)至约2e+06拷贝/gDNA、或约1e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.2e+06拷贝/gDNA的曲线下面积(AUC)。
在某些实施方案中,在对个体施用所述双特异性CAR后,该双特异性CAR在个体血液中产生约0.8e+05拷贝/μg基因组DNA(拷贝/gDNA)至约3.5e+05拷贝/gDNA、约1e+05拷贝/μg基因组DNA(拷贝/gDNA)至约3.5e+05拷贝/gDNA、约1e+05拷贝/μg基因组DNA(拷贝/gDNA)至约1.6e+05拷贝/gDNA、约1e+05拷贝/μg基因组DNA(拷贝/gDNA)至约3.3e+05拷贝/gDNA、约0.8e+05拷贝/μg基因组DNA(拷贝/gDNA)至约1.5e+05拷贝/gDNA、约0.8e+05拷贝/μg基因组DNA(拷贝/gDNA)至约2e+05拷贝/gDNA、约1e+05拷贝/μg基因组DNA(拷贝/gDNA)至约2e+05拷贝/gDNA、约2e+05拷贝/μg基因组DNA(拷贝/gDNA)至约3e+05拷贝/gDNA、约2e+05拷贝/μg基因组DNA(拷贝/gDNA)至约3.5e+05拷贝/gDNA、约2e+05拷贝/μg基因组DNA(拷贝/gDNA)至约2.5e+05拷贝/gDNA、或约1e+05拷贝/μg基因组DNA(拷贝/gDNA)至约3e+05拷贝/gDNA的最大血浆浓度(Cmax)。
在某些实施方案中,所述双特异性CAR具有约3天至约20天、约4天至约18天、约5天至约17天、约6天至约16天、约7天至约15天、约9天至约15天、约10天至约15天、约10天至约14天、约8天至约12天、约6天至约14天、约12天至约14天、约8天至约11天、约8天至约15天、或约10天至约14天的Tmax(所述双特异性CAR达到Cmax所花费的时间)。
应当理解,上述本发明的各种技术特征和下文(如实施例中)具体描述的各种技术特征可以在本发明的范围内相互组合,以构成新的或优选的技术方案,其由于篇幅限制而无需逐一描述。
附图简述
图1显示靶向CD19和CD20的联合嵌合抗原受体的结构。CAR的结构包括信号肽序列(“SP”)、抗原识别序列、铰链区、跨膜区、共刺激因子信号区和CD3ζ信号传导区。
图2A和2B显示T细胞膜表面CD137的表达水平(图2A)和培养上清液中IFNγ的分泌水平(图2B)。具体而言,取1×105个培养7天的CAR-T19/20细胞,在200μl GT-551培养基中,以1:1的比例分别与CD19阳性K562-CD19+肿瘤细胞系、CD20阳性K562-CD20+肿瘤细胞系、CD19和CD20双阳性K562-CD19+CD20+肿瘤细胞系、天然表达CD19和CD20的RAJI肿瘤细胞系、以及CD19和CD20双阴性K562肿瘤细胞系共培养18h,或在无肿瘤细胞的情况下培养18h。然后分别检测T细胞膜表面CD137的表达水平和培养上清液中IFNγ的分泌水平。
图3A显示CAR-T19/20细胞的肿瘤杀伤活性检测,主要通过检测共培养后上清液中LDH的分泌水平来进行。具体而言,按图中所示比例,分别将CD19阳性K562-CD19+肿瘤细胞系、CD20阳性K562-CD20+肿瘤细胞系、CD19和CD20双阳性K562-19+CD20+肿瘤细胞系、天然表达CD19和CD20的RAJI或RAMOS肿瘤细胞系或CD19和CDM20双阴性K562肿瘤细胞系的1×104个细胞与相应的T细胞在100μl GT-551培养基中共培养8h。然后检测LDH的分泌水平,此图显示相应共培养样品中LDH释放百分比的统计分析结果。
图3B显示CAR-T19/20细胞的肿瘤杀伤活性检测,主要通过检测T细胞膜表面CD107a的表达水平来进行。具体而言,取1×105个CAR-T19/20细胞,在200μl GT-551培养基中以1:2的比例分别与CD19阳性K562-CD19+肿瘤细胞系、CD20阳性K562-CD20+肿瘤细胞系、CD19和CD20双阳性K562-19+CD20+肿瘤细胞系、天然表达CD19和CD20的RAJI或RAMOS肿瘤细胞系以及CD19和CDM20双阴性K562肿瘤细胞系共培养4h、或在无肿瘤细胞情况下培养4h。然后分别检测T细胞膜表面的CD137表达水平。
图4A显示注射CAR-T19/20细胞的小鼠在21天内每7天记录一次的平均体重变化和平均荧光强度变化。
图4B显示三组小鼠的平均荧光强度。
图4C显示注射CAR-T19/20细胞的小鼠在注射后第0天(D0)、第7天(D7)、第14天(D14)和第21天(D21)的体内成像。
图5A显示双特异性TN-OF-19CAR-T细胞能够在体内比CD19特异性CAR-T细胞更好地抑制或杀伤肿瘤细胞。
图5B显示4个CAR-T细胞组和NT组的荧光强度IVIS成像。
图6A显示CD20scFv-CD19scFv rabFc的结构。
图6B显示嵌合抗体与具有CD19或CD20或二者的细胞结合,但不与缺乏这两种抗原的细胞结合,表明该双特异性结合结构域只需要一个关联抗原用于结合,并且没有新的特异性识别位点形成。
图7显示具有6种不同的scFV和不同的铰链/TM/信号传导结构域的16种CD20特异性CAR的结构。
图8A显示筛选CAR-T20.1、CAR-T20.5、CAR-T20.6、CAR-T20.7、CAR-T20.8、CAR-T20.9和CAR-T20.10的IFNγ释放测定试验的结果,在这些CAR-T中,只有CAR-T20.9(Leu16)和CAR-T10.10(Leu16)显示了较高的阳性IFNγ释放。
图8B显示筛选CAR-T20.1、CAR-T20.9、CAR-T20.10、CAR-T20.11、CAR-T20.12、CAR-T20.13、CAR-T20.14、CAR-T20.15和CAR-T20.16的IFNγ释放测定试验的结果。在这些CAR-T中,CAR-T20.10(Leu16)和CAR-T20.14(OF)显示了较高的阳性IFNγ释放。
图8C显示筛选CAR-T20.9、CAR-T20.12、CAR-T20.14、CAR-T20.17、CAR-T20.18和CAR-T20.19的IFNγ释放测定试验的结果。在这些CAR-T中,CAR-T20.14(OF)和CAR-T20.19(OF)显示较高的阳性IFNγ释放。
图9A显示通过LDH释放测定试验检测CAR-T20.17(Leu16第三代)、CAR-T20.18(Leu16第二代)、CAR-T20.19(OF第二代)细胞的细胞毒性的结果。
图9B显示NSG小鼠研究中的体内肿瘤生长抑制。注射到动物体内的肿瘤细胞是表达荧光素酶的Raji细胞。
图10显示CAR039 I期临床研究设计和流程图。
图11显示C-CAR039临床结果总结。
图12显示C-CAR039治疗前后的患者实例。
图13显示患者外周血中C-CAR039的增殖和扩增以及B细胞耗竭。结果显示,注射后C-CAR008细胞有效扩增。方形:1x106个CAR-T细胞/kg。三角形:2~2.5x106个CAR-T细胞/kg。圆形:4~5.0x106个CAR-T细胞/kg。实心符号(方形、三角形、圆形):CAR-T DNA拷贝。空心符号(方形、三角形、圆形):CD19/CD20+B细胞水平。
图14显示C-CAR066-NHL研究设计。
图15显示C-CAR066治疗前后患者的PET-CT实例。
图16A-16D:抗CD19/CD20双特异性CAR的最佳抗原结合结构域的鉴定。图16A显示TN-OF-19(C-CAR039)和TN-19-OF的结构。图16B显示,具有奥法木单抗scFv以及之后串联连接的FMC63 scFv的C-CAR039具有优越的抗肿瘤活性。图16C显示TN-OF-19(C-CAR039)、TN-OFR-19、TN-OF-19R和TN-OFR-19R的结构。图16D显示优越的抗肿瘤活性和特异性与C-CAR039抗原结合结构域的最佳结构关联。
图17A显示评价C-CAR039抗原结合结构域的结合特异性的方法。图17B显示鉴定到CD19、CD20和FCGR1A在5.0μg/mL浓度下具有中等结合。未鉴定到其他显著的相互作用。据报道,FCGR1结合rabFc。
图18显示Kaplan-Meyer估计的C-CAR039的无进展生存期(PFS)。
图19显示C-CAR039的药代动力学(PK)/药效学(PD)性质。低剂量(“低”):1x106个CAR-T细胞/kg体重;中剂量(“中”):2x106-2.5x106个CAR-T细胞/kg体重;高剂量(“高”):4x106-5.0x106个CAR-T细胞/kg体重。
图20显示复发患者外周血中的PK/PD曲线(CAR-T扩增和B细胞耗竭)。
发明详述
经过广泛和深入的研究后,本发明人意外地获得了同时靶向CD19和CD20的CAR-T细胞。具体而言,本发明提供同时靶向CD19和CD20的嵌合抗原受体,其包含信号肽、抗CD20scFv、抗CD19 scFv、铰链区、跨膜区和胞内T细胞信号传导区。此外,通过大量筛选获得了抗CD20 scFv和抗CD19 scFv,其通过具有多个重复结构(G4S)的肽片段连接。本发明的CAR-T细胞可以同时识别CD19和CD20抗原,降低了在单靶标CAR-T细胞治疗期间由抗原表达下调或缺失导致的免疫逃逸风险。与靶向单个抗原的CAR-T细胞和其他双靶标CAR-T细胞(靶向CD19和CD20)相比,同时识别两个靶标的本发明CAR-T细胞对肿瘤细胞的杀伤能力更强、细胞毒性更小、副作用更低、治疗范围更广、复发率更低、且疗效更好。在此基础上完成了本发明。
术语
为了使本公开更易于理解,首先定义一些术语。除非另有明确说明,否则本申请中使用的下列术语中的每一个应具有下文给出的含义。其他定义在本申请通篇中阐述。
术语“约”可以指由本领域技术人员确定的特定值或组成的可接受误差范围内的值或组成,其部分取决于如何测量或确定该值或组成。
术语“施用”是指使用本领域技术人员已知的多种方法和递送系统中的任何一种将本发明产品物理引入个体,包括静脉内、肌内、皮下、腹膜内、脊髓或其他胃肠外施用,例如通过注射或输注。
术语“抗体”(Ab)可以包括但不限于特异性结合抗原且包含通过二硫键连接的至少两条重(H)链和两条轻(L)链的免疫球蛋白或其抗原结合部分。每条H链包含重链可变区(本文缩写为VH)和重链恒定区。重链恒定区包含三个恒定结构域CH1、CH2和CH3。每条轻链包含轻链可变区(以下简称VL)和轻链恒定区。轻链恒定区包含一个恒定结构域CL。VH和VL区可进一步细分为称为互补决定区(CDR)的高变区,其散布在称为构架区(FR)的更保守区域内。每个VH和VL包含三个CDR和四个FR,从氨基端到羧基端按以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。重链和轻链的可变区包含与抗原相互作用的结合结构域。
CD20
尽管抗CD19 CAR-T的疗效突出,但许多研究表明,CD19嵌合抗原受体(CAR)T细胞治疗仍存在许多问题。仍有一些患者治疗效果不佳且容易复发。这包括肿瘤细胞对抗原逃逸的易感性。
为了预防CD19 CAR-T抗原的逃逸,本发明人设计了靶向CD19和CD20二者的联合双特异性CAR(即BICAR),以便在CD19抗原逃逸和不在肿瘤细胞中表达时,可以识别CD20来清除体内的肿瘤细胞。
CD20在大多数B细胞急性成淋巴细胞白血病患者中表达,包括一些在抗CD19 CAR-T治疗后的CD19阴性患者。CD20是糖基化蛋白质,是第一个鉴定的B细胞膜标记物。CD20也称为B1,由MS4A基因编码。CD20分子有四个跨膜疏水区,其N端和C端位于胞质侧,在胞外形成两个闭环,分别称为大环和小环。CD20在95%以上的正常和癌性B细胞中特异表达。这些细胞处于前B细胞阶段和随后的发育阶段,CD20直至细胞分化为浆细胞后才停止表达。本发明使用CD20作为B细胞恶性肿瘤免疫治疗的另一个靶标。
靶向CD19和CD20的双特异性嵌合抗原受体
细胞免疫治疗是一种新兴的、具有显著疗效的肿瘤治疗模式,是一种自身免疫抗癌新疗法。作为一种方法,它运用生物技术和生物制剂对从患者采集的免疫细胞进行体外培养和扩增,然后回输到患者体内来刺激和增强机体的自身免疫功能,从而达到治疗肿瘤的目的。本领域技术人员一直致力于开发新的细胞免疫疗法,以提高细胞免疫疗法的效果,并降低其副作用。
本发明提出了一种合理的优化单链设计和系统,即联合双特异性CAR,所述CAR可以有效地整合到原代人T细胞中,在T细胞激活时可以同时靶向CD19和CD20。本发明的CAR-T细胞能够识别两种抗原(CD19和CD20)。本发明提供了一种非常有效的潜在预防抗原逃逸的方法。
本发明使用同时靶向CD19和CD20的CAR。与靶向单个抗原的CAR相比,亲和力增强,T细胞活性提高,并且这些靶标具有相加或协同效应。此外,由于CD19和CD20在肿瘤细胞中的表达水平不均一,双靶向CAR-T治疗具有更广泛的范围。同时靶向肿瘤细胞表面的CD19和CD20的CAR-T可以减少因单一表面抗原下调或缺失造成的抗原逃逸的可能性。
双特异性是指同一个CAR可以特异性结合和免疫识别两种不同的抗原,并且该CAR可以通过结合这些抗原中任何一种而产生免疫反应。
本发明的CD19和CD20双特异性CAR具有单一结构,并且包含抗CD19和抗CD20scFv。其中,CAR包含CD19 scFv和CD20 scFv,且其中CD19 scF v和CD20 scFv的氨基酸序列、排序和铰链是其功能的主要影响因素。
具体而言,本发明的嵌合抗原受体(CAR)包含胞外结构域、跨膜结构域和胞内结构域。胞外结构域包括靶标特异性结合元件(也称为抗原结合结构域)。胞内结构域包括共刺激信号传导区和ζ链。共刺激信号传导区是指包含共刺激分子的胞内结构域的一部分。共刺激分子是淋巴细胞对抗原有效应答所需的细胞表面分子,而不是抗原受体或其配体。
在CAR的胞外结构域和跨膜结构域之间、或者在CAR的胞质结构域和跨膜结构域之间,可以并入接头。本文所用的术语“接头”通常指在多肽链中起到将跨膜结构域连接到的胞外结构域或胞质结构域的作用的任何寡肽或多肽。接头可以包含0-300个氨基酸、优选2-100个氨基酸,最优选3-50个氨基酸。
