CN109970867B - 一种cd40双向激活共刺激分子受体及其用途 - Google Patents
一种cd40双向激活共刺激分子受体及其用途 Download PDFInfo
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Abstract
本发明属于细胞生物学和免疫学领域领域，涉及一种CD40双向激活共刺激分子受体及其用途。具体地，本发明涉及一种CD40双向激活共刺激分子受体，其从N端到C端依次包括下述元件：可选的信号肽、CD40激活型单链抗体、胞外铰链区、跨膜区和胞内共刺激信号分子。当CD40双向激活共刺激分子受体与包含第一信号的第一代CAR‑T共同修饰T细胞时，可以产生强烈的集群效应，杀伤肿瘤细胞。同时，这种双向激活的作用仅仅局限在相互接触的T细胞之间，不会像注射CD40的激活型抗体一样，引发强烈T细胞免疫，造成潜在严重毒副作用。
Description
技术领域
本发明属于细胞生物学和免疫学领域领域，涉及一种CD40双向激活共刺激分子受体，及其用该受体修饰后的T细胞治疗恶性肿瘤的用途。
背景技术
肿瘤过继细胞治疗(adoptive cell therapy，ACT)是将经处理的自体或异体免疫细胞(主要是自体细胞)回输给肿瘤患者，直接杀伤肿瘤细胞，或者通过激发机体的免疫应答杀伤肿瘤细胞，达到治疗目的。当前肿瘤过继细胞治疗发展迅速，在多种恶性肿瘤的临床治疗中取得了非常好的疗效(Nature.2016；Jun16；534(7607):396-401)；(Cell.2016 Oct6；167(2):405-418.e13)。肿瘤免疫细胞治疗被认为是最有前景的治疗恶性肿瘤的手段之一。
T细胞活化需要两个信号的刺激，即两种T细胞活化相关信号。其中，T细胞表面TCR-CD3复合体与抗原肽-MHC分子结合，提供T细胞活化的第一信号，决定T细胞的杀伤特异性；T细胞表面的共刺激分子(如CD28)与相应配体(如B7)结合，提供T细胞活化的第二信号，促进T细胞活化、增殖与存活。但肿瘤细胞第一信号刺激源(如MHC分子)与第二信号配体(如B7)等缺乏或表达下降，无法有效提供T细胞活化相关的信号，从而无法激活T细胞免疫反应。而广泛性的激活T细胞共刺激分子，可能带来强烈的毒副作用。
嵌合抗原受体CAR(chimeric antigen receptors，CAR)通过胞外特异性识别肿瘤抗原的单链抗体片段(Single chain Variable Fragment,scFv)，激活胞内信号CD3ζ或FcεRIγ的ITAM(immunoreceptor tyrosine-based activation motifs)信号传递。但是第一代CAR受体缺乏T细胞的共刺激信号，导致T细胞只能发挥瞬间效应，在体内存在时间短、细胞因子分泌少。
第二代与第三代的CAR是将T细胞激活所需的两个信号进行了合并，将第二信号CD28或/和4-1BB细胞内信号区域直接连接到CD3ζ分子，从而绕过了肿瘤细胞通常第二信号如B7等缺乏所引起T细胞不能激活的障碍。第一信号与第二信号合并后，大大提高了对T细胞激活、增殖及杀伤能力，使之疗效大幅度增加，基于目前对T细胞激活机制的理解，CD28、4-1BB分子能够提供第二个激活信号并进一步加强TCR/CD3信号。
然而，不管何种CAR-T细胞，其只能对改造后的T细胞提供刺激信号，缺乏旁观者功能，并不能激活周围T细胞，产生更强的群集效应，引起一系列激活T细胞功能的级联反应。
发明内容
本发明人经过深入的研究和创造性的劳动，设计了一种双向共刺激分子激活受体(Dual Costimulatory Activated Receptor，DCR)，其通过CD40胞外激活型抗体传递T细胞活化相关的第二信号。经修饰后的T细胞，不仅能通过胞外的CD40激活型抗体，激活自身的CD40共刺激分子信号，还能通过与周围未修饰活化的T细胞接触后，激活被接触的T细胞的胞内的共刺激分子信号，促进T细胞活化、增殖与存活。特别是，当其与包含第一信号的第一代CAR-T共同修饰T细胞时，可以产生强烈的集群效应，杀伤肿瘤细胞。另外，这种双向激活的作用仅仅局限在相互接触的T细胞之间，不会像注射CD40的激活型抗体一样，引发强烈T细胞免疫，造成潜在严重毒副作用。
由此提供了下述发明：
本发明的一个方面涉及一种分离的多肽，其从N端到C端依次包括下述元件：
可选的信号肽、激活CD40的多肽(例如CD40激活型单链抗体或CD40的配体)、胞外铰链区、跨膜区和胞内共刺激信号分子。
在本发明的一个或多个实施方案中，所述的多肽，其特征在于如下的(1)－(5)项中的任意1项、2项、3项、4项或者5项：
(1)所述信号肽为膜蛋白信号肽；优选地，所述信号肽为选自CD8信号肽、CD28信号肽和CD4信号肽中的一种或多种；优选地，所述信号肽是CD8信号肽；优选地，CD8信号肽的氨基酸序列如SEQ ID NO:1所示；
(2)所述CD40激活型单链抗体的氨基酸序列如SEQ ID NO:2所示；所述CD40的配体是CD40L；
(3)所述胞外铰链区为选自IgG4Fc CH2CH3铰链区、CD28铰链区和CD8铰链区的一种或多种；优选地，为IgG4Fc CH2CH3铰链区；优选地，所述IgG4Fc CH2CH3铰链区的氨基酸序列如SEQ ID NO:3所示；
(4)所述跨膜区为选自CD28跨膜区、CD8跨膜区、CD3ζ跨膜区、CD134跨膜区、CD137跨膜区、ICOS跨膜区和DAP10跨膜区中的一种或多种；优选地，所述跨膜区为CD28跨膜区；优选地，所述CD28跨膜区的氨基酸序列如SEQ ID NO:4所示；
(5)所述胞内共刺激信号分子选自CD28胞内结构域、CD134/OX40胞内结构域、CD137/4-1BB胞内结构域、LCK胞内结构域、ICOS胞内结构域和DAP10胞内结构域中的一种或多种；优选地，所述胞内共刺激信号分子为CD28胞内结构域和/或CD137胞内结构域；优选地，所述CD28胞内结构域的氨基酸序列如SEQ ID NO:5所示；优选地，所述CD137胞内结构域的氨基酸序列如SEQ ID NO:6所示。
在本发明的一个或多个实施方案中，所述的多肽，其从N端到C端依次包括下述元件：
可选的CD8信号肽、CD40激活型单链抗体、IgG4Fc CH2CH3铰链区、CD28跨膜区、CD28胞内结构域和/或CD137胞内结构域。
在本发明的一个或多个实施方案中，所述的多肽，其如图1A-图1D所示。
在本发明的一个或多个实施方案中，所述的多肽，其氨基酸序列如SEQ ID NO:7至SEQ ID NO:14中任一序列所示。
本发明的另一方面涉及一种分离的多核苷酸，其编码本发明中任一项所述的分离的多肽；优选地，所述分离的多核苷酸的序列如SEQ ID NO:15至SEQ ID NO:22中任一序列所示。
本发明的再一方面涉及一种核酸构建体，包含本发明的多核苷酸。
本发明的再一方面涉及一种重组载体，其含有本发明的多核苷酸或者本发明的核酸构建体；优选地，所述重组载体为重组克隆载体、重组真核表达质粒或者重组病毒载体；优选地，所述重组表达载体为重组的转座子载体；优选地，所述转座子载体含有选自piggybac、sleeping beauty、frog prince、Tn5或Ty的转座元件；优选地，所述重组表达载体为本发明的多核苷酸与PS328b载体经重组得到的重组载体。
本发明的再一方面涉及一种重组载体组合，其包含重组载体1和重组载体2，其中：
所述重组载体1为本发明的重组载体，
所述重组载体2含有第一代嵌合抗原受体的编码序列；优选地，所述第一代嵌合抗原受体为靶向EGFR的第一代嵌合抗原受体；优选地，所述第一代嵌合抗原受体的氨基酸序列如SEQ ID NO:23所示；优选地，所述第一代嵌合抗原受体的核酸序列如SEQ ID NO:24所示；
优选地，所述重组载体2为重组的pNB328B载体。
本发明的再一方面涉及一种重组宿主细胞，其中，所述细胞含有本发明的多核苷酸、本发明的核酸构建体、本发明的重组载体或者本发明的重组载体组合；优选地，所述重组宿主细胞为重组哺乳动物细胞；优选地，所述重组宿主细胞为重组T细胞；优选地，所述重组T细胞为重组的外周血单核细胞。
本发明的双向激活共刺激分子受体还可以与第一代嵌合抗原受体联用。
本发明的再一方面涉及一种T细胞，其表达有本发明中任一权项所述的多肽，以及第一代嵌合抗原受体；优选地，所述重组T细胞为重组的外周血单核细胞；优选地，所述第一代嵌合抗原受体为靶向EGFR的第一代嵌合抗原受体；优选地，所述第一代嵌合抗原受体的氨基酸序列如SEQ ID NO:23所示。
本发明的再一方面涉及一种药用组合物，其包含本发明中任一项所述的多肽、本发明的多核苷酸、本发明的核酸构建体、本发明的重组载体、本发明的重组载体组合、本发明的重组宿主细胞或者本发明的T细胞；可选地，还包含药学上可接受的辅料。
本发明的再一方面涉及本发明中任一项所述的多肽、本发明的多核苷酸、本发明的核酸构建体、本发明的重组载体、本发明的重组载体组合、本发明的重组宿主细胞或者本发明的T细胞在制备治疗和/或预防癌症的药物中的用途；优选地，所述癌症为其癌细胞表面异常表达EGFR的癌症；优选地，所述癌症选自：腺癌、肺癌、结肠癌、大肠癌、乳腺癌、卵巢癌、***、胃癌、胆管癌、胆囊癌、食管癌、胰腺癌或***癌。
本发明的再一方面涉及本发明中任一项所述的多肽、本发明的多核苷酸、本发明的核酸构建体、本发明的重组载体、本发明的重组载体组合、本发明的重组宿主细胞或者本发明的T细胞在制备抑制癌细胞的药物中的用途；优选地，所述癌细胞为细胞表面异常表达EGFR的癌细胞；优选地，所述癌细胞选自如下癌症的癌细胞：腺癌、肺癌、结肠癌、大肠癌、乳腺癌、卵巢癌、***、胃癌、胆管癌、胆囊癌、食管癌、胰腺癌或***癌。
本发明的再一方面涉及一种在体内或体外抑制癌细胞的方法，包括给予癌细胞以有效量的本发明中任一项所述的多肽、本发明的多核苷酸、本发明的核酸构建体、本发明的重组载体、本发明的重组载体组合、本发明的重组宿主细胞或者本发明的T细胞的步骤；优选地，所述癌细胞为细胞表面异常表达EGFR的癌细胞；优选地，所述癌细胞选自如下癌症的癌细胞：腺癌、肺癌、结肠癌、大肠癌、乳腺癌、卵巢癌、***、胃癌、胆管癌、胆囊癌、食管癌、胰腺癌或***癌。
本发明的再一方面涉及一种治疗和/或预防癌症的方法，包括给予有需求的受试者以有效量的本发明中任一项所述的多肽、本发明的多核苷酸、本发明的核酸构建体、本发明的重组载体、本发明的重组载体组合、本发明的重组宿主细胞或者本发明的T细胞的步骤；优选地，所述癌症为其癌细胞表面异常表达EGFR的癌症；优选地，所述癌症选自：腺癌、肺癌、结肠癌、大肠癌、乳腺癌、卵巢癌、***、胃癌、胆管癌、胆囊癌、食管癌、胰腺癌或***癌。
本发明的再一方面涉及本发明中任一项所述的多肽、本发明的多核苷酸、本发明的核酸构建体、本发明的重组载体、本发明的重组载体组合、本发明的重组宿主细胞或者本发明的T细胞在制备促进细胞因子分泌的药物中的用途，其中，所述细胞因子选自IL-2、IL-4、IL-6、IL-10、TNF-α和IFN-γ中的一种或多种。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用的细胞培养、分子遗传学、核酸化学、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
本发明中，术语“分离的”或“被分离的”指的是，从天然状态下经人工手段获得的。如果自然界中出现某一种“分离”的物质或成分，那么可能是其所处的天然环境发生了改变，或从天然环境下分离出该物质，或二者情况均有发生。例如，某一活体动物体内天然存在某种未被分离的多聚核苷酸或多肽，而从这种天然状态下分离出来的高纯度的相同的多聚核苷酸或多肽即称之为分离的。术语“分离的”或“被分离的”不排除混有人工或合成的物质，也不排除存在不影响物质活性的其它不纯物质。
本发明中，术语“载体(vector)”是指，可将多聚核苷酸***其中的一种核酸运载工具。当载体能使***的多核苷酸编码的蛋白获得表达时，载体称为表达载体。载体可以通过转化，转导或者转染导入宿主细胞，使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的，包括但不限于：质粒；噬菌粒；柯斯质粒；人工染色体，例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC)；噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于，逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、***瘤病毒、***多瘤空泡病毒(如SV40)。一种载体可以含有多种控制表达的元件，包括但不限于，启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外，载体还可含有复制起始位点。
本发明中，术语“宿主细胞”是指，可用于导入载体的细胞，其包括但不限于，如大肠杆菌或枯草菌等的原核细胞，如酵母细胞或曲霉菌等的真菌细胞，如S2果蝇细胞或Sf9等的昆虫细胞，或者如纤维原细胞，CHO细胞，COS细胞，NSO细胞，HeLa细胞，BHK细胞，HEK 293细胞或人细胞等的动物细胞。
本发明中，术语“嵌合抗原受体”是人工改造受体，能够将识别肿瘤抗原的特异性分子(如抗体)锚定在免疫细胞(如T细胞)上，使免疫细胞识别肿瘤抗原或病毒抗原和杀死肿瘤细胞或病毒感染的细胞。
本发明中，术语“CD40”，NCBI基因库的官方ID号为958，表达于T细胞中，可促进T细胞的增殖和活化。在第二代嵌合型抗原受体修饰的T细胞疗法中，常作为胞内共刺激信号，增强T细胞的活化和增殖能力。
本发明中，术语“CD28”，NCBI基因库的官方ID号为940，表达于T细胞中，可促进T细胞的增殖和活化。在第二代嵌合型抗原受体修饰的T细胞疗法中，常作为胞内共刺激信号，增强T细胞的活化和增殖能力。
本发明中，术语“CD137”，NCBI基因库的官方ID号为3604，表达于T细胞中，可促进T细胞的增殖和活化。在第二代嵌合型抗原受体修饰的T细胞疗法中，常作为胞内共刺激信号，增强T细胞的活化和增殖能力。
本发明中，术语“单链抗体”(single-chain antibody variable fragment,scFv)是指由抗体VL区氨基酸序列和VH区氨基酸序列经Linker连接而成，具有结合抗原能力的抗体片段。其中VL和VH结构域通过使其能够产生为单个多肽链的连接体配对形成单价分子(参见，例如,Bird等人,Science 242:423-426(1988)和Huston等人,Proc.Natl.Acad.Sci.USA85:5879-5883(1988))。此类scFv分子可具有一般结构：NH2-VL-接头-VH-COOH或NH2-VH-接头-VL-COOH。合适的现有技术接头由重复的GGGGS氨基酸序列或其变体组成。例如，可使用具有氨基酸序列(GGGGS)4的接头，但也可使用其变体(Holliger等人(1993)，Proc.Natl.Acad.Sci.USA 90:6444-6448)。可用于本发明的其他接头由Alfthan等人(1995)，Protein Eng.8:725-731，Choi等人(2001)，Eur.J.Immunol.31:94-106，Hu等人(1996)，Cancer Res.56:3055-3061，Kipriyanov等人(1999)，J.Mol.Biol.293:41-56和Roovers等人(2001)，Cancer Immunol.描述。
