CN113968913A - 抗cd70嵌合抗原受体 - Google Patents
抗cd70嵌合抗原受体 Download PDFInfo
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- CN113968913A CN113968913A CN202111253336.5A CN202111253336A CN113968913A CN 113968913 A CN113968913 A CN 113968913A CN 202111253336 A CN202111253336 A CN 202111253336A CN 113968913 A CN113968913 A CN 113968913A
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Abstract
本发明提供具有针对CD70的抗原特异性的嵌合抗原受体(CAR),所述CAR包含:抗原结合‑跨膜结构域,其含有缺乏CD27胞内T细胞信号转导结构域的全部或部分的CD27氨基酸序列;4‑1BB胞内T细胞信号转导结构域;CD3ζ胞内T细胞信号转导结构域;以及任选地,CD28胞内T细胞信号转导结构域。还公开了与CAR相关的核酸、重组表达载体、宿主细胞、细胞群以及药物组合物。还公开了检测哺乳动物中的癌症的存在的方法以及治疗或预防哺乳动物中的癌症的方法。
Description
相关申请的交叉引用
本专利申请要求于2014年12月8日提交的美国临时专利申请第62/088,882号的权益,将其通过引用整体并入本文。
关于联邦政府资助研究与开发的声明
本发明是由美国国立卫生研究院国家癌症研究所在政府支持下完成的,项目编号为Z01BC011337-04。政府拥有本发明的某些权利。
通过引用并入电子提交的材料
通过引用整体并入本文的是同时提交并通过如下识别的计算机可读的核苷酸/氨基酸序列表:名为“719062ST25.TXT”的一个55,121个字节的ASCII(Text)文件,日期为2014年12月3日。
发明背景
癌症是公共健康问题。尽管在诸如化疗的治疗中取得进步,但许多癌症的预后可能较差,所述癌症包括肾细胞癌(RCC)、胶质母细胞瘤、非霍奇金氏淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。因此,对癌症,特别是RCC、胶质母细胞瘤、NHL、CLL、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤的其它治疗存在未满足的需求。
发明概述
本发明的实施方案提供具有针对CD70的抗原特异性的嵌合抗原受体(CAR),所述CAR包含:抗原结合-跨膜结构域,其含有缺乏CD27胞内T细胞信号转导结构域的全部或部分的CD27氨基酸序列,其中所述部分为SEQ ID NO:2所限定的至少氨基酸残基237至260;4-1BB胞内T细胞信号转导结构域;CD3ζ胞内T细胞信号转导结构域;以及任选地,CD28胞内T细胞信号转导结构域。
本发明的另一实施方案提供具有针对CD70的抗原特异性的CAR,其包含与SEQ IDNO:11-13中任一项至少约90%相同的氨基酸序列。
本发明的其它实施方案提供与本发明的CAR相关的相关核酸、重组表达载体、宿主细胞、细胞群以及药物组合物。
本发明另外的实施方案提供检测哺乳动物中癌症的存在的方法以及治疗或预防哺乳动物中癌症的方法。
附图几个视图的简要描述
图1A和1B是显示施用mCD27-CD3ζCAR转导的细胞(实心圆)、未转导的细胞(空心圆)、磷酸盐缓冲盐水(PBS)(×)或pmel+VI(正方形)并进行辐射(500Rad)之后一段时间(天数)内,B16/mCD70-(A)或B16-(B)荷瘤小鼠的肿瘤大小(mm2)的图。
图1C和1D是显示在施用每只小鼠1×105(实心正方形)、或1×107(实心圆)个细胞的剂量的mCD27-CD3ζCAR转导的细胞;PBS(空心正方形);转导有空载体的细胞(空心圆);或者pmel+VI(菱形),进行(C)或不进行(D)辐射(500Rad)之后一段时间(天数)内,B16/mCD70荷瘤小鼠的肿瘤大小(mm2)的图。
图1E是显示在施用每只小鼠1×104(菱形)、或1×107(实心圆)个细胞的剂量的mCD27-CD3ζCAR转导的细胞;PBS(空心正方形);转导有空载体的细胞(空心圆);或者pmel+VI(△),随后进行辐射(500Rad)之后一段时间(天数)内,B16/mCD70荷瘤小鼠的存活(%)的图。
图1F是显示在施用mCD27-CD3ζCAR转导的细胞(正方形)、未转导的细胞(△)、转导有空载体的细胞或者pmel+VI(环),随后进行辐射并施用IL-2之后一段时间(天数)内,B16/mCD70荷瘤小鼠的肿瘤大小(mm2)的图。
图2A-2D是显示在施用mCD27-CD3ζCAR转导的细胞(实心圆)、未转导的细胞(空心正方形)、磷酸盐缓冲盐水(PBS)或pmel+VI(△),进行(A和C)或不进行(B和D)辐射(500Rad)之后一段时间(天数)内,B16/mCD70-(A和B)或B16-(C和D)荷瘤小鼠的平均体重(g)的图。
图2E-2H是显示在施用mCD27-CD3ζCAR转导的细胞(交叉线柱)、未转导的细胞(无阴影柱)或者转导有编码绿色荧光蛋白(GFP)的载体的细胞(斜纹柱),进行(E和G)或不进行(F和H)辐射(500Rad)之后一段时间(天数)内,B16/mCD70荷瘤小鼠的绝对白细胞计数(K/μl)(E和F)或脾细胞计数(x107/脾)(G和H)的图。
图2I是显示在施用mCD27-CD3ζCAR转导的细胞,进行(黑柱)或不进行(横纹柱)辐射;或者施用转导有编码GFP的载体,进行(方格柱)或不进行(无阴影柱)辐射(500Rad)之后一段时间(天数)内,B16/mCD70荷瘤小鼠的血清干扰素(IFN)γ(pg/ml)水平的图。
图3是显示在单独培养(培养基)转导有空的逆转录病毒载体(对照)(MSGV1)或者fCD27-CD3ζ(SEQ ID NO:7)、ΔCD27-CD28–CD3ζ(SEQ ID NO:8)、ΔCD27-4-1BB–CD3ζ(SEQID NO:9)、ΔCD27-CD28–4-1BB–CD3ζ(SEQ ID NO:10)、fCD27-CD28–CD3ζ(SEQ ID NO:11)、fCD27-4-1BB–CD3ζ(SEQ ID NO:12)或fCD27-CD28–4-1BB–CD3ζ(SEQ ID NO:13)之一的人T细胞时(竖纹柱);或者在与对照靶细胞624mel(方格柱)、624/CD70(黑柱)、938mel(点状柱)或938/CD70(白柱)、或RCC靶细胞RCC 2245R(正斜杠柱)、RCC 2246R(反斜杠柱)、RCC 2361R(有横纹的柱)或者RCC 1764(人字纹柱)共培养时,分泌的IFN-γ(pg/ml)的图。
图4是显示在单独培养(培养基)未转导的(UT)细胞或者转导有ΔCD27-4-1BB–CD3ζ(SEQ ID NO:9)的逆转录病毒包装克隆A2、A10、B3、C1、E3或G2(竖纹柱)时;或者在与对照靶细胞SNU1079(点状柱)、SNU1196(白柱)、938mel(方格柱)或938/CD70(黑柱)、或RCC靶细胞RCC 2245R(正斜杠柱)、RCC 2246R(反斜杠柱)、RCC 2361R(有横纹的柱)或者RCC 1764(人字纹柱)共培养时,分泌的IFN-γ(pg/ml)的图。
图5是显示在单独培养(培养基)未转导的(UT)细胞或者转导有ΔCD27-4-1BB–CD3ζ(SEQ ID NO:9)的逆转录病毒包装克隆A2、B11、C5或D2(竖纹柱)时;或者与对照靶细胞SNU1079(点状柱)、SNU1196(白柱)、938mel(方格柱)或938/CD70(黑柱)、或RCC靶细胞RCC2245R(正斜杠柱)、RCC 2246R(反斜杠柱)、RCC 2361R(有横纹的柱)或者RCC 1764(人字纹柱)共培养时,分泌的IFN-γ(pg/ml)的图。
发明详述
本发明的实施方案提供具有针对CD70的抗原特异性的嵌合抗原受体(CAR),所述CAR包含:抗原结合-跨膜结构域,其含有缺乏CD27胞内T细胞信号转导结构域的全部或部分的CD27氨基酸序列,其中所述部分为SEQ ID NO:2所限定的至少氨基酸残基237至260;4-1BB胞内T细胞信号转导结构域;CD3ζ胞内T细胞信号转导结构域;以及任选地,CD28胞内T细胞信号转导结构域。在下文中,提及“CAR”,也指CAR的功能部分和功能变体,除非另外指明。
CAR是人工构建的杂合蛋白或多肽,其含有与T细胞信号转导结构域相连的受体(例如,肿瘤坏死因子(TNF)受体)的抗原结合结构域。CAR的特征包括它们利用受体的抗原结合特性,使T细胞的特异性和反应性以不限于主要组织相容性复合体(MHC)的方式重定向至选定靶标的能力。不限于MHC的抗原识别赋予表达CAR的T细胞不依赖于抗原加工而识别抗原的能力,从而绕过肿瘤逃逸的主要机制。此外,当在T细胞中表达时,CAR有利地不与内源T细胞受体(TCR)α和β链二聚化。
本文使用的短语“具有抗原特异性”和“引发抗原特异性应答”意为,CAR能够特异性结合并免疫识别抗原,以使CAR与抗原的结合引发免疫应答。
本发明的CAR具有针对CD70的抗原特异性。CD70属于TNF超家族,并具有SEQ IDNO:1的氨基酸序列。当CD70与其受体CD27相互作用时,其是参与淋巴来源的细胞的增殖和存活的共刺激分子。CD70的正常、非癌表达限于淋巴组织,如激活的T细胞、B细胞、自然杀伤细胞(NK)、单核细胞和树突细胞。CD70在多种人类癌症中表达,如例如RCC(Diegmann等人,Eur.J.Cancer,41:1794-801(2005))(例如透明细胞RCC(ccRCC))、胶质母细胞瘤(Held-Feindt等人,Int.J.Cancer,98:352-56(2002);Wischhusen等人,Cancer Res.,62:2592-99(2002))、NHL和CLL(Lens等人,Br.J.Haematol.,106:491-503(1999))、弥漫性大B细胞淋巴瘤以及滤泡性淋巴瘤。
不受特定理论或机制的束缚,据信通过引发针对CD70的抗原特异性应答,本发明的CAR提供任何下述的一种或多种:靶向并破坏表达CD70的癌细胞,减少或清除癌细胞,促进免疫细胞至肿瘤部位的浸润,以及增强/扩展抗癌应答。由于正常的CD70表达限于诸如激活的T细胞、B细胞、NK细胞、单核细胞和树突细胞的淋巴组织,考虑本发明的CAR有利地大幅避免了靶向/破坏多种正常组织。
本发明的实施方案提供了CAR,其包含含有CD27氨基酸序列的抗原结合-跨膜结构域。就这点而言,CAR可以既包含CD27抗原结合结构域又包含CD27跨膜结构域。CD27可以包含任何合适的人抗原结合-跨膜结构域CD27氨基酸序列或者由其组成。在本发明的实施方案中,包含抗原结合结构域、跨膜结构域和胞内T细胞信号转导结构域的全长CD27具有SEQID NO:2的氨基酸序列。在本发明的实施方案中,CD27的抗原结合结构域由SEQ ID NO:2的氨基酸残基1-188组成,并具有SEQ ID NO:21的氨基酸序列,CD27的跨膜结构域由SEQ IDNO:2的氨基酸残基189-211组成,并具有SEQ ID NO:22的氨基酸序列,以及CD27的胞内T细胞信号转导结构域由SEQ ID NO:2的氨基酸残基212-260组成,并具有SEQ ID NO:23的氨基酸序列。因此,在本发明的实施方案中,CAR包含含有SEQ ID NO:21和22的氨基酸序列的抗原结合-跨膜结构域。CD27的抗原结合结构域特异性结合CD70。
本发明的实施方案提供包含抗原结合-跨膜结构域的CAR,所述抗原结合-跨膜结构域包含缺乏CD27胞内T细胞信号转导结构域的全部或部分的CD27氨基酸序列,其中CAR缺乏的所述部分为SEQ ID NO:2所限定的至少连续氨基酸残基237至260,至少连续氨基酸残基236至260,至少连续氨基酸残基235至260,至少连续氨基酸残基234至260,至少连续氨基酸残基233至260,至少连续氨基酸残基232至260,至少连续氨基酸残基231至260,至少连续氨基酸残基230至260,至少连续氨基酸残基229至260,至少连续氨基酸残基228至260,至少连续氨基酸残基227至260,至少连续氨基酸残基226至260,至少连续氨基酸残基225至260,至少连续氨基酸残基224至260,至少连续氨基酸残基223至260,至少连续氨基酸残基222至260,至少连续氨基酸残基221至260,至少连续氨基酸残基220至260,至少连续氨基酸残基219至260,至少连续氨基酸残基218至260,至少连续氨基酸残基217至260,至少连续氨基酸残基216至260,至少连续氨基酸残基215至260,至少连续氨基酸残基214至260或者至少连续氨基酸残基213至260。在本发明的实施方案中,抗原结合-跨膜结构域包含缺乏SEQ IDNO:2的连续氨基酸残基237至260,连续氨基酸残基236至260,连续氨基酸残基235至260,连续氨基酸残基234至260,连续氨基酸残基233至260,连续氨基酸残基232至260,连续氨基酸残基231至260,连续氨基酸残基230至260,连续氨基酸残基229至260,连续氨基酸残基228至260,连续氨基酸残基227至260,连续氨基酸残基226至260,连续氨基酸残基225至260,连续氨基酸残基224至260,连续氨基酸残基223至260,连续氨基酸残基222至260,连续氨基酸残基221至260,连续氨基酸残基220至260,连续氨基酸残基219至260,连续氨基酸残基218至260,连续氨基酸残基217至260,连续氨基酸残基216至260,连续氨基酸残基215至260,连续氨基酸残基214至260或者连续氨基酸残基213至260的CD27氨基酸序列。缺乏CD27胞内T细胞信号转导结构域的全部或部分的CD27氨基酸序列在本文也被称为“截短的CD27氨基酸序列”或“截短的CD27”。
在优选实施方案中,抗原结合-跨膜结构域包含缺乏CD27胞内T细胞信号转导结构域的全部的CD27氨基酸序列。就这点而言,抗原结合-跨膜结构域包含缺乏SEQ ID NO:2所限定的连续氨基酸残基212至260的CD27氨基酸序列或者缺乏SEQ ID NO:2的连续氨基酸残基212至260的CD27氨基酸序列。在本发明的实施方案中,抗原结合-跨膜结构域包含缺乏SEQ ID NO:23的氨基酸序列的CD27氨基酸序列。在本发明的实施方案中,包含缺乏CD27胞内T细胞信号转导结构域的全部的CD27氨基酸序列的抗原结合-跨膜结构域,包含与SEQ IDNO:3至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列或者由与SEQ ID NO:3至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成,或者包含SEQ IDNO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成。
CAR还可以包含4-1BB胞内T细胞信号转导结构域;CD3ζ胞内T细胞信号转导结构域;以及任选地,CD28胞内T细胞信号转导结构域。在本发明的实施方案中,CAR包含4-1BB胞内T细胞信号转导结构域、CD3ζ胞内T细胞信号转导结构域和CD28胞内T细胞信号转导结构域。在本发明的另一实施方案中,CAR包含4-1BB胞内T细胞信号转导结构域和CD3ζ胞内T细胞信号转导结构域。在优选实施方案中,4-1BB、CD3ζ和CD28胞内T细胞信号转导结构域是人的。CD28是T细胞共刺激中重要的T细胞标志物。4-1BB也被称为CD137,其向T细胞传输强有力的共刺激信号,促进了T淋巴细胞的分化并增强了T淋巴细胞的长期存活。CD3ζ与TCR联合以产生信号,并且其包含免疫受体酪氨酸激活基序(ITAM)。
CD3ζ胞内T细胞信号转导结构域可以包含任何合适的人CD3ζ胞内T细胞信号转导结构域氨基酸序列或者由其组成。在本发明的实施方案中,CD3ζ胞内T细胞信号转导结构域包含与SEQ ID NO:4至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列或者由与SEQ ID NO:4至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,CD3ζ胞内T细胞信号转导结构域包含SEQ ID NO:4的氨基酸序列或者由其组成。
4-1BB胞内T细胞信号转导结构域可以包含任何合适的人4-1BB胞内T细胞信号转导结构域氨基酸序列或者由其组成。在本发明的实施方案中,4-1BB胞内T细胞信号转导结构域包含与SEQ ID NO:5至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列或者由与SEQ ID NO:5至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,4-1BB胞内T细胞信号转导结构域包含SEQ ID NO:5的氨基酸序列或者由其组成。
CD28胞内T细胞信号转导结构域可以包含任何合适的人CD28胞内T细胞信号转导结构域氨基酸序列或者由其组成。在本发明的实施方案中,CD28胞内T细胞信号转导结构域包含与SEQ ID NO:6至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列或者由与SEQ ID NO:6至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,CD28胞内T细胞信号转导结构域包含SEQ ID NO:6的氨基酸序列或者由其组成。