在本发明的一个优选实施方案中,本发明提供的CAR的胞外结构域包含靶向CD19和CD20的抗原结合结构域。本发明的CAR在T细胞中表达时,可以基于抗原结合特异性进行抗原识别。在CAR与其关联抗原结合时,它会影响肿瘤细胞,导致肿瘤细胞无法生长、死亡或受到其他影响,并导致患者的肿瘤负荷缩小或消除。抗原结合结构域优选与来自一个或多个共刺激分子和ζ链的胞内结构域融合。优选地,抗原结合结构域与具有4-1BB信号传导结构域和CD3ζ信号传导结构域的组合的胞内结构域融合。
本文所用的“抗原结合结构域”和“单链抗体片段”指具有抗原结合活性的Fab片段、Fab’片段、F(ab’)2片段或单个Fv片段。Fv抗体包含抗体的重链可变区和轻链可变区,但没有恒定区。Fv抗体是具有所有抗原结合位点的最小抗体片段。通常,Fv抗体还包含VH和VL结构域之间的多肽接头,并且可以形成抗原结合所需的结构。该抗原结合结构域通常是scFv(单链可变片段)。scFv的大小通常是完整抗体的1/6。单链抗体优选是由核苷酸链编码的氨基酸链序列。作为本发明的一个优选实施方案,scFv包含特异识别CD19和CD20的抗体。
对于铰链区和跨膜区(跨膜结构域),CAR可以设计为包含与CAR的胞外结构域融合的跨膜结构域。在一个实施方案中,使用与CAR中的结构域之一天然关联的跨膜结构域。在一些实施方案中,可以选择跨膜结构域或通过氨基酸取代来修饰跨膜结构域,以避免该结构域结合至相同或不同表面膜蛋白的跨膜结构域,从而最小化与受体复合体的其他成员的相互作用。
本发明CAR中的胞内结构域包含4-1BB的信号传导结构域和CD3ζ的信号传导结构域。
优选地,本发明的CAR结构包含信号肽序列(也称为前导序列)、抗原识别序列(抗原结合结构域)、铰链区、跨膜区、共刺激因子信号区和CD3ζ信号传导区(ζ链部分)。连接顺序如图1所示。
在另一个优选实施方案中,本发明的CAR为TN-LEU-19。靶向CD20的抗原结合结构域包含源自Leu16抗体的单链可变区的重链序列(SEQ ID NO:1)和轻链(VL)序列(SEQ IDNO:2)。
源自Leu16抗体的单链可变区的重链序列(VH):
EVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSS(SEQ ID NO:1)
LEU-VH-CDR1:SEQ ID NO:1,位置31-35;
LEU-VH-CDR2:SEQ ID NO:1,位置50-66;
LEU-VH-CDR3:SEQ ID NO:1,位置99-111。
源自Leu16抗体的单链可变区的轻链序列(VL):
DIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIK(SEQ ID NO:2)
LEU-VL-CDR1:SEQ ID NO:2,位置24-33;
LEU-VL-CDR2:SEQ ID NO:2,位置49-55;
LEU-VL-CDR3:SEQ ID NO:2,位置88-96。
在另一个优选实施方案中,本发明的CAR为TN-OF-19。靶向CD20的抗原结合结构域包含源自奥法木单抗的单链可变区的重链序列(SEQ ID NO:3)和轻链序列(SEQ ID NO:4)。
源自奥法木单抗的单链可变区的重链序列(VH):
EVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSTISWNSGSIGYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTVSS(SEQ ID NO:3)
OF-VH-CDR1:SEQ ID NO:3,位置30-35。OF-VH-CDR1的序列为:NDYAMH(SEQ ID NO:40)。
OF-VH-CDR2:SEQ ID NO:3,位置50-66。OF-VH-CDR2的序列为:TISWNSGSIGYADSVKG(SEQ ID NO:41)。
OF-VH-CDR3:SEQ ID NO:3,位置99-111。OF-VH-CDR3的序列为:DIQYGNYYYGMDV(SEQ ID NO:42)。
源自奥法木单抗的单链可变区的轻链序列(VL):
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK(SEQ ID NO:4)
OF-VL-CDR1:SEQ ID NO:4,位置24-34。OF-VL-CDR1的序列为:RASQSVSSYLA(SEQID NO:43)。
OF-VL-CDR2:SEQ ID NO:4,位置50-56。OF-VL-CDR2的序列为:DASNRAT(SEQ IDNO:44)。
OF-VL-CDR3:SEQ ID NO:4,位置89-97。OF-VL-CDR3的序列为:QQRSNWPIT(SEQ IDNO:45)。
在另一个优选实施方案中,本发明的CAR中靶向CD19的抗原结合结构域包含源自FMC63抗体的单链可变区的轻链(VL)序列(SEQ ID NO:5)和重链(VH)序列(SEQ ID NO:6)。
源自FMC63抗体的单链可变区的轻链(VL)的氨基酸序列:
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIT(SEQ ID NO:5)
FMC63-VL-CDR1:SEQ ID NO:5,位置24-34。FMC63-VL-CDR1的序列为:RASQDISKYLN(SEQ ID NO:63)。
FMC63-VL-CDR2:SEQ ID NO:5,位置50-56。FMC63-VL-CDR2的序列为:HTSRLHS(SEQID NO:64)。
FMC63-VL-CDR3:SEQ ID NO:5,位置89-97。FMC63-VL-CDR3的序列为:QQGNTLPYT(SEQ ID NO:39)。
源自FMC63抗体的单链可变区的轻链(VL)的核苷酸序列:
gacatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atcagttgca gggcaagtca ggacattagt aaatatttaa attggtatca gcagaaacca 120
gatggaactg ttaaactcct gatctaccat acatcaagat tacactcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggagcaa 240
gaagatattg ccacttactt ttgccaacag ggtaatacgc ttccgtacac gttcggaggg 300
gggaccaagc tggagatcac a 321(SEQ ID NO:21)
源自FMC63抗体的单链可变区的重链(VH)的氨基酸序列:
EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS(SEQ ID NO:6)
FMC63-VH-CDR1:SEQ ID NO:6,位置31-35。FMC63-VH-CDR1的序列为:DYGVS(SEQID NO:60)。
FMC63-VH-CDR2:SEQ ID NO:6,位置50-65。FMC63-VH-CDR2的序列为:VIWGSETTYYNSALKS(SEQ ID NO:61)。
FMC63-VH-CDR3:SEQ ID NO:6,位置98-109。FMC63-VH-CDR3的序列为:HYYYGGSYAMDY(SEQ ID NO:62)。
源自FMC63抗体的单链可变区的重链(VH)的核苷酸序列:
gaggtgaaac tgcaggagtc aggacctggc ctggtggcgc cctcacagag cctgtccgtc 60
acatgcactg tctcaggggt ctcattaccc gactatggtg taagctggat tcgccagcct 120
ccacgaaagg gtctggagtg gctgggagta atatggggta gtgaaaccac atactataat 180
tcagctctca aatccagact gaccatcatc aaggacaact ccaagagcca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccatttact actgtgccaa acattattac 300
tacggtggta gctatgctat ggactactgg ggccaaggaa cctcagtcac cgtctcctca 360
(SEQ ID NO:22)
特别地,本发明的CAR中的其他元件的序列如下:
前导序列是CD8抗原的前导序列:
MALPVTALLLPLALLLHAARP(SEQ ID NO:8)
单链可变区的重链和轻链之间的接头序列(即柔性接头I)为:
CD20 scfv的VL和VH之间的接头的氨基酸序列:
GSTSGGGSGGGSGGGGSS(SEQ ID NO:19)
CD19 scFv的VH和VL之间的接头的氨基酸序列:
GSTSGSGKPGSGEGSTKG(SEQ ID NO:20)
铰链区选自短形式IgG4铰链的序列:
ESKYGPPCPPCP(SEQ ID NO:9)
跨膜区是CD8(CD8TM)或CD28(CD28TM)抗原的跨膜区序列:
CD8TM:IYIWAPLAGTCGVLLLSLVITLYC(SEQ ID NO:10)
CD28TM:MFWVLVVVGGVLACYSLLVTVAFIIFWV(SEQ ID NO:11)
共刺激因子信号区源自4-1BB或CD28胞质信号传导基序的序列:
4-1BB:
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO:12)
CD28:
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO:13)
CD3ζ的信号传导区源自TCR复合物中CD3ζ的免疫受体酪氨酸激活基序(ITAM)的序列:
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:14)
在优选实施方案中,本发明中构建的两个CAR的完整核酸序列和氨基酸序列如下:
TN-OF-19的完整核酸序列如下:
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAACTATTAGTTGGAATAGTGGTTCCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAGTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATACAGTACGGCAACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGGAGGTGGTGGATCCGAGGTGAAGCTGCAGGAAAGCGGCCCTGGCCTGGTGGCCCCCAGCCAGAGCCTGAGCGTGACCTGCACCGTGAGCGGCGTGAGCCTGCCCGACTACGGCGTGAGCTGGATCCGGCAGCCCCCCAGGAAGGGCCTGGAATGGCTGGGCGTGATCTGGGGCAGCGAGACCACCTACTACAACAGCGCCCTGAAGAGCCGGCTGACCATCATCAAGGACAACAGCAAGAGCCAGGTGTTCCTGAAGATGAACAGCCTGCAGACCGACGACACCGCCATCTACTACTGCGCCAAGCACTACTACTACGGCGGCAGCTACGCCATGGACTACTGGGGCCAGGGCACCAGCGTGACCGTGAGCAGCGGCAGCACCTCCGGCAGCGGCAAGCCTGGCAGCGGCGAGGGCAGCACCAAGGGCGACATCCAGATGACCCAGACCACCTCCAGCCTGAGCGCCAGCCTGGGCGACCGGGTGACCATCAGCTGCCGGGCCAGCCAGGACATCAGCAAGTACCTGAACTGGTATCAGCAGAAGCCCGACGGCACCGTCAAGCTGCTGATCTACCACACCAGCCGGCTGCACAGCGGCGTGCCCAGCCGGTTTAGCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATCTCCAACCTGGAACAGGAAGATATCGCCACCTACTTTTGCCAGCAGGGCAACACACTGCCCTACACCTTTGGCGGCGGAACAAAGCTGGAAATCACCGAGAGCAAGTACGGACCGCCCTGCCCCCCTTGCCCTATGTTCTGGGTGCTGGTGGTGGTCGGAGGCGTGCTGGCCTGCTACAGCCTGCTGGTCACCGTGGCCTTCATCATCTTTTGGGTGAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGGGTGAAGTTCAGCAGAAGCGCCGACGCCCCTGCCTACCAGCAGGGCCAGAATCAGCTGTACAACGAGCTGAACCTGGGCAGAAGGGAAGAGTACGACGTCCTGGATAAGCGGAGAGGCCGGGACCCTGAGATGGGCGGCAAGCCTCGGCGGAAGAACCCCCAGGAAGGCCTGTATAACGAACTGCAGAAAGACAAGATGGCCGAGGCCTACAGCGAGATCGGCATGAAGGGCGAGCGGAGGCGGGGCAAGGGCCACGACGGCCTGTATCAGGGCCTGTCCACCGCCACCAAGGATACCTACGACGCCCTGCACATGCAGGCCCTGCCCCCAAGG(SEQ ID NO:18)
TN-OF-19的完整氨基酸序列如下:
MALPVTALLLPLALLLHAARPEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKGSTSGGGSGGGSGGGGSSEVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSTISWNSGSIGYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTVSSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSGSTSGSGKPGSGEGSTKGDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITESKYGPPCPPCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:16)
TN-LEU-19的完整核酸序列如下:
ATGGAGACAGACACACTCCTGCTATGGGTGCTGCTGCTCTGGGTTCCAGGTTCCACAGGTGACATTGTGCTGACCCAATCTCCAGCTATCCTGTCTGCATCTCCAGGGGAGAAGGTCACAATGACTTGCAGGGCCAGCTCAAGTGTAAATTACATGGACTGGTACCAGAAGAAGCCAGGATCCTCCCCCAAACCCTGGATTTATGCCACATCCAACCTGGCTTCTGGAGTCCCTGCTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGAGTGGAGGCTGAAGATGCTGCCACTTATTACTGCCAGCAGTGGAGTTTTAATCCACCCACGTTCGGAGGGGGGACCAAGCTGGAAATAAAAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGAGGTGCAGCTGCAGCAGTCTGGGGCTGAGCTGGTGAAGCCTGGGGCCTCAGTGAAGATGTCCTGCAAGGCTTCTGGCTACACATTTACCAGTTACAATATGCACTGGGTAAAGCAGACACCTGGACAGGGCCTGGAATGGATTGGAGCTATTTATCCAGGAAATGGTGATACTTCCTACAATCAGAAGTTCAAAGGCAAGGCCACATTGACTGCAGACAAATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGACTATTACTGTGCAAGATCTAATTATTACGGTAGTAGCTACTGGTTCTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCAGGAGGTGGTGGATCCGAGGTGAAGCTGCAGGAAAGCGGCCCTGGCCTGGTGGCCCCCAGCCAGAGCCTGAGCGTGACCTGCACCGTGAGCGGCGTGAGCCTGCCCGACTACGGCGTGAGCTGGATCCGGCAGCCCCCCAGGAAGGGCCTGGAATGGCTGGGCGTGATCTGGGGCAGCGAGACCACCTACTACAACAGCGCCCTGAAGAGCCGGCTGACCATCATCAAGGACAACAGCAAGAGCCAGGTGTTCCTGAAGATGAACAGCCTGCAGACCGACGACACCGCCATCTACTACTGCGCCAAGCACTACTACTACGGCGGCAGCTACGCCATGGACTACTGGGGCCAGGGCACCAGCGTGACCGTGAGCAGCGGCAGCACCTCCGGCAGCGGCAAGCCTGGCAGCGGCGAGGGCAGCACCAAGGGCGACATCCAGATGACCCAGACCACCTCCAGCCTGAGCGCCAGCCTGGGCGACCGGGTGACCATCAGCTGCCGGGCCAGCCAGGACATCAGCAAGTACCTGAACTGGTATCAGCAGAAGCCCGACGGCACCGTCAAGCTGCTGATCTACCACACCAGCCGGCTGCACAGCGGCGTGCCCAGCCGGTTTAGCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATCTCCAACCTGGAACAGGAAGATATCGCCACCTACTTTTGCCAGCAGGGCAACACACTGCCCTACACCTTTGGCGGCGGAACAAAGCTGGAAATCACCGAGAGCAAGTACGGACCGCCCTGCCCCCCTTGCCCTATGTTCTGGGTGCTGGTGGTGGTCGGAGGCGTGCTGGCCTGCTACAGCCTGCTGGTCACCGTGGCCTTCATCATCTTTTGGGTGAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGGGTGAAGTTCAGCAGAAGCGCCGACGCCCCTGCCTACCAGCAGGGCCAGAATCAGCTGTACAACGAGCTGAACCTGGGCAGAAGGGAAGAGTACGACGTCCTGGATAAGCGGAGAGGCCGGGACCCTGAGATGGGCGGCAAGCCTCGGCGGAAGAACCCCCAGGAAGGCCTGTATAACGAACTGCAGAAAGACAAGATGGCCGAGGCCTACAGCGAGATCGGCATGAAGGGCGAGCGGAGGCGGGGCAAGGGCCACGACGGCCTGTATCAGGGCCTGTCCACCGCCACCAAGGATACCTACGACGCCCTGCACATGCAGGCCCTGCCCCCAAGG(SEQ ID NO:17)
TN-LEU-19的完整氨基酸序列如下:
METDTLLLWVLLLWVPGSTGDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKGSTSGGGSGGGSGGGGSSEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSS STAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSGGGGSEVKLQESGPGLVAPSQSLSVTCTVS GVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYY GGSYAMDYWGQGTSVTVSSGSTSGSGKPGSGEGSTKGDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITESKYGPPCPPCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:15)
本发明的BICAR的设计具有以下优势:
首先,CD19和CD20在大多数恶性B细胞肿瘤中表达。其次,一般而言,在扩大CAR结构来提高T细胞识别能力时,经常会遇到诸如不良靶向增加、细胞毒性增加和副作用增加等问题。然而,CD19和CD20没有这种情况,因为两者都只在B细胞中表达,具有相同的肿瘤毒性曲线。最后,CD19和CD20在B细胞中的表达可以促进B细胞的存活。治疗过程中两种抗原都丢失是非常低概率的事件。因此,预期靶向CD19和CD20有望有效预防恶性B细胞的抗原逃逸。
与靶向CD19或CD20的单一CAR相比,BICAR具有以下优势:
首先,与表达两个独立的CAR相比,在单个T细胞中表达BICAR时,DNA足迹显著减少(DNA长度减少40%)。该结构的大小和长度可以显著影响病毒载体的包装和转导效率,从而直接影响临床疗效。其次,与两种不同的单一CAR的混合物相比,BICAR可以显著降低治疗成本(BICAR完全兼容当前的T细胞生产工艺,不增加额外负担),并提高临床治愈率。最后,CD19和CD20已在大量临床研究中得到验证,并且相对安全。
在本发明中,我们基于CD19鼠源单克隆抗体FMC63的序列以及CD20鼠源单克隆抗体leu-16和奥法木单抗的序列,构建了两种靶向CD19和CD20的嵌合抗原受体结构(TN-LEU-19、TH-OF-19)。我们完成了对这两种嵌合抗原受体在原代T细胞中的表达水平、体外活化能力和肿瘤细胞杀伤效力的分析和鉴定。最后,发现用TN-LEU-19或TH-OF-19嵌合抗原受体修饰的T细胞具有很强的体外杀伤和体内清除携带CD19和CD20阳性抗原的恶性肿瘤的能力,并且奥法木单抗优于leu16。这为临床应用CAR-T治疗CD19和CD20阳性白血病和淋巴瘤提供了新的有效方法和制剂。
本发明设计并优化了单特异性和双特异性CAR。这些CAR对表达CD19或CD20的B细胞恶性肿瘤具有强大的杀伤能力。BICAR允许使用单一T细胞产品靶向与B细胞白血病和淋巴瘤相关的两种经临床验证的抗原,最终降低由于单一抗原丢失或逃逸而导致的肿瘤复发风险。本发明可进一步用于新BICAR的设计,从而提高抗原的适用性,提高T细胞治疗癌症的疗效。
嵌合抗原受体T细胞(CAR-T细胞)
本文所使用的术语“CAR-T细胞”、“CAR-T”、“CART”和“本发明的CAR-T细胞”均指本发明第四方面的靶向CD19和CD20二者的CAR-T细胞。具体而言,该CAR-T细胞的CAR结构依次包含抗CD19 scFv、抗CD20 scFv、铰链区、跨膜区和胞内T细胞信号传导区,其中抗CD20scFv和抗CD19 scFv通过具有多个重复结构(G4S)的肽连接。与靶向单个抗原的CAR-T相比,同时识别两个靶标的CAR-T细胞更具杀伤力,治疗范围更广。
载体
可使用本领域已知的重组方法获得编码所需分子的核酸序列,例如,通过筛选来自表达该基因的细胞的文库,通过从已知包含该基因的载体获得该基因,或通过使用标准技术直接从包含该基因的细胞和组织分离。备选地,可以合成产生目的基因。
本发明还提供插入本发明的表达盒的载体。源自逆转录病毒如慢病毒的载体是实现长期基因转移的适宜工具,因为它们允许长期、稳定的转基因整合以及在子细胞中的扩增。慢病毒载体与源自致瘤性逆转录病毒如小鼠白血病病毒的载体相比具有如下优势,它们可以转导非增殖细胞如肝细胞。它们还具有低免疫原性的优势。
简言之,本发明的表达盒或核酸序列通常有效连接到启动子,并掺入表达载体中。该载体可适用于真核生物中的复制和整合。典型的克隆载体包含用于调节所需核酸序列表达的转录和翻译终止子、起始序列和启动子。
使用标准基因递送方案,本发明的表达构建体还可用于核酸免疫和基因治疗。用于基因递送的方法为本领域已知。参见例如美国专利号5399346、5580859、5589466,在此以其整体引入作为参考。在另一个实施方案中,本发明提供基因治疗载体。
可以将核酸克隆到许多类型的载体中。例如,可以将核酸克隆到包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒的载体中。特别感兴趣的载体包括表达载体、复制载体、探针产生载体和测序载体。
此外,表达载体可以以病毒载体的形式提供给细胞。病毒载体技术为本领域公知,并在例如Sambrook等,(2001,Molecular Cloning:A Laboratory Manual,Cold SpringHarbor Laboratory,New York)以及其他病毒学和分子生物学手册中描述。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。通常,合适的载体包含在至少一种生物体中具有功能的复制起点、启动子序列、方便的限制性内切酶位点和一个或多个选择标记(例如WO 01/96584;WO 01/29058;及美国专利号6326193)。
已开发了许多用于将基因转移到哺乳动物细胞中的基于病毒的系统。例如,逆转录病毒为基因递送系统提供了方便的平台。可以使用本领域已知的技术将所选择的基因插入载体并包装在逆转录病毒颗粒中。然后可以分离重组病毒并在体内或离体将其递送到个体的细胞中。本领域已知许多逆转录病毒系统。在一些实施方案中,使用腺病毒载体。本领域已知许多腺病毒载体。在一个实施方案中,使用慢病毒载体。
其他启动子元件(例如增强子)调节转录起始的频率。通常,这些元件位于起始位点上游30-110bp的区域,但最近发现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距通常是灵活的,因此在元件相对于彼此倒置或移动时启动子功能可以保持。在胸苷激酶(tk)启动子中,启动子元件之间的间距可以增加到相距50bp而活性才开始下降。取决于启动子,各元件看起来可以协同或独立地发挥作用来激活转录。
适宜的启动子的一个实例是立即早期巨细胞病毒(CMV)启动子序列。此启动子序列是能够驱动与之有效连接的任何多核苷酸序列高水平表达的强组成型启动子序列。适宜的启动子的另一个实例是延伸生长因子-1α(EF-1α)。然而,也可以使用其他组成型启动子序列,包括但不限于猿猴病毒40(SV40)早期启动子、小鼠乳腺肿瘤病毒(MMTV)、人类免疫缺陷病毒(HIV)长末端重复序列(LTR)启动子、MoMuLV启动子、禽白血病病毒启动子、EB病毒立即早期启动子、Rous肉瘤病毒启动子以及人基因启动子,例如但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。此外,本发明不应局限于组成型启动子的使用,诱导型启动子也视为本发明的一部分。诱导型启动子的使用提供了一个分子开关,该分子开关能够在需要这种表达时打开与之有效连接的多核苷酸序列的表达,或者在不需要表达时关闭表达。诱导型启动子的实例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,待引入细胞的表达载体还可以包含选择标记基因或报告基因或二者,以便于从通过病毒载体转染或感染的细胞群体中鉴定和选择表达细胞。在其他方面,选择标记可携带在分开的DNA片段上,并用于共转染过程。选择标记和报告基因二者的侧翼可以有适宜的调节序列,以允许在宿主细胞中表达。例如,有用的选择标记包括抗生素抗性基因,如neo等。
