CN116390746A - 双car-t细胞 - Google Patents
双car-t细胞 Download PDFInfo
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- CN116390746A CN116390746A CN202180058892.9A CN202180058892A CN116390746A CN 116390746 A CN116390746 A CN 116390746A CN 202180058892 A CN202180058892 A CN 202180058892A CN 116390746 A CN116390746 A CN 116390746A
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Abstract
本发明涉及表达针对两个不同靶点的两种CAR的新工程化免疫细胞、用于制备所述免疫细胞的多核苷酸、包含所述免疫细胞的药物组合物、以及所述免疫细胞在治疗癌症中的用途。
Description
技术领域
本发明涉及细胞免疫疗法领域,并且更具体地涉及表达针对两个不同靶点(target,靶标)的两种CAR的用于癌症治疗的新工程化免疫细胞。
背景技术
在美国(US),大约每3分钟就有一个人被诊断出患有血液癌症。在2020年,预估在US将总计有178,520人被诊断出患有白血病、淋巴瘤或骨髓瘤。预计白血病、淋巴瘤和骨髓瘤的新病例将占在2020年的US的诊断的预估1,806,590例新癌症病例的9.9%(CancerFacts&Figures,2020.美国癌症协会(American Cancer Society))。
用于血液恶性肿瘤的嵌合抗原受体(CAR)T细胞疗法的发展代表了过去十年中最显著的治疗进展之一(Holstein et al,2020,Clin.Pharmacol.Ther.107(1):112-122)。的确,作为肿瘤学中快速发展的领域,CAR-T细胞的过继转移在血液恶性肿瘤的治疗中显示出惊人的功效,并已在多项临床试验中得到报道。
表达嵌合抗原受体(“CAR”)的免疫细胞是被基因工程化以表达通常被设计用于识别特定肿瘤抗原并杀死表达这些肿瘤抗原的癌细胞的CAR的细胞。不排除CAR免疫细胞可以激活免疫系统以消除肿瘤。这些通常是表达CAR的T细胞(“CAR-T细胞”)或表达CAR的自然杀伤细胞(“CAR-NK细胞”)或表达CAR的巨噬细胞。
CAR是由与单个融合分子中的一个或多个信号域相关的靶向部分组成的合成受体。通常,CAR的结合部分由源自单克隆抗体的抗原结合结构域组成,所述抗原结合结构域由单链可变片段(scFv)组成,所述单链可变片段(scFv)包含通过柔性接头连接的单克隆抗体的轻链和重链可变片段。基于受体或配体结构域的结合部分也已经成功使用。第一代CAR的信号域源自CD3ζ或Fc受体γ链的细胞质区域。第一代CAR已经显示出成功地重定向T细胞的细胞毒性,然而,它们未能在体内提供延长的扩增和抗肿瘤活性。来自共刺激分子的包括CD28、OX-40(CD134)、ICOS和4-1BB(CD137)的信号域已经单独添加(第二代)或组合添加(第三代)以增强生存并且增加CAR修饰T细胞的增殖。CAR已经成功地允许T细胞针对在来自各种恶性肿瘤(包括淋巴瘤和实体瘤)的肿瘤细胞表面表达的抗原进行重定向(Jena,Dottiet al.2010,Blood 116(7):1035-44)。
过继免疫疗法,其涉及转移离体产生的自体或同种异体的抗原特异性T细胞,是治疗病毒感染和癌症的一种有前途的策略,如通过美国食品和药物管理局(FDA)批准的CAR-T细胞数量的增加所证实的(例如,Novartis的抗-CD19 CAR-T替沙来塞(tisagenlecleucel)(KymriahTM)用于治疗前体B细胞急性淋巴细胞白血病、Kite Pharma的抗-CD19 CAR-T阿基仑赛(axicabtagene ciloleucel)(YescartaTM)用于治疗成年患者中某些类型的大B细胞淋巴瘤)。
尽管CAR-T细胞疗法的研究和开发取得了进展,但仍然需要改进的CAR-T细胞,所述改进的CAR-T细胞可以靶向更宽范围的癌症以及复发性癌症和/或其中癌症相关抗原表达变化很大并且会随着时间或治疗期间或治疗后发展的癌症。
发明内容
本发明人已经开发了靶向CD20和CD22抗原的新CAR-T细胞,其可以通过表达不同水平的CD20和CD22的肿瘤细胞激活,并且对现有技术的CAR-T细胞进行改进。
第一方面涉及在其细胞表面表达对于CD22特异性的嵌合抗原受体(CAR)(CAR22)和对于CD20特异性的嵌合抗原受体(CAR20)的基因工程化免疫细胞,
a)其中所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含SEQ ID NO:11的可变重链(VH)和SEQID NO:12的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域(hinge domain,铰链域),
ii)来自CD8α的跨膜结构域(transmembrane domain,跨膜域),和
iii包含4-1BB刺激结构域(stimulatory domain,刺激域)和CD3ζ信号结构域(signalling domain,信号域,信号转导结构域)的胞内结构域;并且
b)其中所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含SEQ ID NO:15的可变重链(VH)和SEQID NO:16的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
在特定方面,所述基因工程化免疫细胞是TCR阴性T细胞(TCR negative T-cell)。
另一方面涉及药物组合物,其包含所述工程化免疫细胞或含有所述工程化免疫细胞的细胞群、以及药学上可接受的赋形剂。
另一方面涉及分离的多核苷酸,包含:
a)编码CAR22的核酸,所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含SEQ ID NO:11的可变重链(VH)和SEQID NO:12的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;以及
b)编码CAR20的核酸,所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含SEQ ID NO:15的可变重链(VH)和SEQID NO:16的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
其他方面涉及包含所述多核苷酸的载体,以及包含所述多核苷酸或载体的宿主细胞。
另一方面涉及制备所述工程化免疫细胞的方法。
其他方面涉及用作药物的所述工程化免疫细胞或细胞群。
另一方面依赖于所述工程化免疫细胞用于治疗癌症或炎性病症,特别是与CD20和/或CD22表达相关的癌症或炎性病症。
附图说明
图1:CD20xCD22或CD22xCD20 CAR检测。使用实施例中描述的方案,流式细胞术分析显示出在非转导的(NT)或用CD22或CD22xCD20或CD20xCD22 CAR构建体转导的T细胞中的CAR CD20或CAR CD22的检测。
图3:来自针对表达或不表达CD20和/或CD22抗原的Raji细胞的2个不同供体的CD20xCD22、CD22xCD20和CD22 CAR T细胞的裂解百分比。
图4:随着时间的推移,针对表达CD20和CD22(A)、仅表达CD22(B)或仅表达CD20(C)的Raji细胞的CD20xCD22、CD22xCD20和CD22 CAR T细胞的裂解百分比。
图5:通过生物发光测量在用指定剂量的CD20xCD22、CD22xCD20和CD22 CAR T细胞治疗后体内肿瘤负荷的剂量依赖性控制。
图6:在B细胞淋巴瘤的播散模型中,用指定剂量的CD20xCD22、CD22xCD20和CD22CAR T细胞治疗的动物的存活曲线。
图7:在B细胞淋巴瘤的皮下模型中,用指定剂量的CD20xCD22、CD22xCD20和CD22CAR T细胞治疗的动物的存活曲线。
图8.在Daudi细胞上通过CD20xCD22、CD22xCD20、CD20和CD22CAR T细胞的IFNγ的释放。
在说明书和实例中使用的相应术语如下:
抗-CD20 CAR=CAR20=CD20CAR
抗-CD22 CAR=CAR22=CD22CAR
抗-CD20 CAR/抗-CD22 CAR=CAR20x22或CAR22x20=
CD20xCD22 CAR或CD22xCD20CAR
具体实施方式
除非本文具体定义,否则所有使用的技术和科学术语具有与基因治疗、生物化学、遗传学和分子生物学领域中的技术人员通常理解的相同含义。
与本文所述的那些类似或等同的所有方法和材料都可以用于本发明的实践或测试,其中合适的方法和材料在本文中描述。本文提及的所有出版物、专利申请、专利和其他参考文献均通过以其整体引用并入。在冲突的情况下,以本说明书,包括定义为准。此外,除非另有说明,否则材料、方法和实例仅是说明性的而不旨在限制性的。
除非另有指定,否则本发明的实践将采用细胞生物学、细胞培养、分子生物学、转基因生物学、微生物学、重组DNA和免疫学的常规技术,这些都在本领域的技术范围内。这些技术在文献中有充分的解释。参见,例如,现代分子生物学实验技术(Current Protocolsin Molecular Biology)(Frederick M.AUSUBEL,2000,Wiley and son Inc,国会图书馆(Library of Congress),USA);分子克隆(Molecular Cloning):实验室手册(ALaboratoryManual),第三版,(Sambrook et al,2001,冷泉港(Cold Spring Harbor),纽约:冷泉港实验室出版社(Cold Spring Harbor Laboratory Press));寡核苷酸合成(OligonucleotideSynthesis)(M.J.Gait ed.,1984);Mullis et al.U.S.Pat.No.4,683,195;核酸杂交(Nucleic Acid Hybridization)(B.D.Harries&S.J.Higgins eds.1984);转录和翻译(Transcription And Translation)(B.D.Hames&S.J.Higgins eds.1984);动物细胞培养(Culture Of Animal Cells)(R.I.Freshney,Alan R.Liss,Inc.,1987);固定化细胞和酶(Immobilized Cells And Enzymes)(IRL出版社,1986);B.Perbal,分子克隆实验指南(APractical Guide To Molecular Cloning)(1984);酶学方法系列(the series,MethodsIn ENZYMOLOGY)(J.Abelson和M.Simon主编,Academic Press,Inc.,纽约),具体地,卷154和155(Wu et al.eds.)以及卷185,“基因表达技术(Gene Expression Technology)”(D.Goeddel,ed.);哺乳动物细胞的基因转移载体(Gene Transfer Vectors ForMammalian Cells)(J.H.Miller和M.P.Calos编辑,1987,冷泉港实验室);细胞与分子生物学中的免疫化学方法(Immunochemical Methods In Cell And Molecular Biology)(Mayer和Walker编辑,学术出版社,伦敦,1987);实验免疫学手册(Handbook OfExperimental Immunology),卷I-IV(D.M.Weir和C.C.Blackwell编辑,1986);以及操纵小鼠胚胎(Manipulating the Mouse Embryo),(冷泉港实验室出版社,冷泉港,N.Y.,1986)。
定义
如本文所用,“与疾病状态相关的抗原”是指在给定疾病中存在或过度表达的抗原。在抗原是CD20或CD22的情况下,“CD20相关疾病”或“CD22相关疾病”是指其中CD20或CD22抗原通常存在于肿瘤细胞或引起炎症反应的细胞(特别是B细胞)上的疾病,如癌症或炎性病症。与疾病状态相关的抗原,其中所述疾病状态是癌症,即“与癌症相关的抗原”可以是如本文所定义的肿瘤抗原。
如本文所用,术语“CD20”是指已知在B细胞上可检测到的抗原决定簇。人CD20也称为跨膜4-结构域,亚族A,成员1(MS4A1)。人和鼠的氨基酸和核酸序列可以在公共数据库中找到,如GenBank、UniProt和Swiss-Prot。例如,人CD20的氨基酸序列可以在登录号NP_690605.1和NP_068769.2中找到,以及编码人CD20的转录变体1和3的核酸序列可以分别在登录号NM_152866.2和NM_021950.3中找到。一方面,CAR的抗原结合部分识别并结合CD20蛋白的胞外结构域内的抗原。一方面,CD20蛋白在癌细胞上表达。如本文所用,“CD20”包括包含突变的蛋白,例如全长野生型CD20的点突变、片段、插入、缺失和剪接变体。
如本文所用,术语“CD22”是指已知在白血病前体细胞上可检测到的抗原决定簇。人和鼠的氨基酸和核酸序列可以在公共数据库中找到,如GenBank、UniProt和Swiss-Prot。例如,同工型1-5人CD22的氨基酸序列可以分别在登录号NP 001762.2、NP 001172028.1、NP001172029.1、NP 001172030.1和NP 001265346.1中找到,以及编码人CD22的变体1-5的核酸序列可以分别在登录号NM 001771.3、NM 001185099.1、NM 001185100.1、NM001185101.1和NM 001278417.1中找到。一方面,CAR的抗原结合部分识别并结合CD22蛋白的胞外结构域内的抗原。一方面,CD22蛋白在癌细胞上表达。如本文所用,“CD22”包括包含突变的蛋白,例如全长野生型CD22的点突变、片段、插入、缺失和剪接变体。
术语“肿瘤抗原”是指涵盖“肿瘤特异性抗原”和“肿瘤相关抗原”。肿瘤特异性抗原(TSA)通常仅存在于肿瘤细胞上,而不存在于任何其他细胞上,而肿瘤相关抗原(TAA)存在于某些肿瘤细胞上,并且也存在于某些正常细胞上。如本文所指,肿瘤抗原还指蛋白质的突变形式,其仅以该形式出现在肿瘤中,而非突变形式在非肿瘤组织中观察到。
如本文所用,术语“胞外抗原结合结构域”是指能够结合特定抗原的寡肽或多肽。优选地,该结构域能够与细胞表面分子相互作用。例如,可以选择胞外抗原结合结构域以识别作为与特定疾病状态相关的靶细胞上的细胞表面标志物的抗原。在特定情况下,所述胞外抗原结合结构域包含单链抗体片段(scFv),所述单链抗体片段(scFv)包含通过柔性接头连接的靶抗原特异性单克隆抗体的轻链(VL)和重链(VH)可变片段。在本文所述的工程化免疫细胞的细胞表面上表达的CAR的抗原结合结构域可以是结合靶抗原并且源自,例如单克隆抗体、重组抗体、人抗体、人源化抗体及其功能片段的任何结构域。
“嵌合抗原受体”或“CAR”通常是指包含与单个融合分子中的一个或多个信号结构域相关的靶向部分的合成受体。如本文所定义,术语“嵌合抗原受体”涵盖单链CAR以及多链CAR。通常,CAR的结合部分由单链抗体(scFv)的抗原结合结构域组成,所述单链抗体(scFv)包含通过柔性接头连接的单克隆抗体的轻链和重链可变片段。基于受体或配体结构域的结合部分也已成功使用。第一代CAR的信号结构域源自CD3ζ或Fc受体γ链的细胞质区域。第一代CAR已经显示出成功地重定向T细胞的细胞毒性。然而,它们未能在体内提供延长的扩增和抗肿瘤活性。来自共刺激分子的包括CD28、OX-40(CD134)和4-1BB(CD137)的信号结构域已经单独添加(第二代)或组合添加(第三代)以增强存活并且提高CAR修饰T细胞的增殖。CAR不一定仅是单链多肽,多链CAR也是可以的。根据多链CAR结构,例如在WO2014039523中所描述的,信号结构域和共刺激结构域位于不同的多肽链上。这种多链CAR可以源自FcεRI,通过用胞外配体结合结构域(如scFv)替换FcεRIα链的高亲和性IgE结合结构域,而FcεRIβ和/或γ链的N-和/或C-端尾部分别融合到信号转导结构域和共刺激结构域。胞外配体结合结构域具有将T细胞特异性重定向至细胞靶点的作用,而信号转导结构域激活免疫细胞反应。