本发明中，术语“T细胞活化相关信号”是指与T细胞活化所需要两个信号，即T细胞表面TCR-CD3复合体与抗原肽-MHC分子结合，提供T细胞活化的第一信号，决定T细胞的杀伤特异性；T细胞表面的共刺激分子(如CD28)与相应配体(如B7)结合，提供T细胞活化的第二信号，促进T细胞活化、增殖与存活。
本发明中，所述免疫受体酪氨酸活化基序为CD3ζ和/或FcεRIγ的酪氨酸活化基序；优选地，所述免疫受体酪氨酸活化基序为CD3ζ酪氨酸活化基序，其氨基酸序列如SEQ IDNO:25所示。
本发明中术语“共刺激信号分子”(Co-stimulating molecule)是指免疫细胞表面的一些粘附分子，如CD28、CD134/OX40、CD137/4-1BB、CD40等，通过与其配体结合，激活免疫细胞的第二信号，增强免疫细胞的增殖能力及细胞因子的分泌功能，延长活化免疫细胞的存活时间。
本发明中，术语“PB”转座子，是Piggybac的简称。转座子是一段可移动的遗传因子。一段DNA序列可以从原位上单独复制或断裂下来，环化后***另一位点，并对其后的基因起调控作用，此过程称转座。由于载体上的转座子发挥功能，使EGFR G1 CAR、137DCR整合入T细胞基因组。
抗体分为激活型和阻断型抗体。本发明中，术语“胞外激活型抗体”是将抗体锚定在细胞膜表面，和细胞表面分子的作用位点(即配体和受体结合部位)结合，促进细胞生物学功能。CD40胞外激活型抗体，由于CD40分子存在于大多数T细胞表面，被认为是一种T细胞特有的表面分子,CD40胞外激活型抗体可有效识别并激活CD40分子信号，产生第二信号，CD40可替代APC的第二信号作用。
本发明中，术语“旁观者功能”是指当肿瘤细胞、病毒感染的细胞时，单个CAR-T细胞，只能激活自身细胞第二信号，并不能进一步激活周围T细胞功能，导致周围T细胞不能引起一系列激活T细胞功能。
本发明中，术语“群集效应”是指单个修饰后的T细胞能够不断招募并激活周围未活化的T细胞，并激活周围T细胞下游信号通路，引起多个T细胞级的活化、增殖等功能。
本发明中，术语“EGFR”又称表皮生长因子受体、ErbB-1或HER1，epidermal growthfactor receptor，NCBI基因库的官方ID号为1956。EGFR广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞表面，EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用。EGFR与肿瘤细胞的增殖、血管生成、肿瘤侵袭、转移及细胞凋亡的抑制有关。EGFR的过表达在恶性肿瘤的演进中起重要作用，胶质细胞癌、肾癌、肺癌、***癌、胰腺癌、乳腺癌等。
本发明中，术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂，其是本领域公知的(参见例如Remington'sPharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:MackPublishing Company,1995)，并且包括但不限于：pH调节剂，表面活性剂，佐剂，离子强度增强剂。例如，pH调节剂包括但不限于磷酸盐缓冲液；表面活性剂包括但不限于阳离子，阴离子或者非离子型表面活性剂，例如Tween-80；离子强度增强剂包括但不限于氯化钠。
本发明中，术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如，预防疾病(例如肿瘤)有效量是指，足以预防，阻止，或延迟疾病(例如肿瘤)的发生的量；治疗疾病有效量是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫***的总体状态、患者的一般情况例如年龄，体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
发明的有益效果
当其与包含第一信号的第一代CAR-T共同修饰T细胞时，可以产生强烈的集群效应，杀伤肿瘤细胞。同时，这种双向激活的作用仅仅局限在相互接触的T细胞之间，不会像注射CD40的激活型抗体一样，引发强烈T细胞免疫，造成潜在严重毒副作用。本发明提供的CD40双向共刺激分子激活受体联合EGFR的嵌合抗原受体修饰的T细胞，可以特异性杀伤EGFR高表达的肿瘤细胞株，并且优于EGFR第一代、第二代CAR-T，同时对不表达的肿瘤细胞株杀伤作用较小或无，具有高效、高特异性。本发明能在保持第一代、第二代CAR疗效的基础上，CD40双向共刺激分子激活受体活化的T细胞能够激活自身T细胞第二信号，是针对肿瘤特异性抗原越强，第一信号CD3ζ激活也越强，相应地，CD40胞外激活型抗体传递T细胞活化相关的第二信号也越强，聚集在肿瘤局部周围，并且不断招募并激活周围未活化的T细胞，并激活T细胞下游信号通路，引起T细胞级联式的活化、增殖与存活。
附图说明
图1A：CD40双向激活共刺激分子受体40DCR1的结构示意图。
图1B：CD40双向激活共刺激分子受体40DCR2的结构示意图。
图1C：CD40双向激活共刺激分子受体40DCR3的结构示意图。
图1D：CD40双向激活共刺激分子受体40DCR4的结构示意图。
图1E：EGFR G1 CAR结构示意图。
图1F：EGFR G2 CAR结构示意图。
图2A：双向激活嵌合抗原受体EGFR CAR-T细胞中CD3ζ的表达情况。内参为GADPH。
图2B：双向激活嵌合抗原受体EGFR CAR-T细胞中40DCR1、40DCR2、40DCR3的拷贝数的表达情况。
图3：电转40DCR功能，重组细胞40DCR1/2/3细胞细胞增殖曲线。横坐标代表时间(h)，纵坐标代表细胞数(个)。
图4：双向激活嵌合抗原受体EGFR CAR-T细胞，细胞增殖曲线。
图5A：电转40DCR功能，Mock T的CD40表型。其中，横坐标为单个CD40阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图5B：电转40DCR1功能，重组细胞40DCR1的CD40表型。其中，横坐标为单个CD40阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图5C：电转40DCR2功能，重组细胞40DCR2的CD40表型。其中，横坐标为单个CD40阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图5D：电转40DCR3功能，重组细胞40DCR3的CD40表型。其中，横坐标为单个CD40阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图6A：电转40DCR2联合EGFR G1 CAR的功能，Mock T的CD40表型。其中，横坐标为单个CD40阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图6B：电转40DCR2联合EGFR G1 CAR的功能，重组细胞EGFR G1 CAR的CD40表型。其中，横坐标为单个CD40阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图6C：电转40DCR2联合EGFR G1 CAR的功能，重组细胞EGFR G2 CAR的CD40表型。其中，横坐标为单个CD40阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图6D：电转40DCR2联合EGFR G1 CAR的功能，重组细胞EGFR G1 CAR-40DCR1的CD40表型。其中，横坐标为单个CD40阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图7A：电转40DCR2联合EGFR G1 CAR的功能，Mock T的CD45RO表型。其中，横坐标为单个CD45RO阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图7B：电转40DCR2联合EGFR G1 CAR的功能，重组细胞EGFR G1 CAR的CD45RO表型。其中，横坐标为单个CD45RO阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图7C：电转40DCR2联合EGFR G1 CAR的功能，重组细胞EGFR G2 CAR的CD45RO表型。其中，横坐标为单个CD45RO阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图7D：电转40DCR2联合EGFR G1 CAR的功能，重组细胞EGFR G1 CAR-40DCR1的CD45RO表型。其中，横坐标为单个CD45RO阳性的细胞荧光强度，纵坐标为不同荧光强度的细胞数。
图8A：电转40DCR2联合EGFR G1 CAR的功能，Mock T的记忆T表型。其中，横坐标为单个CD62L阳性的细胞荧光强度，纵坐标为不单个CCR7阳性的细胞荧光强度。
图8B：电转40DCR2联合EGFR G1 CAR的功能，重组细胞EGFRG1 CAR的记忆T表型。其中，横坐标为单个CD62L阳性的细胞荧光强度，纵坐标为不单个CCR7阳性的细胞荧光强度。
图8C：电转40DCR2联合EGFR G1 CAR的功能，重组细胞EGFR G2 CAR的记忆T表型。其中，横坐标为单个CD62L阳性的细胞荧光强度，纵坐标为不单个CCR7阳性的细胞荧光强度。
图8D：电转40DCR联合EGFR G1 CAR的功能，重组细胞EGFR G1 CAR-40DCR1的记忆T表型。其中，横坐标为单个CD62L阳性的细胞荧光强度，纵坐标为不单个CCR7阳性的细胞荧光强度。
图9A：双向激活嵌合抗原受体EGFR CAR-T细胞在体外对H23肿瘤细胞株效靶比为8:1的杀伤。
图9B：双向激活嵌合抗原受体EGFR CAR-T细胞在体外对H23肿瘤细胞株效靶比为4:1的杀伤。
图9C：双向激活嵌合抗原受体EGFR CAR-T细胞在体外对ASPC-1肿瘤细胞株效靶比为8:1的杀伤。
图9D：双向激活嵌合抗原受体EGFR CAR-T细胞在体外对ASPC-1肿瘤细胞株效靶比为4:1的杀伤。
图10：双向激活嵌合抗原受体EGFR CAR-T细胞在EGFR抗原刺激下IL-2，IL-4，IL-6,IL-10，TNF-α和IFN-γ细胞因子的变化。
图11：双向激活嵌合抗原受体EGFR CAR-T细胞对卵巢癌小鼠移植瘤模型的治疗效果。
本发明涉及的部分序列如下：
1.CD8信号肽的氨基酸序列(SEQ ID NO:1)
MALPVTALLLPLALLLHAARPS
2.CD40胞外激活型单链抗体的氨基酸序列(SEQ ID NO:2)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK
3.IgG4Fc CH2CH3铰链区的氨基酸序列(SEQ ID NO:3)
ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
4.CD28跨膜区的氨基酸序列(SEQ ID NO:4)
PFWVLVVVGGVLACYSLLVTVAFIIFWV
5.CD28胞内共刺激信号胞内结构域的氨基酸序列(SEQ ID NO:5)
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
6.CD137胞内共刺激信号胞内结构域的氨基酸序列(SEQ ID NO:6)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
7.40DCR1的氨基酸序列(含信号肽)(SEQ ID NO:7)
MALPVTALLLPLALLLHAARPSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
8.40DCR2的氨基酸序列(含信号肽)(SEQ ID NO:8)
MALPVTALLLPLALLLHAARPSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKPFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
9.40DCR3的氨基酸序列(含信号肽)(SEQ ID NO:9)
MALPVTALLLPLALLLHAARPSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
10.40DCR4的氨基酸序列(含信号肽)(SEQ ID NO:10)
MALPVTALLLPLALLLHAARPSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKPFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
11.40DCR1的氨基酸序列(不含信号肽)(SEQ ID NO:11)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
12.40DCR2的氨基酸序列(不含信号肽)(SEQ ID NO:12)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKPFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
13.40DCR3的氨基酸序列(不含信号肽)(SEQ ID NO:13)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
14.40DCR4的氨基酸序列(不含信号肽)(SEQ ID NO:14)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKPFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
15.40DCR1的核酸序列(含信号肽)(SEQ ID NO:15)