可以使用报告基因,鉴定潜在转染的细胞和评价调节序列的功能。一般而言,报告基因是其在受体生物体或组织中不存在或不表达的基因,其编码多肽的表达可以通过某种可容易地检测到的特性例如酶活性而呈现出来。可以在将DNA引入受体细胞后,在适当的时间测定报告基因的表达。适宜的报告基因可以包含编码萤光素酶、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荧光蛋白的基因(例如Ui-Tei等,2000FEBS Letters479:79-82)。适宜的表达系统是熟知的,并可以使用已知技术制备或商业化获得。一般而言,将显示最高报告基因表达水平的具有最小5’侧翼区的构建体鉴定为启动子。这类启动子区域可以与报告基因相连,并用于评价试剂调节启动子驱动的转录的能力。
将基因引入细胞并在细胞中表达的方法为本领域已知。在表达载体的情况下,可以通过本领域的任何方法将载体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,可以通过物理、化学或生物手段将表达载体转移到宿主细胞中。
用于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、粒子轰击、微注射、电穿孔等。用于产生包含载体和/或外源核酸的细胞的方法为本领域公知。参见例如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一个优选方法是磷酸钙转染。
用于将目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,尤其是逆转录病毒载体,已成为用于将基因插入哺乳动物细胞例如人细胞的最广泛使用的方法。其他病毒载体可以源自慢病毒、痘病毒、单纯疱疹病毒I、腺病毒和腺相关病毒等。参见例如美国专利号5350674和5585362。
用于将多核苷酸引入宿主细胞的化学方法包括胶体分散系统,如大分子复合物、纳米囊、微球、小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。在体外和体内用作递送载体的示例性胶体系统是脂质体(例如人工膜泡)。
在利用非病毒递送系统的情况下,示例性递送载体是脂质体。考虑使用脂质制剂将核酸引入宿主细胞(体外、离体或体内)。在另一个方面,核酸可以与脂质结合。与脂质结合的核酸可以包封在脂质体的水性内部、分散在脂质体的脂双层内、通过与脂质体和寡核苷酸结合的连接分子附着到脂质体上、包裹在脂质体中、与脂质体复合、分散在含有脂质的溶液中、与脂质混合、与脂质组合、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结合。脂质、脂质/DNA或脂质/表达载体相关组合物不受限于溶液中的任何特定结构。例如,它们可以以双层结构、胶束或“塌陷”结构存在。它们也可以只是分散在溶液中,可能形成大小或形状不均一的聚集体。脂质是一种脂肪物质,它可以是天然产生的或合成的脂质。例如,脂质包括天然存在于细胞质中的脂肪滴、以及含有长链脂肪烃及其衍生物的化合物,如脂肪酸、醇、胺、氨基醇和醛类化合物。
在一个实施方案中,载体是慢病毒载体。
制剂
本发明提供包含本发明第四方面的CAR-T细胞和可药用载体、稀释剂或赋形剂的制剂。在一个实施方案中,所述制剂是液体制剂。优选地,所述制剂为注射剂。优选地,制剂中CAR-T细胞的浓度为1×103-1×108细胞/ml,更优选为1×104-1×107细胞/ml。
在一个实施方案中,制剂可以包含缓冲液,例如中性缓冲盐溶液、磷酸缓冲盐溶液等;糖类,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,如甘氨酸;抗氧化剂;螯合剂,如EDTA或谷胱甘肽;佐剂(例如氢氧化铝);和防腐剂。本发明的制剂优选配制用于静脉内施用。
治疗应用
本发明包括使用编码本发明表达盒的慢病毒载体(LV)转导的细胞(例如T细胞)的治疗应用。转导的T细胞可以靶向肿瘤细胞标记物CD19和CD20,协同激活T细胞,引起T细胞免疫反应,从而显著提高对肿瘤细胞的杀伤效力。
因此,本发明还提供在哺乳动物中刺激T细胞介导的针对目标细胞群体或组织的免疫反应的方法,其包括对该哺乳动物施用本发明的CAR-T细胞的步骤。
在一个实施方案中,本发明包括细胞治疗,其中分离、激活和遗传修饰来自自体患者(或异源供体)的T细胞以产生CAR-T细胞,然后注射到所述患者中。以这种方式发生移植物抗宿主病的可能性极低,并且T细胞以非MHC限制的方式识别抗原。此外,一种CAR-T可以治疗表达该抗原的所有癌症。与抗体治疗不同,CAR-T细胞能够在体内复制,从而产生长期持久性,导致持续的肿瘤控制。
在一个实施方案中,本发明的CAR-T细胞可以进行稳健的体内T细胞扩增,并且可以持续更长的时间。此外,CAR介导的免疫反应可以是过继免疫治疗方法的一部分,其中CAR修饰的T细胞诱导特异于CAR抗原结合部分的免疫反应。例如,抗CD19CD20 CAR-T细胞引发特异性针对表达CD19和CD20的细胞的免疫反应。
尽管本文公开的数据具体公开了包含CD19CD20 scFv、铰链和跨膜结构域以及4-1BB和CD3ζ信号传导结构域的慢病毒载体,但应解释本发明涵盖如本文其他地方所述的对构建体的每个组成部分的任何数量的变动。
可以治疗的癌症包括没有被血管化或大部分没有被血管化的肿瘤和血管化的肿瘤。癌症可以包括非实体瘤(例如血液学肿瘤,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、母细胞瘤和肉瘤,以及某些白血病或淋巴恶性肿瘤、良性和恶性肿瘤,以及恶性瘤,例如肉瘤、癌和黑色素瘤。成人肿瘤/癌症和儿童肿瘤/癌症也包括在内。
血液学癌症是血液或骨髓的癌症。血液学(或血源性)癌症的实例包括白血病,包括急性白血病(如急性淋巴细胞性白血病、急性髓细胞白血病、急性髓性白血病和成髓细胞性、前髓细胞性、粒-单核细胞性、单核细胞性和红细胞性白血病)、慢性白血病(如慢性髓细胞性(粒细胞性)白血病、慢性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、霍奇金病、非霍奇金淋巴瘤(惰性和高等级形式)、多发性骨髓瘤、瓦尔登斯特罗氏巨球蛋白血症、重链疾病、骨髓增生异常综合征、毛细胞性白血病和骨髓发育不良。
实体瘤是通常不包含囊肿或液体区的异常组织肿块。实体瘤可以是良性的或恶性的。不同类型的实体瘤以形成它们的细胞类型命名(如肉瘤、癌和淋巴瘤)。实体瘤如肉瘤和癌的实例包括纤维肉瘤、黏液肉瘤、脂肪肉瘤、间皮瘤、恶性淋巴瘤、胰腺癌和卵巢癌。
本发明的CAR修饰的T细胞也可作为疫苗用于离体免疫和/或哺乳动物体内治疗。优选地,哺乳动物是人。
对于离体免疫,在将细胞施用到哺乳动物之前在体外进行以下至少一项: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。
离体程序为本领域公知,下文将更全面地讨论。简言之,从哺乳动物(优选人)分离细胞并用表达本文公开的CAR的载体进行遗传修饰(即体外转导或转染)。CAR修饰的细胞可以对哺乳动物受体施用,以提供治疗益处。哺乳动物受体可以是人,CAR修饰细胞对受体而言可以是自体细胞。备选地,细胞对受体而言可以是同种异基因的、同种同基因的或异种细胞。
除了在离体免疫方面使用基于细胞的疫苗外,本发明还提供用于体内免疫来引发患者中针对抗原的免疫反应的组合物和方法。
本发明提供用于治疗肿瘤的方法,其包括对有需要的个体施用治疗有效量的本发明CAR修饰的T细胞。
本发明的CAR修饰的T细胞可以单独施用,或者作为药物组合物与稀释剂和/或与其他成分(例如IL-2、IL-17或其他细胞因子或细胞群体)组合施用。简言之,本发明的药物组合物可以包含如本文所述的靶细胞群体以及一种或多种可药用或生理上可接受的载体、稀释剂或赋形剂。此类组合物可以包含缓冲液,例如中性缓冲盐溶液、磷酸缓冲盐溶液等;糖类,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,如甘氨酸;抗氧化剂;螯合剂如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合于待治疗(或预防)的疾病的方式施用。施用的数量和频率将取决于患者的病症、患者疾病的类型和严重程度等因素,适当的剂量可以通过临床试验确定。
在提及“免疫学有效量”、“抗肿瘤有效量”、“肿瘤抑制有效量”或“治疗量”时,医生可以考虑患者(个体)年龄、体重、肿瘤大小、感染或转移程度和患者状况的个体差异,确定要施用的本发明组合物的精确量。一般而言,包含本文所述T细胞的药物组合物可以按104至109细胞/kg体重、优选105至106细胞/kg体重的剂量施用,包括这些范围内的所有整数值。T细胞组合物也可以按这些剂量多次施用。细胞可以通过免疫治疗中公知的输注技术进行施用(参见例如Rosenberg等,New Eng.J.of Med.319:1676,1988)。对于特定患者的最佳剂量和治疗方案可以由医学领域的技术人员通过监测患者的疾病病征并相应地调整治疗而容易地确定。
可以以任何方便的方式施用组合物,包括通过气溶胶吸入、注射、吞服、输注、植入或移植。本文所述组合物可通过皮下、皮内、肿瘤内、结节内、髓内、肌内、静脉(i.v.)注射或腹膜内方式,对患者施用。在一个实施方案中,通过皮内或皮下注射对患者施用本发明的T细胞组合物。在另一个实施方案中,优选通过静脉注射施用本发明的T细胞组合物。T细胞组合物可以直接注射到肿瘤、淋巴结或感染部位。
在本发明的某些实施方案中,联合(例如,在之前、同时或之后)任何数量的相关治疗方式,向患者施用激活和扩增的细胞(可以使用本文所述方法或本领域已知的其他方法将T细胞扩增到治疗水平),所述相关治疗方式包括但不限于,使用药剂治疗,例如抗病毒治疗、西多福韦和白细胞介素-2、阿糖胞苷(也称为ARA-C),或用于MS患者的那他珠单抗治疗、或用于银屑病患者的依法利珠单抗治疗、或用于PML患者的其他治疗。在其他实施方案中,本发明的T细胞可以与化疗、放疗、免疫抑制剂(如环孢菌素、硫唑嘌呤、甲氨蝶呤、霉酚酸酯和FK506)、抗体或其他免疫治疗剂联合使用。在另一个实施方案中,本发明的细胞组合物联合(例如,在之前、同时或之后)骨髓移植或化疗剂例如氟达拉滨、外部光束放射治疗(XRT)、环磷酰胺,对患者施用。例如,在一个实施方案中,个体可以接受高剂量化疗的标准治疗,然后进行外周血干细胞移植。在某些实施方案中,在移植后,个体接受扩增的本发明免疫细胞的输注。在另一个实施方案中,在手术之前或之后施用扩增的细胞。
待对患者施用的上述治疗的剂量将随着所治疗病症的确切性质和治疗的受体而变化。用于患者施用的剂量缩放可以根据本领域接受的实践进行。通常,每次治疗或每个疗程,可以通过例如静脉输注,将1×106至1×1010个本发明的修饰T细胞(例如CAR-T-19/20细胞)应用于患者。
本发明的优势:
(1)对于本发明的嵌合抗原受体,胞外抗原结合结构域是特异性抗CD20 scFv和抗CD19scFv;将特异性抗CD20 scFv和抗CD19 scFv与特定铰链区和胞内结构域组合形成的CAR显示出强大的杀伤肿瘤细胞的能力以及低细胞毒性和低副作用。
(2)本发明提供的嵌合抗原受体可以在携带CAR基因的慢病毒感染T细胞后实现CAR蛋白的稳定表达和膜定位。
(3)本发明的CAR修饰T细胞在体内存活时间更长,抗肿瘤疗效强;具有IgG4铰链-CH2-CH3接头区的优化CAR可以避免Fc受体的结合和随后的ADCC效应(抗体依赖性细胞毒性)。
(4)与两个独立的CAR相比,本发明的双特异性嵌合抗原受体包含抗CD20 scFv和抗CD19 scFv二者,DNA足迹显著减少(DNA长度减少40%),结构尺寸较小,有利于病毒载体的包装和转导效率,从而直接改善临床疗效。此外,本发明的双特异性CAR具有更低的成本、更高的治愈率和更高的安全性。
(5)用本发明的TN-LEU-19或TH-OF-19嵌合抗原受体修饰的T细胞具有非常强的体外杀伤和体内清除携带CD19和CD20阳性抗原的恶性肿瘤的能力,且奥法木单抗更强。这为临床应用CAR-T治疗CD19和CD20阳性白血病和淋巴瘤提供了一种新的有效方法和制剂。
(6)本发明的CAR-T细胞对大多数恶性B细胞肿瘤具有杀伤作用,治疗范围更广,覆盖率更高,可以更有效地防止肿瘤细胞逃逸。
下面将参考具体实施例进一步举例说明本发明。应理解,这些实施例仅用于举例说明目的,并非旨在限制本发明的范围。以下实施例中描述的无具体条件的实验方法通常在常规条件下或按照制造商的说明进行。除非另有说明,否则百分比和份数按重量计。
实施例1.慢病毒表达载体的构建
合成并克隆全长DNA,构建编码质粒。选择pWPT慢病毒载体作为克隆载体,克隆位点为BamH I和Sal I位点。其中,本发明设计的两种CAR的结构如图1所示。TN-LEU-19的氨基酸序列如SEQ ID NO:15所示,TN-OF-19的氨基序列如SEQ ID NO:16所示(结构为L-(OF)VL-(OF)VH-I-(FMC63)VH-(FMC63)VL-H-TM-C-CD3ζ)。
实施例2.双特异性CAR的体外激活能力检测
通过密度梯度离心从健康供体的静脉血分离出PBMC。第0天,在事先包被CD3单克隆抗体(OKT3)和重组人纤连蛋白(Retronectin)(TAKARA)的细胞培养瓶中活化PBMC。培养基为含有1%人白蛋白和300U/mL重组人白细胞介素2(IL-2)的GT-551细胞培养基。第3天,用纯化的TN-LEU-19或TN-OF-19慢病毒溶液转导激活的PBMC。从第6天开始,可以取TN-OF-19和TN-LEU-19CAR-T细胞进行相应的活性测定。用蛋白L法测定培养7天的CAR-T细胞中T细胞膜表面CAR基因编码的蛋白质的表达水平。
用培养7天的CD19/20双特异性CAR-T细胞,检测T细胞激活标记物CD137和IFNγ释放。在200μl GT-551培养基中,将1×105个CAR-T细胞,以1:1的比例分别与CD19、CD20阳性K562-CD19+、K562-CD20+、K562-CD19+CD20+和Raji(天然表达CD19和CD20)肿瘤细胞系以及CD19CD20阴性K562肿瘤细胞系共培养18h,或在无肿瘤细胞的存在下培养18h。然后分别检测T细胞表面CD137的表达水平和培养上清中IFNγ的分泌水平。
结果如图2A和2B所示。检测两种CART细胞表面CD137的表达,并检测培养上清液中IFNγ的表达。其中,TN-OF-19细胞具有比TN-LEU-19细胞更高的CD137激活水平和IFNγ释放水平。