在本发明的实施方案中,CAR包含与CD3ζ胞内T细胞信号转导结构域组合的全长CD27氨基酸序列(全长(f)CD27-CD3ζCAR),所述全长CD27氨基酸序列含有CD27抗原结合结构域、CD27跨膜结构域和CD27胞内T细胞信号转导结构域。就这点而言,CAR可以包含与SEQID NO:2至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的全长CD27氨基酸序列和本文就本发明其它方面所描述的任何CD3ζ氨基酸序列,或者由与SEQ ID NO:2至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的全长CD27氨基酸序列和本文就本发明其它方面所描述的任何CD3ζ氨基酸序列组成。例如,fCD27-CD3ζCAR可以包含SEQ ID NO:2的全长CD27氨基酸序列和SEQ ID NO:4的CD3ζ氨基酸序列,或者由SEQ ID NO:2的全长CD27氨基酸序列组成。在本发明的实施方案中,fCD27-CD3ζCAR可以包含与SEQ ID NO:7至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列或者由与SEQID NO:7至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,fCD27-CD3ζCAR包含SEQ ID NO:7的氨基酸序列或者由其组成。在本发明的实施方案中,fCD27-CD3ζCAR缺乏截短的CD19和DsRed之一或两者。
在本发明的实施方案中,CAR包含与CD3ζ胞内T细胞信号转导结构域和CD28胞内T细胞信号转导结构域组合的全长CD27氨基酸序列(fCD27-CD28-CD3ζ),所述全长CD27氨基酸序列含有CD27抗原结合结构域、CD27跨膜结构域和CD27胞内T细胞信号转导结构域。就这点而言,CAR可以包含本文就本发明其它方面所描述的任何全长CD27氨基酸序列、任何CD3ζ氨基酸序列和任何CD28氨基酸序列,或者由本文就本发明其它方面所描述的任何全长CD27氨基酸序列、任何CD3ζ氨基酸序列和任何CD28氨基酸序列组成。例如,fCD27-CD28-CD3ζCAR可以包含SEQ ID NO:2的全长CD27氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列和SEQ IDNO:6的CD28氨基酸序列,或者由SEQ ID NO:2的全长CD27氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列和SEQ ID NO:6的CD28氨基酸序列组成。在本发明的实施方案中,fCD27-CD28-CD3ζCAR可以包含与SEQ ID NO:11至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列,或者由与SEQ ID NO:11至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,fCD27-CD28-CD3ζCAR包含SEQ ID NO:11的氨基酸序列或者由其组成。
在本发明的实施方案中,CAR包含与CD3ζ胞内T细胞信号转导结构域和4-1BB胞内T细胞信号转导结构域组合的全长CD27氨基酸序列(fCD27-4-1BB-CD3ζ),所述全长CD27氨基酸序列含有CD27抗原结合结构域、CD27跨膜结构域和CD27胞内T细胞信号转导结构域。就这点而言,CAR可以包含本文就本发明其它方面所描述的任何全长CD27氨基酸序列、任何CD3ζ氨基酸序列和任何4-1BB氨基酸序列,或者由本文就本发明其它方面所描述的任何全长CD27氨基酸序列、任何CD3ζ氨基酸序列和任何4-1BB氨基酸序列组成。例如,fCD27-4-1BB-CD3ζCAR可以包含SEQ ID NO:2的全长CD27氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列和SEQ ID NO:5的4-1BB氨基酸序列,或者由SEQ ID NO:2的全长CD27氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列和SEQ ID NO:5的4-1BB氨基酸序列组成。在本发明的实施方案中,fCD27-4-1BB-CD3ζCAR可以包含与SEQ ID NO:12至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列,或者由与SEQ ID NO:12至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,fCD27-4-1BB-CD3ζCAR包含SEQ ID NO:12的氨基酸序列或者由其组成。
在本发明的实施方案中,CAR包含与CD3ζ胞内T细胞信号转导结构域、4-1BB胞内T细胞信号转导结构域和CD28胞内信号转导结构域组合的全长CD27氨基酸序列(fCD27-CD28-4-1BB-CD3ζ),所述全长CD27氨基酸序列含有CD27抗原结合结构域、CD27跨膜结构域和CD27胞内T细胞信号转导结构域。就这点而言,CAR可以包含本文就本发明其它方面所描述的任何全长CD27氨基酸序列、任何CD3ζ氨基酸序列、任何4-1BB氨基酸序列以及任何CD28氨基酸序列,或者由本文就本发明其它方面所描述的任何全长CD27氨基酸序列、任何CD3ζ氨基酸序列、任何4-1BB氨基酸序列以及任何CD28氨基酸序列组成。例如,fCD27-CD28-4-1BB-CD3ζCAR可以包含SEQ ID NO:2的全长CD27氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列、SEQ ID NO:5的4-1BB氨基酸序列和SEQ ID NO:6的CD28氨基酸序列,或者由SEQ ID NO:2的全长CD27氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列、SEQ ID NO:5的4-1BB氨基酸序列和SEQ ID NO:6的CD28氨基酸序列组成。在本发明的实施方案中,fCD27-CD28-4-1BB-CD3ζCAR可以包含与SEQ ID NO:13至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列,或者由与SEQ ID NO:13至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,fCD27-CD28-4-1BB-CD3ζCAR包含SEQ ID NO:13的氨基酸序列或者由其组成。
在本发明的实施方案中,CAR包含与小鼠CD3ζ胞内T细胞信号转导结构域组合的全长小鼠CD27氨基酸序列(mCD27-CD3ζ),所述全长小鼠CD27氨基酸序列含有CD27抗原结合结构域、CD27跨膜结构域和CD27胞内T细胞信号转导结构域。就这点而言,CAR可以包含与小鼠CD3ζ氨基酸序列组合的全长小鼠CD27氨基酸序列,或者由与小鼠CD3ζ氨基酸序列组合的全长小鼠CD27氨基酸序列组成,所述全长小鼠CD27氨基酸序列与SEQ ID NO:26至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同,所述小鼠CD3ζ氨基酸序列与SEQ ID NO:27至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同。例如,mCD27-CD3ζCAR可以包含SEQ ID NO:26的全长小鼠CD27氨基酸序列和SEQ ID NO:27的小鼠CD3ζ氨基酸序列,或者由SEQ ID NO:26的全长小鼠CD27氨基酸序列和SEQ ID NO:27的小鼠CD3ζ氨基酸序列组成。在本发明的实施方案中,mCD27-CD3ζCAR可以包含与SEQ ID NO:25至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列,或者由与SEQ ID NO:25至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,mCD27-CD3ζCAR包含SEQ ID NO:25的氨基酸序列或者由其组成。
在本发明的实施方案中,CAR包含与CD3ζ胞内T细胞信号转导结构域和CD28胞内T细胞信号转导结构域组合的,包含截短的CD27氨基酸序列的抗原结合-跨膜结构域(截短的(Δ)CD27-CD28–CD3ζ),所述截短的CD27氨基酸序列缺乏CD27胞内T细胞信号转导结构域的全部。就这点而言,CAR可以包含与本文就本发明其它方面所描述的任何CD3ζ胞内T细胞信号转导结构域氨基酸序列和任何CD28胞内T细胞信号转导结构域氨基酸序列组合的截短的CD27抗原结合-跨膜结构域氨基酸序列,或者由与本文就本发明其它方面所描述的任何CD3ζ胞内T细胞信号转导结构域氨基酸序列和任何CD28胞内T细胞信号转导结构域氨基酸序列组合的截短的CD27抗原结合-跨膜结构域氨基酸序列组成,所述截短的CD27抗原结合-跨膜结构域氨基酸序列与SEQ ID NO:3至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同。例如,ΔCD27-CD28–CD3ζCAR可以包含,SEQ ID NO:3的截短的CD27抗原结合-跨膜结构域氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列和SEQ IDNO:6的CD28氨基酸序列,或者由SEQ ID NO:3的截短的CD27抗原结合-跨膜结构域氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列和SEQ ID NO:6的CD28氨基酸序列组成。在本发明的实施方案中,ΔCD27-CD28–CD3ζCAR可以包含与SEQ ID NO:8至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列,或者由与SEQID NO:8至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,ΔCD27-CD28–CD3ζCAR包含SEQ ID NO:8的氨基酸序列或者由其组成。
在本发明的实施方案中,CAR包含与CD3ζ胞内T细胞信号转导结构域和4-1BB胞内T细胞信号转导结构域组合的,包含截短的CD27氨基酸序列的抗原结合-跨膜结构域(ΔCD27-4-1BB–CD3ζ),所述截短的CD27氨基酸序列缺乏CD27胞内T细胞信号转导结构域的全部。就这点而言,CAR可以包含本文就本发明其它方面所描述的任何截短的CD27抗原结合-跨膜结构域氨基酸序列、任何CD3ζ胞内T细胞信号转导结构域氨基酸序列和任何4-1BB胞内T细胞信号转导结构域氨基酸序列,或者由本文就本发明其它方面所描述的任何截短的CD27抗原结合-跨膜结构域氨基酸序列、任何CD3ζ胞内T细胞信号转导结构域氨基酸序列和任何4-1BB胞内T细胞信号转导结构域氨基酸序列组成。例如,ΔCD27-4-1BB–CD3ζCAR可以包含SEQ ID NO:3的截短的CD27抗原结合-跨膜结构域氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列和SEQ ID NO:5的4-1BB氨基酸序列,或者由SEQ ID NO:3的截短的CD27抗原结合-跨膜结构域氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列和SEQ ID NO:5的4-1BB氨基酸序列组成。在本发明的实施方案中,ΔCD27-4-1BB–CD3ζCAR可以包含与SEQ ID NO:9至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列,或者由与SEQ ID NO:9至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,ΔCD27-4-1BB–CD3ζCAR包含SEQ ID NO:9的氨基酸序列或者由其组成。
在本发明的实施方案中,CAR包含与CD3ζ胞内T细胞信号转导结构域、CD28胞内T细胞信号转导结构域和4-1BB胞内T细胞信号转导结构域组合的,包含截短的CD27氨基酸序列的抗原结合-跨膜结构域(ΔCD27-CD28–4-1BB–CD3ζ),所述截短的CD27氨基酸序列缺乏CD27胞内T细胞信号转导结构域的全部。就这点而言,CAR可以包含本文就本发明其它方面所描述的任何截短的CD27抗原结合-跨膜结构域氨基酸序列、任何CD3ζ胞内T细胞信号转导结构域氨基酸序列、任何CD28胞内T细胞信号转导结构域氨基酸序列以及任何4-1BB胞内T细胞信号转导结构域氨基酸序列,或者由本文就本发明其它方面所描述的任何截短的CD27抗原结合-跨膜结构域氨基酸序列、任何CD3ζ胞内T细胞信号转导结构域氨基酸序列、任何CD28胞内T细胞信号转导结构域氨基酸序列以及任何4-1BB胞内T细胞信号转导结构域氨基酸序列组成。例如,ΔCD27-CD28–4-1BB–CD3ζCAR可以包含SEQ ID NO:3的截短的CD27抗原结合-跨膜结构域氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列、SEQ ID NO:6的CD28氨基酸序列以及SEQ ID NO:5的4-1BB氨基酸序列,或者由SEQ ID NO:3的截短的CD27抗原结合-跨膜结构域氨基酸序列、SEQ ID NO:4的CD3ζ氨基酸序列、SEQ ID NO:6的CD28氨基酸序列以及SEQ ID NO:5的4-1BB氨基酸序列组成。在本发明的实施方案中,ΔCD27-CD28–4-1BB–CD3ζCAR可以包含与SEQ ID NO:10至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列,或者由与SEQ ID NO:10至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的氨基酸序列组成。优选地,ΔCD27-CD28–4-1BB–CD3ζCAR包含SEQ ID NO:10的氨基酸序列或者由其组成。
在本发明的实施方案中,CAR包含与SEQ ID NO:8-10中任一项至少约90%相同的氨基酸序列。在本发明的实施方案中,CAR包含与SEQ ID NO:9或10至少约90%相同的氨基酸序列。在本发明的另一实施方案中,CAR包含与SEQ ID NO:11-13中任一项至少约90%相同的氨基酸序列。在本发明的另一实施方案中,CAR包含与SEQ ID NO:12或13至少约90%相同的氨基酸序列。优选地,CAR包含表1A所示的任一氨基酸序列,由表1A所示的任一氨基酸序列组成,或者基本由表1A所示的任一氨基酸序列组成。在本发明的优选实施方案,CAR包含SEQ ID NO:7-13中任一项的氨基酸序列。优选地,CAR包含SEQ ID NO:9、10、12和13中任一项的氨基酸序列。
表1A
本发明的范围包括本文所述的本发明的CAR的功能部分。当提及CAR使用时,术语“功能部分”指本发明的CAR的任何部分或片段,所述部分或片段保留所述部分或片段所来源的CAR(亲本CAR)的生物活性。功能部分涵盖,例如保留与亲本CAR相似程度、相同程度或者比亲本CAR更高程度地识别靶细胞或者检测、治疗或预防癌症的能力的CAR的那些部分。提及亲本CAR,功能部分可以包含例如亲本CAR的约10%、约25%、约30%、约50%、约68%、约80%、约90%、约95%或更多。
功能部分在所述部分的氨基端或羧基端或这两端可以包含其它氨基酸,所述其它氨基酸在亲本CAR的氨基酸序列中不存在。可取地,所述其它氨基酸不干扰功能部分诸如识别靶细胞、检测癌症、治疗或预防癌症等的生物功能。更可取地,与亲本CAR的生物活性相比,所述其它氨基酸增强了生物活性。
本发明的范围包括本文所述的本发明的CAR的功能变体。本文使用的术语“功能变体”指与亲本CAR具有大量的或显著的序列同一性或相似性的CAR、多肽或蛋白,所述功能变体保留了该变体所来源的CAR的生物活性。功能变体涵盖,例如保留与亲本CAR相似程度、相同程度或比亲本CAR更高程度地识别靶细胞的能力的本文所述CAR(亲本CAR)的那些变体。提及亲本CAR,功能变体可以,例如与亲本CAR在氨基酸序列方面至少约30%、约50%、约75%、约80%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%相同或者更加相同。
功能变体可以,例如包含具有至少一个保守氨基酸置换的亲本CAR的氨基酸序列。可选地或另外,功能变体可以包含具有至少一个非保守氨基酸置换的亲本CAR的氨基酸序列。在这种情况下,非保守氨基酸置换优选不干扰或抑制功能变体的生物活性。非保守氨基酸置换可以增强功能变体的生物活性,以使与亲本CAR相比,功能变体的生物活性增加。