“免疫细胞”是指在功能上涉及先天和/或适应性免疫反应的启动和/或执行的造血来源的细胞,如典型的CD45、CD3或CD4阳性细胞。本文所述的免疫细胞可以是树突状细胞、杀伤树突状细胞、肥大细胞、巨噬细胞、自然杀伤细胞(NK细胞)、细胞因子诱导的杀伤细胞(CIK细胞)、B细胞或选自由炎性T淋巴细胞、细胞毒性T淋巴细胞、调节性T淋巴细胞或辅助性T淋巴细胞、γδT细胞、自然杀伤T细胞(“NKT细胞”)组成的组的T细胞。
鉴于被注入具有不同单体型的患者,“同种异体的”是指细胞源自供体,或由干细胞产生和/或分化。
相对于它们的患者宿主,这种免疫细胞通常被工程化成较低的同种异体反应性和/或变得更持久。更具体地,工程化同种异体免疫细胞的方法可以包括减少或灭活TCR表达进入T细胞或进入待衍生成T细胞的干细胞的步骤。这可以通过不同的序列特异性试剂获得,如通过基因沉默或基因编辑技术(核酸酶、碱基编辑、shRNA、RNAi…)。
“源自供体”是指T细胞不一定作为新鲜细胞直接来自供体,而是可以源自从不是治疗的患者(即不同的单体型)的最初供体中获得的干细胞或细胞系。
“原代细胞(primary cell)”或“原代细胞(primary cells)”是指直接取自活组织(例如活组织检查材料)并建立用于在体外生长有限时间的细胞,这意味着它们可以经历有限数量的种群加倍。原代细胞与连续致瘤或人工永生化细胞系相反。这种细胞系的非限制性实例是CHO-K1细胞;HEK293细胞;Caco2细胞;U2-OS细胞;NIH 3T3细胞;NSO细胞;SP2细胞;CHO-S细胞;DG44细胞;K-562细胞;U-937细胞;MRC5细胞;IMR90细胞;Jurkat细胞;HepG2细胞;HeLa细胞;HT-1080细胞;HCT-116细胞;Hu-h7细胞;Huvec细胞;Molt 4细胞。
原代免疫细胞可以从许多非限制性来源中获得,包括外周血单核细胞(PBMC)、骨髓、淋巴结组织、脐带血、胸腺组织、感染部位的组织、腹水、胸腔积液、脾脏组织和来自肿瘤,如肿瘤浸润淋巴细胞。在一些实施方式中,所述免疫细胞可源自健康供体、被诊断患有癌症的患者或被诊断患有感染的患者。在另一个实施方式中,所述细胞是呈现不同表型特征的混合免疫细胞群的一部分,如包含CD4、CD8和CD56阳性细胞。通过本领域已知的多种方法提供来自供体或患者的原代免疫细胞,例如通过Schwartz J.等综述的白细胞去除术技术(Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Societyfor Apheresis:第六期特刊(the sixth special issue)(2013)J Clin Apher.28(3):145-284)。
源自干细胞的免疫细胞也被认为是根据本发明的原代免疫细胞,特别是源自诱导性多能干细胞(iPS)的那些[Yamanaka,K.et al.(2008)."Generation of Mouse InducedPluripotent Stem Cells Without Viral Vectors".Science.322(5903):949–53]。重编程因子的慢病毒表达已被用于从人外周血细胞中诱导多能细胞[Staerk,J.et al.(2010)."Reprogramming of human peripheral blood cells to induced pluripotentstem cells".Cell stem cell.7(1):20–4][Loh,YH.et al.(2010)."Reprogramming of Tcells from human peripheral blood".Cell stem cell.7(1):15–9]。
免疫细胞可以通过本领域公知的不涉及破坏人类胚胎的技术从人胚胎干细胞中获得[Chung et al.(2008)Human Embryonic Stem Cell lines generated withoutembryo destruction,Cell Stem Cell 2(2):113-117]。
“基因工程”是指旨在从细胞中引入、修改和/或提取遗传物质的任何方法。“基因编辑”是指允许在基因组中的特定位置(基因座)添加、去除或更改遗传物质的基因工程,包括准时突变(punctual mutations)。基因编辑通常涉及序列特异性试剂。
“同一性”,它是指两个核酸分子或多肽之间的序列同一性。同一性可以通过比较在每个序列中的位置来确定,所述序列可以出于比较的目的而对齐。当在比较序列中的位置被相同的碱基占据时,那么分子在该位置是相同的。核酸或氨基酸序列之间的相似性或同一性程度是核酸序列共享位置上相同或配对核苷酸数量的函数。各种对齐算法和/或程序可用于计算两个序列之间的同一性,包括FASTA或BLAST,它们可作为GCG序列分析包(威斯康星大学(University of Wisconsin),麦迪逊,Wis.)的一部分提供,并且可以使用例如默认设置。例如,考虑与本文所述的特定多肽具有至少80%、至少85%、至少90%、至少95%、至少98%或至少99%同一性并且优选表现出基本相同功能的多肽,以及编码这种多肽的多核苷酸。除非另有说明,否则本发明包括与本文所述的那些具有相同功能并且共享至少80%、通常至少85%、优选至少90%、更优选至少95%并且甚至更优选至少97%的多肽和多核苷酸。
本文中的术语“患者”或“受试者”和“供体”包括包含非人类灵长类动物和人类的动物界的所有成员。
本发明基于根据其中表达低水平的CD20抗原和低水平的CD22抗原,同时不能有效激活靶向CD20或CD22的CAR-T细胞的肿瘤细胞,可以令人惊讶地激活表达靶向CD20的CAR和靶向CD22的CAR的双CAR-T细胞的令人惊讶的观察。
不希望受该理论的束缚,在这些条件下,每个肿瘤位点的CD20抗原分子和CD22抗原分子的总数代表超过其双CAR-T细胞被激活,而单CAR-T细胞未被激活的阈值。
这可以表示如下:
X=在肿瘤表面的由抗-CD20 CAR(CAR20)识别的CD20抗原分子的密度;
Y=在肿瘤表面的由抗-CD22 CAR(CAR22)识别的CD22抗原分子的密度;
X+Y=Z=在肿瘤表面的CD20抗原分子和CD22抗原分子的密度;
T=与触发所述T细胞激活的T细胞结合的抗原分子的密度=T细胞激活所需的阈值
如果Z>T,则发生T细胞激活。
表1.CAR T细胞激活与靶抗原CD20和CD22表达水平之间关系的示意性表示
因此,本发明的表达CAR20和CAR22的T细胞(双“CAR20x22-T细胞”或“CAR22x20-T细胞”)的优势之一是用于免疫治疗以靶向具有不同表达水平的CD20和/或CD22抗原的扩展肿瘤细胞群。因此,本发明的双CAR22x20-T细胞不仅可以靶向(并因此杀死)具有低表达水平的CD20抗原和高表达水平的CD22抗原的肿瘤细胞,以及具有高表达水平的CD20抗原和低表达水平的CD22抗原的那些,还令人惊讶地也可以靶向并因此杀死具有低表达水平的CD20和CD22抗原的细胞。
本发明的双CAR-T细胞的另一个优势依赖于其在免疫疗法中的应用,以治疗通过随时间或在治疗期间表达或多或少的CD20和CD22抗原而发展的肿瘤。
本发明的双CAR-T细胞的另一个优势依赖于其在免疫疗法中的应用,以治疗以CD20和CD22抗原的低表达为特征的癌症。
本发明的双CAR-T细胞的另一个优势与两种CAR的协同作用有关,可以通过支持和加强T细胞与其靶肿瘤细胞之间的免疫突触,可以允许更高水平的效应细胞因子产生。
除了上述优势之外,本发明的双CAR-T细胞还用于避免CD20和CD22相关的癌症复发和/或抗原逃逸。
已经在此观察和描述的内容可能是可推广的,因此使得靶向两种不同肿瘤相关抗原的双CAR-T细胞可用于免疫治疗,以靶向如以上详细描述的具有不同表达水平的肿瘤相关抗原的扩展肿瘤细胞群。
本发明的一个方面的另一个令人惊讶的效果涉及根据其中在其细胞表面表达CAR20和CAR22并且具有整合在细胞的基因组中的外源核酸的免疫细胞的由本发明人所做的观察,所述外源核酸从5’到3’包含:
(i)启动子,
(ii)编码所述CAR20的核酸,
(iii)编码自切割肽的核酸,
(iv)编码所述CAR22的核酸,
从而相同的启动子控制所述CAR20和CAR22的表达;
与在其细胞表面表达CAR20和CAR22并且具有整合在细胞的基因组中的外源核酸的免疫细胞相比,表现出在体内更高的肿瘤减少,所述外源核酸从5’到3’包含:
(i)启动子,
(ii)编码所述CAR22的核酸,
(iii)编码自切割肽的核酸,
(iv)编码所述CAR20的核酸。
表达抗-CD20
CAR和抗-CD22
CAR的免疫细胞
本文所述的免疫细胞被赋予两种分别靶向CD20抗原和CD22抗原的合成的嵌合抗原受体(CAR)。
-抗-CD22 CAR(CAR22)和抗-CD20 CAR(CAR20)
本文所述的免疫细胞被赋予两种合成的CAR,这赋予它们对细胞,如包含表达CD20和/或CD22抗原的细胞的肿瘤或对表达CD20和/或CD22抗原的炎性细胞的更高特异性。
重组嵌合抗原受体通常由外源多核苷酸编码,按照在本申请中别处提及的转导步骤之一,所述外源多核苷酸使用病毒载体引入细胞。由外源多核苷酸编码的重组受体也可以以质粒或PCR产物的形式引入细胞。
通常,CAR多肽包含胞外抗原结合结构域、跨膜结构域和包含共刺激结构域和/或初级信号结构域的胞内结构域,其中所述抗原结合结构域结合与疾病状态相关的抗原。
尽管本文所述的抗-CD20和抗-CD22 CAR不限于特定的CAR结构,但可用于基因工程化免疫细胞的核酸通常编码包含以下的CAR:结合到与疾病状态相关的抗原的胞外抗原结合结构域、铰链、跨膜结构域和包含刺激结构域和/或初级信号结构域的胞内结构域。通常,胞外抗原结合结构域是scFv,所述scFv包含通过接头连接的结合到特定抗原(例如,肿瘤抗原)的抗体的重链可变链(VH)和轻链可变链(VL)。跨膜结构域可以是,例如CD8α跨膜结构域或4-1BB跨膜结构域。刺激结构域可以是,例如4-1BB刺激结构域。初级信号结构域可以是,例如CD3ζ信号结构域。
在一个实施方式中,为避免包含编码两种包含相同结构域的CAR的多核苷酸的构建体内的任何重组事件,用于编码用于在构建体中存在两次的相同氨基酸序列(例如相同的跨膜结构域、相同的刺激结构域)的核苷酸序列使用密码子利用和密码简并性优化,使得核苷酸序列发散。
表2:在CAR中通常存在的不同结构域的序列
一方面,对于CD20特异性的抗原结合结构域包含通过接头连接的可变重链(VH)和可变轻链(VL),其中所述VH链包含SEQ ID NO:47、SEQ ID NO:48和SEQ ID NO:49的H-CDR,并且所述VL链包含SEQ ID NO:50、SEQ ID NO:51和SEQ ID NO:52的L-CDR。
例如,对于CD20特异性的抗原结合结构域包含通过接头连接的可变重链(VH)和可变轻链(VL)(形成SEQ ID NO:17的scFv),其中所述VH和VL链包含SEQ ID NO:47、SEQ IDNO:48和SEQ ID NO:49的H-CDR,和SEQ ID NO:50、SEQ ID NO:51和SEQ ID NO:52的L-CDR。
本文所述的抗-CD20 CAR可以包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含具有与SEQ ID NO:15的至少80%同一性、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:47、SEQ ID NO:48和SEQ ID NO:49的H-CDR,所述可变轻链(VL)包含具有与SEQ ID NO:16的至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQID NO:50、SEQ ID NO:51和SEQ ID NO:52的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
在特定方面,由本文所述的通过基因工程化免疫细胞表达的靶向在肿瘤细胞上存在的CD20抗原的CAR在表3和表4中描述。
表3:本文所述在抗-CD20 CAR的scFv中包含并且在实施例部分中说明的VH和VL的序列
表4:本文所述并且在实施例部分说明的抗-CD20 CAR的结构
一方面,对于CD22特异性的抗原结合结构域包含通过接头连接的可变重链(VH)和可变轻链(VL),其中所述VH链包含SEQ ID NO:41、SEQ ID NO:42和SEQ ID NO:43的H-CDR,并且所述VL链包含SEQ ID NO:44、SEQ ID NO:45和SEQ ID NO:46的L-CDR。
例如,对于CD22特异性的抗原结合结构域包含通过接头连接的可变重链(VH)和可变轻链(VL)(形成SEQ ID NO:13的scFv),其中所述VH和VL链包含SEQ ID NO:41、SEQ IDNO:42和SEQ ID NO:43的H-CDR,和SEQ ID NO:44、SEQ ID NO:45和SEQ ID NO:46的L-CDR。
本文所述的抗-CD22 CAR可以包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含具有与SEQ ID NO:11的至少80%同一性、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:41、SEQ ID NO:42和SEQ ID NO:43的H-CDR,所述可变轻链(VL)包含具有与SEQ ID NO:12的至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQID NO:44、SEQ ID NO:45和SEQ ID NO:46的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
在特定方面,由本文所述的通过基因工程化免疫细胞表达的靶向在肿瘤细胞上存在的CD22抗原的CAR在以下表5和表6以及实施例部分中描述。
表5:在本文所述的抗-CD22 CAR的scFv中包含并且在实施例部分中说明的VH和VL的序列
表6:本文所述并且在实施例部分中说明的抗-CD22 CAR的结构
-表达CAR20和CAR22的免疫细胞
本文所述的工程化免疫细胞被赋予如本文所述的分别靶向CD20抗原和CD22抗原的两种合成嵌合抗原受体(CAR)。
在特定情况下,所述免疫细胞不表达靶向除CD20或CD22之外的另一种抗原的任何其他CAR。更具体地,所述免疫细胞不表达除本文所述的CAR22和CAR20之外的其他CAR。
免疫细胞可以是,例如树突状细胞、杀伤树突状细胞、肥大细胞、巨噬细胞、NK细胞、细胞因子诱导的杀伤(CIK)细胞、B细胞或选自由炎性T淋巴细胞、细胞毒性T淋巴细胞、调节性T淋巴细胞或辅助性T淋巴细胞、γδT细胞、NKT细胞和肿瘤浸润淋巴细胞(TILL)组成的组的T细胞。
在特定情况下,工程化以表达两种CAR的免疫细胞选自由T细胞、NK细胞和巨噬细胞组成的组。
在更特定情况下,表达两种CAR的免疫细胞是T细胞,例如细胞毒性T细胞。
在通常情况下,所述免疫细胞包含在细胞群中,如免疫细胞群,特别是T细胞群、NK细胞群和/或巨噬细胞群。
在特定情况下,所述免疫细胞是用于现成免疫疗法的T细胞。
在特定情况下,所述工程化免疫细胞是TCR阴性的T细胞(不在其细胞表面表达TCRα)。
在特定情况下,所述工程化T细胞表达针对编码TCR组件的多核苷酸序列的短发夹RNA(shRNA)或小干扰(siRNA)。
在另一个特定情况下,所述工程化T细胞在其TCRα和/或TCRβ等位基因中发生突变。
特别地,所述工程化T细胞可以具有至少一种编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因。
在另一个情况下,所述工程化T细胞具有至少一个选自已经失活的β2m、PD1、CTLA4、dCK、CD52和/或GR的等位基因。
在另一个情况下,工程化免疫细胞不表达SEQ ID NO:22的利妥昔单抗特异性模拟表位。
一个特定方面涉及在其细胞表面表达CAR22和CAR20的基因工程化T细胞,其中所述CAR22包含SEQ ID NO:11的VH和SEQ ID NO:12的VL,并且所述CAR20包含SEQ ID NO:15的VH和SEQ ID NO:16的VL。
更具体地,提供了在其细胞表面表达CAR22和CAR20的基因工程化T细胞,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,并且其中所述CAR20包含SEQ ID NO:18的氨基酸序列。