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGAGCCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAACAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGCCCCTAGGATATTGTACTAATGGTGTATGCTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTTACAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACATTTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAACCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
16.40DCR2的核酸序列(含信号肽)(SEQ ID NO:16)
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGAGCCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAACAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGCCCCTAGGATATTGTACTAATGGTGTATGCTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTTACAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACATTTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAACCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
17.40DCR3的核酸序列(含信号肽)(SEQ ID NO:17)
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGAGCCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAACAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGCCCCTAGGATATTGTACTAATGGTGTATGCTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTTACAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACATTTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAACCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAAACGGGGCAGAAAGAAGCTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG
18.40DCR4的核酸序列(含信号肽)(SEQ ID NO:18)
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGAGCCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAACAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGCCCCTAGGATATTGTACTAATGGTGTATGCTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTTACAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACATTTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAACCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAAACGGGGCAGAAAGAAGCTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
19.40DCR1的核酸序列(不含信号肽)(SEQ ID NO:19)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAACAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGCCCCTAGGATATTGTACTAATGGTGTATGCTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTTACAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACATTTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAACCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
20.28DCR2的核酸序列(不含信号肽)(SEQ ID NO:20)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAACAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGCCCCTAGGATATTGTACTAATGGTGTATGCTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTTACAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACATTTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAACCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
21.40DCR3的核酸序列(不含信号肽)(SEQ ID NO:21)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAACAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGCCCCTAGGATATTGTACTAATGGTGTATGCTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTTACAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACATTTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAACCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAAACGGGGCAGAAAGAAGCTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG
22.40DCR4的核酸序列(不含信号肽)(SEQ ID NO:22)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAACAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGCCCCTAGGATATTGTACTAATGGTGTATGCTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTTACAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACATTTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAACCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAAACGGGGCAGAAAGAAGCTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
23.EGFR G1 CAR的氨基酸序列(SEQ ID NO:23)
ATMALPVTALLLPLALLLHAARPSDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKGGGGSGGGGSGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSSFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
24.EGFR G1 CAR的核酸序列(SEQ ID NO:24)
GCCACCATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGAGCGACATCTTGCTGACTCAGTCTCCAGTCATCCTGTCTGTGAGTCCAGGAGAAAGAGTCAGTTTCTCCTGCAGGGCCAGTCAGAGTATTGGCACAAACATACACTGGTATCAGCAAAGAACAAATGGTTCTCCAAGGCTTCTCATAAAGTATGCTTCTGAGTCTATCTCTGGGATCCCTTCCAGGTTTAGTGGCAGTGGATCAGGGACAGATTTTACTCTTAGCATCAACAGTGTGGAGTCTGAAGATATTGCAGATTATTACTGTCAACAAAATAATAACTGGCCAACCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGCAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGGTGGAAACACAGACTATAATACACCTTTCACATCCAGACTGAGCATCAACAAGGACAATTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAATCTAATGACACAGCCATATATTACTGTGCCAGAGCCCTCACCTACTATGATTACGAGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTTCGTTCGTGCCGGTCTTCCTGCCAGCGAAGCCCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCCCTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAACCACAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTGATAA
25.CD3ζ的酪氨酸活化基序(SEQ ID NO:25)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
26.EGFR G2 CAR的核苷酸序列(SEQ ID NO:26)
GCCACCATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGAGCGACATCTTGCTGACTCAGTCTCCAGTCATCCTGTCTGTGAGTCCAGGAGAAAGAGTCAGTTTCTCCTGCAGGGCCAGTCAGAGTATTGGCACAAACATACACTGGTATCAGCAAAGAACAAATGGTTCTCCAAGGCTTCTCATAAAGTATGCTTCTGAGTCTATCTCTGGGATCCCTTCCAGGTTTAGTGGCAGTGGATCAGGGACAGATTTTACTCTTAGCATCAACAGTGTGGAGTCTGAAGATATTGCAGATTATTACTGTCAACAAAATAATAACTGGCCAACCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAAGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGCAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGGTGGAAACACAGACTATAATACACCTTTCACATCCAGACTGAGCATCAACAAGGACAATTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAATCTAATGACACAGCCATATATTACTGTGCCAGAGCCCTCACCTACTATGATTACGAGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTTCGTTCGTGCCGGTCTTCCTGCCAGCGAAGCCCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCCCTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAACCACAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTGATAA
27.PS328b载体的核酸序列(SEQ ID NO:27)