本发明的CAR的氨基酸置换优选保守氨基酸置换。保守氨基酸置换在本领域是已知的,并且包含这样的氨基酸置换,其中具有某些物理和/或化学特性的一个氨基酸被换成具有相同或相似化学或物理特性的另一氨基酸。例如,保守氨基酸置换可以是酸性/带负电荷的极性氨基酸被另一酸性/带负电荷的极性氨基酸(例如Asp或Glu)置换,具有非极性侧链的氨基酸被另一具有非极性侧链的氨基酸(例如Ala、Gly、Val、Ile、Leu、Met、Phe、Pro、Trp、Cys、Val等)置换,碱性/带正电荷的极性氨基酸被另一碱性/带正电荷的极性氨基酸(例如Lys、His、Arg等)置换,具有极性侧链的不带电荷的氨基酸被另一具有极性侧链的不带电荷的氨基酸(例如Asn、Gln、Ser、Thr、Tyr等)置换,具有β分支侧链的氨基酸被另一具有β分支侧链的氨基酸(例如Ile、Thr和Val)置换,具有芳香族侧链的氨基酸被另一具有芳香族侧链的氨基酸(例如His、Phe、Trp和Tyr)置换等。
CAR可以基本由指定的氨基酸序列或者本文所述的序列组成,以使其它成分(例如其它氨基酸)不实质性改变功能变体的生物活性。
本发明的实施方案的CAR可以是任何长度,即可以包含任何数目的氨基酸,条件是所述CAR保留它们的生物活性,例如特异性结合抗原、检测哺乳动物中的癌细胞或者治疗或预防哺乳动物中的癌症等的能力。例如,CAR的长度可以是约50至约5000个氨基酸,如50、70、75、100、125、150、175、200、300、400、500、600、700、800、900、1000或更多个氨基酸。
本发明的实施方案的CAR可以包含合成的氨基酸代替一个或多个天然存在的氨基酸。此类合成的氨基酸在本领域是已知的,并且包括例如,氨基环己羧酸、正亮氨酸、α-氨基n-癸酸、高丝氨酸、S-乙酰氨甲基-半胱氨酸、反式-3-和反式-4-羟脯氨酸、4-氨基苯丙氨酸、4-硝基苯丙氨酸、4-氯苯丙氨酸、4-羧基苯丙氨酸、β-苯基丝氨酸β-羟基苯丙氨酸、苯基甘氨酸、α-萘基丙氨酸、环己基丙氨酸、环己基甘氨酸、吲哚啉-2-羧酸、1,2,3,4-四氢异喹啉-3-羧酸、氨基丙二酸、氨基丙二酸单酰胺、N’-苯甲基-N’-甲基-赖氨酸、N’,N’-二苄基-赖氨酸、6-羟赖氨酸、鸟氨酸、α-氨基环戊烷羧酸、α-氨基环己羧酸、α-氨基环庚烷羧酸、α-(2-氨基-2-降莰烷)-羧酸、α,γ-二氨基丁酸、α,β-二氨基丙酸、高苯丙氨酸以及α-叔-丁基甘氨酸。
本发明的实施方案的CAR可被糖基化、酰胺化、羧酸化、磷酸化、酯化、N-酰化、经例如二硫键环化,或者转变为酸加成盐和/或任选地二聚化或多聚化或缀合。
本发明的实施方案的CAR可以通过本领域已知的方法获得,如例如从头合成。另外,可以利用标准重组方法,利用本文所述的核酸重组产生多肽和蛋白。参见,例如Green和Sambrook,Molecular Cloning:ALaboratory Manual,第4版,Cold Spring Harbor Press,Cold Spring Harbor,NY(2012)。可选地,本文所述的CAR可以通过公司商业合成,如Synpep(Dublin,CA)、Peptide Technologies Corp.(Gaithersburg,MD)以及Multiple PeptideSystems(San Diego,CA)。在这方面,本发明的CAR可以是合成的、重组的、分离的和/或纯化的。
本发明的实施方案还提供了包含编码本文所述的任何CAR的核苷酸序列的核酸。本发明的核酸可以包含编码本文所述的任何抗原结合结构域、跨膜结构域和/或胞内T细胞信号转导结构域的核苷酸序列。在本发明的实施方案中,核酸包含表1B所示的任一核苷酸序列,或者由表1B所示的任一核苷酸序列组成,或者基本由表1B所示的任一核苷酸序列组成。优选地,核酸包含SEQ ID NO:14-20中任一项的核苷酸序列。优选地,核酸包含SEQ IDNO:16、17、19和20中任一项的核苷酸序列。在本发明的实施方案中,编码fCD27-CD3ζCAR的核苷酸序列不编码截短的CD19和DsRed之一或两者。
表1B
本文使用的“核酸”包括“多核苷酸”、“寡核苷酸”和“核酸分子”,并且通常意为DNA或RNA的聚合物,其可以是单链或双链,合成的或从天然来源获得的(例如分离的和/或纯化的),其可以包含天然的、非天然的或改变的核苷酸,并且其可以包含天然的、非天然的或改变的核苷酸间连键,如氨基磷酸酯键或硫代磷酸酯键,替代存在于未修饰的寡核苷酸的核苷酸之间的磷酸二酯。在一些实施方案中,核酸不包含任何插入、缺失、倒位和/或置换。然而,如本文所讨论的,在一些情况下核酸包含一个或多个插入、缺失、倒位和/或置换可能是合适的。在一些实施方案中,核酸可以编码这样的其它氨基酸序列:其不影响CAR的功能,并且其在宿主细胞表达核酸时可能被翻译或者可能不被翻译。
本发明的实施方案的核酸可以是重组体。本文使用的术语“重组体”指(i)通过将天然的或合成的核酸区段与可在活细胞中复制的核酸分子连接而在活细胞外构建的分子,或者(ii)由以上(i)中所述的那些分子的复制而产生的分子。出于本文的目的,复制可以是体外复制或体内复制。
重组核酸可以是具有非天然存在的序列或者具有通过序列的两个原本分离的区段的人工组合而制备的序列的一种核酸。该人工组合通常通过化学合成来完成,或者更通常通过人工操纵分离的核酸区段来完成,例如通过诸如以上的Green和Sambrook中所述的那些技术的基因工程技术来完成。可以利用本领域已知的程序,基于化学合成和/或酶连接反应构建核酸。参见,例如以上的Green和Sambrook。例如,可以利用天然存在的核苷酸或者设计以增加分子的生物稳定性或者增加杂交时所形成的双链体的物理稳定性的不同修饰的核苷酸(例如硫代磷酸酯衍生物和吖啶取代的核苷酸)来化学合成核酸。可用于产生核酸的修饰的核苷酸的实例包括但不限于:5-氟尿嘧啶、5-溴尿嘧啶、5-氯尿嘧啶、5-碘尿嘧啶、次黄嘌呤、黄嘌呤、4-乙酰胞嘧啶、5-(羧基羟甲基)尿嘧啶、5-羧基甲基氨基甲基-2-硫脲苷、5-羧基甲基氨基甲基尿嘧啶、二氢尿嘧啶、β-D半乳糖基Q核苷(beta-D-galactosylqueosine)、肌酐、N6-异戊烯腺嘌呤、1-甲基鸟嘌呤、1-甲基肌苷、2,2-二甲基鸟嘌呤、2-甲基腺嘌呤、2-甲基鸟嘌呤、3-甲基胞嘧啶、5-甲基胞嘧啶、N6-取代的腺嘌呤、7-甲基鸟嘌呤、5-甲基氨基甲基尿嘧啶、5-甲氧基氨基甲基-2-硫脲嘧啶、β-D-甘露糖基Q核苷(beta-D-mannosylqueosine)、5'-甲氧基羧甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N6-异戊烯腺嘌呤、尿嘧啶-5-羟乙酸(v)、怀丁苷(wybutoxosine)、假尿嘧啶、Q核苷(queosine)、2-巯基胞嘧啶、5-甲基-2-硫脲嘧啶、2-硫脲嘧啶、4-硫脲嘧啶、5-甲基尿嘧啶、尿嘧啶-5-羟乙酸甲酯、3-(3-氨基-3-N-2-羧丙基)尿嘧啶以及2,6-二氨基嘌呤。可选地,本发明的核酸中的一种或多种可购自诸如Macromolecular Resources(Fort Collins,CO)和Synthegen(Houston,TX)的公司。
核酸可以包含编码本文就本发明其它方面所描述的任何CAR的任何分离或纯化的核苷酸序列。可选地,核苷酸序列可以包含任何序列简并的核苷酸序列或者简并序列的组合。
本发明的实施方案还提供分离或纯化的核酸,其含有与本文所述的任何核酸的核苷酸序列互补的核苷酸序列或者含有在严紧条件下与本文所述的任何核酸的核苷酸序列杂交的核苷酸序列。
在严紧条件下杂交的核苷酸序列可以在高度严紧条件下杂交。“高度严紧条件”意为核苷酸序列以可检测地比非特异性杂交更强的量与靶序列(本文所述的任何核酸的核苷酸序列)特异性杂交。高度严紧条件包括将含有准确互补序列的多核苷酸或者仅含有数个分散的错配的多核苷酸与恰巧具有匹配核苷酸序列的数个小的区域(例如3-10个碱基)的随机序列区分开的条件。此类小的互补区域比14-17个或者更多个碱基的全长互补体更易熔化,并且高度严紧杂交使其易于区分。相对高度严紧的条件将包括,例如低盐和/或高温条件,如由约0.02-0.1M NaCl或等同物,在约50-70℃的温度下所提供的条件。此类高度严紧条件容忍极少(如果存在)核苷酸序列与模板或靶标链之间的错配,并且特别适合于检测任何本发明的CAR的表达。普遍认为通过添加增加量的甲酰胺可以导致更严紧的条件。
本发明还提供这样的核酸,其包含与本文所述的任何核酸至少约70%或者更多,例如约80%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%相同的核苷酸序列。
在实施方案中,可将本发明的核酸并入重组表达载体。就这点而言,本发明的实施方案提供包含本发明的任何核酸的重组表达载体。出于本文的目的,术语“重组表达载体”意为遗传修饰的寡核苷酸或多核苷酸构建体,当构建体包含编码mRNA、蛋白、多肽或肽的核苷酸序列,并且在足以使mRNA、蛋白、多肽或肽在细胞内表达的条件下将载体与细胞接触时,其允许由宿主细胞表达mRNA、蛋白、多肽或肽。本发明的载体作为整体不是天然存在的。然而,载体的部分可以是天然存在的。本发明的重组表达载体可以包含任何类型的核苷酸,包括但不限于DNA和RNA,其可以是单链的或双链的,合成的或者部分由天然来源获得的,并且其可以含有天然的、非天然的或改变的核苷酸。重组表达载体可以包含天然存在的或非天然存在的核苷酸间连键或者两种类型的连键。优选地,非天然存在的或改变的核苷酸或核苷酸间连键不妨碍载体的转录或复制。在本发明的实施方案中,包含编码fCD27-CD3ζCAR的核苷酸序列的重组表达载体不编码截短的CD19和DsRed之一或两者。
在实施方案中,本发明的重组表达载体可以是任何合适的重组表达载体,并且可被用于转化或转染任何合适的宿主细胞。合适的载体包括设计以用于增殖和扩增或者用于表达或者用于这两种的那些载体,如质粒和病毒。载体可以选自:pUC系列(Fermentas LifeSciences,Glen Burnie,MD)、pBluescript系列(Stratagene,LaJolla,CA)、pET系列(Novagen,Madison,WI)、pGEX系列(Pharmacia Biotech,Uppsala,Sweden)以及pEX系列(Clontech,Palo Alto,CA)。也可使用诸如λGT10、λGT11、λZapII(Stratagene)、λEMBL4和λNM1149的噬菌体载体。植物表达载体的实例包括pBI01、pBI101.2、pBI101.3、pBI121和pBIN19(Clontech)。动物表达载体的实例包括pEUK-Cl、pMAM和pMAMneo(Clontech)。重组表达载体可以是病毒载体,例如逆转录病毒载体或慢病毒载体。在一些实施方案中,载体可以是转座子。
在实施方案中,可以利用例如以上Green和Sambrook中所述的标准重组DNA技术来制备本发明的重组表达载体。可将环状或线性表达载体的构建体制备为含有在原核或真核宿主细胞中发挥功能的复制系统。复制系统可以来源于,例如ColEl、2μ质粒、λ、SV40、牛乳头瘤病毒等。
重组表达载体可以包含调控序列,如转录和翻译起始和终止密码子,视情况而定并且考虑载体是基于DNA的还是基于RNA的,其对于待引入载体的宿主细胞的类型(例如细菌、真菌、植物或动物)具有特异性。重组表达载体可以包含限制位点以促进克隆。
重组表达载体可以包含允许对转化或转染的宿主细胞进行选择的一种或多种标志物基因。标志物基因包括抗微生物剂抗性(例如对抗生素、重金属等的抗性),在营养缺陷型宿主中互补以提供原营养等。用于本发明的表达载体的合适的标志物基因包括,例如新霉素/G418抗性基因、潮霉素抗性基因、组氨醇抗性基因、四环素抗性基因以及氨苄西林抗性基因。
重组表达载体可以包含与以下序列可操作地连接的天然或非天然的启动子:编码CAR的核苷酸序列或者与编码CAR的核苷酸序列互补或杂交的核苷酸序列。启动子的选择,例如强、弱、可诱导的、组织特异性的和发育特异性的,在本领域技术人员的普通技术内。类似地,核苷酸序列与启动子的组合也在本领域技术人员的技术内。启动子可以是非病毒启动子或病毒启动子,例如巨细胞病毒(CMV)启动子、SV40启动子、RSV启动子或鼠干细胞病毒的长末端重复中存在的启动子。
可将本发明的重组表达载体设计为瞬时表达、稳定表达或者设计为这两种。另外,可将重组表达载体制备为组成型表达或诱导型表达。
此外,可将重组表达载体制备为包含自杀基因。本文使用的术语“自杀基因”指引起表达自杀基因的细胞死亡的基因。自杀基因可以是赋予基因在其中表达的细胞针对试剂(例如药物)的敏感性的基因,并且当细胞与所述试剂接触或者暴露于所述试剂时引起细胞死亡。自杀基因在本领域是已知的,并且包括例如单纯疱疹病毒(HSV)胸苷激酶(TK)基因、胞嘧啶脱氨酶、嘌呤核苷磷酸化酶和硝基还原酶。
本发明的实施方案还提供包含本文所述的任何重组表达载体的宿主细胞。本文使用的术语“宿主细胞”指可以含有本发明的重组表达载体的任何类型的细胞。宿主细胞可以是真核细胞,例如植物、动物、真菌或藻类;或者可以是原核细胞,例如细菌或原生动物。宿主细胞可以是培养的细胞或原代细胞,即直接由生物体如人分离到的细胞。宿主细胞可以是贴壁细胞或悬浮细胞,即悬浮生长的细胞。合适的宿主细胞在本领域是已知的,并且包括,例如DH5α大肠杆菌细胞、中国仓鼠卵巢细胞、猴VERO细胞、COS细胞、HEK293细胞等。出于扩增或复制重组表达载体的目的,宿主细胞可以是原核细胞,例如DH5α细胞。出于产生重组CAR的目的,宿主细胞可以是哺乳动物细胞。宿主细胞可以是人细胞。尽管宿主细胞可以是任何类型的细胞、可以来源于任何类型的组织,并且可以处于任何发育阶段,但是宿主细胞可以是外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。宿主细胞可以是T细胞。
出于本文的目的,T细胞可以是任何T细胞,如培养的T细胞,例如原代T细胞;或者是来自培养的T细胞系的T细胞,例如Jurkat、SupT1等;或者是获自哺乳动物的T细胞。如果获自哺乳动物,T细胞可以获自多种来源,包括但不限于血液、骨髓、淋巴结、胸腺或者其它组织或液体。T细胞也可以是富集的或纯化的。T细胞可以是人T细胞。T细胞可以是分离自人的T细胞。T细胞可以是任何类型的T细胞,并且可以处于任何发育阶段,包括但不限于CD4+/CD8+双阳性T细胞、CD4+辅助T细胞(例如Th1和Th2细胞)、CD8+T细胞(例如细胞毒性T细胞)、肿瘤浸润细胞、记忆T细胞、初始T细胞等。T细胞可以是CD8+T细胞或CD4+T细胞。
本发明的实施方案还提供包含至少一种本文所述的宿主细胞的细胞群。细胞群可以是除了至少一种其它细胞外还包含含有所述任何重组表达载体的宿主细胞的异质群,所述其它细胞例如不包含任何重组表达载体的宿主细胞(例如T细胞)或者除了T细胞之外的细胞,例如B细胞、巨噬细胞、嗜中性粒细胞、红细胞、肝细胞、内皮细胞、上皮细胞、肌细胞、脑细胞等。可选地,细胞群可以是基本同质的群体,其中所述群体主要包含含有重组表达载体的宿主细胞(例如基本由含有重组表达载体的宿主细胞组成)。群体也可以是克隆细胞群,其中群体的所有细胞均为含有重组表达载体的单个宿主细胞的克隆,以使群体的所有细胞均包含重组表达载体。在本发明的一个实施方案中,细胞群是包含含有本文所述的重组表达载体的宿主细胞的克隆群体。
在本发明的实施方案中,群体中细胞的数目可以快速扩增。表达CAR的细胞的数目的扩增可以通过如以下中所述的本领域已知的多种方法中的任何方法来完成,例如美国专利8,034,334;美国专利8,383,099;美国专利申请公开号2012/0244133;Dudley等人,J.Immunother.,26:332-42(2003);以及Riddell等人,J.Immunol.Methods,128:189-201(1990)。在实施方案中,通过将T细胞与OKT3抗体、IL-2和饲养PBMC(例如受辐射的同种异体PBMC)一起培养来进行细胞数目的扩增。
在下文中CAR、核酸、重组表达载体和宿主细胞(包括其群体)共同被称作“本发明的CAR材料”,其可以是分离的和/或纯化的。本文使用的术语“分离的”意为已从其天然环境中移出。术语“纯化的”或“分离的”不要求绝对的纯度和分离;而是其意图作为相对术语。因此,例如纯化的(或分离的)宿主细胞制备物是一种这样的制备物,其中宿主细胞比其体内天然环境中的细胞更纯。此类宿主细胞可以,例如通过标准纯化技术产生。在一些实施方案中,将宿主细胞制备物进行纯化,以使宿主细胞代表制备物总细胞含量的至少约50%,,例如至少约70%。例如,纯度可以是至少约50%,可以高于约60%、约70%或约80%,或者可以是约100%。
可将本发明的CAR材料配制为组合物,如药物组合物。就这点而言,本发明的实施方案提供包含任何CAR、核酸、表达载体和宿主细胞(包括其群体)以及药学可接受的载体的药物组合物。含有任何本发明的CAR材料的本发明的药物组合物可以包含多种本发明的CAR材料,例如CAR和核酸,或者两种或更多种不同的CAR。可选地,药物组合物可以包含与其它药学活性剂或药物组合的本发明的CAR材料,所述其它药学活性剂或药物如化疗剂,例如天冬酰胺酶、白消安、卡铂、顺铂、道诺霉素、多柔比星、氟尿嘧啶、吉西他滨、羟基脲、甲氨蝶呤、紫杉酚、利妥昔单抗、长春花碱、长春新碱等。在优选实施方案中,药物组合物包含本发明的宿主细胞或其群体。
优选地,载体是药学可接受的载体。关于药物组合物,载体可以是常规用于所考虑的具体的本发明的CAR材料的那些载体中的任何载体。此类药学可接受的载体对于本领域技术人员而言众所周知,并且公众容易获得。优选地,药学可接受的载体是在使用条件下,无有害副作用或毒性的载体。