一个特定方面涉及在其细胞表面表达CAR22和CAR20的基因工程化T细胞,其中所述CAR22包含SEQ ID NO:11的VH和SEQ ID NO:12的VL,其中所述CAR20包含SEQ ID NO:15的VH和SEQ ID NO:16的VL,并且其中所述工程化T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因。
一个特定方面涉及在其细胞表面表达CAR22和CAR20的基因工程化T细胞,其中所述CAR22包含SEQ ID NO:11的VH和SEQ ID NO:12的VL,其中所述CAR20包含SEQ ID NO:15的VH和SEQ ID NO:16的VL,并且其中所述工程化T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因,并且具有至少一个选自已经失活的CD52和β2m的等位基因,特别是其中所述工程化T细胞具有已经通过突变失活的TCRα和/或TCRβ和CD52。
更具体地,提供了在其细胞表面表达CAR22和CAR20的基因工程化T细胞,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,其中所述CAR20包含SEQ ID NO:18的氨基酸序列,并且其中所述工程化T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因。
更具体地,提供了在其细胞表面表达CAR22和CAR20的基因工程化T细胞,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,其中所述CAR20包含SEQ ID NO:18的氨基酸序列,并且其中所述工程化T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因并且具有至少一个选自已经失活的CD52和β2m的等位基因,特别是其中所述工程化T细胞具有已经通过突变失活的TCRα和/或TCRβ和CD52。
本文还提供了在其细胞表面表达CAR22和CAR20的基因工程化免疫细胞,如上所述,其中所述CAR由并入所述免疫细胞基因组中的外源核酸编码,并且其中所述外源核酸从5’到3’包含:
(i)启动子(如EF1α启动子)
(ii)编码所述CAR20的核酸,
(iii)编码自切割肽的核酸(如SEQ ID NO:19的P2A),
(iv)编码所述CAR22的核酸,
从而相同的启动子控制所述CAR20和CAR22的表达。
更具体地,还提供了在其细胞表面表达CAR22和CAR20的基因工程化免疫细胞,如上所述,其中所述外源核酸从5’到3’包含:
(i)控制所述CAR20表达的启动子(如EF1α启动子);
(ii)编码所述CAR20的核酸,所述CAR20包含SEQ ID NO:1的信号肽、SEQ ID NO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域;
(iii)编码自切割肽的核酸(如SEQ ID NO:19的P2A);
(iv)编码所述CAR22的核酸,所述CAR22包含SEQ ID NO:1的信号肽、SEQ ID NO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域;
从而相同的启动子控制所述CAR20和CAR22的表达。
可替代地,本文还提供了在其细胞表面表达CAR22和CAR20的基因工程化免疫细胞,如上所述,其中所述CAR由并入所述免疫细胞基因组中的外源核酸编码,并且其中所述外源核酸从5’到3’包含:
(i)启动子(如EF1α启动子)
(ii)编码所述CAR22的核酸,
(iii)编码自切割肽的核酸(如SEQ ID NO:19的P2A),
(iv)编码所述CAR20的核酸,
从而相同的启动子控制所述CAR20和CAR22的表达。
更具体地,还提供了在其细胞表面表达CAR22和CAR20的基因工程化免疫细胞,如上所述,其中所述外源核酸从5’到3’包含:
(i)控制所述CAR22表达的启动子(如EF1α启动子);
(ii)编码所述CAR22的核酸序列,所述CAR22包含SEQ ID NO:1的信号肽、SEQ IDNO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域;
(iii)编码自切割肽的核酸(如SEQ ID NO:19的P2A),
(iv)编码所述CAR20的核酸,所述CAR20包含SEQ ID NO:1的信号肽、SEQ ID NO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域。
基因工程化免疫细胞的制备方法
可以通过引入一种或多种编码所述CAR的外源多核苷酸来制备如本文所述的待基因工程化以表达CAR20和CAR22的免疫细胞。可以使用病毒载体通过转导将所述多核苷酸引入细胞。所述多核苷酸也可以以质粒或PCR产物的形式引入细胞。
使用例如病毒载体(例如慢病毒载体、逆转录病毒载体、腺相关病毒(AAV)载体)或转座子/转座酶系统或质粒或PCR产物整合可以实现在上述免疫细胞中的CAR的稳定表达,特别是本文所述的CAR20和CAR22。其他方法包括直接mRNA电穿孔。
为同时将两种CAR递送到细胞中,编码本文所述的抗-CD22 CAR(CAR22)和抗-CD20CAR(CAR20)的多核苷酸可以具有不同的结构,如:
(a)多顺反子排列,其中2个转录单元均由单一启动子控制,具有相同的转录方向,并且通过“自切割”肽如2A肽(例如P2A、T2A、E2A、F2A)隔开,
(b)双向排列,其中2个转录单元中的每一个都由以头对头配置的独立的启动子控制,并且以相反的方向转录,和
(c)单顺反子排列,所述排列具有scFV转录物均由基因组间隔区隔开。
如本文所用,“多顺反子”mRNA是指包含两个或更多个编码序列(即顺反子)并且编码超过一种蛋白的单个信使RNA。多顺反子mRNA可以包含本领域已知的任何元件,以允许用于来自相同mRNA分子的两个或更多个基因的翻译,包括但不限于自切割肽,如P2A元件、T2A元件、E2A元件和F2A元件,或IRES元件。
包含在本文所述的多核苷酸中的自切割肽可以选自2A肽、2A样肽、P2A肽、E2A肽、F2A肽、T2A肽,特别是2A肽,更特别是SEQ ID NO:19的P2A肽、SEQ ID NO:38的T2A肽、SEQ IDNO:39的E2A肽或SEQ ID NO:40的F2A肽,更特别是SEQ ID NO:19的P2A肽。
IRES陈述了“内部核糖体进入位点”,任何允许转录然后翻译并入基因中的编码序列的IRES都可以在这里使用。例如,包含在本文所述的多核苷酸中的IRES可以具有SEQ IDNO:37。
本文所述的CAR20和CAR22可以由两个核酸编码,其中:
1)一个编码CAR20的核酸,所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含具有与SEQ ID NO:15的至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:47、SEQ ID NO:48和SEQID NO:49的H-CDR,所述可变轻链(VL)包含具有与SEQ ID NO:16的至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:50、SEQ ID NO:51和SEQ ID NO:52的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;和
2)另一个编码CAR22的核酸,所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含具有与SEQ ID NO:11的至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:41、SEQ ID NO:42和SEQID NO:43的H-CDR,所述可变轻链(VL)包含具有与SEQ ID NO:12的至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:44、SEQ ID NO:45和SEQ ID NO:46的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
在一种情况下,CAR22和CAR20由两个独立的核酸a)和b)编码,其中:
(1)编码CAR22的核酸a),所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含SEQ ID NO:11的可变重链(VH)和SEQID NO:12的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;和
(2)编码CAR20的核酸b),所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含SEQ ID NO:15的可变重链(VH)和SEQID NO:16的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
在特定情况下,提供了分离的多核苷酸,包含:
a)编码CAR22的核酸,所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含SEQ ID NO:11的可变重链(VH)和SEQID NO:12的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;和
b)编码CAR20的核酸,所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含SEQ ID NO:15的可变重链(VH)和SEQID NO:16的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
在另一种情况下,a)和b)的核酸在单个核酸分子上并且分离的多核苷酸包含位于a)和b)的核酸之间的编码自切割肽(如P2A、T2A、E2A、F2A)的核酸序列。
因此,在通常方面,本文公开了多核苷酸,从5’到3’包含:
(i)启动子(如EF1α启动子)
(ii)编码如本文所述的CAR20的核酸,
(iii)编码自切割肽(如SEQ ID NO:19的P2A)的核酸,
(iv)编码如本文所述的CAR22的核酸,
从而相同的启动子控制所述CAR20和CAR22的表达。
本文还公开了多核苷酸,从5’到3’包含:
(i)启动子(如EF1α启动子)
(ii)编码如本文所述的CAR22的核酸,
(iii)编码自切割肽(如SEQ ID NO:19的P2A)的核酸;
(iv)编码如本文所述的CAR20的核酸,
从而相同的启动子控制所述CAR20和CAR22的表达。
在特定情况下,本文所述的分离的多核苷酸不包含编码除所述CAR22和CAR20之外的其他CAR的核酸。
在特定情况下,本文所述的分离的多核苷酸不包含编码SEQ ID NO:22的利妥昔单抗特异性模拟表位(rituximab-specific mimotope)的核酸。
在一种情况下,编码如本文所述的CAR20和CAR22的分离的多核苷酸包含:
a)启动子(如EF1α启动子),控制所述CAR20的表达,随后是编码所述CAR20的核酸,其中所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含与SEQ ID NO:15具有至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:47、SEQ ID NO:48和SEQ IDNO:49的H-CDR,所述可变轻链(VL)包含与SEQ ID NO:16具有至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:50、SEQ ID NO:51和SEQ ID NO:52的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;和
b)编码CAR22的核酸,其中所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含与SEQ ID NO:11具有至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:41、SEQ ID NO:42和SEQ IDNO:43的H-CDR,所述可变轻链(VL)包含与SEQ ID NO:12具有至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:44、SEQ ID NO:45和SEQ ID NO:46的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;
其中a)和b)的所述核酸在单个核酸分子上并且其中编码自切割肽(如P2A、T2A、E2A或F2A)的核酸序列位于a)和b)的所述核酸之间。
在替代情况下,编码如本文所述的CAR20和CAR22的分离的多核苷酸包含:
a)启动子(如EF1α启动子),控制所述CAR22的表达,随后是编码所述CAR22的核酸,其中所述CAR22由以下组成:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含与SEQ ID NO:11具有至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:41、SEQ ID NO:42和SEQ IDNO:43的H-CDR,所述可变轻链(VL)包含与SEQ ID NO:12具有至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:44、SEQ ID NO:45和SEQ ID NO:46的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;和
b)编码CAR20的核酸,其中所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含与SEQ ID NO:15具有至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:47、SEQ ID NO:48和SEQ IDNO:49的H-CDR,所述可变轻链(VL)包含与SEQ ID NO:16具有至少80%、至少90%、至少95%、至少97%、至少99%或100%同一性的氨基酸序列且包含氨基酸序列SEQ ID NO:50、SEQ ID NO:51和SEQ ID NO:52的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;
其中a)和b)的所述核酸在单个核酸分子上并且其中编码自切割肽(如P2A、T2A、E2A或F2A)的核酸序列位于a)和b)的所述核酸之间。
在另一种情况下,如本文所述的编码CAR20和CAR22的分离的多核苷酸包含:
a)编码CAR22的核酸,包含控制所述CAR22表达的启动子(如EF1α启动子),所述CAR22由SEQ ID NO:1的信号肽、SEQ ID NO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ IDNO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;
b)编码CAR20的核酸,所述CAR20由SEQ ID NO:1的信号肽、SEQ ID NO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;和
c)位于a)的核酸和b)的核酸之间的编码自切割肽(如SEQ ID NO:19的P2A)的核酸,允许所述CAR20和CAR22的同时表达。
在另一种情况下,提供了编码如本文所述的CAR20和CAR22的分离的多核苷酸,包含:
a)编码CAR20的核酸,包含控制所述CAR20表达的启动子(如EF1α启动子),所述CAR20由SEQ ID NO:1的信号肽、SEQ ID NO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ IDNO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;
b)编码CAR22的核酸,所述CAR22由SEQ ID NO:1的信号肽、SEQ ID NO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;和
c)位于a)的核酸和b)的核酸之间的编码自切割肽(如SEQ ID NO:19的P2A)的核酸,允许所述CAR22和CAR20的同时表达。