实施例3.鉴定抗CD19/CD20双特异性CAR的最佳抗原结合结构域
我们制备了两种具有相同的抗CD20 scFv和抗CD19 scFv但顺序不同的双特异性CAR:TN-OF-19(C-CAR039)具有抗CD20 scFv(“OF”),然后是抗CD19 scFv(“FMC63”);而TN-19-OF具有抗CD19 scFv(”FMC63“),然后是抗CD20 scFv(”OF“)(图16A)。
如图16B所示,TN-OF-19(C-CAR039)对CD19和CD20阳性细胞展示了高于CAR-T20-29(VL-VH)的体外活性(例如,诱导干扰素-γ或IFN-γ释放)。
此外,我们制备了不同的双特异性CAR,其具有相同的抗CD20 scFv和抗CD19 scFv顺序(即,抗CD20 scFv(“OF”)之后跟随抗CD19 scFv(“FMC63”)),但在所述抗CD20 scFv(OF)或所述抗CD19 scFv(FMC63)中VH和VL的顺序不同(图16C)。
如图16D所示,与具有不同VH和VL顺序的其他双特异性CAR相比,TN-OF-19(C-CAR039)展示了优越的抗肿瘤活性。
我们的体外数据显示,双特异性CAR中,抗CD20 scFv和抗CD19 scFv的顺序、以及scFv中VH和VL的顺序,可以影响双特异性CAR的性质。
实施例4.CD19/20双特异性CAR-T细胞体外细胞毒性检测
通过LDH释放测定试验,检测实施例2中制备的CAR-T细胞的细胞毒性。靶细胞为K562、K562-CD19+、K562-CD20+、K562-CD19+CD20+和Raji细胞;效应细胞为NT、TN-LEU-19和TN-OF-19细胞。设置效靶比,其中效应细胞数:靶细胞数=5:1、10:1、20:1和40:1。结果如图3A所示。TN-LEU-19和TN-OF-19CAR-T细胞均可以很好地诱导CD19/20阳性肿瘤细胞凋亡并释放LDH。
通过流式细胞术分析在CAR-T19/20细胞诱导肿瘤细胞杀伤期间CD107a(T细胞脱颗粒标志物)的释放水平。将1×105个效应细胞CAR-T19/20(TN-OF-19和TN-LEU-19)分别与2×105个靶肿瘤细胞共培养。靶细胞分别为K562-CD19+、K562-CD20+、K562-CD19+CD20+和K562细胞、Raji细胞、Romas细胞(CD19+CD20+)。结果如图3B所示。两种CART细胞都可以很好地诱导肿瘤细胞杀伤期间CD107a的释放。其中,TN-OF-19细胞具有比TN-LEU-19细胞略高的细胞毒性标记物CD107a的释放。
实施例5.CAR-T19/20对小鼠中移植的肿瘤细胞的抑制作用
注射到动物体内的肿瘤细胞是携带荧光素酶报告基因的Raji细胞(表达荧光素酶的Raji)。在本实验中,将肿瘤细胞Raji注射到小鼠体内并生长一周,然后注射效应T细胞。将效应T细胞分为三组:NT、TN-LEU-19和TN-OF-19。将扩增的效应T细胞通过尾静脉注入NSG小鼠,然后每7天记录小鼠的荧光强度(通过IVIS荧光成像)和小鼠体重。实验于第21天停止,并分析统计结果。
结果如图4A-4C所示。图4A显示将效应T细胞注射入三组小鼠后小鼠的体重变化。与两种类型的CART细胞CART-TN-OF-19和CART-TN-LEU-19相比,NT小鼠体重显著下降,而两种CART细胞组的小鼠体重略有增加。在体内研究中,NSG小鼠异种移植了Raji-Luc细胞,该细胞是表达萤火虫萤光素酶作为报告分子的人伯基特淋巴瘤Raji细胞。然后对小鼠施用不同的CAR-T细胞或阴性对照。治疗后,测定异种移植Raji-Luc的动物的荧光强度,其反映肿瘤细胞在动物体内的增殖情况。图4B显示三组小鼠的平均荧光强度。结果显示,NT组小鼠的平均荧光强度显著增加,而两个CART细胞组小鼠的荧光强度平均值降低,表明与NT相比,TN-OF-19和TN-LEU-19CART细胞均可以抑制肿瘤的生长。其中,TN-OF-19细胞在14天后对肿瘤生长的抑制作用优于TN-LEU-19细胞,TN-LEU-9组肿瘤生长曲线显示明显复发。图4C显示两个CART细胞组和NT组荧光强度的IVIS成像。TN-OF-19CAR-T细胞可以比TN-LEU-19细胞更好地在体内抑制或杀伤肿瘤细胞。
因此,比较具有Leu16 scFv的CD20/CD19 bi-CAR(由Nirav NS或Tong C用于临床研究),C-CAR039在体外和体内对单阳性和双阳性肿瘤靶标均显示出优越的抗肿瘤活性。
实施例6.比较TN-OF-19CAR-T细胞和CD19特异性CAR-T细胞的体内抑制作用
通过尾静脉注射对6-8周龄NPG小鼠(NOD-Cg.PrkdcSCID IL-2Rgcnull/vst)施用1×106个表达萤火虫萤光素酶的Raji细胞。7天后,通过i.p.注射D-荧光素并在10-15分钟后在Bruker In Vivo Xtreme成像系统(Bruker,Xtreme BI)上成像180秒来测量肿瘤植入。根据肿瘤负荷将小鼠均等地分配到研究组(n=6/组)。TN-OF-19(L)、TN-OF-19(M)和TN-OF-19(H)组经尾静脉注射分别用1×106、2.5×106和5×106个CAR+T细胞治疗。来自同一供体的1×106个未转导T细胞(N.T.)和单靶标CD19特异性CAR-T细胞作为对照。根据注射后第7天、第10天和第21天小鼠全身平均辐射度评估肿瘤生长。图5A显示,双特异性TN-OF-19CAR-T细胞可以比CD19特异性CAR-T细胞更好地在体内抑制或杀伤肿瘤细胞。特别是在治疗的早期阶段,双特异性TN-OF-19CAR-T显示出显著更快的抑制作用。图5B显示4个CAR-T细胞组和NT细胞组的荧光强度IVIS成像。
实施例7.CD20/CD19双特异性CAR的抗原特异性
为了检查TN-OF 19CAR中双特异性scFv的亲和力和特异性,通过将CD20 scFv(例如源自奥法木单抗)和CD19 scFv(例如源自FMC63单克隆抗体)与兔IgG1 Fc区符合读框地连接,产生嵌合兔单克隆抗体。备选地,将CD19和CD20 scFv通过G4S接头连接。分子顺序为OF VL-VH-G4S-FMC63 VH-VL,与TN-OF-19中scFV的顺序相同。瞬时转染后在293T细胞中表达嵌合抗体。通过流式细胞术验证这种嵌合抗体的染色特异性。简言之,用三种稳定细胞系(A549-CD19、A549-CD20、A549-CD19-CD20)作为靶标,用CD19-CD20-A549细胞和CD19+CD20+Raji细胞作为对照。洗涤所有细胞并重悬,用2%血清封闭30分钟。将5×105个细胞转移到FACS小瓶中,洗涤,并用重组抗体(终浓度20μg/mL)在4℃下染色1小时。洗涤后,加入二抗(山羊抗兔IgG),4℃避光30分钟。最后,洗涤细胞并重悬在200μLFACS缓冲液中进行FACS分析。图6B显示,嵌合抗体与具有CD19或CD20或两者的细胞结合但不与缺乏这两种抗原的细胞结合,表明双特异性结合结构域只需要一个关联抗原进行结合,并且没有形成新的特异性识别位点。
组织交叉反应性和全基因组膜蛋白质组阵列研究确认了C-CAR039的结合特异性。
图17A显示评价C-CAR039抗原结合结构域的结合特异性的方法。表1显示,在血液、骨髓、淋巴结、脾脏、胸腺中的人淋巴细胞上观察到了强烈的特异性膜染色(IHC-GLP研究)。
鉴定到CD19、CD20和FCGR1A在5.0μg/mL浓度下具有中等结合,未鉴定到其他显著的相互作用。据报道,FCGR1结合rabFc(图17B)。
表1
a.阳性强度——特异性染色的百分比。0,无染色细胞;1,轻微或不明确的染色;2,弱阳性染色;3,中度阳性染色。0,无染色细胞;1,<25%细胞染色;2,25-50%细胞染色;3,50%-75%细胞染色。
实施例8.CD20特异性CAR的筛选和功能验证(用于制备CD20/19双特异性CAR)
在构建CD20/CD19双特异性CAR之前,我们进行了广泛的研究,以筛选和缩小CD20特异性scFV候选物。图7显示具有6种不同的scFV和不同的铰链/TM/信号传导结构域的16种CD20特异性CAR的结构。合成并克隆全长DNA以构建编码质粒,我们用多种表达CD20的靶细胞测试了这些CAR的抗肿瘤活性。
图8A显示筛选CAR-T20.1、CAR-T20.5、CAR-T20.6、CAR-T20.7、CAR-T20.8、CAR-T20.9和CAR-T20.10的IFNγ释放测定试验的结果,在这些CAR-T中,只有CAR-T20.9(Leu16)和CAR-T20.10(Leu16)显示较高的阳性IFNγ释放。
图8B显示筛选CAR-T20.1、CAR-T20.9、CAR-T20.10、CAR-T20.11、CAR-T20.12、CAR-T20.13、CAR-T20.14、CAR-T20.15和CAR-T20.16的IFNγ释放测定试验的结果。在这些CAR-T中,CAR-T20.10(Leu16)和CAR-T20.14(OF)显示较高的阳性IFNγ释放。
图8C显示筛选CAR-T20.9、CAR-T20.12、CAR-T20.14、CAR-T20.17、CAR-T20.18和CAR-T20.19的IFNγ释放测定试验的结果。在这些CAR-T中,CAR-T20.14(OF)和CAR-T20.19(OF)显示较高的阳性IFNγ释放。
图9A显示通过LDH释放测定试验检测CAR-T20.17(Leu16第三代)、CAR-T20.18(Leu16第二代)、CAR-T20.19(OF第二代)细胞的细胞毒性的结果。靶细胞为CD20阳性细胞系Raji和Ramos以及CD20阴性Molt4。这三种CD20 CAR-T细胞均可以诱导CD20阳性肿瘤细胞凋亡并释放LDH,表明CAR-T20.17、CAR-T20.18和CAR-T20.19对靶细胞CD20阳性Raji和Romas细胞具有强杀伤作用。
图9B显示NSG小鼠研究中的体内肿瘤生长抑制。动物体内注射的肿瘤细胞是表达荧光素酶的Raji。在本实验中,将肿瘤细胞Raji注射到小鼠体内并生长一周,然后通过尾静脉注射效应T细胞,然后每7天记录小鼠的荧光强度(通过IVIS荧光成像)和小鼠体重。实验于第21天停止,并分析统计结果。结果显示,CAR-T20.19(OF)细胞在14天后对肿瘤生长的抑制作用优于CAR-T20.17(Leu16)和CAR-T20.18(Leu16)细胞。
综上所述,通过大量实验和比较,发现20.1、20.2、20.4、20.5、20.6、20.7、20.8和20.15基本无效,20.11、20.12和20.13有一定的效果,但它们的效果小于20.9、20.10、20.14、20.16、20.17、20.18和20.19,其中20.19(OF)的效果最好。基于上述结构,将CD20scFv(OF)和CD19 scFv(FMC63)串联用于新的双特异性嵌合抗原受体TN-OF-19,并作为最佳候选者进行进一步分析。
实施例7所涉及的CD20特异性CAR的氨基酸序列显示在表2中。
表2嵌合抗原受体及其序列
实施例9.TN-OF-19 CAR-T细胞的I期临床试验
在复发/难治性非霍奇金淋巴瘤(R/R NHL)患者中进行了一项I期试验,以评估C-CAR039(即TN-OF-19CAR-T细胞,NCT04317885)的安全性和功效。在通过单采血液成分术收集T细胞后,制备C-CAR039,并在标准的3天环磷酰胺/氟达拉滨预处理方案(conditioningregimen)后作为单次静脉注射剂量进行输注。在无血清、半自动化、数字化封闭系统中制备C-CAR039,中位静脉到静脉时间为18天。制备成功率为100%。截至2020年8月3日,16名患者输注了C-CAR039,剂量范围为1.0x106至5.0x106个CAR-T细胞/kg。14名患者有至少一个月的可评估安全性数据,13名患者(11名DLBCL,2名FL患者)有一个月或更长时间的功效数据。
关键的合格标准(eligibility criteria)包括:(1)18-75岁;(2)r/r B-NHL,包括DLBCL、FL、MCL;(3)CD19或CD20阳性疾病;(4)无过往抗CD19治疗;(5)无活动性CNS受累。安全性评估包括治疗引起的不良事件的发生率和严重程度(CTCAE V5.0)。功效评估包括Lugano Classification 2014:ORR;DOR;PFS;OS。
截至2021年1月31日的数据,已在四个临床中心登记了30名患者;28名患者已给药;中位静脉到静脉时间为19天。25名患者有1个月的数据;17名患者有3个月的数据;12名患者有6个月的数据。1名输注患者在基线检查时没有可评估的疾病活动。
我们的双特异性CAR治疗开始之前患者的基线人口统计学和临床特征如表3所示。
给药患者的中位年龄为54岁(范围:28-71岁)。过往治疗线的中位数为3(范围:1-5种过往治疗)。有5名(20%)患者曾接受过自体干细胞移植(ASCT)。
表3患者基线临床特征总结
图10显示CAR039 r/r NHL研究设计和流程图。具体而言,患者在治疗前21天(D-21)接受筛查。登记合格个体,并采集外周血白细胞。使用收集的外周血白细胞产生CAR-T细胞。在CAR-T输注前-5(D-5)、-4(D-4)和-3(D-3)天,患者接受淋巴细胞耗竭预处理,包括氟达拉滨(30mg/m2/d,静脉内,每天一次,共三天)和环磷酰胺(300mg/m2/d,静脉内,每天一次,共三天)。淋巴耗竭后约72小时,患者在第0天(D0)接受单次输注1.0x106、2.5x106或5.0x106个CAR-T细胞/kg体重。在输注后第4天、第7天、第10天、第2周、第3周、第4周、第8周、第12周、第6个月、第9个月和第12个月进行患者随访。在CAR-T输注后第4周进行第一次临床反应评估。
记录患者的不良反应(治疗引起的不良事件,TEAE)(表4)。只有1例(4%)为3级或以上的细胞因子释放综合征(CRS)。仅在两名患者(8.0%)中观察到神经毒性,无3级或以上神经毒性。细胞减少(如中性粒细胞减少和血小板减少)主要与氟达拉滨/环磷酰胺(Cy/Flu)淋巴耗竭有关。细胞减少也是可逆的。这证明双特异性CAR具有良好的安全性特性。
表4治疗引起的不良事件(AE)汇总
*CTCAE V5.0.