载体的选择部分将由具体的本发明的CAR材料以及由用于施用本发明的CAR材料的具体方法决定。因此,存在多种合适的本发明的药物组合物的制剂。合适的制剂可以包括用于口服、肠胃外、皮下、静脉内、肌肉内、动脉内、鞘内或腹膜间施用的那些制剂中的任何制剂。可以利用多种途径来施用本发明的CAR材料,并且在某些情况下,特定途径可以比另一途径提供更直接以及更有效的应答。
优选地,通过注射,例如静脉内注射施用本发明的CAR材料。当本发明的CAR材料是表达本发明的CAR的宿主细胞时,用于注射的细胞的药学可接受的载体可以包括任何等张载体,如例如生理盐水(含约0.90%w/v NaCl的水,含约300mOsm/L NaCl的水,或者每升水约9.0g NaCl)、NORMOSOL R电解质溶液(Abbott,Chicago,IL)、PLASMA-LYTE A(Baxter,Deerfield,IL)、含约5%葡萄糖的水或者乳酸林格氏液。在实施方案中,用人血清白蛋白补充药学可接受的载体。
本发明的CAR材料的剂量也将由可能伴随具体的本发明的CAR材料的施用的任何不良副反应的存在、性质和程度决定。通常,考虑多种因素,如年龄、体重、整体健康、饮食、性别、待施用的本发明的CAR材料、施用途径以及被治疗的癌症的严重性,主治医师将决定用于治疗各个体患者的本发明的CAR材料的剂量。在本发明的CAR材料是细胞群的实施方案中,每次输注施用的细胞的数目可以不同,例如从约1×106至约1×1012个细胞或更多。在某些实施方案中,可以施用少于1×106个细胞。
出于本发明的目的,施用的本发明的CAR材料的量或剂量应当足以在合理的时间框内在对象或动物中产生治疗应答或预防应答。例如,本发明的CAR材料的剂量应当足以在离施用时间约2小时或更长,例如约12至约24或者更多个小时的时间段内结合抗原,或者检测、治疗或预防癌症。在某些实施方案中,时间段甚至可能更长。剂量将由具体的本发明的CAR材料的效力和动物(例如人)的情况以及待治疗的动物(例如人)的体重决定。
出于本发明的目的,可以使用下述分析来确定向哺乳动物施用的起始剂量:其包括例如比较各给予不同剂量的表达本发明的CAR的T细胞的一组哺乳动物中,在向哺乳动物施用给定剂量的此类T细胞时,靶细胞裂解的程度和/或此类T细胞分泌IFN-γ的程度。可以通过本领域已知的方法来分析施用某一剂量时,靶细胞裂解和/或IFN-γ分泌的程度。
本领域普通技术人员将容易地理解,可以以多种方式对本发明的CAR材料进行修饰,以通过修饰增加本发明的CAR材料的治疗或预防效力。例如,可将本发明的CAR材料直接或经接头间接与靶向部分缀合。将化合物,例如本发明的CAR材料与靶向部分缀合的实践在本领域是已知的。
当将本发明的CAR材料与一种或多种其它治疗剂一起施用时,一种或多种其它治疗剂可以共施用至哺乳动物。“共施用”意为在时间上足够接近地施用一种或多种其它治疗剂和本发明的CAR材料,以使本发明的CAR材料可以增强一种或多种其它治疗剂的作用,反之亦然。就这点而言,可以首先施用本发明的CAR材料,之后施用一种或多种其它治疗剂,反之亦然。可选地,可以同时施用本发明的CAR材料和一种或多种其它治疗剂。可与CAR材料共施用的示例性治疗剂是IL-2。据信,IL-2增强本发明的CAR材料的治疗效果。
考虑可将本发明的药物组合物、CAR、核酸、重组表达载体、宿主细胞或细胞群用于治疗或预防哺乳动物中的癌症的方法中。不受特定理论或机制的束缚,本发明的CAR具有生物活性,例如识别抗原(例如CD70)的能力,以使当由细胞表达时,CAR能够介导针对表达CAR特异性抗原(例如CD70)的细胞的免疫应答。就这点而言,本发明的实施方案提供治疗或预防哺乳动物中的癌症的方法,其包括向哺乳动物施用有效治疗或预防哺乳动物中的癌症的量的本发明的CAR、核酸、重组表达载体、宿主细胞、细胞群和/或药物组合物。
本发明的实施方案还包括在施用本发明的CAR材料前,对哺乳动物进行淋巴细胞清除。淋巴细胞清除的实例包括但可能不限于:非骨髓根除性淋巴细胞清除化疗、骨髓根除性淋巴细胞清除化疗、全身辐射等。
出于施用宿主细胞或细胞群的本发明的方法的目的,细胞可以是与哺乳动物同种异体的细胞或是其自体的细胞。优选地,细胞是哺乳动物自体的。
本文提及的哺乳动物可以是任何哺乳动物。本文使用的术语“哺乳动物”指任何哺乳动物,包括但不限于啮齿目的哺乳动物,如小鼠和仓鼠;以及兔形目的哺乳动物,如兔。哺乳动物可以来自食肉目,包括猫科(猫)和犬科(狗)。哺乳动物可以来自偶蹄目,包括牛科(牛)和猪科(猪);或者来自奇蹄目,包括马科(马)。哺乳动物可以来自灵长目、猿(Ceboids)目或猴(Simoids)目(猴),或者来自类人猿目(人和类人猿)。优选地,哺乳动物是人。
关于本发明的方法,癌症可以是任何癌症,包括任何急性淋巴细胞癌、急性髓性白血病、小泡型横纹肌肉瘤、膀胱癌(bladder cancer)(例如膀胱癌(bladder carcinoma))、骨癌、脑癌(例如髓母细胞瘤)、乳腺癌、肛门癌、肛管癌或肛肠癌、眼癌、肝内胆管癌、关节癌、颈癌、胆囊癌或胸膜癌、鼻癌、鼻腔癌或中耳癌、口腔癌、外阴癌、慢性淋巴细胞白血病(CLL)、慢性骨髓癌、结肠癌、食管癌、宫颈癌、纤维肉瘤、胃肠道类癌瘤、头颈癌(例如头颈鳞状细胞癌)、胶质母细胞瘤、何杰金氏淋巴瘤、下咽癌、肾癌(kidney cancer)、喉癌、白血病、液体肿瘤、肝癌、肺癌(例如非小细胞肺癌)、淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、恶性间皮瘤、肥大细胞瘤、黑素瘤、多发性骨髓瘤、鼻咽癌、非霍奇金氏淋巴瘤(NHL)、B-慢性淋巴细胞白血病、毛细胞白血病、急性淋巴细胞白血病(ALL)和伯基特淋巴瘤、卵巢癌、胰腺癌、腹膜癌、网膜癌和肠系膜癌、舌咽癌、前列腺癌、RCC、ccRCC、直肠癌、肾癌(renalcancer)、皮肤癌、小肠癌、软组织癌、实体瘤、胃癌、睾丸癌、甲状腺癌以及输尿管癌。优选地,癌症的特征为CD70的表达。在优选实施方案中,癌症是RCC(例如ccRCC)、胶质母细胞瘤、NHL、CLL、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤中的任何癌症。
本文使用的术语“治疗”和“预防”以及尤其衍生的词语不一定意指100%或完全的治疗或预防。而是,存在本领域普通技术人员认为具有潜在益处或治疗效果的不同程度的治疗或预防。在这方面,本发明的方法可以提供任何量任何水平的哺乳动物中癌症的治疗或预防。此外,本发明的方法提供的治疗或预防可以包括被治疗或预防的疾病(例如癌症)的一种或多种病况或症状的治疗或预防。另外,出于本文的目的,“预防”可以涵盖延迟疾病或其症状或病况的发作。
本发明的另一实施方案提供本发明的CAR、核酸、重组表达载体、宿主细胞、细胞群或药物组合物在哺乳动物中的癌症的治疗或预防中的用途。
本发明的另一实施方案提供检测哺乳动物中癌症的存在的方法,其包括:(a)使包含来自所述哺乳动物的一种或多种细胞的样本与本发明的CAR、核酸、重组表达载体、宿主细胞或细胞群接触,从而形成复合物,(b)以及检测复合物,其中检测到复合物指示哺乳动物中癌症的存在。
样本可以通过任何合适的方法获得,例如活检或尸检。活检是从个体中移出组织和/或细胞。此类移出可以是从个体中收集组织和/或细胞,以便对移出的组织和/或细胞进行实验。该实验可以包括确定个体是否患有和/或正在遭受某种病况或病势的实验。病况或疾病可以是,例如癌症。
关于检测哺乳动物中癌症的存在的本发明的方法的实施方案,包含哺乳动物细胞的样本可以是包含全细胞、其裂解物或全细胞裂解物的一部分(例如细胞核或细胞质部分、全蛋白部分或核酸部分)的样本。如果样本包含全细胞,则细胞可以是任何哺乳动物细胞,例如任何器官或组织的细胞,包括血细胞或内皮细胞。
出于本发明的检测方法的目的,关于哺乳动物,接触可以发生在体外或体内。优选地,接触是在体外。
另外,复合物的检测可以通过本领域已知的多种方式进行。例如,可用可检测的标记来标记本文所述的本发明的CAR、多肽、蛋白、核酸、重组表达载体、宿主细胞或细胞群,所述可检测的标记如例如,放射性同位素、荧光团(例如异硫氰酸荧光素(FITC)、藻红蛋白(PE))、酶(例如碱性磷酸酶、辣根过氧化物酶)以及元素颗粒(例如金颗粒)。
测试CAR识别靶细胞的能力以及其抗原特异性的方法在本领域是已知的。例如Clay等人,J.Immunol.,163:507-513(1999)教导了测量细胞因子(例如,干扰素-γ、粒细胞/单核细胞集落刺激因子(GM-CSF)、肿瘤坏死因子a(TNF-α)或者白介素2(IL-2))的释放的方法。此外,如Zhao等人,J.Immunol.,174:4415-4423(2005)中所述,可以通过测量细胞的细胞毒性来评估CAR的功能。
下述实施例进一步阐明本发明,但是当然不应当被解释为以任何方式限制本发明的范围。
实施例1
本实施例显示了编码CAR(mCD27-CD3ζCAR)的逆转录病毒载体的转导效率以及mCD27-CD3ζCAR在体外针对表达mCD70的肿瘤细胞的反应性,所述CAR含有全长小鼠CD27和小鼠CD3ζT细胞胞内信号转导结构域并具有SEQ ID NO:25的氨基酸序列。
构建编码CAR(mCD27-CD3ζCAR)的逆转录病毒载体,所述CAR含有全长小鼠CD27和小鼠CD3ζT细胞胞内信号转导结构域并具有SEQ ID NO:25的氨基酸序列。用mCD27-CD3ζCAR逆转录病毒载体以逆转录病毒的方式转导鼠T细胞。转导效率确定为62.6%。
由脾细胞产生的小鼠T细胞是未转导的(UT)或者转导有编码GFP或mCD27-CD3ζCAR的载体(效应细胞),并且单独培养(培养基)或者与不表达小鼠CD70的B16黑素瘤细胞(B16细胞)或转导以表达小鼠CD70的B16细胞(B16/mCD70)靶细胞共培养。将识别B16肿瘤的小鼠T细胞Pmel细胞用作阳性对照效应细胞。测量IFN-γ分泌。结果显示于表2中。如表2所示,mCD27-CD3ζCAR转导的细胞显示出在体外针对表达CD70的肿瘤的高反应性。
表2
实施例2
本实施例显示,由转导有编码CAR(mCD27-CD3ζCAR)的核苷酸序列的脾细胞产生的小鼠T细胞降低了肿瘤负荷并增加了表达CD70的荷瘤小鼠的存活,所CAR含有全长小鼠CD27和小鼠CD3ζT细胞胞内信号转导结构域并具有SEQ ID NO:25的氨基酸序列。
在将表达CAR的细胞转移至小鼠前11天,通过用B16细胞或B16/mCD70细胞注射小鼠在小鼠中建立肿瘤。4天之后,从小鼠中移出脾细胞,并用伴刀豆球蛋白A(ConA)和IL-7或者抗小鼠CD3(mCD3)以及可溶的CD28(sCD28)对其进行刺激。两天之后,用编码具有SEQ IDNO:25的氨基酸序列的mCD27-CD3ζCAR的MSGV1逆转录病毒载体,转导由刺激的脾细胞产生的小鼠T细胞。5天之后,向荷瘤小鼠施用转导mCD27-CD3ζCAR的细胞(1×107),并且对小鼠进行辐射(500rad)。向对照荷瘤小鼠施用未转导的细胞、磷酸盐缓冲盐水(PBS)或者pmel细胞(pmel)、gp100疫苗(V)和IL-2(I)的组合(“pmel+VI”),并进行辐射。在治疗后长至约35天的时间段内,测量肿瘤大小。结果显示于图1A-1B中。如图1A-1B所示,mCD27-CD3ζCAR转导的细胞降低了B16/mCD70荷瘤小鼠中的肿瘤负荷,但是未降低B16荷瘤小鼠中的肿瘤负荷。因此,负荷有CD70+肿瘤的小鼠可成功地用mCD27-CD3ζCAR转导的细胞进行治疗,并且治疗是CD70特异性的。
用B16/mCD70荷瘤小鼠重复实验,除了用抗mCD3和sCD28刺激脾细胞,以及还在辐射以及施用转导的细胞之后向小鼠施用IL-2。向对照荷瘤小鼠施用未转导的细胞、空载体转导的细胞或者pmel+VI,之后进行辐射并施用IL-2。在治疗后长至约24天的时间段内,测量肿瘤大小。结果显示于图1F中。如图1F所示,当与IL-2共施用时,mCD27-CD3ζCAR转导的细胞降低了B16/mCD70荷瘤小鼠中的肿瘤负荷。
细胞转移后21天,从被治疗的小鼠中移出肿瘤,并使其体外生长7天。通过FACS测量小鼠CD70在肿瘤中的表达。观察到CD70的表达在用mCD27-CD3ζCAR转导的细胞进行治疗的小鼠中丧失,但在用Pmel+V或未转导的细胞进行治疗的小鼠中未丧失。不受特定理论或机制的束缚,据信肿瘤生长的复发最可能是由于B16/mCD70肿瘤中CD70表达的丧失。
用B16/mCD70荷瘤小鼠再次重复与图1B对应的实验,包括下述例外。以每只小鼠1×104、1×105、1×106或1×107个细胞的剂量向B16/mCD70荷瘤小鼠施用mCD27-CD3ζCAR转导的细胞,进行或不进行辐射(500Rad)。向对照荷瘤小鼠施用PBS、pmel+VI或者转导有空载体的小鼠T细胞,进行或不进行辐射(500Rad)。结果显示于图1C-1D中。如图1C所示,当对小鼠进行辐射时,治疗肿瘤的最低有效剂量是每只小鼠1×105个mCD27-CD3ζCAR转导的细胞。如图1C-1D所示,在每只小鼠1×107个细胞的剂量下,辐射似乎未影响治疗效力。
也在治疗后长至约42天的时间段内对荷瘤小鼠的存活进行评估。结果显示于图1E中。如图1E所示,用mCD27-CD3ζCAR转导的细胞治疗的受辐射的荷瘤小鼠存活更久,特别是在每只小鼠1×106或1×107个细胞的剂量下。
实施例3
本实施例显示,向荷瘤小鼠施用转导有mCD27-CD3ζCAR的细胞导致一些毒性。该实施例还显示,小鼠可以从毒性中恢复。
向B16或B16/mCD70荷瘤小鼠施用未转导的细胞或者转导有具有SEQ ID NO:25的氨基酸序列的mCD27-CD3ζCAR的细胞、PBS或pmel+V,进行或不进行辐射(500Rad)。在从细胞转移后约6天开始长至治疗后约17天的时间段内,测量小鼠的平均体重。结果显示于图2A-2D中。如图2A-2D所示,用mCD27-CD3ζCAR治疗的B16/mCD70和B16-荷瘤小鼠均观察到瞬时较低的体重。在mCD27-CD3ζCAR治疗的小鼠中观察到的较低体重与移植的肿瘤无关。不受特定理论或机制的束缚,据信较低的体重指示内源细胞被mCD27-CD3ζCAR靶向。当向小鼠施用含水的水凝胶、亲水胶体(hydrocolloid)、食用酸以及苯甲酸钠时,小鼠恢复失去的体重。
向B16或B16/mCD70-荷瘤小鼠施用未转导的细胞或者转导有具有SEQ ID NO:25的氨基酸序列的mCD27-CD3ζCAR的细胞,或者转导有编码GFP的载体的细胞,进行或不进行辐射(500Rad)。在从细胞转移后约6天开始长至治疗之后约14天的时间段内,测量小鼠中的绝对白细胞(WBC)计数。结果显示于图2E-2H中。如图2E-2F所示,在用mCD27-CD3ζCAR进行治疗的小鼠中观察到瞬时较低的WBC计数。如图2G-2H所示,在用mCD27-CD3ζCAR进行治疗的小鼠中也观察到瞬时较低的脾细胞计数。
向B16/mCD70-荷瘤小鼠施用转导有具有SEQ ID NO:25的氨基酸序列的mCD27-CD3ζCAR的细胞或者转导有编码GFP的载体的细胞,进行或不进行辐射(500Rad)。测量血清IFN-γ水平,持续从细胞转移之后约3天开始长至治疗之后约7天的时间段。结果显示于图2I中,如图2I所示,在用mCD27-CD3ζCAR治疗的受辐射的小鼠中观察到瞬时IFN-γ分泌。
实施例4
本实施例显示,mCD27-CD3ζCAR的施用对于非荷瘤小鼠的长期免疫功能无可测量的影响。
向非荷瘤小鼠施用转导有具有SEQ ID NO:25的氨基酸序列的mCD27-CD3ζCAR的细胞或者转导有编码GFP的载体的细胞(GFP),进行或不进行辐射(500Rad)。在转移转导的细胞之后32天或50天,用卵清蛋白(OVA)或人(h)gp100免疫小鼠。在免疫之后7天,从小鼠的脾脏和淋巴结(LN)移出T细胞。用OT-1、OT-II或hgp100肽体外刺激细胞。结果显示于表3(第32天-脾脏)、表4(第32天-LN)以及表5(第50天-脾脏)中。在表5中,将免疫的C57BL/6(免疫活性)小鼠(B6/Im)用作阳性对照。将初始C57BL/6小鼠(B6/初始)用作阴性对照。如表3-5中所示,mCD27-CD3ζCAR的施用对于非荷瘤小鼠的长期免疫功能无可测量的影响。
在细胞转移之后3至7天,对各器官的组织学进行检验,所述器官包括脑、肺、肝脏、肾脏、肠、心脏、脾脏和骨。在细胞转移之后3天至7天,对血液的化学成分,特别是下述的血液水平进行检验:钠、钾、氯化物、钙、镁、磷、葡萄糖、血尿素氮(BUN)、肌酸酐、尿酸、白蛋白、蛋白、胆固醇、甘油三酯、碱性磷酸酶(ALK P)、丙氨酸氨基转移酶(ALT/GPT)、天冬氨酸氨基转移酶(AST/GOT)、淀粉酶、肌酸激酶(CK)、以及乳酸脱氢酶(LD)。未观察到组织学或血液化学成分的改变。
表3
表4
表5
实施例5
本实施例显示,转导有编码含有全长人CD27和人CD3ζT细胞胞内信号转导结构域的CAR(fCD27-CD3ζCAR)的核苷酸序列的T细胞,在转导的细胞的数目扩增之后表达所述CAR。
用OKT3非特异性刺激PBL,并且产生自PBL的T细胞是(a)未转导的(UT),(b)用编码全长人CD27(fCD27)的核苷酸序列转导,或者(c)用编码具有SEQ ID NO:7的氨基酸序列的fCD27-CD3ζCAR的核苷酸序列转导。使细胞生长,通过荧光激活细胞分选(FACS)对CAR的表达进行分析,并基于IFN-γ的产生对肿瘤反应性进行测试。通常如Riddell等人,J.Immunol.Methods,128:189-201(1990)中所述,对CD70反应性细胞的数目进行快速扩增(REP)。使扩增数目的细胞生长,并通过FACS对CD27、CD70、CD45RO和CD62L的表达进行分析。表6显示了通过FACS所测量的具有指示的表型的细胞的百分数。表7显示了刺激之后(但是REP之前)以及REP之后细胞的倍数扩增以及活力(%)。如表6和7所示,扩增数目的转导细胞表达CAR,有活力且具有效应记忆表型。