在另一种情况下,提供了包含SEQ ID NO:31的核酸序列(CAR22xCAR20构建体)的编码CAR20和CAR22的分离的多核苷酸。
在另一种特定情况下,提供了包含SEQ ID NO:32的核酸序列(CAR20xCAR22构建体)的编码CAR20和CAR22的分离的多核苷酸。
本文还公开了包含本文所述的任何分离的多核苷酸的载体。
本文还公开了包含本文所述的载体的宿主细胞。
待工程化的免疫细胞群通常通过单采术从患者或健康供体的血液中提取,并进一步工程化以在其表面表达嵌合抗原受体。可替代地,待工程化的免疫细胞群可源自脐带血细胞或干细胞,这些细胞被进一步工程化以在其表面表达嵌合抗原受体。
所述表达CAR的免疫细胞可以源自患者或相容供体的免疫细胞,这些细胞已经工程化以在其表面表达特定的CAR。
所述表达CAR的免疫细胞也可以源自干细胞,如iPS细胞,所述干细胞源自这种患者或相容的供体或源自肿瘤浸润淋巴细胞(TILL)。
在其他方面,所述表达CAR的免疫细胞是所谓的“现成的”免疫细胞组合物,从而并非专门属于待治疗患者的免疫细胞已经工程化以表达CAR并变得适用于同种异体治疗。
鉴于被注入具有不同单体型的患者,“同种异体的”是指细胞源自供体,或由干细胞产生和/或分化。
这种免疫细胞通常被工程化为相对于它们的患者宿主的较低的同种异体反应性和/或变得更持久。更具体地,工程化同种异体免疫细胞的方法可以包括减少或灭活TCR表达进入T细胞,或进入待衍生成T细胞的干细胞的步骤。这可以通过不同的序列特异性试剂获得,如通过基因沉默或基因编辑技术(核酸酶、碱基编辑、RNAi…)。
申请人以前已经提供了可靠的方案和基因编辑策略以从PBMC中生产同种异体治疗级T细胞,特别是通过提供TALE-核酸酶()形式的非常安全和特异性的核酸内切酶试剂。实现了所谓的“通用T细胞”,即来自供体的[TCR]阴性T细胞的生产,并成功注射到患有减少的移植物抗宿主病(GVhD)的患者中(Poirot et al.2015,Cancer.Res.75(18):3853-3864;Qasim et al.,2017,Science Translational 9(374))。同时,在原代T细胞中TCR或β2m组件的失活可以与编码检查点抑制剂蛋白的其他基因的失活相结合,例如如WO2014184744中所述的。
在另一种情况下,可以进一步修饰工程化免疫细胞以赋予对至少一种免疫抑制药物的抗性,如通过使作为抗-CD52抗体(例如阿仑单抗(alemtuzumab))的靶点的CD52失活,例如如WO2013176915中所述的。
在另一种情况下,可以进一步修饰工程化免疫细胞以赋予对和/或化疗药物的抗性,特别是嘌呤类似物药物,例如通过使DCK失活,如WO201575195中所述的。
在另一种情况下,可以进一步修饰工程化免疫细胞以提高其在患者体内的持久性或寿命,特别是使编码MHC-I组件(如HLA或β2m)的基因失活,例如如WO2015136001或Liu等(2017,Cell Res 27:154–157)中所述的。
在另一种情况下,工程化免疫细胞被突变以提高其CAR依赖性免疫激活,特别是减少或抑制免疫检查点蛋白和/或其受体的表达,例如如WO2014184744中描述的PD1或CTLA4。
药物组合物
一方面涉及药物组合物,其包含如本文所述在其细胞表面表达对CD22特异性的嵌合抗原受体(CAR)(CAR22)和对CD20特异性的嵌合抗原受体(CAR20)的基因工程化免疫细胞,以及药学上可接受的赋形剂。
还公开了包含免疫细胞群的药物组合物,所述免疫细胞群包含在其细胞表面表达如本文所述的对CD22特异性的嵌合抗原受体(CAR)(CAR22)和对CD20特异性的嵌合抗原受体(CAR20)的基因工程化免疫细胞,和药学上可接受的赋形剂。
一个特定方面涉及药物组合物,包含如本文所述的基因工程化T细胞和药学上可接受的赋形剂。
另一个特定方面涉及包括包含如本文所述的基因工程化T细胞的T细胞群和药学上可接受的赋形剂的药物组合物。
另一个特定方面涉及包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:11的VH和SEQ ID NO:12的VL,并且所述CAR20包含SEQ ID NO:15的VH和SEQ ID NO:16的VL。
更具体地,提供了包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,并且其中所述CAR20包含SEQ ID NO:18的氨基酸序列。
另一个特定方面涉及包括包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞的T细胞群和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:11的VH和SEQ IDNO:12的VL,并且所述CAR20包含SEQ ID NO:15的VH和SEQ ID NO:16的VL。
另一个特定方面涉及包括包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞的T细胞群和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,并且其中所述CAR20包含SEQ ID NO:18的氨基酸序列。
另一个特定方面涉及包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:11的VH和SEQ ID NO:12的VL,并且所述CAR20包含SEQ ID NO:15的VH和SEQ ID NO:16的VL,并且其中所述T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因,和/或其中所述工程化T细胞具有至少一个选自已经失活的β2m和CD52的等位基因。
更具体地,提供了包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,其中所述CAR20包含SEQ ID NO:18的氨基酸序列,并且其中所述T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因。
更具体地,提供了包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,其中所述CAR20包含SEQ ID NO:18的氨基酸序列,并且其中所述T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因,和/或其中所述工程化T细胞具有至少一个选自已经失活的β2m和CD52的等位基因。
另一个特定方面涉及包括包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞的T细胞群和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:11的VH和SEQ IDNO:12的VL,所述CAR20包含SEQ ID NO:15的VH和SEQ ID NO:16的VL,并且其中所述T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因,和/或其中所述工程化T细胞具有至少一种选自已经失活的β2m和CD52的等位基因。
另一个特定方面涉及包括包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞的T细胞群和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,其中所述CAR20包含SEQ ID NO:18的氨基酸序列,并且其中所述T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因。
另一个特定方面涉及包括包含在其细胞表面表达CAR22和CAR20的基因工程化T细胞的T细胞群和药物赋形剂的药物组合物,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,其中所述CAR20包含SEQ ID NO:18的氨基酸序列,并且其中所述T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因,和/或其中所述工程化T细胞具有至少一个选自已经失活的β2m和CD52的等位基因。
本文还提供了表达如本文所述的CAR20和CAR22的基因工程化免疫细胞用作药物。
本文还提供了包含表达如本文所述的CAR20和CAR22的基因工程化免疫细胞的免疫细胞群用作药物。
治疗方法
另一方面涉及治疗癌症和/或炎性病症的方法,包括向有此需要的患者施用表达如本文所述的CAR20和CAR22的基因工程化免疫细胞。
类似的方面涉及表达如本文所述的CAR20和CAR22的基因工程化免疫细胞,用于在治疗癌症和/或炎性病症的方法中。
类似的方面涉及免疫细胞群,其包含表达如本文所述的CAR20和CAR22的基因工程化免疫细胞,用于在治疗癌症和/或炎性病症的方法中。
类似的方面涉及表达如本文所述的CAR20和CAR22的基因工程化免疫细胞或包含表达如本文所述的CAR20和CAR22的基因工程化免疫细胞的免疫细胞群在制备药物中的用途。
类似的方面涉及表达如本文所述的CAR20和CAR22的基因工程化免疫细胞或包含表达如本文所述CAR20和CAR22的基因工程化免疫细胞的免疫细胞群在制备用于治疗癌症和/或炎性病症的药物中的用途。
该治疗可以用于治疗癌症,包括血液癌症,如选自(淋巴瘤、霍奇金(Hodgkin)淋巴瘤(HL)、非霍奇金淋巴瘤(NHL)、白血病、多发性骨髓瘤(MM)、B-慢性淋巴细胞白血病(B-CLL)、毛细胞白血病(HCL)、急性淋巴细胞白血病(ALL)(也称为急性淋巴母细胞白血病)、急性淋巴细胞癌、急性髓性白血病(AML)的血液癌症,特别是CD22-和/或CD20-相关的血液癌症,更特别是复发难治性CD22-和/或CD20-相关的血液癌症,甚至更特别是所述CD22-和/或CD20-相关的血液癌症的侵袭性形式。
该治疗可以涉及预防或减轻与CD20和/或CD22相关的炎性病症。
在特定方面,该治疗用于治疗患有复发难治性NHL的患者。
在另一个特定方面,该治疗用于治疗遭受其中CD20和CD22抗原表达低的癌症的患者。
在特定方面,该治疗用于治疗先前已经用利妥昔单抗(作为NHL治疗中的标准治疗的抗-CD20抗体)治疗的患者。
“非霍奇金淋巴瘤(NHL)”是用于共享单一特征的不同血液癌症组的术语:它们都起源于淋巴细胞。世界卫生组织(WHO)已经对超过60种特定的NHL亚型进行确定并分配名字,称为“诊断名称”。
特别是,术语“非霍奇金淋巴瘤(NHL)”包括以下用于非霍奇金淋巴瘤(NHL)的诊断名称:
1.成熟B-细胞淋巴瘤(约占NHL病例的85%-90%):
-侵袭性:弥漫性大B细胞淋巴瘤(DLBCL)(31%)、套细胞淋巴瘤(MCL)(可表现为侵袭性或惰性)(6%)、淋巴母细胞淋巴瘤(2%)、伯基特(Burkitt)淋巴瘤(BL)(2%)、原发性纵隔(胸腺)大B细胞淋巴瘤(PMBCL)(2%)、转化的滤泡和转化的粘膜相关淋巴组织(MALT)淋巴瘤、具有双或三重打击的高级B细胞淋巴瘤(HBL)、原发性皮肤DLBCL(腿型)、中枢神经系统的原发性DLBCL、原发性中枢神经系统(CNS)淋巴瘤、获得性免疫缺陷综合征(AIDS)相关淋巴瘤;
-惰性:滤泡性淋巴瘤(FL)(22%)、边缘区淋巴瘤(MZL)(8%)、慢性淋巴细胞白血病/小细胞淋巴细胞淋巴瘤(CLL/SLL)(6%)、胃粘膜相关淋巴组织(MALT)淋巴瘤(5%)、淋巴浆细胞淋巴瘤(1%)、华氏巨球蛋白血症(WM)、淋巴结边缘区淋巴瘤(NMZL)(1%)、脾边缘区淋巴瘤(SMZL)。
2.成熟T细胞和自然杀伤(NK)细胞淋巴瘤(约占NHL病例的10%-15%)
-侵袭性:未另行说明的外周T细胞淋巴瘤(PTCL)(6%)、系统性间变性大细胞淋巴瘤(ALCL)(2%)、淋巴母细胞淋巴瘤(2%)、肝脾γ/δT细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤(SPTCL)、肠病型肠T细胞淋巴瘤、原发性皮肤间变性大细胞淋巴瘤;
-惰性:皮肤T细胞淋巴瘤(CTCL)(4%)、蕈样肉芽肿(MF)、塞泽里(Sézary)综合征(SS)、血管免疫母细胞T细胞淋巴瘤(AITL)、成人T细胞白血病/淋巴瘤、结外NK/T-细胞淋巴瘤(ENK/TCL),鼻型。
本发明的以上书面描述提供了制造和使用它的方式和过程,使得本领域的任何技术人员都能够制造并使用它,这种实现是特别为所附权利要求的主题提供的,这些所附权利要求构成原始描述的一部分。
在本文陈述数值限制或范围的情况下,端点被包括在内。此外,数字限制或范围内的所有数值和子范围都被如同明确写出的明确被包括在内。
已经概括地描述本发明之后,可以通过参考某些具体的实例来获得进一步的理解,本文提供的这些实例仅用于说明的目的,并且不旨在限制要求保护的发明的范围。
特定的实施方式
1.一种基因工程化T细胞,在其细胞表面表达对于CD22特异性的嵌合抗原受体(CAR)(CAR22)和对于CD20特异性的嵌合抗原受体(CAR20),
a)其中所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含SEQ ID NO:11的可变重链(VH)和SEQID NO:12的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;并且
b)其中所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含SEQ ID NO:15的可变重链(VH)和SEQID NO:16的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;并且
c)其中所述工程化T细胞是TCR阴性的。
2.根据实施方式1的基因工程化T细胞,其中所述CAR22包含SEQ ID NO:14的氨基酸序列,并且其中所述CAR20包含SEQ ID NO:18的氨基酸序列。
3.根据实施方式1至2中任一项的基因工程化T细胞,其中所述CAR20和CAR22的胞外结构域均不包含SEQ ID NO:22的利妥昔单抗特异性模拟表位。
4.根据实施方式1至3中任一项的基因工程化T细胞,其中所述工程化T细胞表达直接针对编码TCR组件的多核苷酸序列的短发夹RNA(shRNA)或小干扰(siRNA)。
5.根据实施方式1至3中任一项的基因工程化T细胞,其中所述工程化T细胞在其TCRα和/或TCRβ等位基因中发生突变。
6.根据实施方式1至3和5中任一项的基因工程化T细胞,其中所述工程化T细胞具有至少一个编码已经通过突变失活的TCRα、TCRβ和/或CD3的等位基因。
7.根据实施方式1至6中任一项的基因工程化T细胞,其中所述工程化T细胞具有已经失活的CD52等位基因。
8.根据实施方式1至7中任一项的基因工程化T细胞,其中所述工程化T细胞具有已经失活的β2m等位基因。
9.根据实施方式1至8中任一项的基因工程化T细胞,其中所述工程化T细胞具有已经失活的PD1等位基因。
10.根据实施方式1至9中任一项的基因工程化T细胞,其中所述工程化T细胞具有已经失活的CTLA4等位基因。
11.根据实施方式1至10中任一项的基因工程化T细胞,其中所述工程化T细胞具有已经失活的dCK等位基因。
12.根据实施方式1至11中任一项的基因工程化T细胞,其中所述工程化T细胞具有已经失活的GR等位基因。
13.根据实施方式1至12中任一项的基因工程化T细胞,其中所述工程化免疫细胞是细胞毒性T细胞。
14.根据实施方式1至13中任一项的基因工程化T细胞,其中所述工程化T细胞被包含在T细胞群中。
15.根据实施方式1至14中任一项的基因工程化T细胞,其中所述工程化T细胞是原代细胞。
16.根据实施方式1至15中任一项的基因工程化T细胞,其中所述T细胞是哺乳动物细胞,优选人细胞。
17.根据实施方式1至16中任一项的基因工程化T细胞,其中所述工程化T细胞不表达除所述CAR22和CAR20之外的其他CAR。
18.一种包含根据实施方式1至17中任一项的工程化T细胞的T细胞群。
19.一种包含根据实施方式1至17中任一项的工程化T细胞和药学上可接受的赋形剂的药物组合物。
20.一种包含根据实施方式18的T细胞群和药学上可接受的赋形剂的药物组合物。
21.一种分离的多核苷酸,包含:
a)编码CAR22的核酸,所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,包含SEQ ID NO:11的可变重链(VH)和SEQID NO:12的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;和