表5安全性特性
**2019年免疫效应细胞相关细胞因子释放综合征和神经毒性分级的ASTCT共识。
表6 CRS&神经毒性
*至截止日期,1名患者尚未消退。
C-CAR039治疗耐受性良好,25名患者中有1例3级CRS和2例1级神经毒性事件。细胞减少主要与预处理方案(Cy/Flu淋巴耗竭)有关,而且是常见和可逆的。
在为期一个月的评估中,有12/13名患者表现出临床改善(总反应率或ORR=92%),11/11名DLBCL患者对治疗有反应(ORR=100%)。中位随访时间为70天(范围:35-257天)。最佳总体反应(BOR)包括10例完全反应(CR)和2例部分反应(PR)。
图11显示C-CAR039临床结果总结。共施用三(3)种剂量:(1)4.0x106或5.0x106/kg(N=7);(2)2.0x106或2.5x106/kg(N=14);和(3)1.0x106/kg(N=4)。
大约14个月后,ORR为92%(25名患者中有23名);CR为84%(25名患者中有21名)。6个月时的CR率为82%(11名患者中有9名)。中位随访(F/U)为5.3个月(范围:1.0-14.3个月)。
图18显示Kaplan-Meyer估计的C-CAR039的PFS。6个月的PFS为87.31%,95%置信区间(CI)为71.2至100.0。中位反应持续时间(DOR)尚未达到。
图19显示C-CAR039的PK/PD性质。不同剂量组间PK性质没有统计差异。
图20显示复发患者外周血中的PK/PD曲线(CAR-T扩增和B细胞耗竭)。
图12显示C-CAR039治疗前后的患者实例。清楚地显示了,在CAR T治疗后三个月,肿瘤病灶的大小显著减小。
实施例10.C-CAR039的PK特征
外周血中C-CAR039的增殖和扩增与肿瘤消退呈正相关。观察到C-CAR039 AUC(0-28天)和Cmax与临床反应之间的早期正相关趋势。
图13显示患者血液中C-CAR039的增殖和扩增。结果显示,注射后C-CAR008细胞有效扩增。
表7显示复发患者中CD19/CD20的表达。
表7 IHC检测肿瘤组织中的CD19/CD20表达
治疗前 | CCAR066治疗后复发 | |
患者编号8 | CD19(+)CD20(+) | CD19(+)CD20(+) |
患者编号21 | CD19(+)CD20(+) | CD19(-)CD20(+) |
表8.PK特征(AUC0~28天,Cmax,Tmax,Tlast)、CAR-T细胞剂量与临床反应的关系
外周血中C-CAR039的增殖和扩增与肿瘤消退呈正相关。观察到C-CAR039 AUC(0-28天)和Cmax与临床反应之间的早期正相关趋势。
表9 SCHOLAR-1:非CAR T细胞治疗难治性DLBCL的结果(合并的回顾性分析)
Crump.Blood.2017;130:1800.
表10 C-CAR039与市售抗CD19 CART产品比较
1.Neelapu.NEJM.2017;377:2531.2.Schuster.NEJM.2019;380:45.3.Schuster.NEJM.2019;380:45
表11 C-CAR039与其他CD19/CD20双特异性CAR-T产品比较
C-CAR039在r/r NHL患者的临床试验中显示出有前景的有效性和良好的安全性特征。有效性优于抗CD19 CAR-T治疗。
实施例11.C-CAR066(CAR-T20.19(OF))的I期临床试验
由CD19靶向表位丢失引起的复发是CD19 CAR-T治疗面临的治疗挑战。这些患者普遍效果不佳。CD20是经证明的B细胞非霍奇金淋巴瘤(B-NHL)的治疗靶标,得到了先前批准并广泛使用的单克隆抗体治疗的支持。C-CAR066是一种新的第二代嵌合抗原受体T(CAR-T)治疗。临床前研究表明,C-CAR066(源自奥法木单抗的scFV)与源自Leu16、利妥昔单抗(Rituximab)和奥妥珠单抗(Obinutuzumab)的scFV的CAR T相比具有优良的抗肿瘤活性。
NCT04036019是一项单臂、单中心、非随机I期临床试验,旨在评价C-CAR066在先前接受过抗CD19 CAR-T治疗的r/r B细胞淋巴瘤患者中的安全性和有效性。本研究的主要目标是评价治疗引起的不良事件的发生率和严重程度。次要目标包括确定总反应率(ORR)、PFS和OS。在无血清、半自动化、数字化封闭系统中制备C-CAR066。在标准的3天环磷酰胺/氟达拉滨预处理方案后作为单次静脉注射剂量对患者施用C-CAR066。
图14显示C-CAR066-NHL研究设计。
截至2020年8月3日,共有7名患者(均为DLBCL)登记并进行了C-CAR039输注,剂量范围为2.0x106至5.0x106CAR-T细胞。制备成功率为100%。所有患者在抗CD19 CAR-T治疗后均复发,只有一名患者在抗CD19 CAR-T治疗后达到CR。
表12患者的临床特征
C-CAR066治疗耐受性良好,6名患者出现可逆的1~2级CRS,另一名患者出现3级CRS,且无神经毒性事件。6/7名患者显示临床改善(最佳总反应率,ORR=85.7%)。最佳总体反应包括3例CR和3例PR。所有患者对C-CAR066治疗均有反应,并表现出不同程度的肿瘤消退(45-100%)。
表13 C-CAR066治疗引起的不良事件汇总
6/7名患者显示症状改善(最佳总反应率,ORR=85.7%)。最佳总体反应包括3例CR和3例PR。所有患者对C-CAR066治疗均有反应,并表现出不同程度的肿瘤消退(45-100%)。
表14 C-CAR066临床有效性总结
图15显示C-CAR066治疗前后患者的PET-CT实例。
C-CAR066具有良好的安全性特性,在CD19 CAR-T治疗后的r/r NHL患者中显示出有前景的早期有效性。这表明,与抗CD-19CAR-T治疗相比,C-CAR066具有不同的作用机制。在B细胞恶性肿瘤患者中,通过靶向CD20和CD19肿瘤抗原二者可以产生优于靶向单独CD19或CD20的临床益处。
本发明的范围不受限于上文具体给出和描述的内容。本领域技术人员将认识到,对于所描述的材料、配置、结构和尺寸的实例,存在适宜的替代方案。在本发明的描述中引用并讨论了许多参考文献,包括专利和多种出版物。引用和讨论这些参考文献只是为了澄清本发明的描述,并不意味着承认任何参考文献是本文所述发明的现有技术。本说明书中引用和讨论的所有参考文献全部通以其整体引入作为参考。在不偏离本发明精神和范围的情况下,本领域普通技术人员可对本文所述内容进行变更、修改和其他实施。虽然已经展示和描述了本发明的某些实施方案,但对本领域技术人员而言显而易见的是,可以在不背离本发明精神和范围的情况下进行更改和修改。提供上述描述和附图中给出的内容仅作为举例说明而非限制性目的。
序列表
<110> 西比曼生物科技(香港)有限公司(CELLULAR BIOMEDICINE GROUP HKLIMITED)
<120> 靶向CD19和CD20的联合嵌合抗原受体及其应用
<130> 11299/008882-WO1
<150> CN202010188038.1
<151> 2020-03-17
<150> US16/877,069
<151> 2020-05-18
<150> PCT/CN20/109645
<151> 2020-08-17
<150> US63/154,032
<151> 2021-02-26
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<213> 人工序列
<220>
<223> 来自Ofatumumab抗体的单链可变区的重链序列(VH)
<400> 3
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 4
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 来自Ofatumumab抗体的单链可变区的轻链序列(VL)
<400> 4
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 5
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 来自FMC63抗体的单链可变区的轻链氨基酸序列(VL)
<400> 5
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
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 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 6
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 来自FMC63抗体的单链可变区的重链氨基酸序列(VH)
<400> 6
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 7
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 7
Gly Gly Gly Gly Ser
1 5
<210> 8
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> CD8抗原前导序列
<400> 8
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
20
<210> 9
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 铰链区
<400> 9
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 10
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> CD8跨膜区
<400> 10
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 11
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> CD28跨膜区
<400> 11
Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
1 5 10 15
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 12
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 来自4-1BB的共刺激信号区
<400> 12
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> 13
<211> 41
<212> PRT
<213> 人工序列
<220>
<223> 来自CD28的共刺激因子信号区
<400> 13
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 14
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3ζ的信号传导序列
<400> 14
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 Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 15
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> TN-LEU-19的氨基酸序列
<400> 15
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Val Leu Thr Gln Ser Pro Ala Ile Leu Ser
20 25 30
Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser
35 40 45
Val Asn Tyr Met Asp Trp Tyr Gln Lys Lys Pro Gly Ser Ser Pro Lys
50 55 60
Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg
85 90 95
Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe
100 105 110
Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Ser
115 120 125
Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser
130 135 140
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
145 150 155 160
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
165 170 175
Asn Met His Trp Val Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Ile
180 185 190
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
195 200 205
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
210 215 220
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Asp Tyr Tyr Cys
225 230 235 240
Ala Arg Ser Asn Tyr Tyr Gly Ser Ser Tyr Trp Phe Phe Asp Val Trp
245 250 255
Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Glu
260 265 270
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
275 280 285
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
290 295 300
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
305 310 315 320
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
325 330 335
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
340 345 350
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
355 360 365
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
370 375 380
Thr Ser Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro
385 390 395 400
Gly Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile Gln Met Thr Gln Thr
405 410 415
Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys
420 425 430
Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys
435 440 445
Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His
450 455 460
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr
465 470 475 480
Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe
485 490 495
Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys
500 505 510
Leu Glu Ile Thr Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
515 520 525
Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
530 535 540
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys Arg Gly Arg
545 550 555 560
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
565 570 575
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
580 585 590
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
595 600 605
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
610 615 620
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
625 630 635 640
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
645 650 655
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
660 665 670
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
675 680 685
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
690 695 700
Gln Ala Leu Pro Pro Arg
705 710
<210> 16
<211> 712
<212> PRT
<213> 人工序列
<220>
<223> TN-OF-19的氨基酸序列
<400> 16
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 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
20 25 30
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
35 40 45
Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg
100 105 110
Ser Asn Trp Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
115 120 125
Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn
165 170 175
Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
180 185 190
Trp Val Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp
195 200 205
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser
210 215 220
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr
225 230 235 240
Tyr Cys Ala Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp
245 250 255
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly
260 265 270
Ser Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser
275 280 285
Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp
290 295 300
Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp
305 310 315 320
Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu
325 330 335
Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe
340 345 350
Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys
355 360 365
Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly
370 375 380
Gln Gly Thr Ser Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly
385 390 395 400
Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile Gln Met Thr
405 410 415
Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile
420 425 430
Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln
435 440 445
Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg
450 455 460
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
465 470 475 480
Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr
485 490 495
Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly
500 505 510
Thr Lys Leu Glu Ile Thr Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
515 520 525
Cys Pro Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys
530 535 540
Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys Arg
545 550 555 560
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
565 570 575
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
580 585 590
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
595 600 605
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
610 615 620
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
625 630 635 640
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
645 650 655
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
660 665 670
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
675 680 685
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
690 695 700
His Met Gln Ala Leu Pro Pro Arg
705 710
<210> 17
<211> 2130
<212> DNA
<213> 人工序列
<220>
<223> TN-OF-19的氨基酸序列
<400> 17
atggagacag acacactcct gctatgggtg ctgctgctct gggttccagg ttccacaggt 60
gacattgtgc tgacccaatc tccagctatc ctgtctgcat ctccagggga gaaggtcaca 120
atgacttgca gggccagctc aagtgtaaat tacatggact ggtaccagaa gaagccagga 180
tcctccccca aaccctggat ttatgccaca tccaacctgg cttctggagt ccctgctcgc 240
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagagt ggaggctgaa 300
gatgctgcca cttattactg ccagcagtgg agttttaatc cacccacgtt cggagggggg 360
accaagctgg aaataaaagg cagtactagc ggtggtggct ccgggggcgg ttccggtggg 420
ggcggcagca gcgaggtgca gctgcagcag tctggggctg agctggtgaa gcctggggcc 480
tcagtgaaga tgtcctgcaa ggcttctggc tacacattta ccagttacaa tatgcactgg 540
gtaaagcaga cacctggaca gggcctggaa tggattggag ctatttatcc aggaaatggt 600
gatacttcct acaatcagaa gttcaaaggc aaggccacat tgactgcaga caaatcctcc 660
agcacagcct acatgcagct cagcagcctg acatctgagg actctgcgga ctattactgt 720
gcaagatcta attattacgg tagtagctac tggttcttcg atgtctgggg cgcagggacc 780
acggtcaccg tctcctcagg aggtggtgga tccgaggtga agctgcagga aagcggccct 840
ggcctggtgg cccccagcca gagcctgagc gtgacctgca ccgtgagcgg cgtgagcctg 900
cccgactacg gcgtgagctg gatccggcag ccccccagga agggcctgga atggctgggc 960
gtgatctggg gcagcgagac cacctactac aacagcgccc tgaagagccg gctgaccatc 1020
atcaaggaca acagcaagag ccaggtgttc ctgaagatga acagcctgca gaccgacgac 1080
accgccatct actactgcgc caagcactac tactacggcg gcagctacgc catggactac 1140
tggggccagg gcaccagcgt gaccgtgagc agcggcagca cctccggcag cggcaagcct 1200
ggcagcggcg agggcagcac caagggcgac atccagatga cccagaccac ctccagcctg 1260
agcgccagcc tgggcgaccg ggtgaccatc agctgccggg ccagccagga catcagcaag 1320
tacctgaact ggtatcagca gaagcccgac ggcaccgtca agctgctgat ctaccacacc 1380
agccggctgc acagcggcgt gcccagccgg tttagcggca gcggctccgg caccgactac 1440
agcctgacca tctccaacct ggaacaggaa gatatcgcca cctacttttg ccagcagggc 1500
aacacactgc cctacacctt tggcggcgga acaaagctgg aaatcaccga gagcaagtac 1560
ggaccgccct gccccccttg ccctatgttc tgggtgctgg tggtggtcgg aggcgtgctg 1620
gcctgctaca gcctgctggt caccgtggcc ttcatcatct tttgggtgaa acggggcaga 1680
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1740
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgcgggtg 1800
aagttcagca gaagcgccga cgcccctgcc taccagcagg gccagaatca gctgtacaac 1860
gagctgaacc tgggcagaag ggaagagtac gacgtcctgg ataagcggag aggccgggac 1920
cctgagatgg gcggcaagcc tcggcggaag aacccccagg aaggcctgta taacgaactg 1980
cagaaagaca agatggccga ggcctacagc gagatcggca tgaagggcga gcggaggcgg 2040
ggcaagggcc acgacggcct gtatcagggc ctgtccaccg ccaccaagga tacctacgac 2100
gccctgcaca tgcaggccct gcccccaagg 2130
<210> 18
<211> 2136
<212> DNA
<213> 人工序列
<220>
<223> TN-OF-19的核酸序列
<400> 18
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggaaattg tgttgacaca gtctccagcc accctgtctt tgtctccagg ggaaagagcc 120
accctctcct gcagggccag tcagagtgtt agcagctact tagcctggta ccaacagaaa 180
cctggccagg ctcccaggct cctcatctat gatgcatcca acagggccac tggcatccca 240
gccaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagcctagag 300
cctgaagatt ttgcagttta ttactgtcag cagcgtagca actggccgat caccttcggc 360
caagggacac gactggagat taaaggcagt actagcggtg gtggctccgg gggcggttcc 420
ggtgggggcg gcagcagcga agtgcagctg gtggagtctg ggggaggctt ggtacagcct 480
ggcaggtccc tgagactctc ctgtgcagcc tctggattca cctttaatga ttatgccatg 540
cactgggtcc ggcaagctcc agggaagggc ctggagtggg tctcaactat tagttggaat 600
agtggttcca taggctatgc ggactctgtg aagggccgat tcaccatctc cagagacaac 660
gccaagaagt ccctgtatct gcaaatgaac agtctgagag ctgaggacac ggccttgtat 720
tactgtgcaa aagatataca gtacggcaac tactactacg gtatggacgt ctggggccaa 780
gggaccacgg tcaccgtctc ctcaggaggt ggtggatccg aggtgaagct gcaggaaagc 840
ggccctggcc tggtggcccc cagccagagc ctgagcgtga cctgcaccgt gagcggcgtg 900
agcctgcccg actacggcgt gagctggatc cggcagcccc ccaggaaggg cctggaatgg 960
ctgggcgtga tctggggcag cgagaccacc tactacaaca gcgccctgaa gagccggctg 1020
accatcatca aggacaacag caagagccag gtgttcctga agatgaacag cctgcagacc 1080
gacgacaccg ccatctacta ctgcgccaag cactactact acggcggcag ctacgccatg 1140
gactactggg gccagggcac cagcgtgacc gtgagcagcg gcagcacctc cggcagcggc 1200
aagcctggca gcggcgaggg cagcaccaag ggcgacatcc agatgaccca gaccacctcc 1260
agcctgagcg ccagcctggg cgaccgggtg accatcagct gccgggccag ccaggacatc 1320
agcaagtacc tgaactggta tcagcagaag cccgacggca ccgtcaagct gctgatctac 1380
cacaccagcc ggctgcacag cggcgtgccc agccggttta gcggcagcgg ctccggcacc 1440
gactacagcc tgaccatctc caacctggaa caggaagata tcgccaccta cttttgccag 1500
cagggcaaca cactgcccta cacctttggc ggcggaacaa agctggaaat caccgagagc 1560
aagtacggac cgccctgccc cccttgccct atgttctggg tgctggtggt ggtcggaggc 1620
gtgctggcct gctacagcct gctggtcacc gtggccttca tcatcttttg ggtgaaacgg 1680
ggcagaaaga aactcctgta tatattcaaa caaccattta tgagaccagt acaaactact 1740
caagaggaag atggctgtag ctgccgattt ccagaagaag aagaaggagg atgtgaactg 1800
cgggtgaagt tcagcagaag cgccgacgcc cctgcctacc agcagggcca gaatcagctg 1860
tacaacgagc tgaacctggg cagaagggaa gagtacgacg tcctggataa gcggagaggc 1920
cgggaccctg agatgggcgg caagcctcgg cggaagaacc cccaggaagg cctgtataac 1980
gaactgcaga aagacaagat ggccgaggcc tacagcgaga tcggcatgaa gggcgagcgg 2040
aggcggggca agggccacga cggcctgtat cagggcctgt ccaccgccac caaggatacc 2100
tacgacgccc tgcacatgca ggccctgccc ccaagg 2136
<210> 19
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> CD20 scfv的VL和VL之间接头的氨基酸序列
<400> 19
Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Ser
<210> 20
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> CD19 scfv的VH和VL之间接头的氨基酸序列
<400> 20
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 21
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 来自FMC63抗体的单链可变区轻链核苷酸序列(VL)
<400> 21
gacatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atcagttgca gggcaagtca ggacattagt aaatatttaa attggtatca gcagaaacca 120
gatggaactg ttaaactcct gatctaccat acatcaagat tacactcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggagcaa 240
gaagatattg ccacttactt ttgccaacag ggtaatacgc ttccgtacac gttcggaggg 300
gggaccaagc tggagatcac a 321
<210> 22
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 来自FMC63抗体的单链可变区重链核苷酸序列(VH)
<400> 22
gaggtgaaac tgcaggagtc aggacctggc ctggtggcgc cctcacagag cctgtccgtc 60
acatgcactg tctcaggggt ctcattaccc gactatggtg taagctggat tcgccagcct 120
ccacgaaagg gtctggagtg gctgggagta atatggggta gtgaaaccac atactataat 180
tcagctctca aatccagact gaccatcatc aaggacaact ccaagagcca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccatttact actgtgccaa acattattac 300
tacggtggta gctatgctat ggactactgg ggccaaggaa cctcagtcac cgtctcctca 360
<210> 23
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 23
Met Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro
1 5 10 15
Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Leu Ser Phe
20 25 30
Met His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile
35 40 45
Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Thr Val Glu Ala
65 70 75 80
Glu Asp Ala Ala Ser Tyr Phe Cys His Gln Trp Ser Ser Asn Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Ser Ser Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Asp Val Met Gly Val Asp Ser Gly Gly
115 120 125
Gly Leu Val Gln Pro Gly Gly Ser Arg Lys Leu Ser Cys Ala Ala Pro
130 135 140
Gly Phe Thr Phe Ser Ser Phe Gly Met His Trp Val Arg Gln Ala Pro
145 150 155 160
Glu Lys Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Pro Ser Ser Thr
165 170 175
Leu His Tyr Ala Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
180 185 190
Asn Pro Lys Asn Thr Leu Phe Leu Gln Met Lys Leu Pro Ser Leu Cys
195 200 205
Tyr Gly Leu Leu Gly Pro Arg Asp His Val His Arg Leu Leu Lys Thr
210 215 220
Arg Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val Phe
225 230 235 240
Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
245 250 255
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
260 265 270
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
275 280 285
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
290 295 300
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Glu Phe Arg Val Lys Phe Ser Arg Ser Ala
355 360 365
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
370 375 380
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
385 390 395 400
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
405 410 415
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
420 425 430
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
435 440 445
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
450 455 460
His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 24
<211> 377
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 24
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 Leu Thr Gln Ser Pro Ala Ile Leu
20 25 30
Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser
35 40 45
Ser Leu Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro
50 55 60
Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser
85 90 95
Thr Val Glu Ala Glu Asp Ala Ala Ser Tyr Phe Cys His Gln Trp Ser