表6
表7
实施例6
本实施例显示,转导有编码含有全长人CD27和人CD3ζT细胞胞内信号转导结构域的CAR(fCD27-CD3ζCAR)的核苷酸序列的T细胞,在与表达CD70的细胞共培养时增殖,并且在体外特异性识别表达CD70的肿瘤细胞系。
T细胞产生自人PBL。将未转导的(UT)T细胞或转导有编码fCD27或fCD27-CD3ζCAR的核苷酸序列的T细胞(效应细胞)单独培养,或者与表达CD70的肿瘤细胞系624mel或转导有CD70的624mel细胞(624/CD70)(靶细胞)共培养。在共培养第4天,利用羧基荧光素琥珀酰亚胺酯(CFSE)测量效应细胞的增殖。转导有fCD27-CD3ζCAR的T细胞仅在与表达CD70的肿瘤细胞系624/CD70共培养时才增殖。UT T细胞和转导有fCD27的T细胞在任何培养中均不增殖。
将UT T细胞或者转导有编码fCD27或fCD27-CD3ζCAR(SEQ ID NO:7)的核苷酸序列的T细胞(效应细胞)单独培养(培养基),或者与以下表8中显示的人RCC细胞系或对照细胞系624、624/CD70、SNU245、SNU1079或SNU1196(靶细胞)中的一种共培养。所有SNU细胞系均为CD70阴性。测量IFN-γ的分泌。结果显示于表8中。如表8所示,转导有核苷酸序列fCD27-CD3ζCAR(SEQ ID NO:7)的T细胞对表达CD70的人RCC细胞系具有反应性。
表8
实施例7
本实施例显示了抗CD70人CAR构建体的转导效率。
用空的逆转录病毒载体(模拟)或编码表9A-9C中所示的构建体中的一种的逆转录病毒载体转导人T细胞。含有截短的(Δ)CD27的CAR缺乏CD27胞内T细胞信号转导结构域的全部,即截短的CD27缺乏SEQ ID NO:2的连续氨基酸残基212-260。通过FACS分析转导的细胞的CD3、CD27、CD62L和CD45RO的表达。表9A-9C显示了通过FACS所测量的具有指示的表型的细胞的百分数。如图表9B所示,转导有CAR的细胞具有效应记忆表型。
表9A
表9B
表9C
实施例8
本实施例显示,转导有f CD27-CD3ζ(SEQ ID NO:7)、ΔCD27-4-1BB–CD3ζ(SEQ IDNO:9)、ΔCD27-CD28–4-1BB–CD3ζ(SEQ ID NO:10)、fCD27-4-1BB–CD3ζ(SEQ ID NO:12)或fCD27-CD28–4-1BB–CD3ζ(SEQ ID NO:13)的人T细胞在体外识别表达CD70的RCC肿瘤细胞。
用空的逆转录病毒载体(MSGV1)或编码表9A中所示的构建体中的一种的逆转录病毒载体转导人T细胞。将转导的细胞单独培养(培养基)或与对照靶细胞624mel、624/CD70、938mel或者转导以表达CD70的938mel细胞(938/CD70)或者RCC靶细胞RCC 2245R、RCC2246R、RCC 2361R或RCC 1764细胞共培养。测量IFN-γ的分泌。结果显示于图3中。如图3所示,转导有fCD27-CD3ζ(SEQ ID NO:7)、ΔCD27-4-1BB–CD3ζ(SEQ ID NO:9)、ΔCD27-CD28–4-1BB–CD3ζ(SEQ ID NO:10)、fCD27-4-1BB–CD3ζ(SEQ ID NO:12)或fCD27-CD28–4-1BB–CD3ζ(SEQ ID NO:13)的人T细胞在体外识别表达CD70的RCC肿瘤细胞。
实施例9
本实施例显示了产生ΔCD27-4-1BB–CD3ζ(SEQ ID NO:9)逆转录病毒载体的包装克隆的选择。
逆转录病毒包装细胞系PG13克隆A2、A10、B3、C1、E3、G2未转导或者用编码ΔCD27-4-1BB–CD3ζ(SEQ ID NO:9)的逆转录病毒载体转导。表10显示了通过FACS所测量的具有指示的表型的细胞的百分数。
表10
将转导的克隆单独培养(培养基)或者与靶对照细胞938mel、938/CD70、SNU1079、SNU1196或者靶RCC细胞系RCC 2245R、RCC 2246R、RCC 2361R或RCC 1764共培养。测量IFN-γ的分泌。结果显示于图4中。如图4所示,逆转录病毒包装克隆E3显示出针对表达CD70的靶肿瘤细胞系的反应性。
用如表11中所示的CAR转导逆转录病毒包装细胞克隆。表11显示了通过FACS所测量的具有指示的表型的细胞的百分数。
表11
将转导的克隆单独培养(培养基)或者与靶对照细胞938mel、938/CD70、SNU1079、SNU1196或者靶RCC细胞系RCC 2245R、RCC 2246R、RCC 2361R或RCC 1764共培养。测量IFN-γ的分泌。结果显示于图5中。如图5所示,逆转录病毒包装克隆E3显示出针对表达CD70的靶肿瘤细胞系的反应性。
基于逆转录病毒包装克隆E3/ΔCD27-4-1BB–CD3ζ(SEQ ID NO:9)的转导效率和肿瘤活性,选择其用于临床用途。
在此将本文引用的所有参考文献,包括出版物、专利申请和专利通过引用并入,其程度如同将各参考文献单独且明确指明通过引用并入,并且在本文整体示出一样。
术语“一个/一种(a)”和“一个/一种(an)”和“所述(the)”以及类似的指代物在描述本发明的上下文中(特别是在下述权利要求的上下文中)的使用被解释为既涵盖单数又涵盖复数,除非本文另外指明或者上下文明显矛盾。术语“包含(comprising)”、“具有(having)”、“包括(including)”以及“含有(containing)”被解释为开放式术语(即,意为“包括但不限于”)除非另外标注。本文数值范围的叙述仅意图作为单独指落入范围内的各独立数值的速记法,除非本文另外指明,并且各独立的数值并入说明书如同本文单独对其进行叙述一样。可以以任何合适的顺序实施本文所述的所有方法,除非本文另外指明或者在其它方面与上下文明显矛盾。本文提供的任何或所有实施例或者示例性语言(例如“如”)的使用仅意图更好地阐明本发明,并且不对本发明的范围构成限制,除非另外声明。说明书中的语言均不应被解释为指示任何未要求保护的元素对于本发明的实践是必要的。
本文描述了本发明的优选实施方案,包括发明人已知的实施本发明的最佳方式。经阅读前述描述,那些优选实施方案的改变对于本领域普通技术人员而言可以变得显而易见。发明人期望本领域技术人员视情况应用此类改变,并且发明人意图以与本文具体所述的不同的方式实践本发明。因此,如适用的法律所允许的,本发明包括在此所附的权利要求中所述的主题的所有修饰和等同物。此外,本发明涵盖以上所述元素的所有可能的改变的任何组合,除非本文另外指明或者在其它方面与上下文明显矛盾。
序列表
<110> 美国卫生和人力服务部
<120> 抗CD70嵌合抗原受体
<130> 720305
<150> US 62/088,882
<151> 2014-12-08
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Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
180 185 190
Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
195 200 205
Leu Phe Leu
210
<210> 4
<211> 112
<212> PRT
<213> 智人
<400> 4
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> 5
<211> 47
<212> PRT
<213> 智人
<400> 5
Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
1 5 10 15
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
20 25 30
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40 45
<210> 6
<211> 41
<212> PRT
<213> 智人
<400> 6
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 7
<211> 372
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 7
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
20 25 30
Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
35 40 45
Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
180 185 190
Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
195 200 205
Leu Phe Leu His Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser
210 215 220
Pro Val Glu Pro Ala Glu Pro Cys Arg Tyr Ser Cys Pro Arg Glu Glu
225 230 235 240
Glu Gly Ser Thr Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro
245 250 255
Ala Cys Ser Pro Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
260 265 270
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
275 280 285
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
290 295 300
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
305 310 315 320
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
325 330 335
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
340 345 350
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
355 360 365
Leu Pro Pro Arg
370
<210> 8
<211> 364
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 8
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
20 25 30
Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
35 40 45
Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
180 185 190
Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
195 200 205
Leu Phe Leu Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
290 295 300
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
305 310 315 320
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
325 330 335
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
340 345 350
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360
<210> 9
<211> 370
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 9
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
20 25 30
Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
35 40 45
Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
180 185 190
Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
195 200 205
Leu Phe Leu Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu
210 215 220
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
225 230 235 240
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
245 250 255
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
260 265 270
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
275 280 285
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
290 295 300
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
305 310 315 320
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
325 330 335
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
340 345 350
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
355 360 365
Pro Arg
370
<210> 10
<211> 411
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 10
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
20 25 30
Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
35 40 45
Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
180 185 190
Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
195 200 205
Leu Phe Leu Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Phe Ser Val
245 250 255
Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
260 265 270
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
275 280 285
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
290 295 300
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
305 310 315 320
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
325 330 335
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
340 345 350
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
355 360 365
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
370 375 380
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
385 390 395 400
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
405 410
<210> 11
<211> 413