b)编码CAR20的核酸,所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,包含SEQ ID NO:15的可变重链(VH)和SEQID NO:16的可变轻链(VL),任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
22.根据实施方式21的多核苷酸,其中a)和b)的核酸在单个核酸分子上并且其中编码自切割肽(如P2A、T2A、E2A或F2A)的核酸序列位于a)和b)的核酸之间。
23.根据实施方式21或22的多核苷酸,其中所述分离的多核苷酸不包含编码除所述CAR22和CAR20之外的其他CAR的核酸。
24.根据实施方式21至23的多核苷酸,其中所述分离的多核苷酸不包含编码SEQID NO:22的利妥昔单抗特异性模拟表位的核酸。
25.根据实施方式21至24中任一项的多核苷酸,其中a)的核酸包含控制所述CAR22表达的启动子(如EF1α启动子),所述CAR22由SEQ ID NO:1的信号肽、SEQ ID NO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;
其中b)的核酸编码所述CAR20,所述CAR20由SEQ ID NO:1的信号肽、SEQ ID NO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;并且
其中编码自切割肽(如SEQ ID NO:19的P2A)的核酸存在于a)的核酸和b)的核酸之间,允许所述CAR20和CAR22的同时表达。
26.根据实施方式21至24中任一项的多核苷酸,其中b)的核酸包含控制所述CAR20表达的启动子(如EF1α启动子),所述CAR20由SEQ ID NO:1的信号肽、SEQ ID NO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;
其中a)的核酸编码所述CAR22,所述CAR22由SEQ ID NO:1的信号肽、SEQ ID NO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;并且其中编码自切割肽(如SEQ ID NO:19的P2A)的核酸存在于a)的核酸和b)的核酸之间,允许所述CAR22和CAR20的同时表达。
27.根据实施方式25的分离的多核苷酸,包含SEQ ID NO:31的核酸序列(CAR22xCAR20构建体)。
28.根据实施方式26的分离的多核苷酸,包含SEQ ID NO:32的核酸序列(CAR20xCAR22构建体)。
29.一种包含实施方式21至28中任一项的分离的多核苷酸的载体。
30.一种包含实施方式29的载体的宿主细胞。
31.一种制备根据实施方式1至17中任一项的工程化T细胞的方法,包括将根据实施方式21至28中任一项的多核苷酸或根据实施方式29的载体引入免疫细胞。
32.根据实施方式1至17中任一项的工程化T细胞,用作药物。
33.根据实施方式1至17中任一项的工程化T细胞,用于治疗与CD20和/或CD22表达相关的癌症。
34.根据实施方式1至17中任一项的工程化T细胞,用于治疗血液癌症,特别是CD22-和/或CD20-相关的血液癌症,更特别是复发难治性CD22-和/或CD20-相关的血液癌症,甚至更特别是所述CD22-和/或CD20-相关的血液癌症的侵袭性形式。
35.根据实施方式33或34使用的工程化T细胞,其中所述癌症选自由淋巴瘤、霍奇金淋巴瘤(HL)、非霍奇金淋巴瘤(NHL)、白血病、多发性骨髓瘤(MM)、B-慢性淋巴细胞白血病(B-CLL)、毛细胞白血病(HCL)、急性淋巴细胞白血病(ALL)、急性淋巴细胞癌、急性髓性白血病(AML)组成的组。
36.根据实施方式35使用的工程化T细胞,其中所述癌症是非霍奇金淋巴瘤或急性淋巴细胞白血病。
37.根据实施方式33至36中任一项使用的工程化T细胞,其中所述癌症与CD20和/或CD22的低表达相关。
38.根据实施方式33至37中任一项使用的工程化T细胞,其中所述癌症是复发性非霍奇金淋巴瘤。
39.一种治疗遭受与CD20和/或CD22表达相关的癌症的患者的方法,包括向所述患者施用有效量的根据实施方式1至17中任一项的工程化T细胞或根据实施方式18的T细胞群。
40.根据实施方式39的治疗方法,其中所述癌症选自由淋巴瘤、霍奇金淋巴瘤(HL)、非霍奇金淋巴瘤(NHL)、白血病、多发性骨髓瘤(MM)、B-慢性淋巴细胞白血病(B-CLL)、毛细胞白血病(HCL)、急性淋巴细胞白血病(ALL)、急性淋巴细胞癌、急性髓性白血病(AML)组成的组。
41.根据实施方式39或40的治疗方法,其中所述癌症是非霍奇金淋巴瘤或急性淋巴细胞白血病。
42.根据实施方式39至41中任一项的治疗方法,其中所述癌症与CD20和/或CD22的低表达相关。
43.根据实施方式39至42中任一项的治疗方法,其中所述癌症是复发性非霍奇金淋巴瘤。
实施例
本文提供的实施例描述了如何生成靶向CD20和CD22抗原的双CAR-T细胞(“CD20xCD22”或“CD20xCD22”CAR-T细胞)并且展示它们裂解CD22和/或CD20低表达或不表达的肿瘤细胞的能力。
实施例1.双CD20和CD22 CAR构建体的产生及其控制;
双CAR的两个方向被设计并构建到重组慢病毒载体中,以便比较表达、活性和效率。第一个构建体(CD22xCD20)包含驱动第一CD22 CAR表达的EF1α启动子,所述第一CD22CAR由信号肽(SEQ ID NO:1)、SEQ ID NO:13的scFv、CD8α铰链(SEQ ID NO:4)和TM结构域(SEQ ID NO:6)、4-1BB共刺激结构域(SEQ ID NO:8)以及CD3ζ信号结构域(SEQ ID NO:9)组成。该第一CAR随后是允许第二CD20 CAR表达的自切割肽P2A(SEQ ID NO:19),所述第二CD20 CAR由信号肽(SEQ ID NO:1)、SEQ ID NO:17的抗-CD20 scFv、CD8α铰链(SEQ ID NO:4)和TM结构域(SEQ ID NO:6)、4-1BB共刺激结构域(SEQ ID NO:8)以及CD3ζ信号结构域(SEQ ID NO:9)组成。为避免rLV构建体内的任何重组事件,用于编码用于在构建体中存在两次的相同氨基酸序列的核苷酸序列使用密码子利用和密码简并性优化,使得核苷酸序列发散。第二双构建体(CD20xCD22)含有完全相同的序列(核苷酸和氨基酸),但CD20 CAR位于在EF1α启动子之后的右侧。
为了比较,将CD22或CD20 CAR构建到重组慢病毒载体中。那些构建体包含驱动靶向CD22(SEQ ID NO:14)或CD20(SEQ ID NO:18)的单CAR表达的EF1α启动子。
实施例2:CD20xCD22或CD22xCD20双CAR-T细胞的产生
使用来自至少3个不同供体的冷冻保存的PBMC。PBMC在37℃下解冻、洗涤并重悬于补充有AB人血清(5%)重组人白介素-2(rhIL-2,350IU/ml)的OpTmizer培养基中,在5%CO2培养箱中在37℃下孵育过夜。然后在补充有AB人血清(5%)(和在扩增期间额外的5%CTSTM免疫细胞SR)和重组人白介素-2(rhIL-2,350IU/ml)的OpTmizer培养基中用抗-CD3/CD28涂覆珠在CO2培养箱中培养3天来活化细胞。然后,在Lentiboost(Mayflowerbioscience SB-P-LV-101-12)的存在下以MOI 15(MOI代表感染复数)用表达CD20xCD22或CD22xCD20 CAR(分别为SEQ ID NO:31和SEQ ID NO:32)的慢病毒颗粒转导扩增的T细胞。也以MOI 5用单独表达CD20 CAR或CD22 CAR(SEQ ID NO:14和SEQ ID NO:18)的慢病毒颗粒转导扩增的T细胞。转导后两天,使用AgilePulse Max系统,细胞用4个mRNA电穿孔,两个编码TRAC_T01 TALEN臂(SEQ ID NO:23和SEQ ID NO:24)和两个编码CD52_T01 TALEN臂(SEQ IDNO:25和SEQ ID NO:26)。细胞在培养基中重悬,在30℃下孵育16至18h并且在添加新鲜培养基并不时调整细胞浓度后在37℃下扩增。在培养的最后一天(解冻后18天),T细胞用于不同测定或冷冻在冷冻培养基(FBS 90%,DMSO 10%)中。细胞在-150℃下冷冻保存直至使用。
实施例3.CD20和CD22双CAR-T细胞检测
为了检测CD20 CAR,使用与His标签融合的重组蛋白CD20(Acro#CD0-H52H3,SEQID NO:20)与APC标记的抗-His抗体(BioLegend#362605)偶联。对于CD22 CAR检测,CD22-Fc蛋白(SEQ ID NO:21)与抗-Fcγ亚族1标签Cy3(Jackson ImmunoResearch#115-165-205)结合使用。
将实施例1中产生的不同CAR T细胞(未转导的,CD20xCD22 CAR、CD22xCD20 CAR或CD22 CAR)与100ng CD22-Fc蛋白和200ng CD20-His蛋白一起孵育,洗涤并进一步与抗-Fcγ(50ng)或抗-His(50ng)一起孵育,然后在PFA 2%中固定。然后通过流式细胞术分析细胞。
图1中的结果表明,单独用CD22 CAR转导导致40%的CD22 CAR阳性T细胞,而用CD22xCD20或CD20xCD22 CAR转导分别导致39%和25%的双CAR阳性T细胞。使用三个不同供体重现了这些结果。有趣的是,CD22xCD20导致CD22 CAR染色的更高MFI,而CD20xCD22导致CD20 CAR染色的更高MFI。
实施例4.用于测试CD20和CD22双CAR-T细胞的细胞系
Raji细胞系表达高水平的CD20和CD22。该细胞系经过修饰以表达萤光素酶基因,并用作阳性对照,即表达CD20和CD22的靶细胞。此外,用CD22和/或CD20 TALEN处理Raji细胞系。简而言之,使用AgilePulse Max系统,用编码CD22 TALEN臂(SEQ ID NO:27和SEQ IDNO:28)的mRNA和编码CD20 TALEN(SEQ ID NO:29和SEQ ID NO:30)的mRNA对Raji细胞进行电穿孔。细胞在RPMI1640 10%胎牛血清(FBS)和1%青霉素/链霉亲和素(培养基)中在30℃下孵育16至18小时,并且在%CO2培养箱中在37℃下在新鲜培养基中生长直至分选。不同的细胞群使用抗生物素微珠和抗-CD20-生物素、抗-CD22生物素或两者(Biolegend)纯化,以获得表达i)CD20但不表达CD22、ii)CD22但不表达CD20或iii)既不表达CD20也不表达CD22的不同细胞群。图2说明了这些选定种群的表型。
实施例5.CD20和CD22双CAR T细胞的细胞毒性
测试了在实施例1中产生并且来自三个不同供体的CD20xCD22、CD22xCD20和CD22CAR T细胞对实施例4中产生的不同Raji细胞的细胞毒性能力。
解冻T细胞并使用设备(Chemometec NC-250)对活细胞计数。在96孔板中将不同的CAR T细胞与表达荧光素酶的不同的Raji细胞(CD20+CD22+、CD20+CD22-、CD22-CD20+和CD20-CD22-)以不同的效应物/靶点比率共培养4至16小时(在5% CO2培养箱中在37℃下)。在孵育期结束时,根据供应方的方案,使用/>试剂盒(Promega#E6110)测量释放的荧光素酶。图3显示,对于使用的所有供体,CD22 CAR T细胞可以有效裂解CD20+CD22+和CD20-CD22+Raji克隆体,而CD22xCD20或CD20xCD22 CAR T细胞比CD22 CAR增加了相同的裂解水平,但也可以裂解至相同水平的CD20+CD22-Raji克隆体。
还在再攻击或连续杀伤测定中测试了如实施例1中产生的CD20xCD22、CD22xCD20和CD22 CAR T细胞的杀伤能力。将不同的CAR T细胞解冻、计数并以1:1比率的CAR阳性T细胞/Raji细胞与不同的Raji细胞(CD20+CD22+、CD20-CD22+、CD20+CD22-)一起孵育。孵育3天后,一半的孔用于使用试剂盒(Promega#E6110)测量荧光素酶的释放,而另一半被转移到含有Raji细胞的新板上进行额外孵育。在第7天、第10天、第14天和第17天重复荧光素酶测量。
图4显示CD22xCD20或CD20xCD22 CAR T细胞能够有效杀死所有测试的Raji细胞,而CD22 CAR T细胞只能有效杀死CD20+CD22+和CD20-CD22+Raji细胞。令人惊讶的是,CD22CAR T对CD20+CD22-Raji细胞的活性较低,表明CD22表达在该克隆中并未完全消除。这也表明双CAR可以有效地杀死具有低表达的两种靶抗原的靶肿瘤细胞。
表7:使用的TALEN列表
实施例6.在B细胞淋巴瘤的播散性体内模型中的肿瘤负荷控制
表达CD20和CD22的Daudi细胞被修饰以表达荧光素酶和GFP。将Daudi细胞静脉注射到NSG免疫缺陷小鼠中(NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ,Jackson laboratories)。肿瘤植入七天后,将CD20xCD22(1和3百万)、CD22xCD20(1和3百万)和CD22(1千万)CAR T细胞静脉注射到个体小鼠中。注射D荧光素后的生物发光信号(BLI)每两周监测一次,直到CART细胞注射后第60天,且数值如图5所示。对于测试的CART细胞的所有处理条件,与载体对照或未转导的T细胞相比,BLI信号减少。令人惊讶的是,以1百万个CAR+T细胞的低剂量,CD20xCD22 CAR T细胞具有比CD22xCD20 CAR T细胞更高的强杀伤活性。
实施例7.在B细胞淋巴瘤的播散性体内模型中的治疗功效
监测注射Daudi细胞并随后静脉注射来自实施例6的CD20xCD22(1百万)、CD22xCD20(1百万)和CD22(1千万)CAR T细胞的动物在60天内的存活率。如图6所示,用任何测试的CART细胞治疗的动物比用载体或非转导T细胞(NTD)治疗的动物存活时间更长。此外,令人惊讶的是,用CD20xCD22 CAR T细胞治疗的动物比用CD22xCD20 CAR T细胞治疗的动物存活时间更长。
实施例8.在B细胞淋巴瘤的播散性体内模型中的治疗功效
将实施例2中描述的Raji细胞系皮下注射到NSG免疫缺陷小鼠(NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ,Jackson laboratories)中。将所有三种细胞系同时注射到每只个体动物中,具体地,Raji WT细胞注射到一个侧腹,Raji CD22-细胞注射到另一个侧腹且CD20-细胞注射到第三侧腹。肿瘤注射后一周,静脉注射CD20xCD22(3和8百万)、CD22xCD20(3和8百万)和CD22(8百万)CAR T细胞,并监测动物的存活率。如图7所示,用CD22 CAR T细胞治疗的动物很快死于该疾病,因为它们携带CD22 CAR T细胞不能靶向的CD22-肿瘤细胞。用三和八百万的双CAR T细胞的治疗表明,虽然两种治疗都是有效的,但CD20xCD22治疗的动物令人惊讶地比用CD22xCD20治疗的动物存活更长的时间。
实施例9.CD20和CD22双CAR T细胞的IFNγ释放
表达CD20和CD22的Daudi细胞被修饰以表达荧光素酶基因和GFP。这些Daudi细胞与CD20xCD22、CD22xCD20、CD22或CD20阳性CAR T细胞以1:1(效应物-靶点)的比率孵育过夜。第二天,将板离心,并收集上清液。按照制造商的说明使用人IFN-γQuantikine ELISA试剂盒(R&Dsystems,DIF50C)量化肿瘤与CAR T细胞孵育后释放的IFNγ水平。作为阳性对照,CAR-T细胞与醋酸佛波醇肉豆蔻酸酯(phorbol myristate acetate)(PMA,Sigma AldrichP8139)和离子霉素(Sigma aldrich I0634)一起孵育。IFNγ释放的最终值被归一化为阳性对照的那些值。图8显示双CD20xCD22 CAR-T细胞以及CD22xCD20 CAR T细胞在肿瘤细胞上的抗原识别后被激活,并释放比单CAR(CD20或CD22)T细胞更高水平的IFN-γ。这个观察结果指向使用双CD20、CD22 CAR T细胞的协同效益。
序列表
<110> 塞勒克提斯公司(Cellectis S.A.)