GGCGCGCCTTAACCCTAGAAAGATAATCATATTGTGACGTACGTTAAAGATAATCATGCGTAAAATTGACGCATGTCTAGAGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCAGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCAAGGATCTGCGATCGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACGGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGCTGAAGCTTCGAGGGGCTCGCATCTCTCCTTCACGCGCCCGCCGCCCTACCTGAGGCCGCCATCCACGCCGGTTGAGTCGCGTTCTGCCGCCTCCCGCCTGTGGTGCCTCCTGAACTGCGTCCGCCGTCTAGGTAAGTTTAAAGCTCAGGTCGAGACCGGGCCTTTGTCCGGCGCTCCCTTGGAGCCTACCTAGACTCAGCCGGCTCTCCACGCTTTGCCTGACCCTGCTTGCTCAACTCTACGTCTTTGTTTCGTTTTCTGTTCTGCGCCGTTACAGATCCAAGCTGTGACCGGCGCCTACGAATTCGGATCCTGCACTAGTGCTGTCGACCAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAAAGCAAGTAAAACCTCTACAAATGTGGTAGCATGCGTCAATTTTACGCAGACTATCTTTCTAGGGTTAAATCGATCCCGCTAGCCCCGATATCCCCTTAATTAAGAGGGGGAGACCAAAGGGCGAGACGTTAAGGCCTCACGTGACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACGGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGCCGTCTCAGAAGAACTCGTCAAGAAGGCGATAGAAGGCGATGCGCTGCGAATCGGGAGCGGCGATACCGTAAAGCACGAGGAAGCGGTCAGCCCATTCGCCGCCAAGCTCTTCAGCAATATCACGGGTAGCCAACGCTATGTCCTGATAGCGGTCCGCCACACCCAGCCGGCCACAGTCGATGAATCCAGAAAAGCGGCCATTTTCCACCATGATATTCGGCAAGCAGGCATCGCCATGGGTCACGACGAGATCCTCGCCGTCGGGCATGCTCGCCTTGAGCCTGGCGAACAGTTCGGCTGGCGCGAGCCCCTGATGCTCTTCGTCCAGATCATCCTGATCGACAAGACCGGCTTCCATCCGAGTACGTGCTCTCTCGATGCGATGTTTCGCTTGGTGGTCGAATGGGCAGGTAGCCGGATCAAGCGTATGCAGCCGCCGCATTGCATCAGCCATGATGGATACTTTCTCGGCAGGAGCAAGGTGAGATGACAGGAGATCCTGCCCCGGCACTTCGCCCAATAGCAGCCAGTCCCTTCCCGCTTCAGTGACAACGTCGAGTACAGCTGCGCAAGGAACGCCCGTCGTGGCCAGCCACGATAGCCGCGCTGCCTCGTCTTGCAGTTCATTCAGGGCACCGGACAGGTCGGTCTTGACAAAAAGAACCGGGCGCCCCTGCGCTGACAGCCGGAACACGGCGGCATCAGAGCAGCCGATTGTCTGTTGTGCCCAGTCATAGCCGAATAGCCTCTCCACCCAAGCGGCCGGAGAACCTGCGTGCAATCCATCTTGTTCAATCATAATATTATTGAAGCATTTATCAGGGTTCGTCTCGTCCCGGTCTCCTCCCATGCATG
28.引物CD40-F的碱基序列(SEQ ID NO:28)
ACCTCCTGATCTATACTG
29.引物CD40-R的碱基序列(SEQ ID NO:29)
GATGGTGAGAGTGAAATC
30.探针Taqman中的碱基序列(SEQ ID NO:30)
CACTGCCGCTGAACCTTGATG
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件(例如参考J.萨姆布鲁克等著，黄培堂等译的《分子克隆实验指南》，第三版，科学出版社)或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市场购买获得的常规产品。
实施例1：5种重组质粒即pNB328-EGFR G1 CAR、pNB328-EGFR
G2 CAR、PS328b
40DCR1、PS328b 40DCR2和PS328b 40DCR3的构建
1.人工合成40DCR1的基因(SEQ ID NO:15)、40DCR2的基因(SEQ ID NO:16)、40DCR3的基因(SEQ ID NO:17)、EGFR G1 CAR基因(SEQ ID NO:24)以及EGFR G2 CAR基因(SEQ ID NO:26)，其结构示意图分别如图1A、图1B、图1C、图1F和图1D所示。将合成的5个基因分别装入pNB328载体和PS328b载体，EcoRI和SalI酶切位点之间，
pNB328载体中包含EF1α启动子、PB转座子等原件，pNB328载体的构建请参见WO2017054647A1的实施例2。PS328b是人工合成序列，由上海捷瑞生物工程有限公司合成，序列如SEQ ID NO:27所示。
构建出的重组质粒分别命名为pNB328-EGFR G1 CAR质粒、pNB328-EGFR G2 CAR质粒、PS328b 40DCR1质粒、PS328b 40DCR2质粒和PS328b 40DCR3质粒。构建出的重组质粒分别可以携带外源基因整合到宿主细胞的基因组中。
实施例2：9种嵌合型抗原受体修饰T细胞即重组细胞EGFR G1CAR、EGFR G2 CAR、
EGFR G1 CAR-40DCR1、EGFR G1
CAR-40DCR2、EGFR G1 CAR-40DCR3、40DCR1、40DCR2、40DCR3
和Mock T的构建和鉴定
(1)9种重组细胞的构建
将外周血单核细胞(PBMCs)贴壁培养2-4h，其中未贴壁的悬浮细胞即为初始T细胞。将悬浮细胞收集到15ml离心管中，1200rmp离心3min，弃上清；加入生理盐水，1200rmp离心3min，弃生理盐水，并重复“加入生理盐水，1200rmp离心3min，弃生理盐水”的步骤3次。
取8个1.5ml离心管，每管加入5×106个上述细胞，编号分别为a、b、c、d、e、f、g、h，1200rmp离心3min，弃上清，取电转试剂盒(来自Lonza公司)，每管按比例加入电转试剂共100μl，其中：
a管加入pNB328-EGFR G1 CAR质粒8μg，
b管加入pNB328-EGFR G2 CAR质粒8μg，
c管加入PS328b 40DCR1质粒和pNB328-EGFR G1 CAR质粒各4μg，
d管加入PS328b 40DCR2质粒和pNB328-EGFR G1 CAR质粒各4μg，
e管加入PS328b 40DCR3质粒和pNB328-EGFR G1 CAR质粒各4μg，
f管加入PS328b 40DCR1质粒8μg，
g管加入PS328b 40DCR2质粒8μg，
h管加入PS328b 40DCR3质粒8μg，
将上述8管各自重悬混匀，分别得到混合液。
将各混合液分别转移至电转杯中，放入电转仪，选取所需程序，进行电击；使用试剂盒中的微量吸管将电转好的细胞悬液转移到加好培液的六孔板中(含2％FBS的AIM-Ⅴ培液)，混匀，置于37℃，5％CO2培养箱培养6小时，然后加入刺激因子IL-2和EGFR/anti-CD28，37℃，5％CO2培养3-4天，观察T细胞的生长情况。由此分别获得了表达pNB328-EGFR G1CAR、pNB328-EGFR G2 CAR、pNB328-EGFR G1 CAR-40DCR1、pNB328-EGFR G1 CAR-40DCR2、pNB328-EGFR G1 CAR-40DCR3、PS328b 40DCR1、PS328b 40DCR2和PS328b 40DCR3基因的重组T细胞，依次命名为重组细胞EGFR G1 CAR、重组细胞EGFR G2 CAR、重组细胞EGFR G1CAR-40DCR1、重组细胞EGFR G1 CAR-40DCR2和重组细胞EGFR G1 CAR-40DCR3、重组细胞40DCR1、重组细胞40DCR2以及重组细胞40DCR3。
此外，在另一离心管(编号j)，加入5×106个细胞，1200rmp离心3min，弃上清，取电转试剂盒(购自Lonza公司)，按比例加入电转试剂共100μl，并加入8μg对照质粒(PNB328)，按前文所述方法构建得到对照T细胞，命名为Mock T。
(2)阳性重组细胞的鉴定
①western blot方法检测EGFR G1 CAR或EGFR G2 CAR基因的表达
分别收集上述重组细胞EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR1、EGFRG1CAR-40DCR2、EGFR G1 CAR-40DCR3和Mock-T细胞，生理盐水洗涤两遍，
分别加入160μl细胞裂解液，冰上放置10min；待细胞充***解后，12000rmp，4℃，离心10min，收集上清。加入40μl 5×loading Buffer，100℃煮10min，然后冰上放置5min。
使用CD3ζ抗体(购自abcam公司)、GAPDH抗体(购自Beyotime公司)、HRP羊抗鼠二抗(购自Jackson公司)，通过western blot等等检测前面构建的5种重组细胞中的CD3ζ的表达，结果如图2A所示。
结果显示，CD3ζ在这构建的5种重组T细胞中均为高表达。
②RT-PCR检测40DCR基因表达
分别提取重组细胞EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR1、EGFR G1CAR-40DCR2、EGFR G1 CAR-40DCR3和Mock-T的基因组DNA(试剂盒法)，实验步骤参照试剂盒内附带的说明书。
测定各重组细胞DNA的浓度，采用荧光实时定量PCR的方法检测40DCR基因的表达水平，反应为：95℃，15s；95℃，5s；60℃，15s。40个循环。
PCR反应体系(20μl)如下：
Taqman：10μl
CD40-F:0.4μl
CD40-R:0.4μl
CD40-probe:0.2μl
Actin mix:1μl
H2O:7μl
引物序列如下：
CD40-F：ACCTCCTGATCTATACTG(SEQ ID NO:28)
CD40-R：GATGGTGAGAGTGAAATC(SEQ ID NO:29)
Taqman：5'FAM-CACTGCCGCTGAACCTTGATG-Trama(SEQ ID NO:30)
结果如图2B所示。结果显示，重组细胞EGFR G1 CAR-40DCR1、EGFR G1 CAR-40DCR2、EGFR G1 CAR-40DCR3细胞中，40DCR基因的表达量很高。
实施例3：细胞增殖活力试剂盒检测细胞技术检测细胞增殖活力
1.实验样品和试剂
实施例2制得的重组细胞EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR2、40DCR1、40DCR2、40DCR3和Mock T。
2.实验方法
(1)准备96孔白色板，分别取培养第8天的上述各细胞，每孔加入100μL含细胞的AIM-V培养基。
(2)准备不含细胞的空白对照，以获得背景荧光值。
(3)在孔板中加入待测复合物，在培养箱中孵育30min。
(4)加入100μL CellTiter-Glo试剂，在震荡仪上混匀2min，并在室温下孵育10min，读数。
(5)培养的第8、9、10天，每天都按以上步骤检测。
3.实验结果
分别如图3和图4所示。
图3表明，Mock T增殖速率最慢，40DCR增殖速率均较快。
图4表明，Mock T增殖速率最慢，EGFR G1 CAR增殖速率较慢，EGFR G2 CAR增殖速率较快，EGFR G1 CAR-40DCR2增殖速率最快。
实施例4：流式检测EGFR抗原刺激下双向共刺激分子激活受体40DCR联合EGFR G1
CAR-T细胞表型
1.实验样品
实施例2制得的重组细胞EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR3、40DCR1，40DCR2，40DCR 3和Mock T。
2.实验方法
分别收集上述各细胞，计数后以1×106个细胞/管分别加入1.5ml的EP管中，PBS洗两遍，1200rpm离心5min，分别加入2μl的同型对照抗体IgG1-PE，荧光流式抗体anti-CD137、同型对照(IgG1FITC+IgG1PC5+IgG1PE)，(anti-CD45RO-PC5，anti-CD62L-FITC,anti-CCR7-PE)，轻弹沉淀使其混合均匀，室温避光孵育30min，PBS清洗一遍，加400μlPBS将细胞转移至流式管中，上机检测。
3.实验结果
如图5A－5D、图6A－6D、图7A－7D和图8A－8D所示。其中：
图5A－5D为3种40DCR1、40DCR2、40DCR3的3种单转细胞，CD137表型相对于Mock T有很大提高；
图6A－6D为Mock T、EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR2的CD137表型，相对于其他三组，EGFR G1 CAR-40DCR2有很大提高；
图7A－7D为Mock T、EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR2的CD45RO表型，表示细胞活化程度，均已大量活化；
图8A－8D为Mock T、EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR2的记忆T表型,相对于其他三组，EGFR G1 CAR-40DCR2能促进记忆T的形成。
实施例5：实时无标记细胞功能分析仪检测双向共刺激分子激活受体40DCR联合
EGFR G1 CAR-T细胞对肿瘤细胞的体外杀伤作用
1.实验样品
效应细胞：实施例2制得的重组细胞EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR1、EGFR G1 CAR-40DCR3、40DCR1、40DCR2、40DCR3和Mock T。
靶细胞：***细胞Hela、卵巢癌细胞SK-OV-3(均购买于美国菌种保藏中心ATCC)。
2.实验方法
选取MHC class I分型匹配的效应细胞与靶细胞，应用实时无标记细胞功能分析仪(RTCA)检测上述细胞的体外杀伤活性，具体步骤如下：
(1)调零：每孔加入50μl DMEM或1640培养液，放入仪器中，选择step 1，调零；
(2)靶细胞铺板：***细胞Hela、卵巢癌细胞SK-OV-3分别按每孔104个细胞/50μl铺在含有检测电极的板中，放置数分钟，待细胞稳定一下，再放入仪器中，开始step 2，培养细胞；
(3)加入效应细胞：靶细胞培养24h后，暂停step 2，加入效应细胞，每孔50μl，效靶比分别设置为8:1、4:(肿瘤细胞均为104个)1，以未转质粒的Mock T细胞作为对照，开始step 3，继续共培养24h后，观察细胞增殖曲线。
2.实验结果
如图9A－9D所示。
结果显示，Mock T对肿瘤细胞的杀伤作用最弱，EGFR G1 CAR对肿瘤细胞的杀伤作用较弱，EGFR G2 CAR对肿瘤细胞的杀伤作用较强，EGFR G1 CAR-40DCR1、EGFR G1 CAR-40DCR3对肿瘤细胞的杀伤作用最强。