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 11
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
20 25 30
Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
35 40 45
Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
180 185 190
Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
195 200 205
Leu Phe Leu His Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser
210 215 220
Pro Val Glu Pro Ala Glu Pro Cys Arg Tyr Ser Cys Pro Arg Glu Glu
225 230 235 240
Glu Gly Ser Thr Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro
245 250 255
Ala Cys Ser Pro Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr
260 265 270
Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln
275 280 285
Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys
290 295 300
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
305 310 315 320
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
325 330 335
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
340 345 350
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
355 360 365
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
370 375 380
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
385 390 395 400
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
405 410
<210> 12
<211> 419
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 12
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
20 25 30
Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
35 40 45
Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
180 185 190
Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
195 200 205
Leu Phe Leu His Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser
210 215 220
Pro Val Glu Pro Ala Glu Pro Cys Arg Tyr Ser Cys Pro Arg Glu Glu
225 230 235 240
Glu Gly Ser Thr Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro
245 250 255
Ala Cys Ser Pro Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu
260 265 270
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
275 280 285
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
290 295 300
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
305 310 315 320
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
325 330 335
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
340 345 350
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
355 360 365
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
370 375 380
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
385 390 395 400
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
405 410 415
Pro Pro Arg
<210> 13
<211> 460
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 13
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
20 25 30
Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
35 40 45
Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
180 185 190
Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
195 200 205
Leu Phe Leu His Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser
210 215 220
Pro Val Glu Pro Ala Glu Pro Cys Arg Tyr Ser Cys Pro Arg Glu Glu
225 230 235 240
Glu Gly Ser Thr Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro
245 250 255
Ala Cys Ser Pro Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr
260 265 270
Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln
275 280 285
Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Phe Ser
290 295 300
Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
305 310 315 320
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
325 330 335
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe
340 345 350
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
355 360 365
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
370 375 380
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
385 390 395 400
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
405 410 415
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
420 425 430
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
435 440 445
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
450 455 460
<210> 14
<211> 1119
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 14
atggcacggc cacatccctg gtggctgtgc gttctgggga ccctggtggg gctctcagct 60
actccagccc ccaagagctg cccagagagg cactactggg ctcagggaaa gctgtgctgc 120
cagatgtgtg agccaggaac attcctcgtg aaggactgtg accagcatag aaaggctgct 180
cagtgtgatc cttgcatacc gggggtctcc ttctctcctg accaccacac ccggccccac 240
tgtgagagct gtcggcactg taactctggt cttctcgttc gcaactgcac catcactgcc 300
aatgctgagt gtgcctgtcg caatggctgg cagtgcaggg acaaggagtg caccgagtgt 360
gatcctcttc caaacccttc gctgaccgct cggtcgtctc aggccctgag cccacaccct 420
cagcccaccc acttacctta tgtcagtgag atgctggagg ccaggacagc tgggcacatg 480
cagactctgg ctgacttcag gcagctgcct gcccggactc tctctaccca ctggccaccc 540
caaagatccc tgtgcagctc cgattttatt cgcatccttg tgatcttctc tggaatgttc 600
cttgttttca ccctggccgg ggccctgttc ctccatcaac gaaggaaata tagatcaaac 660
aaaggagaaa gtcctgtgga gcctgcagag ccttgtcgtt acagctgccc cagggaggag 720
gagggcagca ccatccccat ccaggaggat taccgaaaac cggagcctgc ctgctccccc 780
agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 840
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 900
cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 960
gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 1020
cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 1080
tacgacgccc ttcacatgca ggccctgccc cctcgctaa 1119
<210> 15
<211> 1095
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 15
atggcacggc cacatccctg gtggctgtgc gttctgggga ccctggtggg gctctcagct 60
actccagccc ccaagagctg cccagagagg cactactggg ctcagggaaa gctgtgctgc 120
cagatgtgtg agccaggaac attcctcgtg aaggactgtg accagcatag aaaggctgct 180
cagtgtgatc cttgcatacc gggggtctcc ttctctcctg accaccacac ccggccccac 240
tgtgagagct gtcggcactg taactctggt cttctcgttc gcaactgcac catcactgcc 300
aatgctgagt gtgcctgtcg caatggctgg cagtgcaggg acaaggagtg caccgagtgt 360
gatcctcttc caaacccttc gctgaccgct cggtcgtctc aggccctgag cccacaccct 420
cagcccaccc acttacctta tgtcagtgag atgctggagg ccaggacagc tgggcacatg 480
cagactctgg ctgacttcag gcagctgcct gcccggactc tctctaccca ctggccaccc 540
caaagatccc tgtgcagctc cgattttatt cgcatccttg tgatcttctc tggaatgttc 600
cttgttttca ccctggccgg ggccctgttc ctcaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccagag tgaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgagaagga agaaccctca ggaaggcctg tacaatgaac tgcagaaaga taagatggcg 960
gaggcctaca gtgagattgg gatgaaaggc gagcgccgga ggggcaaggg gcacgatggc 1020
ctttaccagg gtctcagtac agccaccaag gacacctacg acgcccttca catgcaggcc 1080
ctgccccctc gctaa 1095
<210> 16
<211> 1113
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 16
atggcacggc cacatccctg gtggctgtgc gttctgggga ccctggtggg gctctcagct 60
actccagccc ccaagagctg cccagagagg cactactggg ctcagggaaa gctgtgctgc 120
cagatgtgtg agccaggaac attcctcgtg aaggactgtg accagcatag aaaggctgct 180
cagtgtgatc cttgcatacc gggggtctcc ttctctcctg accaccacac ccggccccac 240
tgtgagagct gtcggcactg taactctggt cttctcgttc gcaactgcac catcactgcc 300
aatgctgagt gtgcctgtcg caatggctgg cagtgcaggg acaaggagtg caccgagtgt 360
gatcctcttc caaacccttc gctgaccgct cggtcgtctc aggccctgag cccacaccct 420
cagcccaccc acttacctta tgtcagtgag atgctggagg ccaggacagc tgggcacatg 480
cagactctgg ctgacttcag gcagctgcct gcccggactc tctctaccca ctggccaccc 540
caaagatccc tgtgcagctc cgattttatt cgcatccttg tgatcttctc tggaatgttc 600
cttgttttca ccctggccgg ggccctgttc ctccgtttct ctgttgttaa acggggcaga 660
aagaagctcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 720
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 780
aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 840