<120> 双CAR-T细胞
<130> P242859PC00
<150> PA202070509
<151> 2020-07-31
<160> 52
<170> PatentIn version 3.5
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<223> 4-1BB跨膜结构域
<400> 7
Ile Ile Ser Phe Phe Leu Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu
1 5 10 15
Leu Phe Phe Leu Thr Leu Arg Phe Ser Val Val
20 25
<210> 8
<211> 42
<212> PRT
<213> 人工的
<220>
<223> 4-1BB刺激结构域
<400> 8
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> 9
<211> 112
<212> PRT
<213> 人工的
<220>
<223> CD3ζ信号结构域
<400> 9
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> 10
<211> 15
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 10
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 11
<211> 124
<212> PRT
<213> 人工的
<220>
<223> CAR22 VH
<400> 11
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30
Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala
50 55 60
Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Arg Glu Val Thr Gly Asp Leu Glu Asp Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 12
<211> 107
<212> PRT
<213> 人工的
<220>
<223> CAR22 VL
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Trp Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Gln
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 13
<211> 246
<212> PRT
<213> 人工的
<220>
<223> CAR22 scFv
<400> 13
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30
Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala
50 55 60
Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Arg Glu Val Thr Gly Asp Leu Glu Asp Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Thr Ile Trp Ser Tyr Leu Asn Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile Tyr Ala Ala Ser Ser
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Gln Thr Phe Gly Gln Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys
245
<210> 14
<211> 490
<212> PRT
<213> 人工的
<220>
<223> CAR22全部
<400> 14
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu
20 25 30
Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp
35 40 45
Ser Val Ser Ser Asn Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro
50 55 60
Ser Arg Gly Leu Glu Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp
65 70 75 80
Tyr Asn Asp Tyr Ala Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro
85 90 95
Asp Thr Ser Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Val Thr Gly Asp Leu
115 120 125
Glu Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
145 150 155 160
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
165 170 175
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Trp Ser Tyr
180 185 190
Leu Asn Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile
195 200 205
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
210 215 220
Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
225 230 235 240
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Gln
245 250 255
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala
260 265 270
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
275 280 285
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
290 295 300
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
305 310 315 320
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
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 Arg Val Lys Phe Ser Arg
370 375 380
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
385 390 395 400
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
405 410 415
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
420 425 430
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
435 440 445
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
450 455 460
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
465 470 475 480
Ala Leu His Met Gln Ala Leu Pro Pro Arg
485 490
<210> 15
<211> 122
<212> PRT
<213> 人工的
<220>
<223> CAR20 VH
<400> 15
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> 16
<211> 107
<212> PRT
<213> 人工的
<220>
<223> CAR20 VL
<400> 16
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> 17
<211> 244
<212> PRT
<213> 人工的
<220>
<223> CAR20scFv
<400> 17
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 Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
130 135 140
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
145 150 155 160
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala
180 185 190
Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe Gly Gln Gly Thr Arg
225 230 235 240
Leu Glu Ile Lys
<210> 18
<211> 488
<212> PRT
<213> 人工的
<220>
<223> CAR20全部
<400> 18
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 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 Lys Arg
325 330 335
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
340 345 350
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
355 360 365
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
370 375 380
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
385 390 395 400
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
405 410 415
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg
485
<210> 19
<211> 22
<212> PRT
<213> 人工的
<220>
<223> P2A肽
<400> 19
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
1 5 10 15
Glu Glu Asn Pro Gly Pro
20
<210> 20
<211> 317
<212> PRT
<213> 人工的
<220>
<223> CD20-6His
<400> 20
Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro
1 5 10 15
Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg
20 25 30
Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu
35 40 45
Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile
50 55 60
Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile
65 70 75 80
Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile
85 90 95
Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu
100 105 110
Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile
115 120 125
Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser
130 135 140
His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro
145 150 155 160
Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn
165 170 175
Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly
180 185 190
Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile
195 200 205
Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys
210 215 220
Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile
225 230 235 240
Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro
245 250 255
Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu
260 265 270
Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser
275 280 285
Ser Pro Ile Glu Asn Asp Ser Ser Pro Gly Gly Gly Ser Gly Gly Gly
290 295 300
Ser His His His His His His His His His His His His
305 310 315
<210> 21
<211> 916
<212> PRT
<213> 人工的
<220>
<223> CD22-Fc
<400> 21
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Asp Ser Ser Lys Trp Val Phe Glu His Pro Glu Thr Leu
20 25 30
Tyr Ala Trp Glu Gly Ala Cys Val Trp Ile Pro Cys Thr Tyr Arg Ala
35 40 45
Leu Asp Gly Asp Leu Glu Ser Phe Ile Leu Phe His Asn Pro Glu Tyr
50 55 60
Asn Lys Asn Thr Ser Lys Phe Asp Gly Thr Arg Leu Tyr Glu Ser Thr
65 70 75 80
Lys Asp Gly Lys Val Pro Ser Glu Gln Lys Arg Val Gln Phe Leu Gly
85 90 95
Asp Lys Asn Lys Asn Cys Thr Leu Ser Ile His Pro Val His Leu Asn
100 105 110
Asp Ser Gly Gln Leu Gly Leu Arg Met Glu Ser Lys Thr Glu Lys Trp
115 120 125
Met Glu Arg Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His
130 135 140
Ile Gln Leu Pro Pro Glu Ile Gln Glu Ser Gln Glu Val Thr Leu Thr
145 150 155 160
Cys Leu Leu Asn Phe Ser Cys Tyr Gly Tyr Pro Ile Gln Leu Gln Trp
165 170 175
Leu Leu Glu Gly Val Pro Met Arg Gln Ala Ala Val Thr Ser Thr Ser
180 185 190
Leu Thr Ile Lys Ser Val Phe Thr Arg Ser Glu Leu Lys Phe Ser Pro
195 200 205
Gln Trp Ser His His Gly Lys Ile Val Thr Cys Gln Leu Gln Asp Ala
210 215 220
Asp Gly Lys Phe Leu Ser Asn Asp Thr Val Gln Leu Asn Val Lys His
225 230 235 240
Thr Pro Lys Leu Glu Ile Lys Val Thr Pro Ser Asp Ala Ile Val Arg
245 250 255
Glu Gly Asp Ser Val Thr Met Thr Cys Glu Val Ser Ser Ser Asn Pro
260 265 270
Glu Tyr Thr Thr Val Ser Trp Leu Lys Asp Gly Thr Ser Leu Lys Lys
275 280 285
Gln Asn Thr Phe Thr Leu Asn Leu Arg Glu Val Thr Lys Asp Gln Ser
290 295 300
Gly Lys Tyr Cys Cys Gln Val Ser Asn Asp Val Gly Pro Gly Arg Ser
305 310 315 320
Glu Glu Val Phe Leu Gln Val Gln Tyr Ala Pro Glu Pro Ser Thr Val
325 330 335
Gln Ile Leu His Ser Pro Ala Val Glu Gly Ser Gln Val Glu Phe Leu
340 345 350
Cys Met Ser Leu Ala Asn Pro Leu Pro Thr Asn Tyr Thr Trp Tyr His
355 360 365
Asn Gly Lys Glu Met Gln Gly Arg Thr Glu Glu Lys Val His Ile Pro
370 375 380
Lys Ile Leu Pro Trp His Ala Gly Thr Tyr Ser Cys Val Ala Glu Asn
385 390 395 400
Ile Leu Gly Thr Gly Gln Arg Gly Pro Gly Ala Glu Leu Asp Val Gln
405 410 415
Tyr Pro Pro Lys Lys Val Thr Thr Val Ile Gln Asn Pro Met Pro Ile
420 425 430
Arg Glu Gly Asp Thr Val Thr Leu Ser Cys Asn Tyr Asn Ser Ser Asn
435 440 445
Pro Ser Val Thr Arg Tyr Glu Trp Lys Pro His Gly Ala Trp Glu Glu
450 455 460
Pro Ser Leu Gly Val Leu Lys Ile Gln Asn Val Gly Trp Asp Asn Thr
465 470 475 480
Thr Ile Ala Cys Ala Ala Cys Asn Ser Trp Cys Ser Trp Ala Ser Pro
485 490 495
Val Ala Leu Asn Val Gln Tyr Ala Pro Arg Asp Val Arg Val Arg Lys
500 505 510
Ile Lys Pro Leu Ser Glu Ile His Ser Gly Asn Ser Val Ser Leu Gln
515 520 525
Cys Asp Phe Ser Ser Ser His Pro Lys Glu Val Gln Phe Phe Trp Glu
530 535 540
Lys Asn Gly Arg Leu Leu Gly Lys Glu Ser Gln Leu Asn Phe Asp Ser
545 550 555 560
Ile Ser Pro Glu Asp Ala Gly Ser Tyr Ser Cys Trp Val Asn Asn Ser
565 570 575
Ile Gly Gln Thr Ala Ser Lys Ala Trp Thr Leu Glu Val Leu Tyr Ala
580 585 590
Pro Arg Arg Leu Arg Val Ser Met Ser Pro Gly Asp Gln Val Met Glu
595 600 605
Gly Lys Ser Ala Thr Leu Thr Cys Glu Ser Asp Ala Asn Pro Pro Val
610 615 620
Ser His Tyr Thr Trp Phe Asp Trp Asn Asn Gln Ser Leu Pro Tyr His
625 630 635 640
Ser Gln Lys Leu Arg Leu Glu Pro Val Lys Val Gln His Ser Gly Ala
645 650 655
Tyr Trp Cys Gln Gly Thr Asn Ser Val Gly Lys Gly Arg Ser Pro Leu
660 665 670
Ser Thr Leu Thr Val Tyr Tyr Ser Pro Glu Thr Ile Gly Arg Arg Gly
675 680 685
Gly Gly Gly Ala Gly Gly Gly Gly Cys Lys Pro Cys Ile Cys Thr Val
690 695 700
Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val
705 710 715 720
Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile
725 730 735
Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val
740 745 750
Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser
755 760 765
Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu
770 775 780
Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala
785 790 795 800
Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro
805 810 815
Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Asp Lys Val
820 825 830
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
835 840 845
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
850 855 860
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
865 870 875 880
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
885 890 895
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
900 905 910
Ser Pro Gly Lys
915
<210> 22
<211> 9
<212> PRT
<213> 人工的
<220>
<223> 利妥昔单抗特异性表位
<400> 22
Cys Pro Tyr Ser Asn Pro Ser Leu Cys
1 5
<210> 23
<211> 925
<212> PRT
<213> 人工的
<220>
<223> TRAC_T01-L
<400> 23
Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu
1 5 10 15
Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys
20 25 30
Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly
35 40 45
Phe Thr His Ala His Ile Val Ala Leu Ser Gln His Pro Ala Ala Leu
50 55 60
Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu
65 70 75 80
Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala
85 90 95
Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro
100 105 110
Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly
115 120 125
Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr
130 135 140
Gly Ala Pro Leu Asn Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser
145 150 155 160
Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
165 170 175
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
180 185 190
Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
195 200 205
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
210 215 220
Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
225 230 235 240
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
245 250 255
Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr
260 265 270
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
275 280 285
Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu
290 295 300
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
305 310 315 320
Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln
325 330 335
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
340 345 350
Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly
355 360 365
Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln
370 375 380
Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp
385 390 395 400
Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu
405 410 415
Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
420 425 430
Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro
435 440 445
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
450 455 460
Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
465 470 475 480
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val
485 490 495
Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
500 505 510
Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln
515 520 525
Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr
530 535 540
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
545 550 555 560
Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu
565 570 575
Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
580 585 590
Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln
595 600 605
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
610 615 620
Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly
625 630 635 640
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
645 650 655
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
660 665 670
Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro
675 680 685
Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala
690 695 700
Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly
705 710 715 720
Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys
725 730 735
Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile
740 745 750
Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu
755 760 765
Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys
770 775 780
His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly
785 790 795 800
Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly
805 810 815
Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val
820 825 830
Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp
835 840 845
Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser
850 855 860
Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His
865 870 875 880
Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile
885 890 895
Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg
900 905 910
Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp
915 920 925
<210> 24
<211> 925
<212> PRT
<213> 人工的
<220>
<223> TRAC_T01-R
<400> 24
Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu
1 5 10 15
Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys
20 25 30
Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly
35 40 45
Phe Thr His Ala His Ile Val Ala Leu Ser Gln His Pro Ala Ala Leu
50 55 60
Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu
65 70 75 80
Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala
85 90 95
Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro
100 105 110
Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly
115 120 125
Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr
130 135 140
Gly Ala Pro Leu Asn Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
145 150 155 160
His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
165 170 175
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
180 185 190
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
195 200 205
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val
210 215 220
Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
225 230 235 240
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
245 250 255
Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr
260 265 270
Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
275 280 285
Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu
290 295 300
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
305 310 315 320
Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln
325 330 335
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
340 345 350
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly
355 360 365
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
370 375 380
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn
385 390 395 400
Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu
405 410 415
Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser
420 425 430
Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
435 440 445
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
450 455 460
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
465 470 475 480
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val
485 490 495
Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
500 505 510
Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
515 520 525
Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr
530 535 540
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
545 550 555 560
Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu
565 570 575
Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
580 585 590
Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln
595 600 605
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
610 615 620
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly
625 630 635 640
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
645 650 655
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
660 665 670
Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro
675 680 685
Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala
690 695 700
Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly
705 710 715 720
Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys
725 730 735
Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile
740 745 750
Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu
755 760 765
Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys
770 775 780
His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly
785 790 795 800
Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly
805 810 815
Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val
820 825 830
Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp
835 840 845
Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser
850 855 860
Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His
865 870 875 880
Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile
885 890 895
Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg
900 905 910
Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp
915 920 925
<210> 25
<211> 925
<212> PRT
<213> 人工的
<220>
<223> CD52_T01-L
<400> 25
Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu
1 5 10 15
Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys
20 25 30
Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly
35 40 45
Phe Thr His Ala His Ile Val Ala Leu Ser Gln His Pro Ala Ala Leu
50 55 60
Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu
65 70 75 80
Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala
85 90 95
Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro
100 105 110
Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly
115 120 125
Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr
130 135 140
Gly Ala Pro Leu Asn Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser
145 150 155 160
Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