实施例6：流式检测EGFR抗原刺激下EGFR CAR-T细胞因子分泌量
1.实验样品
实施例2制得的重组细胞EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR1和MockT。
2.实验方法
1.用5μg/ml的EGFR抗原包被96孔板，4℃包被过夜，PBS清洗3遍，分别加入1×105的各样品细胞，培养24h后收集细胞上清。用BDTMCBA Human Th1/Th2 Cytokine Kit II检测EGFR CAR-T细胞受EGFR抗原刺激后细胞因子的分泌情况。
具体步骤如下：
(1)混合人的IL-2、IL-4、IL-6、IL-10、TNF、IFN-γ捕获磁珠，涡旋振荡混匀捕获磁珠，每管加入50μl混匀后的捕获磁珠；
(2)加入50μl人的Th1/Th2细胞因子标准品(倍比稀释5000pg/ml、2500pg/ml、1250pg/ml、625pg/ml、312.5pg/ml、156pg/ml、80pg/ml、40pg/ml、20pg/ml、0pg/ml)和50μl的待测样品(经稀释液2倍稀释)。
(3)每管加入50μl的人的Th1/Th2-II-PE的检测抗体；
(4)室温避光孵育3h；
(5)每管加入1ml的Wash Buffer，200离心5min，弃上清；
(6)每管加入300μl的Wash Buffer重悬细胞，并转移至流式管中，用流式细胞仪检测荧光值。
3.实验结果
如图10所示。
结果显示，相较于Mock T细胞，其余细胞各种细胞因子(IL-2、IL-4、IL-6、IL-10、TNF-α和IFN-γ)的分泌量都有很大的提高。Mock T各种细胞因子的分泌量最弱，EGFR G1CAR各种细胞因子的分泌量较弱，EGFR G2 CAR各种细胞因子的分泌量较强，EGFR G1 CAR-40DCR1各种细胞因子的分泌量最强。
实施例7:双向共刺激分子激活受体40DCR联合EGFR G1
CAR-T细胞的体内功能实
验
1.实验样品和实验动物
4－6周龄NSG完全免疫缺陷小鼠20只，平均重量22-27g，由北京维通达生物技术有限公司提供，SPF级动物实验室饲养。
实施例2制得的重组细胞EGFR G1 CAR、EGFR G2 CAR、EGFR G1 CAR-40DCR3和MockT。
卵巢癌细胞SK-OV-3-luc(购自上海慧颖生物科技有限公司)。
2.实验方法
(1)体外培育人卵巢癌细胞SK-OV-3-luc，取对数生长期贴壁生长细胞，0.25％胰酶消化，离心、收集细胞后用PBS液重悬，1000rmp室温离心2分钟，弃上清，再用PBS液重悬后离心收集细胞，调整细胞悬液浓度至5×107个/ml。
(2)于小鼠右肋背部皮下接种SK-OV-3-luc细胞，0.1ml/只。接种10天后，可通过活体成像仪观察肿瘤大小。
(3)将NSG免疫缺陷小鼠随机分为4组，每组5只。给药途径为直接尾静脉注射，每只0.1ml/只，即5×106个阳性细胞，溶剂为PBS。只给药一次。
(4)每日观察小鼠的生活状态并每隔10天通过活体成像仪观察小鼠肿瘤变化。
3.实验结果
如图11所示。
结果显示，Mock T是对照组，肿瘤细胞荧光强度强，EGFR G1 CAR是靶向EGFR的一代CAR,肿瘤细胞荧光强度减弱，表明有一定的治疗效果，EGFR G2 CAR肿瘤细胞荧光强度更弱，表明有进一步的好的治疗效果，EGFR G1 CAR-40DCR3肿瘤细胞荧光强度最弱，表明有最好的治疗效果。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
SEQUENCE LISTING
<110> 上海细胞治疗研究院
上海细胞治疗工程技术研究中心集团有限公司
<120> 一种CD40双向激活共刺激分子受体及其用途
<130> IDC170228
<160> 30
<170> PatentIn version 3.5
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<212> PRT
<213> Artificial Sequence
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<223> CD8信号肽的氨基酸序列
<400> 1
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 Ser
20
<210> 2
<211> 248
<212> PRT
<213> Artificial Sequence
<220>
<223> CD40胞外激活型单链抗体的氨基酸序列
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr Asn Gly Val Cys Ser Tyr
100 105 110
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Tyr Ser Trp Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile Tyr Thr Ala
180 185 190
Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile Phe Pro Leu Thr Phe Gly
225 230 235 240
Gly Gly Thr Lys Val Glu Ile Lys
245
<210> 3
<211> 229
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4Fc CH2CH3铰链区的氨基酸序列
<400> 3
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 4
<211> 28
<212> PRT
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<223> CD28跨膜区的氨基酸序列
<400> 4
Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
1 5 10 15
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 5
<211> 41
<212> PRT
<213> Artificial Sequence
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<223> CD28胞内共刺激信号胞内结构域的氨基酸序列
<400> 5
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> 6
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> CD137胞内共刺激信号胞内结构域的氨基酸序列
<400> 6
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> 7
<211> 568
<212> PRT
<213> Artificial Sequence
<220>
<223> 40DCR1的氨基酸序列（含信号肽）
<400> 7
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 Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Thr Phe Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr
65 70 75 80
Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr
85 90 95
Ser Ile Ser Thr Ala Tyr Met Glu Leu Asn Arg Leu Arg Ser Asp Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr
115 120 125
Asn Gly Val Cys Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala
165 170 175
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
180 185 190
Tyr Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn
195 200 205
Leu Leu Ile Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
210 215 220
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
225 230 235 240
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile
245 250 255
Phe Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Glu Ser
260 265 270
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
275 280 285
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
290 295 300
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
305 310 315 320
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
325 330 335
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
340 345 350
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
355 360 365
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
370 375 380
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
385 390 395 400
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
405 410 415
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
420 425 430
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
435 440 445
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
450 455 460
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
465 470 475 480
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
485 490 495
Leu Gly Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala
500 505 510
Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg
515 520 525
Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro
530 535 540
Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro
545 550 555 560
Arg Asp Phe Ala Ala Tyr Arg Ser
565
<210> 8
<211> 569
<212> PRT
<213> Artificial Sequence
<220>
<223> 40DCR2的氨基酸序列（含信号肽）
<400> 8
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Thr Phe Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr
65 70 75 80
Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr
85 90 95
Ser Ile Ser Thr Ala Tyr Met Glu Leu Asn Arg Leu Arg Ser Asp Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr
115 120 125
Asn Gly Val Cys Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala
165 170 175
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
180 185 190
Tyr Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn
195 200 205
Leu Leu Ile Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
210 215 220
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
225 230 235 240
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile
245 250 255
Phe Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Glu Ser
260 265 270
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
275 280 285
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
290 295 300