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 900
cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 960
cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1020
ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1080
gcccttcaca tgcaggccct gccccctcgc taa 1113
<210> 17
<211> 1236
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 17
atggcacggc cacatccctg gtggctgtgc gttctgggga ccctggtggg gctctcagct 60
actccagccc ccaagagctg cccagagagg cactactggg ctcagggaaa gctgtgctgc 120
cagatgtgtg agccaggaac attcctcgtg aaggactgtg accagcatag aaaggctgct 180
cagtgtgatc cttgcatacc gggggtctcc ttctctcctg accaccacac ccggccccac 240
tgtgagagct gtcggcactg taactctggt cttctcgttc gcaactgcac catcactgcc 300
aatgctgagt gtgcctgtcg caatggctgg cagtgcaggg acaaggagtg caccgagtgt 360
gatcctcttc caaacccttc gctgaccgct cggtcgtctc aggccctgag cccacaccct 420
cagcccaccc acttacctta tgtcagtgag atgctggagg ccaggacagc tgggcacatg 480
cagactctgg ctgacttcag gcagctgcct gcccggactc tctctaccca ctggccaccc 540
caaagatccc tgtgcagctc cgattttatt cgcatccttg tgatcttctc tggaatgttc 600
cttgttttca ccctggccgg ggccctgttc ctcaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctcccgtt tctctgttgt taaacggggc 780
agaaagaagc tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 840
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgaga 900
gtgaagttca gcaggagcgc agacgccccc gcgtaccagc agggccagaa ccagctctat 960
aacgagctca atctaggacg aagagaggag tacgatgttt tggacaagag acgtggccgg 1020
gaccctgaga tggggggaaa gccgagaagg aagaaccctc aggaaggcct gtacaatgaa 1080
ctgcagaaag ataagatggc ggaggcctac agtgagattg ggatgaaagg cgagcgccgg 1140
aggggcaagg ggcacgatgg cctttaccag ggtctcagta cagccaccaa ggacacctac 1200
gacgcccttc acatgcaggc cctgccccct cgctaa 1236
<210> 18
<211> 1242
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 18
atggcacggc cacatccctg gtggctgtgc gttctgggga ccctggtggg gctctcagct 60
actccagccc ccaagagctg cccagagagg cactactggg ctcagggaaa gctgtgctgc 120
cagatgtgtg agccaggaac attcctcgtg aaggactgtg accagcatag aaaggctgct 180
cagtgtgatc cttgcatacc gggggtctcc ttctctcctg accaccacac ccggccccac 240
tgtgagagct gtcggcactg taactctggt cttctcgttc gcaactgcac catcactgcc 300
aatgctgagt gtgcctgtcg caatggctgg cagtgcaggg acaaggagtg caccgagtgt 360
gatcctcttc caaacccttc gctgaccgct cggtcgtctc aggccctgag cccacaccct 420
cagcccaccc acttacctta tgtcagtgag atgctggagg ccaggacagc tgggcacatg 480
cagactctgg ctgacttcag gcagctgcct gcccggactc tctctaccca ctggccaccc 540
caaagatccc tgtgcagctc cgattttatt cgcatccttg tgatcttctc tggaatgttc 600
cttgttttca ccctggccgg ggccctgttc ctccatcaac gaaggaaata tagatcaaac 660
aaaggagaaa gtcctgtgga gcctgcagag ccttgtcgtt acagctgccc cagggaggag 720
gagggcagca ccatccccat ccaggaggat taccgaaaac cggagcctgc ctgctccccc 780
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 840
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 900
tccagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 960
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 1020
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 1080
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 1140
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 1200
acctacgacg cccttcacat gcaggccctg ccccctcgct aa 1242
<210> 19
<211> 1260
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 19
atggcacggc cacatccctg gtggctgtgc gttctgggga ccctggtggg gctctcagct 60
actccagccc ccaagagctg cccagagagg cactactggg ctcagggaaa gctgtgctgc 120
cagatgtgtg agccaggaac attcctcgtg aaggactgtg accagcatag aaaggctgct 180
cagtgtgatc cttgcatacc gggggtctcc ttctctcctg accaccacac ccggccccac 240
tgtgagagct gtcggcactg taactctggt cttctcgttc gcaactgcac catcactgcc 300
aatgctgagt gtgcctgtcg caatggctgg cagtgcaggg acaaggagtg caccgagtgt 360
gatcctcttc caaacccttc gctgaccgct cggtcgtctc aggccctgag cccacaccct 420
cagcccaccc acttacctta tgtcagtgag atgctggagg ccaggacagc tgggcacatg 480
cagactctgg ctgacttcag gcagctgcct gcccggactc tctctaccca ctggccaccc 540
caaagatccc tgtgcagctc cgattttatt cgcatccttg tgatcttctc tggaatgttc 600
cttgttttca ccctggccgg ggccctgttc ctccatcaac gaaggaaata tagatcaaac 660
aaaggagaaa gtcctgtgga gcctgcagag ccttgtcgtt acagctgccc cagggaggag 720
gagggcagca ccatccccat ccaggaggat taccgaaaac cggagcctgc ctgctccccc 780
cgtttctctg ttgttaaacg gggcagaaag aagctcctgt atatattcaa acaaccattt 840
atgagaccag tacaaactac tcaagaggaa gatggctgta gctgccgatt tccagaagaa 900
gaagaaggag gatgtgaact gagagtgaag ttcagcagga gcgcagacgc ccccgcgtac 960
cagcagggcc agaaccagct ctataacgag ctcaatctag gacgaagaga ggagtacgat 1020
gttttggaca agagacgtgg ccgggaccct gagatggggg gaaagccgag aaggaagaac 1080
cctcaggaag gcctgtacaa tgaactgcag aaagataaga tggcggaggc ctacagtgag 1140
attgggatga aaggcgagcg ccggaggggc aaggggcacg atggccttta ccagggtctc 1200
agtacagcca ccaaggacac ctacgacgcc cttcacatgc aggccctgcc ccctcgctaa 1260
<210> 20
<211> 1383
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 20
atggcacggc cacatccctg gtggctgtgc gttctgggga ccctggtggg gctctcagct 60
actccagccc ccaagagctg cccagagagg cactactggg ctcagggaaa gctgtgctgc 120
cagatgtgtg agccaggaac attcctcgtg aaggactgtg accagcatag aaaggctgct 180
cagtgtgatc cttgcatacc gggggtctcc ttctctcctg accaccacac ccggccccac 240
tgtgagagct gtcggcactg taactctggt cttctcgttc gcaactgcac catcactgcc 300
aatgctgagt gtgcctgtcg caatggctgg cagtgcaggg acaaggagtg caccgagtgt 360
gatcctcttc caaacccttc gctgaccgct cggtcgtctc aggccctgag cccacaccct 420
cagcccaccc acttacctta tgtcagtgag atgctggagg ccaggacagc tgggcacatg 480
cagactctgg ctgacttcag gcagctgcct gcccggactc tctctaccca ctggccaccc 540
caaagatccc tgtgcagctc cgattttatt cgcatccttg tgatcttctc tggaatgttc 600
cttgttttca ccctggccgg ggccctgttc ctccatcaac gaaggaaata tagatcaaac 660
aaaggagaaa gtcctgtgga gcctgcagag ccttgtcgtt acagctgccc cagggaggag 720
gagggcagca ccatccccat ccaggaggat taccgaaaac cggagcctgc ctgctccccc 780
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 840
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 900
tcccgtttct ctgttgttaa acggggcaga aagaagctcc tgtatatatt caaacaacca 960
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080
taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380
taa 1383
<210> 21
<211> 188
<212> PRT
<213> 智人
<400> 21
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
20 25 30
Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
35 40 45
Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
85 90 95
Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
100 105 110
Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
115 120 125
Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
130 135 140
Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
145 150 155 160
Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
165 170 175
His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp
180 185
<210> 22
<211> 23
<212> PRT
<213> 智人
<400> 22
Phe Ile Arg Ile Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr
1 5 10 15
Leu Ala Gly Ala Leu Phe Leu
20
<210> 23
<211> 49
<212> PRT
<213> 智人
<400> 23
His Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser Pro Val Glu
1 5 10 15
Pro Ala Glu Pro Cys Arg Tyr Ser Cys Pro Arg Glu Glu Glu Gly Ser
20 25 30
Thr Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro Ala Cys Ser
35 40 45
Pro
<210> 24
<211> 1092
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 24
atggcatggc cacctcccta ctggctctgc atgctgggga ccttggtagg actctcagct 60
accctagccc caaacagctg tccagacaaa cactactgga ctgggggagg actctgctgc 120
cggatgtgtg agccaggtac attctttgtg aaggactgtg aacaagacag aacagctgct 180
cagtgtgatc cctgtatacc aggcacctcc ttctctccag actaccacac ccggccccac 240
tgcgagagct gcaggcattg taactctggt tttcttatcc gcaactgcac agtcactgcc 300
aatgctgagt gcagctgttc caagaactgg cagtgcaggg accaggaatg tacagagtgt 360