100 105 110
Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Met
130 135 140
Gly Val Asp Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Arg Lys
145 150 155 160
Leu Ser Cys Ala Ala Pro Gly Phe Thr Phe Ser Ser Phe Gly Met His
165 170 175
Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala Tyr Ile
180 185 190
Ser Ser Pro Ser Ser Thr Leu His Tyr Ala Asp Arg Val Lys Gly Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe Leu Gln Met
210 215 220
Lys Leu Pro Ser Leu Cys Tyr Gly Leu Leu Gly Pro Arg Asp His Val
225 230 235 240
His Arg Leu Leu Thr Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
245 250 255
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
260 265 270
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
275 280 285
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
290 295 300
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Gly
305 310 315 320
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
325 330 335
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
340 345 350
Glu Glu Gly Gly Cys Glu Leu Glu Phe Glu Leu Gly Thr Phe Lys Thr
355 360 365
Asn Asp Leu Gln Gly Ser Cys Arg Ser
370 375
<210> 25
<211> 377
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 25
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 Val Met Gly Val Asp Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Arg Lys Leu Ser Cys Ala Ala Pro Gly Phe
35 40 45
Thr Phe Ser Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys
50 55 60
Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Pro Ser Ser Thr Leu His
65 70 75 80
Tyr Ala Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro
85 90 95
Lys Asn Thr Leu Phe Leu Gln Met Lys Leu Pro Ser Leu Cys Tyr Gly
100 105 110
Leu Leu Gly Pro Arg Asp His Val His Arg Leu Leu Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr
130 135 140
Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met
145 150 155 160
Thr Cys Arg Ala Ser Ser Ser Leu Ser Phe Met His Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu
180 185 190
Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser
195 200 205
Tyr Ser Leu Thr Ile Ser Thr Val Glu Ala Glu Asp Ala Ala Ser Tyr
210 215 220
Phe Cys His Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr
225 230 235 240
Lys Leu Glu Ile Thr Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
245 250 255
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
260 265 270
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
275 280 285
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
290 295 300
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Gly
305 310 315 320
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
325 330 335
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
340 345 350
Glu Glu Gly Gly Cys Glu Leu Glu Phe Glu Leu Gly Thr Phe Lys Thr
355 360 365
Asn Asp Leu Gln Gly Ser Cys Arg Ser
370 375
<210> 26
<211> 396
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 26
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 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu
20 25 30
Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser
35 40 45
Ser Val Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro
50 55 60
Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser
85 90 95
Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr
100 105 110
Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
130 135 140
Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val
145 150 155 160
Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met
165 170 175
His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala
180 185 190
Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly
195 200 205
Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
210 215 220
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
225 230 235 240
Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly
245 250 255
Thr Thr Val Thr Val Ser Ala Thr Arg Thr Thr Thr Pro Ala Pro Arg
260 265 270
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
275 280 285
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
290 295 300
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
305 310 315 320
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser
325 330 335
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
340 345 350
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
355 360 365
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Glu Phe Glu Leu Gly Thr
370 375 380
Phe Lys Thr Asn Asp Leu Gln Gly Ser Cys Arg Ser
385 390 395
<210> 27
<211> 396
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 27
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 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu
20 25 30
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg
50 55 60
Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
65 70 75 80
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr
115 120 125
Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val
145 150 155 160
Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val
165 170 175
Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile His Trp Phe
180 185 190
Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser
195 200 205
Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly
210 215 220
Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala
225 230 235 240
Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr Phe Gly Gly
245 250 255
Gly Thr Lys Leu Glu Ile Lys Thr Arg Thr Thr Thr Pro Ala Pro Arg
260 265 270
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
275 280 285
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
290 295 300
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
305 310 315 320
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser
325 330 335
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
340 345 350
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
355 360 365
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Glu Phe Glu Leu Gly Thr
370 375 380
Phe Lys Thr Asn Asp Leu Gln Gly Ser Cys Arg Ser
385 390 395
<210> 28
<211> 715
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 28
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 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
65 70 75 80
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Asp Tyr Tyr Cys Ala Arg Ser Asn Tyr Tyr Gly Ser Ser Tyr Trp
115 120 125
Phe Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys
165 170 175
Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Met Asp Trp
180 185 190
Tyr Gln Lys Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr
195 200 205
Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala
225 230 235 240
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly
245 250 255
Gly Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
260 265 270
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
275 280 285
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
290 295 300
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
305 310 315 320
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
325 330 335
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
340 345 350
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
355 360 365
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
370 375 380
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
385 390 395 400
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
405 410 415
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
420 425 430
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
435 440 445
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
450 455 460
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
465 470 475 480
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Phe Trp Val
485 490 495
Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr
500 505 510
Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu
515 520 525
His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg
530 535 540
Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg
545 550 555 560
Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
565 570 575
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
580 585 590
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
595 600 605
Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
610 615 620
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
625 630 635 640
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
645 650 655
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
660 665 670
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
675 680 685
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
690 695 700
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
705 710 715
<210> 29
<211> 715
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 29
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 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
65 70 75 80
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Asp Tyr Tyr Cys Ala Arg Ser Asn Tyr Tyr Gly Ser Ser Tyr Trp
115 120 125
Phe Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys
165 170 175
Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Met Asp Trp
180 185 190
Tyr Gln Lys Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr
195 200 205
Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala
225 230 235 240
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly
245 250 255
Gly Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
260 265 270
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
275 280 285
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
290 295 300
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
305 310 315 320
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
325 330 335
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
340 345 350
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
355 360 365
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
370 375 380
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
385 390 395 400
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
405 410 415
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
420 425 430
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
435 440 445
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
450 455 460
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
465 470 475 480
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Phe Trp Val
485 490 495
Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr
500 505 510
Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu
515 520 525
His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg
530 535 540
Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg
545 550 555 560
Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
565 570 575
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
580 585 590
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
595 600 605
Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
610 615 620
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
625 630 635 640
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
645 650 655
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
660 665 670
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
675 680 685
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
690 695 700
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
705 710 715
<210> 30
<211> 671
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 30
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 Val Leu Thr Gln Ser Pro Ala Ile Leu
20 25 30
Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser
35 40 45
Ser Val Asn Tyr Met Asp Trp Tyr Gln Lys Lys Pro Gly Ser Ser Pro
50 55 60
Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser
85 90 95
Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser
100 105 110
Phe Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
130 135 140
Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val
145 150 155 160
Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met
165 170 175
His Trp Val Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Ile Gly Ala
180 185 190
Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly
195 200 205
Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
210 215 220
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Asp Tyr Tyr Cys Ala Arg
225 230 235 240
Ser Asn Tyr Tyr Gly Ser Ser Tyr Trp Phe Phe Asp Val Trp Gly Ala
245 250 255
Gly Thr Thr Val Thr Val Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys
260 265 270
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
275 280 285
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
290 295 300
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
305 310 315 320
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
325 330 335
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
340 345 350
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
355 360 365
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
370 375 380
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
385 390 395 400
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
405 410 415
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
420 425 430
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
435 440 445
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
450 455 460
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
465 470 475 480
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Tyr Ile
485 490 495
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
500 505 510
Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
515 520 525
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
530 535 540
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
545 550 555 560
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln
565 570 575
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
580 585 590
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
595 600 605
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
610 615 620
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
625 630 635 640
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
645 650 655
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
660 665 670
<210> 31
<211> 671
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 31
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 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
65 70 75 80
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Asp Tyr Tyr Cys Ala Arg Ser Asn Tyr Tyr Gly Ser Ser Tyr Trp
115 120 125
Phe Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys
165 170 175
Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Met Asp Trp
180 185 190
Tyr Gln Lys Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr
195 200 205
Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala
225 230 235 240
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly
245 250 255
Gly Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
260 265 270
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
275 280 285
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
290 295 300
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
305 310 315 320
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
325 330 335
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
340 345 350
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
355 360 365
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
370 375 380
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
385 390 395 400
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
405 410 415
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
420 425 430
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
435 440 445
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
450 455 460
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
465 470 475 480
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Tyr Ile
485 490 495
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
500 505 510
Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
515 520 525
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
530 535 540
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
545 550 555 560
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln
565 570 575
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
580 585 590
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
595 600 605
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
610 615 620
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
625 630 635 640
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
645 650 655
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
660 665 670
<210> 32
<211> 677
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 32
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ala Phe Ser Tyr Ser Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp
65 70 75 80
Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser
85 90 95
Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr
145 150 155 160
Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile
165 170 175
Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr
180 185 190
Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile
195 200 205
Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly
210 215 220
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala
225 230 235 240
Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr
245 250 255
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Glu Ser
260 265 270
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
275 280 285
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
290 295 300
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
305 310 315 320
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
325 330 335
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
340 345 350
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
355 360 365
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
370 375 380
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
385 390 395 400
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
405 410 415
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
420 425 430
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
435 440 445
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
450 455 460
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
465 470 475 480
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
485 490 495
Leu Gly Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
500 505 510
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
515 520 525
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
530 535 540
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
545 550 555 560
Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
565 570 575
Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
580 585 590
Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
595 600 605
Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
610 615 620
Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
625 630 635 640
Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
645 650 655
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
660 665 670
Ala Leu Pro Pro Arg
675
<210> 33
<211> 672
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 33
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 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Asn Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
100 105 110
Ala Leu Tyr Tyr Cys Ala Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr
115 120 125
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg
165 170 175
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp
195 200 205
Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
210 215 220