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
305 310 315 320
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
325 330 335
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
340 345 350
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
355 360 365
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
370 375 380
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
385 390 395 400
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
405 410 415
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
420 425 430
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
435 440 445
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
450 455 460
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
465 470 475 480
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
485 490 495
Leu Gly Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala
500 505 510
Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys
515 520 525
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
530 535 540
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
545 550 555 560
Glu Glu Glu Glu Gly Gly Cys Glu Leu
565
<210> 9
<211> 610
<212> PRT
<213> Artificial Sequence
<220>
<223> 40DCR3的氨基酸序列（含信号肽）
<400> 9
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 Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Thr Phe Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr
65 70 75 80
Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr
85 90 95
Ser Ile Ser Thr Ala Tyr Met Glu Leu Asn Arg Leu Arg Ser Asp Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr
115 120 125
Asn Gly Val Cys Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala
165 170 175
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
180 185 190
Tyr Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn
195 200 205
Leu Leu Ile Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
210 215 220
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
225 230 235 240
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile
245 250 255
Phe Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Glu Ser
260 265 270
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
275 280 285
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
290 295 300
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
305 310 315 320
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
325 330 335
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
340 345 350
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
355 360 365
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
370 375 380
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
385 390 395 400
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
405 410 415
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
420 425 430
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
435 440 445
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
450 455 460
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
465 470 475 480
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
485 490 495
Leu Gly Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala
500 505 510
Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg
515 520 525
Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro
530 535 540
Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro
545 550 555 560
Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu
565 570 575
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
580 585 590
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
595 600 605
Glu Leu
610
<210> 10
<211> 610
<212> PRT
<213> Artificial Sequence
<220>
<223> 40DCR4的氨基酸序列（含信号肽）
<400> 10
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 Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Thr Phe Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr
65 70 75 80
Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr
85 90 95
Ser Ile Ser Thr Ala Tyr Met Glu Leu Asn Arg Leu Arg Ser Asp Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr
115 120 125
Asn Gly Val Cys Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala
165 170 175
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
180 185 190
Tyr Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn
195 200 205
Leu Leu Ile Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
210 215 220
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
225 230 235 240
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile
245 250 255
Phe Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Glu Ser
260 265 270
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
275 280 285
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
290 295 300
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
305 310 315 320
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
325 330 335
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
340 345 350
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
355 360 365
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
370 375 380
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
385 390 395 400
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
405 410 415
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
420 425 430
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
435 440 445
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
450 455 460
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
465 470 475 480
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
485 490 495
Leu Gly Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala
500 505 510
Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys
515 520 525
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
530 535 540
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
545 550 555 560
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Ser Lys Arg Ser Arg Leu
565 570 575
Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
580 585 590
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
595 600 605
Arg Ser
610
<210> 11
<211> 546
<212> PRT
<213> Artificial Sequence
<220>
<223> 40DCR1的氨基酸序列（不含信号肽）
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr Asn Gly Val Cys Ser Tyr
100 105 110
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Tyr Ser Trp Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile Tyr Thr Ala
180 185 190
Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile Phe Pro Leu Thr Phe Gly
225 230 235 240
Gly Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
245 250 255