165 170 175
Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile
180 185 190
Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
195 200 205
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val
210 215 220
Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
225 230 235 240
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln
245 250 255
Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr
260 265 270
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
275 280 285
Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu
290 295 300
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
305 310 315 320
Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln
325 330 335
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
340 345 350
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly
355 360 365
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
370 375 380
Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile
385 390 395 400
Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu
405 410 415
Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
420 425 430
His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
435 440 445
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
450 455 460
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
465 470 475 480
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val
485 490 495
Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
500 505 510
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
515 520 525
Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr
530 535 540
Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
545 550 555 560
Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu
565 570 575
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
580 585 590
Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln
595 600 605
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
610 615 620
Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly
625 630 635 640
Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln
645 650 655
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
660 665 670
Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro
675 680 685
Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala
690 695 700
Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly
705 710 715 720
Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys
725 730 735
Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile
740 745 750
Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu
755 760 765
Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys
770 775 780
His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly
785 790 795 800
Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly
805 810 815
Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val
820 825 830
Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp
835 840 845
Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser
850 855 860
Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His
865 870 875 880
Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile
885 890 895
Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg
900 905 910
Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp
915 920 925
<210> 26
<211> 925
<212> PRT
<213> 人工的
<220>
<223> CD52_T01-R
<400> 26
Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu
1 5 10 15
Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys
20 25 30
Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly
35 40 45
Phe Thr His Ala His Ile Val Ala Leu Ser Gln His Pro Ala Ala Leu
50 55 60
Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu
65 70 75 80
Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala
85 90 95
Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro
100 105 110
Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly
115 120 125
Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr
130 135 140
Gly Ala Pro Leu Asn Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser
145 150 155 160
Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
165 170 175
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
180 185 190
Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
195 200 205
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val
210 215 220
Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
225 230 235 240
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln
245 250 255
Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr
260 265 270
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
275 280 285
Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu
290 295 300
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
305 310 315 320
Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln
325 330 335
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
340 345 350
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly
355 360 365
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
370 375 380
Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile
385 390 395 400
Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu
405 410 415
Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
420 425 430
His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
435 440 445
Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile
450 455 460
Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
465 470 475 480
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
485 490 495
Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
500 505 510
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln
515 520 525
Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr
530 535 540
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
545 550 555 560
Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu
565 570 575
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
580 585 590
Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln
595 600 605
Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His
610 615 620
Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly
625 630 635 640
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
645 650 655
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
660 665 670
Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro
675 680 685
Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala
690 695 700
Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly
705 710 715 720
Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys
725 730 735
Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile
740 745 750
Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu
755 760 765
Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys
770 775 780
His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly
785 790 795 800
Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly
805 810 815
Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val
820 825 830
Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp
835 840 845
Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser
850 855 860
Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His
865 870 875 880
Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile
885 890 895
Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg
900 905 910
Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp
915 920 925
<210> 27
<211> 925
<212> PRT
<213> 人工的
<220>
<223> CD22_T01-L
<400> 27
Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu
1 5 10 15
Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys
20 25 30
Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly
35 40 45
Phe Thr His Ala His Ile Val Ala Leu Ser Gln His Pro Ala Ala Leu
50 55 60
Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu
65 70 75 80
Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala
85 90 95
Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro
100 105 110
Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly
115 120 125
Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr
130 135 140
Gly Ala Pro Leu Asn Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
145 150 155 160
His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
165 170 175
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
180 185 190
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
195 200 205
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
210 215 220
Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
225 230 235 240
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln
245 250 255
Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr
260 265 270
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
275 280 285
Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu
290 295 300
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
305 310 315 320
Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln
325 330 335
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
340 345 350
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly
355 360 365
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
370 375 380
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
385 390 395 400
Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu
405 410 415
Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
420 425 430
His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
435 440 445
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
450 455 460
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
465 470 475 480
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
485 490 495
Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
500 505 510
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
515 520 525
Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr
530 535 540
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
545 550 555 560
Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu
565 570 575
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
580 585 590
Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln
595 600 605
Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His
610 615 620
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly
625 630 635 640
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
645 650 655
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
660 665 670
Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro
675 680 685
Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala
690 695 700
Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly
705 710 715 720
Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys
725 730 735
Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile
740 745 750
Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu
755 760 765
Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys
770 775 780
His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly
785 790 795 800
Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly
805 810 815
Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val
820 825 830
Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp
835 840 845
Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser
850 855 860
Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His
865 870 875 880
Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile
885 890 895
Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg
900 905 910
Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp
915 920 925
<210> 28
<211> 925
<212> PRT
<213> 人工的
<220>
<223> CD22_T01-R
<400> 28
Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu
1 5 10 15
Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys
20 25 30
Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly
35 40 45
Phe Thr His Ala His Ile Val Ala Leu Ser Gln His Pro Ala Ala Leu
50 55 60
Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu
65 70 75 80
Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala
85 90 95
Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro
100 105 110
Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly
115 120 125
Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr
130 135 140
Gly Ala Pro Leu Asn Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser
145 150 155 160
Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
165 170 175
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
180 185 190
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
195 200 205
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
210 215 220
Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
225 230 235 240
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
245 250 255
Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr
260 265 270
Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
275 280 285
Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu
290 295 300
Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
305 310 315 320
Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln
325 330 335
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
340 345 350
Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly
355 360 365
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
370 375 380
Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile
385 390 395 400
Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu
405 410 415
Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
420 425 430
His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
435 440 445
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
450 455 460
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
465 470 475 480
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
485 490 495
Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
500 505 510
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln
515 520 525
Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr
530 535 540
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
545 550 555 560
Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu
565 570 575
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
580 585 590
Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln
595 600 605
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
610 615 620
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly
625 630 635 640
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
645 650 655
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
660 665 670
Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro
675 680 685
Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala
690 695 700
Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly
705 710 715 720
Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys
725 730 735
Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile
740 745 750
Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu
755 760 765
Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys
770 775 780
His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly
785 790 795 800
Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly
805 810 815
Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val
820 825 830
Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp
835 840 845
Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser
850 855 860
Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His
865 870 875 880
Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile
885 890 895
Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg
900 905 910
Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp
915 920 925
<210> 29
<211> 925
<212> PRT
<213> 人工的
<220>
<223> CD20_T01-L
<400> 29
Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu
1 5 10 15
Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys
20 25 30
Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly
35 40 45
Phe Thr His Ala His Ile Val Ala Leu Ser Gln His Pro Ala Ala Leu
50 55 60
Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu
65 70 75 80
Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala
85 90 95
Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro
100 105 110
Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly
115 120 125
Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr
130 135 140
Gly Ala Pro Leu Asn Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser
145 150 155 160
Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
165 170 175
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
180 185 190
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
195 200 205
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
210 215 220
Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
225 230 235 240
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
245 250 255
Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr
260 265 270
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
275 280 285
Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu
290 295 300
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
305 310 315 320
Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln
325 330 335
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
340 345 350
Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly
355 360 365
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
370 375 380
Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp
385 390 395 400
Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu
405 410 415
Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
420 425 430
Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro
435 440 445
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
450 455 460
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
465 470 475 480
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
485 490 495
Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
500 505 510
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln
515 520 525
Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr
530 535 540
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
545 550 555 560
Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu
565 570 575
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
580 585 590
Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln
595 600 605
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
610 615 620
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly
625 630 635 640
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
645 650 655
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
660 665 670
Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro
675 680 685
Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala
690 695 700
Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly
705 710 715 720
Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys
725 730 735
Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile
740 745 750
Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu
755 760 765
Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys
770 775 780
His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly
785 790 795 800
Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly
805 810 815
Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val
820 825 830
Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp
835 840 845
Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser
850 855 860
Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His
865 870 875 880
Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile
885 890 895
Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg
900 905 910
Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp
915 920 925
<210> 30
<211> 925
<212> PRT
<213> 人工的
<220>
<223> CD20_T01-R
<400> 30
Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu
1 5 10 15
Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys
20 25 30
Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly
35 40 45
Phe Thr His Ala His Ile Val Ala Leu Ser Gln His Pro Ala Ala Leu
50 55 60
Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu
65 70 75 80
Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala
85 90 95
Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro
100 105 110
Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly
115 120 125
Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr
130 135 140
Gly Ala Pro Leu Asn Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser
145 150 155 160
Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro
165 170 175
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
180 185 190
Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
195 200 205
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
210 215 220
Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
225 230 235 240
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
245 250 255
Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr
260 265 270
Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
275 280 285
Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu
290 295 300
Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
305 310 315 320
Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln
325 330 335
Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His
340 345 350
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly
355 360 365
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
370 375 380
Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile
385 390 395 400
Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu
405 410 415
Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser
420 425 430
Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro
435 440 445
Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile
450 455 460
Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu
465 470 475 480
Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val
485 490 495
Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln
500 505 510
Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln
515 520 525
Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr
530 535 540
Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro
545 550 555 560
Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu
565 570 575
Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu
580 585 590
Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln
595 600 605
Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His
610 615 620
Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly
625 630 635 640
Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln
645 650 655
Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly
660 665 670
Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro
675 680 685
Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala
690 695 700
Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly
705 710 715 720
Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys
725 730 735
Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile
740 745 750
Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu
755 760 765
Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys
770 775 780
His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly
785 790 795 800
Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly
805 810 815
Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val
820 825 830
Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp
835 840 845
Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser
850 855 860
Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His
865 870 875 880
Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile
885 890 895
Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg
900 905 910
Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp
915 920 925
<210> 31
<211> 3003
<212> DNA
<213> 人工的
<220>
<223> nt seq CAR22xCAR20
<400> 31
atggctctgc ccgtcaccgc tctgctgctg ccactggccc tgctgctgca cgcagcaaga 60
ccacaggtgc agctgcagca gagcggccct ggcctggtga agccaagcca gacactgtcc 120
ctgacctgcg ccatcagcgg cgattccgtg agctccaact ccgccgcctg gaattggatc 180
aggcagtccc cttctcgggg cctggagtgg ctgggaagga catactatcg gtctaagtgg 240
tacaacgatt atgccgtgtc tgtgaagagc agaatcacaa tcaaccctga cacctccaag 300
aatcagttct ctctgcagct gaatagcgtg acaccagagg acaccgccgt gtactattgc 360
gccagggagg tgaccggcga cctggaggat gcctttgaca tctggggcca gggcacaatg 420
gtgaccgtgt ctagcggagg aggaggatcc ggaggaggag gatctggcgg cggcggcagc 480
gatatccaga tgacacagtc cccatcctct ctgagcgcct ccgtgggcga cagagtgaca 540
atcacctgta gggcctccca gaccatctgg tcttacctga actggtatca gcagaggccc 600
ggcaaggccc ctaatctgct gatctacgca gcaagctccc tgcagagcgg agtgccatcc 660
agattctctg gcaggggctc cggcacagac ttcaccctga ccatctctag cctgcaggcc 720
gaggacttcg ccacctacta ttgccagcag tcttatagca tcccccagac atttggccag 780
ggcaccaagc tggagatcaa gaccacaacc ccagcaccaa ggccacctac acctgcacca 840
accatcgcct ctcagcccct gagcctgaga cctgaggcat gtaggccagc agcaggagga 900
gcagtccata caaggggtct ggattttgca tgcgacatct acatctgggc acctctggca 960
ggaacatgtg gcgtgctcct gctcagcctg gtcatcaccc tgtactgcaa gagaggcagg 1020
aagaagctgc tgtatatctt caagcagccc ttcatgcgcc ccgtgcagac aacccaggag 1080
gaggatggct gctcctgtag gttcccagaa gaggaggagg gaggatgtga gctgcgcgtg 1140
aagttttccc ggtctgccga cgcacctgca taccagcagg gccagaacca gctgtataac 1200
gagctgaatc tgggccggag agaggagtac gatgtgctgg acaagaggcg cggcagagat 1260
ccagagatgg gcggcaagcc ccggagaaag aaccctcagg agggcctgta caatgagctg 1320
cagaaggata agatggccga ggcctattct gagatcggca tgaagggaga gaggcgccgg 1380
ggcaagggac acgacggact gtaccaggga ctgagcacag ccaccaagga tacctatgac 1440
gccctgcata tgcaggcact gcctccaagg ggaagcggag ctactaactt cagcctgctg 1500
aagcaggctg gagacgtgga ggagaaccct ggacctatgg ctctgcctgt caccgctctg 1560
ctgctgcccc tggctctgct gctgcacgcc gcacgccccg aagtccagct ggtcgaatct 1620
gggggcgggc tggtgcagcc aggaagatca ctgaggctga gctgcgccgc ttccggcttc 1680
accttcaacg actatgccat gcactgggtg agacaggctc ccggaaaggg cctggagtgg 1740
gtctctacca tcagttggaa ttccgggtct attggatatg ccgacagcgt gaaaggccgc 1800
ttcacaatct ctcgagataa cgctaagaaa agtctgtacc tgcagatgaa ttcactgagg 1860
gcagaggaca ctgccctgta ctattgcgcc aaggatattc agtacggcaa ctactattac 1920
gggatggacg tctgggggca gggaaccaca gtgaccgtca gctccggagg aggaggatcc 1980
ggaggaggag gaagcggagg aggaggatcc gagatcgtgc tgacacagag cccagccact 2040
ctgagtctgt cacccggcga acgagctaca ctgtcctgtc gggcaagcca gtccgtctct 2100
agttatctgg cttggtacca gcagaagcca ggacaggcac cacgactgct gatctacgat 2160
gctagcaaca gagcaacagg gattcctgca aggttctctg gcagtgggtc aggaactgac 2220
tttacactga ctatctcaag cctggagcct gaagatttcg ccgtgtatta ctgccagcag 2280
cggtccaatt ggccaatcac ctttggccag gggacacgcc tggagatcaa gactaccaca 2340
cctgctccac gaccacctac tccagcacct accattgctt ctcagcccct gagtctgcgg 2400
cctgaagcat gtagaccagc agcaggagga gcagtgcata ccagaggact ggactttgcc 2460
tgcgatatct atatttgggc accactggct ggaacttgtg gagtgctgct gctgtctctg 2520
gtcatcaccc tgtattgcaa gcgaggccgg aagaaactgc tgtacatttt caaacagcct 2580
tttatgagac cagtgcagac tacccaggag gaagacggct gcagctgtag gttccccgag 2640
gaagaggaag ggggatgtga gctgagggtc aagtttagcc gctccgctga tgcacctgcc 2700
tatcagcagg ggcagaatca gctgtacaac gagctgaatc tgggacggag agaggaatac 2760
gacgtgctgg ataaaaggcg aggacgagat ccagaaatgg gagggaagcc ccgacggaaa 2820
aaccctcagg agggcctgta taatgaactg cagaaggaca aaatggctga ggcatactct 2880
gaaatcggaa tgaagggcga gagaaggcgc ggaaaaggcc acgatgggct gtatcaggga 2940
ctgagtaccg ccacaaagga cacctacgat gcactgcata tgcaggccct gccaccccgg 3000
tga 3003
<210> 32
<211> 3003
<212> DNA
<213> 人工的
<220>
<223> nt seq CAR20xCAR22
<400> 32
atggctctgc ctgtcaccgc tctgctgctg cccctggctc tgctgctgca cgccgcacgc 60
cccgaagtcc agctggtcga atctgggggc gggctggtgc agccaggaag atcactgagg 120
ctgagctgcg ccgcttccgg cttcaccttc aacgactatg ccatgcactg ggtgagacag 180
gctcccggaa agggcctgga gtgggtctct accatcagtt ggaattccgg gtctattgga 240
tatgccgaca gcgtgaaagg ccgcttcaca atctctcgag ataacgctaa gaaaagtctg 300
tacctgcaga tgaattcact gagggcagag gacactgccc tgtactattg cgccaaggat 360
attcagtacg gcaactacta ttacgggatg gacgtctggg ggcagggaac cacagtgacc 420
gtcagctccg gaggaggagg atccggagga ggaggaagcg gaggaggagg atccgagatc 480
gtgctgacac agagcccagc cactctgagt ctgtcacccg gcgaacgagc tacactgtcc 540
tgtcgggcaa gccagtccgt ctctagttat ctggcttggt accagcagaa gccaggacag 600
gcaccacgac tgctgatcta cgatgctagc aacagagcaa cagggattcc tgcaaggttc 660
tctggcagtg ggtcaggaac tgactttaca ctgactatct caagcctgga gcctgaagat 720
ttcgccgtgt attactgcca gcagcggtcc aattggccaa tcacctttgg ccaggggaca 780
cgcctggaga tcaagactac cacacctgct ccacgaccac ctactccagc acctaccatt 840
gcttctcagc ccctgagtct gcggcctgaa gcatgtagac cagcagcagg aggagcagtg 900
cataccagag gactggactt tgcctgcgat atctatattt gggcaccact ggctggaact 960
tgtggagtgc tgctgctgtc tctggtcatc accctgtatt gcaagcgagg ccggaagaaa 1020
ctgctgtaca ttttcaaaca gccttttatg agaccagtgc agactaccca ggaggaagac 1080
ggctgcagct gtaggttccc cgaggaagag gaagggggat gtgagctgag ggtcaagttt 1140
agccgctccg ctgatgcacc tgcctatcag caggggcaga atcagctgta caacgagctg 1200
aatctgggac ggagagagga atacgacgtg ctggataaaa ggcgaggacg agatccagaa 1260
atgggaggga agccccgacg gaaaaaccct caggagggcc tgtataatga actgcagaag 1320
gacaaaatgg ctgaggcata ctctgaaatc ggaatgaagg gcgagagaag gcgcggaaaa 1380
ggccacgatg ggctgtatca gggactgagt accgccacaa aggacaccta cgatgcactg 1440
catatgcagg ccctgccacc ccgaggaagc ggagctacta acttcagcct gctgaagcag 1500
gctggagacg tggaggagaa ccctggacct atggctctgc ccgtcaccgc tctgctgctg 1560
ccactggccc tgctgctgca cgcagcaaga ccacaggtgc agctgcagca gagcggccct 1620
ggcctggtga agccaagcca gacactgtcc ctgacctgcg ccatcagcgg cgattccgtg 1680
agctccaact ccgccgcctg gaattggatc aggcagtccc cttctcgggg cctggagtgg 1740
ctgggaagga catactatcg gtctaagtgg tacaacgatt atgccgtgtc tgtgaagagc 1800
agaatcacaa tcaaccctga cacctccaag aatcagttct ctctgcagct gaatagcgtg 1860
acaccagagg acaccgccgt gtactattgc gccagggagg tgaccggcga cctggaggat 1920
gcctttgaca tctggggcca gggcacaatg gtgaccgtgt ctagcggagg aggaggatcc 1980
ggaggaggag gatctggcgg cggcggcagc gatatccaga tgacacagtc cccatcctct 2040
ctgagcgcct ccgtgggcga cagagtgaca atcacctgta gggcctccca gaccatctgg 2100
tcttacctga actggtatca gcagaggccc ggcaaggccc ctaatctgct gatctacgca 2160
gcaagctccc tgcagagcgg agtgccatcc agattctctg gcaggggctc cggcacagac 2220
ttcaccctga ccatctctag cctgcaggcc gaggacttcg ccacctacta ttgccagcag 2280
tcttatagca tcccccagac atttggccag ggcaccaagc tggagatcaa gaccacaacc 2340
ccagcaccaa ggccacctac acctgcacca accatcgcct ctcagcccct gagcctgaga 2400
cctgaggcat gtaggccagc agcaggagga gcagtccata caaggggtct ggattttgca 2460
tgcgacatct acatctgggc acctctggca ggaacatgtg gcgtgctcct gctcagcctg 2520
gtcatcaccc tgtactgcaa gagaggcagg aagaagctgc tgtatatctt caagcagccc 2580
ttcatgcgcc ccgtgcagac aacccaggag gaggatggct gctcctgtag gttcccagaa 2640
gaggaggagg gaggatgtga gctgcgcgtg aagttttccc ggtctgccga cgcacctgca 2700
taccagcagg gccagaacca gctgtataac gagctgaatc tgggccggag agaggagtac 2760
gatgtgctgg acaagaggcg cggcagagat ccagagatgg gcggcaagcc ccggagaaag 2820
aaccctcagg agggcctgta caatgagctg cagaaggata agatggccga ggcctattct 2880
gagatcggca tgaagggaga gaggcgccgg ggcaagggac acgacggact gtaccaggga 2940
ctgagcacag ccaccaagga tacctatgac gccctgcata tgcaggcact gcctccaagg 3000
tga 3003
<210> 33
<211> 49
<212> DNA
<213> 人工的
<220>
<223> TRAC_T01-靶标
<400> 33
ttgtcccaca gatatccaga accctgaccc tgccgtgtac cagctgaga 49
<210> 34
<211> 49
<212> DNA
<213> 人工的
<220>
<223> CD52_T01-靶标
<400> 34
ttcctcctac tcaccatcag cctcctggtt atggtacagg taagagcaa 49
<210> 35
<211> 49
<212> DNA
<213> 人工的
<220>
<223> CD22_T01 靶标
<400> 35
tctggttttc ttccagatcc tcccaagaag gtgaccacag tgattcaaa 49
<210> 36
<211> 49
<212> DNA
<213> 人工的
<220>
<223> CD20_T01 靶标
<400> 36
tttgctgcca tttctggaat gattctttca atcatggaca tacttaata 49
<210> 37
<211> 588
<212> DNA
<213> 人工的
<220>
<223> IRES
<400> 37
gcccctctcc ctcccccccc cctaacgtta ctggccgaag ccgcttggaa taaggccggt 60
gtgcgtttgt ctatatgtta ttttccacca tattgccgtc ttttggcaat gtgagggccc 120
ggaaacctgg ccctgtcttc ttgacgagca ttcctagggg tctttcccct ctcgccaaag 180
gaatgcaagg tctgttgaat gtcgtgaagg aagcagttcc tctggaagct tcttgaagac 240
aaacaacgtc tgtagcgacc ctttgcaggc agcggaaccc cccacctggc gacaggtgcc 300
tctgcggcca aaagccacgt gtataagata cacctgcaaa ggcggcacaa ccccagtgcc 360
acgttgtgag ttggatagtt gtggaaagag tcaaatggct ctcctcaagc gtattcaaca 420
aggggctgaa ggatgcccag aaggtacccc attgtatggg atctgatctg gggcctcggt 480
gcacatgctt tacatgtgtt tagtcgaggt taaaaaaacg tctaggcccc ccgaaccacg 540
gggacgtggt tttcctttga aaaacacgat gataatatgg ccacaacc 588
<210> 38
<211> 21
<212> PRT
<213> 人工的
<220>
<223> T2A 肽
<400> 38
Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu
1 5 10 15
Glu Asn Pro Gly Pro
20
<210> 39
<211> 23
<212> PRT
<213> 人工的
<220>
<223> E2A肽
<400> 39
Gly Ser Gly Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp
1 5 10 15
Val Glu Ser Asn Pro Gly Pro
20
<210> 40
<211> 25
<212> PRT
<213> 人工的
<220>
<223> F2A肽
<400> 40
Gly Ser Gly Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala
1 5 10 15
Gly Asp Val Glu Ser Asn Pro Gly Pro
20 25
<210> 41
<211> 11
<212> PRT
<213> 人工的
<220>
<223> CAR22 H-CDR1
<400> 41
Ser Gly Asp Ser Val Ser Ser Asn Ser Ala Ala
1 5 10
<210> 42
<211> 9
<212> PRT
<213> 人工的
<220>
<223> CAR22 H-CDR2
<400> 42
Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn
1 5
<210> 43
<211> 13
<212> PRT
<213> 人工的
<220>
<223> CAR22 H-CDR3
<400> 43
Ala Arg Glu Val Thr Gly Asp Leu Glu Asp Ala Phe Asp
1 5 10
<210> 44
<211> 6
<212> PRT
<213> 人工的
<220>
<223> CAR22 L-CDR1
<400> 44
Gln Thr Ile Trp Ser Tyr
1 5
<210> 45
<211> 3
<212> PRT
<213> 人工的
<220>
<223> CAR22 L-CDR2
<400> 45
Ala Ala Ser
1
<210> 46
<211> 9
<212> PRT
<213> 人工的
<220>
<223> CAR22 L-CDR3
<400> 46
Gln Gln Ser Tyr Ser Ile Pro Gln Thr
1 5
<210> 47
<211> 8
<212> PRT
<213> 人工的
<220>
<223> CAR20 H-CDR1
<400> 47
Gly Phe Thr Phe Asn Asp Tyr Ala
1 5
<210> 48
<211> 8
<212> PRT
<213> 人工的
<220>
<223> CAR20 H-CDR2
<400> 48
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 49
<211> 15
<212> PRT
<213> 人工的
<220>
<223> CAR20 H-CDR3
<400> 49
Ala Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 50
<211> 6
<212> PRT
<213> 人工的
<220>
<223> CAR20 L-CDR1
<400> 50
Gln Ser Val Ser Ser Tyr
1 5
<210> 51
<211> 3
<212> PRT
<213> 人工的
<220>
<223> CAR20 L-CDR2
<400> 51
Asp Ala Ser
1
<210> 52
<211> 9
<212> PRT
<213> 人工的
<220>
<223> CAR20 L-CDR3
<400> 52
Gln Gln Arg Ser Asn Trp Pro Ile Thr
1 5
Claims (47)
1.一种基因工程化免疫细胞,所述免疫细胞在它的细胞表面表达对于CD22特异性的嵌合抗原受体(CAR)(CAR22)和对于CD20特异性的嵌合抗原受体(CAR20),
a)其中,所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,所述对于CD22特异性的抗原结合结构域包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含与SEQ ID NO:11具有至少80%同一性的氨基酸序列并且包含氨基酸序列SEQ ID NO:41、SEQ ID NO:42和SEQ ID NO:43的H-CDR,所述可变轻链(VL)包含与SEQ ID NO:12具有至少80%同一性的氨基酸序列并且包含氨基酸序列SEQ IDNO:44、SEQ ID NO:45和SEQ ID NO:46的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;并且
b)其中,所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,所述对于CD20特异性的抗原结合结构域包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含与SEQ ID NO:15具有至少80%同一性的氨基酸序列并且包含氨基酸序列SEQ ID NO:47、SEQ ID NO:48和SEQ ID NO:49的H-CDR,所述可变轻链(VL)包含与SEQ ID NO:16具有至少80%同一性的氨基酸序列并且包含氨基酸序列SEQ IDNO:50、SEQ ID NO:51和SEQ ID NO:52的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
2.根据权利要求1所述的基因工程化免疫细胞,其中,所述CAR22包含SEQ ID NO:14的氨基酸序列,并且其中,所述CAR20包含SEQID NO:18的氨基酸序列。
3.根据权利要求1或2所述的基因工程化免疫细胞,其中,所述CAR20和所述CAR22的胞外结构域均不包含安全开关,所述安全开关包含利妥昔单抗特异性模拟表位,如SEQ IDNO:22。
4.根据权利要求1至3中任一项所述的基因工程化免疫细胞,其中,所述CAR由并入所述免疫细胞的基因组中的外源核酸编码,并且其中,所述外源核酸从5’到3’包含:
(i)启动子(如EF1α启动子),
(ii)编码所述CAR20的核酸,
(iii)编码自切割肽(如SEQ ID NO:19的P2A)的核酸,
(iv)编码所述CAR22的核酸,
从而相同的启动子控制所述CAR20和所述CAR22的表达。
5.根据权利要求4所述的基因工程化免疫细胞,其中:
-(ii)的所述核酸包含SEQ ID NO:1的信号肽、SEQ ID NO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ IDNO:9的CD3ζ信号结构域);并且
-(iv)的所述核酸包含SEQ ID NO:1的信号肽、SEQ ID NO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ IDNO:9的CD3ζ信号结构域。
6.根据权利要求4和5中任一项所述的基因工程化免疫细胞,其中,所述外源核酸包含SEQ ID NO:32的核酸序列。
7.根据权利要求1至6中任一项所述的基因工程化免疫细胞,其中,所述工程化免疫细胞选自由T细胞、NK细胞和巨噬细胞组成的组。
8.根据权利要求1至7中任一项所述的基因工程化免疫细胞,其中,所述工程化免疫细胞是T细胞,例如细胞毒性T细胞。
9.根据权利要求1至8中任一项所述的基因工程化免疫细胞,其中,所述工程化免疫细胞包含在细胞群中,所述细胞群如免疫细胞群,特别是T细胞群、NK细胞群和/或巨噬细胞群。
10.根据权利要求1至9中任一项所述的基因工程化免疫细胞,其中,所述工程化免疫细胞是T细胞,所述T细胞是TCR阴性的。
11.根据权利要求10所述的基因工程化免疫细胞,其中,工程化的所述T细胞表达直接针对编码TCR组件的多核苷酸序列的短发夹RNA(shRNA)或小干扰(siRNA)。
12.根据权利要求10所述的基因工程化免疫细胞,其中,工程化的所述T细胞在它的TCRα和/或TCRβ等位基因中发生突变。
13.根据权利要求10或12中任一项所述的基因工程化免疫细胞,其中,工程化的所述T细胞具有编码已经通过突变失活的TCRα、TCRβ和/或CD3的至少一个等位基因。
14.根据权利要求8至13中任一项所述的基因工程化免疫细胞,其中,工程化的所述T细胞具有选自已经失活的β2m、PD1、CTLA4、dCK、CD52和/或GR的至少一个等位基因。
15.根据权利要求9至14中任一项所述的基因工程化免疫细胞,其中,工程化的所述T细胞具有已经失活的CD52等位基因。
16.根据权利要求1至15中任一项所述的基因工程化免疫细胞,其中,工程化的所述细胞、优选T细胞是原代细胞。
17.根据权利要求1至16中任一项所述的基因工程化免疫细胞,其中,工程化的所述细胞、优选T细胞是哺乳动物细胞、优选人细胞。
18.根据权利要求1至17中任一项所述的基因工程化免疫细胞,其中,工程化的所述细胞、优选T细胞不表达除所述CAR22和所述CAR20之外的其他CAR。
19.一种免疫细胞群,包含根据权利要求1至18中任一项所述的工程化免疫细胞。
20.一种T细胞群,包含根据权利要求9至18中任一项所述的工程化T细胞。
21.一种药物组合物,包含根据权利要求1至18中任一项所述的工程化免疫细胞和药学上可接受的赋形剂。
22.一种药物组合物,包含根据权利要求19至20中任一项所述的免疫细胞群和药学上可接受的赋形剂。
23.一种药物组合物,包含根据权利要求10至18中任一项所述的工程化T细胞和药学上可接受的赋形剂。
24.一种药物组合物,包含根据权利要求20所述的T细胞群和药学上可接受的赋形剂。
25.一种分离的多核苷酸,包含:
a)编码CAR22的核酸,所述CAR22包含:
i)至少一个胞外结构域,包含:
-对于CD22特异性的抗原结合结构域,所述对于CD22特异性的抗原结合结构域包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含与SEQ ID NO:11具有至少80%同一性的氨基酸序列并且包含氨基酸序列SEQ ID NO:41、SEQ ID NO:42和SEQ ID NO:43的H-CDR,所述可变轻链(VL)包含与SEQ ID NO:12具有至少80%同一性的氨基酸序列并且包含氨基酸序列SEQ IDNO:44、SEQ ID NO:45和SEQ ID NO:46的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域;以及
b)编码CAR20的核酸,所述CAR20包含:
i)至少一个胞外结构域,包含:
-对于CD20特异性的抗原结合结构域,所述对于CD20特异性的抗原结合结构域包含可变重链(VH)和可变轻链(VL),所述可变重链(VH)包含与SEQ ID NO:15具有至少80%同一性的氨基酸序列并且包含氨基酸序列SEQ ID NO:47、SEQ ID NO:48和SEQ ID NO:49的H-CDR,所述可变轻链(VL)包含与SEQ ID NO:16具有至少80%同一性的氨基酸序列并且包含氨基酸序列SEQ IDNO:50、SEQ ID NO:51和SEQ ID NO:52的L-CDR,任选地前导序列,
-来自CD8α的铰链结构域,
ii)来自CD8α的跨膜结构域,和
iii)包含4-1BB刺激结构域和CD3ζ信号结构域的胞内结构域。
26.根据权利要求25所述的多核苷酸,其中,a)的所述核酸和b)的所述核酸在单个核酸分子上,并且其中,编码自切割肽(如P2A、T2A、E2A或F2A)的核酸序列位于a)的所述核酸和b)的所述核酸之间。
27.根据权利要求25或26所述的多核苷酸,其中,所述多核苷酸不包含编码除所述CAR22和所述CAR20之外的其他CAR的核酸。
28.根据权利要求25至27中任一项所述的多核苷酸,其中,所述多核苷酸不包含编码SEQ ID NO:22的利妥昔单抗特异性模拟表位的核酸。
29.根据权利要求25至28中任一项所述的多核苷酸:
-其中,a)的所述核酸包含控制所述CAR22的表达的启动子(如EF1α启动子),所述CAR22由SEQ ID NO:1的信号肽、SEQ IDNO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;
-其中,b)的所述核酸编码所述CAR20,所述CAR20由SEQID NO:1的信号肽、SEQ ID NO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;并且
-其中,编码自切割肽(如SEQ ID NO:19的P2A)的核酸存在于a)的所述核酸和b)的所述核酸之间,允许所述CAR20和所述CAR22的同时表达。
30.根据权利要求25至28中任一项所述的多核苷酸,
-其中,b)的所述核酸包含控制所述CAR20的表达的启动子(如EF1α启动子),所述CAR20由SEQ ID NO:1的信号肽、SEQ IDNO:17的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;
-其中,a)的所述核酸编码所述CAR22,所述CAR22由SEQID NO:1的信号肽、SEQ ID NO:13的scFv、SEQ ID NO:4的CD8α铰链、SEQ ID NO:6的CD8α跨膜结构域、SEQ ID NO:8的4-1BB共刺激结构域和SEQ ID NO:9的CD3ζ信号结构域组成;并且
-其中,编码自切割肽(如SEQ ID NO:19的P2A)的核酸存在于b)的所述核酸和a)的所述核酸之间,允许所述CAR22和所述CAR20的同时表达。
31.根据权利要求29所述的分离的多核苷酸,包含SEQ ID NO:31的核酸序列(CAR22xCAR20构建体)。
32.根据权利要求30所述的分离的多核苷酸,包含SEQ ID NO:32的核酸序列(CAR20xCAR22构建体)。
33.一种载体,包含权利要求25至32中任一项所述的分离的多核苷酸。
34.一种宿主细胞,包含权利要求33所述的载体。
35.一种制备根据权利要求1至18中任一项所述的工程化免疫细胞的方法,包括将根据权利要求25至32中任一项所述的多核苷酸或根据权利要求33所述的载体引入免疫细胞中。
36.根据权利要求1至18中任一项所述的工程化免疫细胞,用作药物。
37.根据权利要求1至18中任一项所述的工程化免疫细胞,用于在治疗与CD20和/或CD22表达相关的癌症中使用。
38.根据权利要求1至18中任一项所述的工程化免疫细胞,用于在治疗血液癌症中使用,所述血液癌症特别是CD22-和/或CD20-相关的血液癌症,更特别是复发难治性CD22-和/或CD20-相关的血液癌症,甚至更特别是所述CD22-和/或CD20-相关的血液癌症的侵袭性形式。
39.根据权利要求37或38所述的用于使用的工程化免疫细胞,其中,所述癌症选自由淋巴瘤、霍奇金淋巴瘤(HL)、非霍奇金淋巴瘤(NHL)、白血病、多发性骨髓瘤(MM)、B-慢性淋巴细胞白血病(B-CLL)、毛细胞白血病(HCL)、急性淋巴细胞白血病(ALL)、急性淋巴细胞癌、急性髓性白血病(AML)组成的组。
40.根据权利要求39所述的用于使用的工程化免疫细胞,其中,所述癌症是非霍奇金淋巴瘤或急性淋巴细胞白血病。
41.根据权利要求37至40中任一项所述的用于使用的工程化免疫细胞,其中,所述癌症与CD20和/或CD22的低表达相关。
42.根据权利要求37至41中任一项所述的用于使用的工程化免疫细胞,其中,所述癌症是复发性非霍奇金淋巴瘤。
43.一种治疗遭受与CD20和/或CD22表达相关的癌症的患者的方法,包括向所述患者施用有效量的根据权利要求1至18中任一项所述的工程化免疫细胞或根据权利要求19至20中任一项所述的免疫细胞群。
44.根据权利要求43所述的治疗方法,其中,所述癌症选自由淋巴瘤、霍奇金淋巴瘤(HL)、非霍奇金淋巴瘤(NHL)、白血病、多发性骨髓瘤(MM)、B-慢性淋巴细胞白血病(B-CLL)、毛细胞白血病(HCL)、急性淋巴细胞白血病(ALL)、急性淋巴细胞癌、急性髓性白血病(AML)组成的组。
45.根据权利要求43至44中任一项所述的治疗方法,其中,所述癌症是非霍奇金淋巴瘤或急性淋巴细胞白血病。
46.根据权利要求43至45中任一项所述的治疗方法,其中,所述癌症与CD20和/或CD22的低表达相关。
47.根据权利要求43至46中任一项所述的治疗方法,其中,所述癌症是复发性非霍奇金淋巴瘤。
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US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
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CA2912375C (en) | 2013-05-13 | 2023-03-14 | Cellectis | Methods for engineering highly active t cell for immunotherapy |
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AU2021316677A1 (en) | 2023-02-23 |
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