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp
225 230 235 240
Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe
245 250 255
Gly Gln Gly Thr Arg Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro
260 265 270
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
275 280 285
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
290 295 300
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
305 310 315 320
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
325 330 335
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
340 345 350
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
355 360 365
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
370 375 380
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
385 390 395 400
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
405 410 415
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
420 425 430
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
435 440 445
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
450 455 460
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
465 470 475 480
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Tyr
485 490 495
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
500 505 510
Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
515 520 525
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
530 535 540
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
545 550 555 560
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
565 570 575
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
580 585 590
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
595 600 605
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
610 615 620
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
625 630 635 640
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
645 650 655
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
660 665 670
<210> 34
<211> 653
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 34
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 Gly Asp Val Met Gly Val Asp Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Arg Lys Leu Ser Cys Ala Ala Pro Gly
35 40 45
Phe Thr Phe Ser Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu
50 55 60
Lys Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Pro Ser Ser Thr Leu
65 70 75 80
His Tyr Ala Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Pro Lys Asn Thr Leu Phe Leu Gln Met Lys Leu Pro Ser Leu Cys Tyr
100 105 110
Gly Leu Leu Gly Pro Arg Asp His Val His Arg Leu Leu Lys Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Leu Thr Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val
145 150 155 160
Thr Met Thr Cys Arg Ala Ser Ser Ser Leu Ser Phe Met His Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser
180 185 190
Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Ser Tyr Ser Leu Thr Ile Ser Thr Val Glu Ala Glu Asp Ala Ala
210 215 220
Ser Tyr Phe Cys His Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala
225 230 235 240
Gly Thr Lys Leu Glu Ile Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
370 375 380
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Tyr Ile Trp Ala
465 470 475 480
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490 495
Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
500 505 510
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
515 520 525
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
530 535 540
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln
545 550 555 560
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
565 570 575
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
580 585 590
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
595 600 605
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
610 615 620
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
625 630 635 640
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
645 650
<210> 35
<211> 670
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 35
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 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu
20 25 30
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg
50 55 60
Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
65 70 75 80
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr
115 120 125
Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val
145 150 155 160
Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val
165 170 175
Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile His Trp Phe
180 185 190
Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser
195 200 205
Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly
210 215 220
Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala
225 230 235 240
Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr Phe Gly Gly
245 250 255
Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro
260 265 270
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
275 280 285
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
290 295 300
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
305 310 315 320
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
325 330 335
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
340 345 350
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
355 360 365
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
370 375 380
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
385 390 395 400
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
405 410 415
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
420 425 430
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
435 440 445
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
450 455 460
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
465 470 475 480
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Tyr Ile Trp
485 490 495
Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile
500 505 510
Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
515 520 525
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
530 535 540
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
545 550 555 560
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn
565 570 575
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
580 585 590
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
595 600 605
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
610 615 620
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
625 630 635 640
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
645 650 655
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
660 665 670
<210> 36
<211> 715
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 36
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 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
65 70 75 80
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Asp Tyr Tyr Cys Ala Arg Ser Asn Tyr Tyr Gly Ser Ser Tyr Trp
115 120 125
Phe Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys
165 170 175
Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Met Asp Trp
180 185 190
Tyr Gln Lys Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr
195 200 205
Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala
225 230 235 240
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly
245 250 255
Gly Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
260 265 270
Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu
275 280 285
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
290 295 300
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
305 310 315 320
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
325 330 335
Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu
340 345 350
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
355 360 365
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
370 375 380
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
385 390 395 400
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
405 410 415
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
420 425 430
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
435 440 445
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
450 455 460
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
465 470 475 480
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Phe Trp Val
485 490 495
Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr
500 505 510
Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu
515 520 525
His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg
530 535 540
Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg
545 550 555 560
Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
565 570 575
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
580 585 590
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
595 600 605
Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
610 615 620
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
625 630 635 640
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
645 650 655
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
660 665 670
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
675 680 685
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
690 695 700
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
705 710 715
<210> 37
<211> 660
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 37
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 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
65 70 75 80
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Asp Tyr Tyr Cys Ala Arg Ser Asn Tyr Tyr Gly Ser Ser Tyr Trp
115 120 125
Phe Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys
165 170 175
Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Met Asp Trp
180 185 190
Tyr Gln Lys Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr
195 200 205
Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala
225 230 235 240
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly
245 250 255
Gly Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
260 265 270
Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu
275 280 285
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
290 295 300
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
305 310 315 320
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
325 330 335
Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu
340 345 350
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
355 360 365
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
370 375 380
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
385 390 395 400
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
405 410 415
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
420 425 430
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
435 440 445
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
450 455 460
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
465 470 475 480
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Tyr Ile
485 490 495
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
500 505 510
Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
515 520 525
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
530 535 540
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
545 550 555 560
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln
565 570 575
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
580 585 590
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
595 600 605
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
610 615 620
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
625 630 635 640
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
645 650 655
Lys Asp Thr Tyr
660
<210> 38
<211> 672
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗原受体
<400> 38
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 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Asn Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
100 105 110
Ala Leu Tyr Tyr Cys Ala Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr
115 120 125
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg
165 170 175
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp
195 200 205
Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
210 215 220
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp
225 230 235 240
Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe
245 250 255
Gly Gln Gly Thr Arg Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro
260 265 270
Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe
275 280 285
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
290 295 300
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
305 310 315 320
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
325 330 335
Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val
340 345 350
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
355 360 365
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
370 375 380
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
385 390 395 400
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
405 410 415
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
420 425 430
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
435 440 445
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
450 455 460
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
465 470 475 480
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Tyr
485 490 495
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
500 505 510
Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
515 520 525
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
530 535 540
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
545 550 555 560
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
565 570 575
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
580 585 590
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
595 600 605
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
610 615 620
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
625 630 635 640
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
645 650 655
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
660 665 670
<210> 39
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 39
Gln Gln Gly Asn Thr Leu Pro Tyr Thr
1 5
<210> 40
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 40
Asn Asp Tyr Ala Met His
1 5
<210> 41
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 41
Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 42
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 42
Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp Val
1 5 10
<210> 43
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 43
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 44
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 44
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 45
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 45
Gln Gln Arg Ser Asn Trp Pro Ile Thr
1 5
<210> 46
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 框架区
<400> 46
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 47
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 47
Ser Tyr Asn Met His
1 5
<210> 48
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 框架区
<400> 48
Trp Val Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 49
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 49
Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 50
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 框架区
<400> 50
Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Asp Tyr Tyr Cys Ala Arg
20 25 30
<210> 51
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 51
Ser Asn Tyr Tyr Gly Ser Ser Tyr Trp Phe Phe Asp Val
1 5 10
<210> 52
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 框架区
<400> 52
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 53
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 框架区
<400> 53
Asp Ile Val Leu Thr Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys
20
<210> 54
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 54
Arg Ala Ser Ser Ser Val Asn Tyr Met Asp
1 5 10
<210> 55
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 框架区
<400> 55
Trp Tyr Gln Lys Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
1 5 10 15
<210> 56
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 56
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 57
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 框架区
<400> 57
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
1 5 10 15
Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
20 25 30
<210> 58
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 58
Gln Gln Trp Ser Phe Asn Pro Pro Thr
1 5
<210> 59
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 框架区
<400> 59
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 60
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 60
Asp Tyr Gly Val Ser
1 5
<210> 61
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 61
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
1 5 10 15
<210> 62
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 62
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
1 5 10
<210> 63
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 63
Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
1 5 10
<210> 64
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 互补决定区
<400> 64
His Thr Ser Arg Leu His Ser
1 5
Claims (26)
1.双特异性嵌合抗原受体(CAR),其包含:
(i)含有轻链可变区(VL1)和重链可变区(VH1)的抗CD20抗原结合区,其中VL1包含三个互补决定区(CDR),即CDR1、CDR2和CDR3,其分别具有与SEQ ID NO:43、SEQ ID NO:44、SEQID NO:45所示的氨基酸序列约80%至约100%同一性的氨基酸序列,并且其中VH1包含三个CDR,即CDR1、CDR2和CDR3,其分别具有与SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42所示的氨基酸序列约80%至约100%同一性的氨基酸序列;和
(ii)含有轻链可变区(VL2)和重链可变区(VH2)的抗CD19抗原结合区,其中VL2包含三个互补决定区(CDR),即CDR1、CDR2和CDR3,其分别具有与SEQ ID NO:63、SEQ ID NO:64、SEQID NO:39所示的氨基酸序列约80%至约100%同一性的氨基酸序列,并且其中VH2包含三个CDR,即CDR1、CDR2和CDR3,其分别具有与SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62所示的氨基酸序列约80%至约100%同一性的氨基酸序列。
2.权利要求1的双特异性CAR,其中VL1位于VH1的N端。
3.权利要求1的双特异性CAR,其中VH2位于VL2的N端。
4.权利要求1的双特异性CAR,其中VL1和VH1分别具有与SEQ ID NO:4和SEQ IDNO:3所示的氨基酸序列约80%至约100%同一性的氨基酸序列。
5.权利要求1的双特异性CAR,其中VL2和VH2分别具有与SEQ ID NO:5和SEQ IDNO:6所示的氨基酸序列约80%至约100%同一性的氨基酸序列。
6.权利要求1的双特异性CAR,其中所述抗CD20抗原结合区是特异性结合CD20的单链可变片段(scFv),并且其中所述抗CD19抗原结合区是特异性结合CD19的scFv。
7.权利要求1的双特异性CAR,其中该双特异性CAR进一步包含以下的一种或多种:
(a)信号肽;
(b)铰链区;
(c)跨膜结构域;
(d)共刺激区;和
(e)胞质信号传导结构域。
8.权利要求7的双特异性CAR,其中所述共刺激区包含4-1BB(CD137)、CD28、OX40、CD2、CD7、CD27、CD30、CD40、CD70、CD134、PD1、Dap10、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、NKG2D、GITR、TLR2或其组合的共刺激区。
9.权利要求7的双特异性CAR,其中所述胞质信号传导结构域包含CD3ζ的胞质信号传导结构域。
10.权利要求7的双特异性CAR,其中所述铰链区包含Ig4、CD8、CD28、CD137或其组合的铰链区。
11.权利要求7的双特异性CAR,其中所述跨膜结构域包含CD8、CD28、CD3ε、CD45、CD4、CD5、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154或其组合的跨膜结构域。
12.权利要求1的双特异性CAR,其包含与SEQ ID NO.16所示的氨基酸序列约80%至约100%同一性的氨基酸序列。
13.免疫细胞,其表达权利要求1的双特异性CAR。
14.权利要求13的免疫细胞,其中该免疫细胞是T细胞或自然杀伤(NK)细胞。
15.核酸,其编码权利要求1的双特异性CAR。
16.载体,其包含权利要求15的核酸。
17.治疗癌症的方法,该方法包括对有需要的个体施用权利要求13的免疫细胞。
18.权利要求17的方法,其中该癌症是血液癌症。
19.权利要求17的方法,其中该癌症是B细胞恶性肿瘤。
20.权利要求17的方法,其中该癌症是霍奇金淋巴瘤、非霍奇金淋巴瘤、白血病和/或多发性骨髓瘤。
21.权利要求17的方法,其中该癌症是急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、慢性髓细胞性白血病、急性成淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)或其组合。
22.权利要求17的方法,其中该免疫细胞是同种异体的或自体的。
23.治疗癌症的方法,该方法包括对有需要的个体施用权利要求13的免疫细胞,其中该双特异性CAR在施用后约28天中在个体血液中产生约1e+06拷贝/μg基因组DNA(拷贝/gDNA)至约3.2e+06拷贝/gDNA的曲线下面积(AUC)。
24.用于治疗癌症的方法,该方法包括对有需要的个体施用权利要求13的免疫细胞,其中该双特异性CAR在个体血液中产生约1e+05拷贝/μg基因组DNA(拷贝/gDNA)至约3e+05拷贝/gDNA的最大血浆浓度(Cmax)。
25.权利要求24的方法,其中该双特异性CAR具有约8天至约15天的Tmax。
26.权利要求25的方法,其中该双特异性CAR具有约10天至约14天的Tmax。
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PCT/CN2020/109645 WO2021184673A1 (en) | 2020-03-17 | 2020-08-17 | Combined chimeric antigen receptor targeting cd19 and cd20 and application thereof |
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