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
260 265 270
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
275 280 285
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
290 295 300
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
305 310 315 320
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
325 330 335
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
340 345 350
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
355 360 365
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
370 375 380
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
385 390 395 400
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
405 410 415
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
420 425 430
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
435 440 445
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
450 455 460
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Pro Phe Trp
465 470 475 480
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
485 490 495
Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu
500 505 510
Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
515 520 525
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
530 535 540
Arg Ser
545
<210> 12
<211> 547
<212> PRT
<213> Artificial Sequence
<220>
<223> 40DCR2的氨基酸序列（不含信号肽）
<400> 12
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr Asn Gly Val Cys Ser Tyr
100 105 110
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Tyr Ser Trp Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile Tyr Thr Ala
180 185 190
Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile Phe Pro Leu Thr Phe Gly
225 230 235 240
Gly Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
245 250 255
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
260 265 270
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
275 280 285
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
290 295 300
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
305 310 315 320
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
325 330 335
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
340 345 350
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
355 360 365
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
370 375 380
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
385 390 395 400
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
405 410 415
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
420 425 430
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
435 440 445
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
450 455 460
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Pro Phe Trp
465 470 475 480
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
485 490 495
Thr Val Ala Phe Ile Ile Phe Trp Val Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu
545
<210> 13
<211> 588
<212> PRT
<213> Artificial Sequence
<220>
<223> 40DCR3的氨基酸序列（不含信号肽）
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr Asn Gly Val Cys Ser Tyr
100 105 110
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Tyr Ser Trp Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile Tyr Thr Ala
180 185 190
Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile Phe Pro Leu Thr Phe Gly
225 230 235 240
Gly Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
245 250 255
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
260 265 270
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
275 280 285
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
290 295 300
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
305 310 315 320
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
325 330 335
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
340 345 350
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
355 360 365
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
370 375 380
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
385 390 395 400
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
405 410 415
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
420 425 430
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
435 440 445
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
450 455 460
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Pro Phe Trp
465 470 475 480
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
485 490 495
Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu
500 505 510
Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
515 520 525
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
530 535 540
Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
545 550 555 560
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
565 570 575
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
580 585
<210> 14
<211> 588
<212> PRT
<213> Artificial Sequence
<220>
<223> 40DCR4的氨基酸序列（不含信号肽）
<400> 14
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr Asn Gly Val Cys Ser Tyr
100 105 110
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Tyr Ser Trp Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile Tyr Thr Ala
180 185 190
Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ile Phe Pro Leu Thr Phe Gly
225 230 235 240
Gly Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys
245 250 255
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
260 265 270
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
275 280 285
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
290 295 300
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
305 310 315 320
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
325 330 335
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
340 345 350
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
355 360 365
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
370 375 380
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
385 390 395 400
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
405 410 415
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
420 425 430
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
435 440 445
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
450 455 460
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Pro Phe Trp
465 470 475 480
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
485 490 495
Thr Val Ala Phe Ile Ile Phe Trp Val Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
545 550 555 560
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
565 570 575