gaccctcctc taaaccctgc actgaccaga cagccatctg agaccccgag cccacagcca 420
ccacccaccc acttacctca tggcacagag aagccatcct ggcccctaca caggcagctt 480
cccaactcga ctgtctatag ccagcggtca tcccatagac ccctgtgcag ctcggactgc 540
atccggatct ttgtgacctt ctccagcatg tttcttatct tcgtcctggg tgcaatcttg 600
ttcttccatc aaagaagaaa ccacgggcca aatgaagacc ggcaggcagt gcctgaagag 660
ccttgtcctt acagctgccc cagggaagag gagggcagtg ctatccctat ccaggaggac 720
taccggaaac ccgagcctgc tttctaccct agagcaaaat tcagcaggag tgcagagact 780
gctgccaacc tgcaggaccc caaccagctc tacaatgagc tcaatctagg gcgaagagag 840
gaatatgacg tcttggagaa gaagcgggct cgcgatccag agatgggagg caaacagcag 900
aggaggagga acccccagga aggcgtatac aatgcactgc agaaagacaa gatggcagaa 960
gcctacagtg agatcggcac aaaaggcgag aggcggagag gcaaggggca cgatggcctt 1020
taccagggtc tcagcactgc caccaaggac acctatgatg ccctgcatat gcagaccctg 1080
gcccctcgct aa 1092
<210> 25
<211> 363
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 25
Met Ala Trp Pro Pro Pro Tyr Trp Leu Cys Met Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Leu Ala Pro Asn Ser Cys Pro Asp Lys His Tyr
20 25 30
Trp Thr Gly Gly Gly Leu Cys Cys Arg Met Cys Glu Pro Gly Thr Phe
35 40 45
Phe Val Lys Asp Cys Glu Gln Asp Arg Thr Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Thr Ser Phe Ser Pro Asp Tyr His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Phe Leu Ile Arg Asn Cys
85 90 95
Thr Val Thr Ala Asn Ala Glu Cys Ser Cys Ser Lys Asn Trp Gln Cys
100 105 110
Arg Asp Gln Glu Cys Thr Glu Cys Asp Pro Pro Leu Asn Pro Ala Leu
115 120 125
Thr Arg Gln Pro Ser Glu Thr Pro Ser Pro Gln Pro Pro Pro Thr His
130 135 140
Leu Pro His Gly Thr Glu Lys Pro Ser Trp Pro Leu His Arg Gln Leu
145 150 155 160
Pro Asn Ser Thr Val Tyr Ser Gln Arg Ser Ser His Arg Pro Leu Cys
165 170 175
Ser Ser Asp Cys Ile Arg Ile Phe Val Thr Phe Ser Ser Met Phe Leu
180 185 190
Ile Phe Val Leu Gly Ala Ile Leu Phe Phe His Gln Arg Arg Asn His
195 200 205
Gly Pro Asn Glu Asp Arg Gln Ala Val Pro Glu Glu Pro Cys Pro Tyr
210 215 220
Ser Cys Pro Arg Glu Glu Glu Gly Ser Ala Ile Pro Ile Gln Glu Asp
225 230 235 240
Tyr Arg Lys Pro Glu Pro Ala Phe Tyr Pro Arg Ala Lys Phe Ser Arg
245 250 255
Ser Ala Glu Thr Ala Ala Asn Leu Gln Asp Pro Asn Gln Leu Tyr Asn
260 265 270
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Glu Lys Lys
275 280 285
Arg Ala Arg Asp Pro Glu Met Gly Gly Lys Gln Gln Arg Arg Arg Asn
290 295 300
Pro Gln Glu Gly Val Tyr Asn Ala Leu Gln Lys Asp Lys Met Ala Glu
305 310 315 320
Ala Tyr Ser Glu Ile Gly Thr Lys Gly Glu Arg Arg Arg Gly Lys Gly
325 330 335
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
340 345 350
Asp Ala Leu His Met Gln Thr Leu Ala Pro Arg
355 360
<210> 26
<211> 250
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 26
Met Ala Trp Pro Pro Pro Tyr Trp Leu Cys Met Leu Gly Thr Leu Val
1 5 10 15
Gly Leu Ser Ala Thr Leu Ala Pro Asn Ser Cys Pro Asp Lys His Tyr
20 25 30
Trp Thr Gly Gly Gly Leu Cys Cys Arg Met Cys Glu Pro Gly Thr Phe
35 40 45
Phe Val Lys Asp Cys Glu Gln Asp Arg Thr Ala Ala Gln Cys Asp Pro
50 55 60
Cys Ile Pro Gly Thr Ser Phe Ser Pro Asp Tyr His Thr Arg Pro His
65 70 75 80
Cys Glu Ser Cys Arg His Cys Asn Ser Gly Phe Leu Ile Arg Asn Cys
85 90 95
Thr Val Thr Ala Asn Ala Glu Cys Ser Cys Ser Lys Asn Trp Gln Cys
100 105 110
Arg Asp Gln Glu Cys Thr Glu Cys Asp Pro Pro Leu Asn Pro Ala Leu
115 120 125
Thr Arg Gln Pro Ser Glu Thr Pro Ser Pro Gln Pro Pro Pro Thr His
130 135 140
Leu Pro His Gly Thr Glu Lys Pro Ser Trp Pro Leu His Arg Gln Leu
145 150 155 160
Pro Asn Ser Thr Val Tyr Ser Gln Arg Ser Ser His Arg Pro Leu Cys
165 170 175
Ser Ser Asp Cys Ile Arg Ile Phe Val Thr Phe Ser Ser Met Phe Leu
180 185 190
Ile Phe Val Leu Gly Ala Ile Leu Phe Phe His Gln Arg Arg Asn His
195 200 205
Gly Pro Asn Glu Asp Arg Gln Ala Val Pro Glu Glu Pro Cys Pro Tyr
210 215 220
Ser Cys Pro Arg Glu Glu Glu Gly Ser Ala Ile Pro Ile Gln Glu Asp
225 230 235 240
Tyr Arg Lys Pro Glu Pro Ala Phe Tyr Pro
245 250
<210> 27
<211> 113
<212> PRT
<213> 小家鼠
<400> 27
Arg Ala Lys Phe Ser Arg Ser Ala Glu Thr Ala Ala Asn Leu Gln Asp
1 5 10 15
Pro Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Glu Lys Lys Arg Ala Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Gln Gln Arg Arg Arg Asn Pro Gln Glu Gly Val Tyr Asn Ala Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Thr Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Thr Leu Ala Pro
100 105 110
Arg
Claims (39)
1.具有针对CD70的抗原特异性的嵌合抗原受体(CAR),其包含与SEQ ID NO:11-13任一项至少约90%相同的氨基酸序列。
2.如权利要求1所述的CAR,其包含SEQ ID NO:11-13任一项的氨基酸序列。
3.如权利要求2所述的CAR,其包含SEQ ID NO:11的氨基酸序列。
4.如权利要求2所述的CAR,其包含SEQ ID NO:12的氨基酸序列。
5.如权利要求2所述的CAR,其包含SEQ ID NO:13的氨基酸序列。
6.核酸,其包含编码权利要求1-5中任一项所述的CAR的核苷酸序列。
7.如权利要求6所述的核酸,其包含SEQ ID NO:18-20任一项的核苷酸序列。
8.如权利要求7所述的核酸,其包含SEQ ID NO:18的核苷酸序列。
9.如权利要求7所述的核酸,其包含SEQ ID NO:19的核苷酸序列。
10.如权利要求7所述的核酸,其包含SEQ ID NO:20的核苷酸序列。
11.重组表达载体,其包含权利要求6-10任一项所述的核酸。
12.分离的宿主细胞,其包含权利要求11所述的重组表达载体。
13.细胞群,其包含至少一种权利要求12所述的宿主细胞。
14.权利要求13所述的细胞群在制备用于治疗或预防哺乳动物中癌症的药物中的用途。
15.药物组合物,其包含:
(i)权利要求1所述的CAR,
(ii)包含编码(i)中所述的CAR的核苷酸序列的核酸,
(iii)包含(ii)中所述的核酸的重组表达载体,
(iv)包含(iii)中所述的重组表达载体的宿主细胞,或者
(v)包含至少一种(iv)中所述的宿主细胞的细胞群,
以及药学可接受的载体。
16.(i)权利要求1所述的CAR,(ii)编码(i)中所述的CAR的核酸,(iii)包含(ii)中所述的核酸的重组表达载体,(iv)包含(iii)中所述的重组表达载体的宿主细胞,(v)包含至少一种(iv)中所述的宿主细胞的细胞群,或者(vi)包含(i)-(v)中任一项的药物组合物在制备用于检测哺乳动物中癌症的药物中的用途。
17.细胞群在制备用于治疗或预防哺乳动物中癌症的药物中的用途,所述细胞群包括包含重组表达载体的至少一种宿主细胞,所述重组表达载体包含编码具有针对CD70的抗原特异性的CAR的核酸,所述CAR包括包含SEQ ID NO:3的氨基酸序列的CD70结合-跨膜结构域、包含SEQ ID NO:4的氨基酸序列的CD3ζ胞内T细胞信号转导结构域、以及以下中的一项或两项:(i)包含SEQ ID NO:5的氨基酸序列的4-1BB胞内T细胞信号转导结构域和(ii)包含SEQ ID NO:6的氨基酸序列的CD28胞内T细胞信号转导结构域,其中所述CD70结合-跨膜结构域不包含SEQ ID NO:2的氨基酸序列的残基212至260。
18.(i)具有针对CD70的抗原特异性的CAR,(ii)编码(i)中所述CAR的核酸,(iii)包含(ii)中所述核酸的重组表达载体,(iv)包含(iii)中所述重组表达载体的宿主细胞,(v)包含至少一种(iv)中所述宿主细胞的细胞群,或者(vi)包含(i)-(v)中任一项的药物组合物在制备用于检测哺乳动物中癌症的药物中的用途,所述CAR包括包含SEQ ID NO:3的氨基酸序列的CD70结合-跨膜结构域、包含SEQ ID NO:4的氨基酸序列的CD3ζ胞内T细胞信号转导结构域、以及包含SEQ ID NO:5的氨基酸序列的4-1BB胞内T细胞信号转导结构域和包含SEQID NO:6的氨基酸序列的CD28胞内T细胞信号转导结构域中的一项或两项,其中所述CD70结合-跨膜结构域不包含SEQ ID NO:2的氨基酸序列的残基212至260。
19.包含以下(i)-(v)中一项或多项的制剂,其用于施用至个体:
(i)具有针对CD70的抗原特异性的嵌合抗原受体(CAR),所述CAR包含:
抗原结合-跨膜结构域,其含有缺乏CD27胞内T细胞信号转导结构域的全部的CD27氨基酸序列,
CD3ζ胞内T细胞信号转导结构域,以及
4-1BB胞内T细胞信号转导结构域和CD28胞内T细胞信号转导结构域之一或两者;
(ii)包含编码(i)中所述的CAR的核苷酸序列的核酸;
(iii)包含(ii)中所述的核酸的重组表达载体;
(iv)包含(iii)中所述的重组表达载体的分离的宿主细胞;
(v)包含至少一种(iv)中所述的宿主细胞的细胞群。
20.根据权利要求19所述的制剂,其中所述CAR包含4-1BB胞内T细胞信号转导结构域、CD3ζ胞内T细胞信号转导结构域和CD28胞内T细胞信号转导结构域。
21.根据权利要求19所述的制剂,其中所述CAR包含4-1BB胞内T细胞信号转导结构域和CD3ζ胞内T细胞信号转导结构域。
22.根据权利要求19所述的制剂,其中所述CD28胞内T细胞信号转导结构域包含与SEQID NO:6至少约90%相同的氨基酸序列。
23.根据权利要求22所述的制剂,其中所述CD28胞内T细胞信号转导结构域包含与SEQID NO:6至少约95%相同的氨基酸序列。
24.根据权利要求19所述的制剂,其中所述4-1BB胞内T细胞信号转导结构域包含与SEQID NO:5至少约90%相同的氨基酸序列。
25.根据权利要求24所述的制剂,其中所述4-1BB胞内T细胞信号转导结构域包含与SEQID NO:5至少约95%相同的氨基酸序列。
26.根据权利要求19所述的制剂,其中所述CD3ζ胞内T细胞信号转导结构域包含与SEQID NO:4至少约90%相同的氨基酸序列。
27.根据权利要求26所述的制剂,其中所述CD3ζ胞内T细胞信号转导结构域包含与SEQID NO:4至少约95%相同的氨基酸序列。
28.根据权利要求19所述的制剂,其中所述CD27抗原结合-跨膜结构域包含与SEQ IDNO:3至少约90%相同的氨基酸序列。
29.根据权利要求28所述的制剂,其中所述CD27抗原结合-跨膜结构域包含与SEQ IDNO:3至少约95%相同的氨基酸序列。
30.根据权利要求19所述的制剂,其中所述CAR包含与SEQ ID NO:8-10中的任一项至少约90%相同的氨基酸序列。
31.根据权利要求30所述的制剂,其中所述CAR包含SEQ ID NO:8-10中任一项的氨基酸序列。
32.根据权利要求19的制剂,其适用于口服、肠胃外、皮下、静脉内、肌肉内、动脉内、鞘内或腹膜内给药。
33.根据权利要求19的制剂,其还包含药学上可接受的载体。
34.根据权利要求19的制剂,其包含(iv)中所述分离的宿主细胞和任选的人血清白蛋白。
35.根据权利要求19的制剂,其包含(v)中所述细胞群,其中所述制剂包含1×106至1×1012个细胞。
36.根据权利要求19所述的制剂,其包含(i)中所述的CAR,其中所述制剂适合以足以使CAR在离施用时间约2小时或更长的时间段内结合抗原,或者检测、治疗或预防癌症的剂量施用。
37.根据权利要求36所述的制剂,其中所述制剂适合以足以使CAR在离施用时间约12至约24或者更多个小时的时间段内结合抗原,或者检测、治疗或预防癌症的剂量施用。
38.包含(i)中所述CAR的权利要求19-37中任一项所述的制剂在制备用于检测、治疗或预防个体的癌症的药物中的用途。
39.根据权利要求38所述的用途,其中所述药物以足以使CAR在离施用时间约2小时或更长的时间段内检测、治疗或预防个体的癌症的剂量施用。
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