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
580 585
<210> 15
<211> 1704
<212> DNA
<213> Artificial Sequence
<220>
<223> 40DCR1的核酸序列（含信号肽）
<400> 15
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccgagccagg tgcagctggt gcagtctggg gctgaggtga agaagcctgg ggcctcagtg 120
aaggtctcct gcaaggcttc tggatacacc ttcaccggct actatatgca ctgggtgcga 180
caggcccctg gacaagggct tgagtggatg ggatggatca accctgacag tggtggcaca 240
aactatgcac agaagtttca gggcagggtc accatgacca gggacacgtc catcagcaca 300
gcctacatgg agctgaacag gctgagatct gacgacacgg ccgtgtatta ctgtgcgaga 360
gatcagcccc taggatattg tactaatggt gtatgctcct actttgacta ctggggccag 420
ggaaccctgg tcaccgtctc ctcaggtgga ggcggttcag gcggaggtgg cagcggcggt 480
ggcgggtcgg acatccagat gacccagtct ccatcttccg tgtctgcatc tgtaggagac 540
agagtcacca tcacttgtcg ggcgagtcag ggtatttaca gctggttagc ctggtatcag 600
cagaaaccag ggaaagcccc taacctcctg atctatactg catccacttt acaaagtggg 660
gtcccatcaa ggttcagcgg cagtggatct gggacagatt tcactctcac catcagcagc 720
ctgcaacctg aagattttgc aacttactat tgtcaacagg ctaacatttt cccgctcact 780
ttcggcggag ggaccaaggt ggagatcaaa gagtccaaat atggtccccc atgcccacca 840
tgcccagcac ctgagttcct ggggggacca tcagtcttcc tgttcccccc aaaacccaag 900
gacactctca tgatctcccg gacccctgag gtcacgtgcg tggtggtgga cgtgagccag 960
gaagaccccg aggtccagtt caactggtac gtggatggcg tggaggtgca taatgccaag 1020
acaaagccgc gggaggagca gttcaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1080
ctgcaccagg actggctgaa cggcaaggag tacaagtgca aggtctccaa caaaggcctc 1140
ccgtcctcca tcgagaaaac catctccaaa gccaaagggc agccccgaga gccacaggtg 1200
tacaccctgc ccccatccca ggaggagatg accaagaacc aggtcagcct gacctgcctg 1260
gtcaaaggct tctaccccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1320
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1380
aggctaaccg tggacaagag caggtggcag gaggggaatg tcttctcatg ctccgtgatg 1440
catgaggctc tgcacaacca ctacacacag aagagcctct ccctgtctct gggtaaaccc 1500
ttttgggtgc tggtggtggt tggtggagtc ctggcttgct atagcttgct agtaacagtg 1560
gcctttatta ttttctgggt gaggagtaag aggagcaggc tcctgcacag tgactacatg 1620
aacatgactc cccgccgccc cgggcccacc cgcaagcatt accagcccta tgccccacca 1680
cgcgacttcg cagcctatcg ctcc 1704
<210> 16
<211> 1704
<212> DNA
<213> Artificial Sequence
<220>
<223> 40DCR2的核酸序列（含信号肽）
<400> 16
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccgagccagg tgcagctggt gcagtctggg gctgaggtga agaagcctgg ggcctcagtg 120
aaggtctcct gcaaggcttc tggatacacc ttcaccggct actatatgca ctgggtgcga 180
caggcccctg gacaagggct tgagtggatg ggatggatca accctgacag tggtggcaca 240
aactatgcac agaagtttca gggcagggtc accatgacca gggacacgtc catcagcaca 300
gcctacatgg agctgaacag gctgagatct gacgacacgg ccgtgtatta ctgtgcgaga 360
gatcagcccc taggatattg tactaatggt gtatgctcct actttgacta ctggggccag 420
ggaaccctgg tcaccgtctc ctcaggtgga ggcggttcag gcggaggtgg cagcggcggt 480
ggcgggtcgg acatccagat gacccagtct ccatcttccg tgtctgcatc tgtaggagac 540
agagtcacca tcacttgtcg ggcgagtcag ggtatttaca gctggttagc ctggtatcag 600
cagaaaccag ggaaagcccc taacctcctg atctatactg catccacttt acaaagtggg 660
gtcccatcaa ggttcagcgg cagtggatct gggacagatt tcactctcac catcagcagc 720
ctgcaacctg aagattttgc aacttactat tgtcaacagg ctaacatttt cccgctcact 780
ttcggcggag ggaccaaggt ggagatcaaa gagtccaaat atggtccccc atgcccacca 840
tgcccagcac ctgagttcct ggggggacca tcagtcttcc tgttcccccc aaaacccaag 900
gacactctca tgatctcccg gacccctgag gtcacgtgcg tggtggtgga cgtgagccag 960
gaagaccccg aggtccagtt caactggtac gtggatggcg tggaggtgca taatgccaag 1020
acaaagccgc gggaggagca gttcaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1080
ctgcaccagg actggctgaa cggcaaggag tacaagtgca aggtctccaa caaaggcctc 1140
ccgtcctcca tcgagaaaac catctccaaa gccaaagggc agccccgaga gccacaggtg 1200
tacaccctgc ccccatccca ggaggagatg accaagaacc aggtcagcct gacctgcctg 1260
gtcaaaggct tctaccccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1320
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1380
aggctaaccg tggacaagag caggtggcag gaggggaatg tcttctcatg ctccgtgatg 1440
catgaggctc tgcacaacca ctacacacag aagagcctct ccctgtctct gggtaaaccc 1500
ttttgggtgc tggtggtggt tggtggagtc ctggcttgct atagcttgct agtaacagtg 1560
gcctttatta ttttctgggt gaggagtaag aggagcaggc tcctgcacag tgactacatg 1620
aacatgactc cccgccgccc cgggcccacc cgcaagcatt accagcccta tgccccacca 1680
cgcgacttcg cagcctatcg ctcc 1704
<210> 17
<211> 1830
<212> DNA
<213> Artificial Sequence
<220>
<223> 40DCR3的核酸序列（含信号肽）
<400> 17
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccgagccagg tgcagctggt gcagtctggg gctgaggtga agaagcctgg ggcctcagtg 120
aaggtctcct gcaaggcttc tggatacacc ttcaccggct actatatgca ctgggtgcga 180
caggcccctg gacaagggct tgagtggatg ggatggatca accctgacag tggtggcaca 240
aactatgcac agaagtttca gggcagggtc accatgacca gggacacgtc catcagcaca 300
gcctacatgg agctgaacag gctgagatct gacgacacgg ccgtgtatta ctgtgcgaga 360
gatcagcccc taggatattg tactaatggt gtatgctcct actttgacta ctggggccag 420
ggaaccctgg tcaccgtctc ctcaggtgga ggcggttcag gcggaggtgg cagcggcggt 480
ggcgggtcgg acatccagat gacccagtct ccatcttccg tgtctgcatc tgtaggagac 540
agagtcacca tcacttgtcg ggcgagtcag ggtatttaca gctggttagc ctggtatcag 600
cagaaaccag ggaaagcccc taacctcctg atctatactg catccacttt acaaagtggg 660
gtcccatcaa ggttcagcgg cagtggatct gggacagatt tcactctcac catcagcagc 720
ctgcaacctg aagattttgc aacttactat tgtcaacagg ctaacatttt cccgctcact 780
ttcggcggag ggaccaaggt ggagatcaaa gagtccaaat atggtccccc atgcccacca 840
tgcccagcac ctgagttcct ggggggacca tcagtcttcc tgttcccccc aaaacccaag 900
gacactctca tgatctcccg gacccctgag gtcacgtgcg tggtggtgga cgtgagccag 960
gaagaccccg aggtccagtt caactggtac gtggatggcg tggaggtgca taatgccaag 1020
acaaagccgc gggaggagca gttcaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1080
ctgcaccagg actggctgaa cggcaaggag tacaagtgca aggtctccaa caaaggcctc 1140
ccgtcctcca tcgagaaaac catctccaaa gccaaagggc agccccgaga gccacaggtg 1200
tacaccctgc ccccatccca ggaggagatg accaagaacc aggtcagcct gacctgcctg 1260
gtcaaaggct tctaccccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1320
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1380
aggctaaccg tggacaagag caggtggcag gaggggaatg tcttctcatg ctccgtgatg 1440
catgaggctc tgcacaacca ctacacacag aagagcctct ccctgtctct gggtaaaccc 1500
ttttgggtgc tggtggtggt tggtggagtc ctggcttgct atagcttgct agtaacagtg 1560
gcctttatta ttttctgggt gaggagtaag aggagcaggc tcctgcacag tgactacatg 1620
aacatgactc cccgccgccc cgggcccacc cgcaagcatt accagcccta tgccccacca 1680
cgcgacttcg cagcctatcg ctccaaacgg ggcagaaaga agctcctgta tatattcaaa 1740
caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1800
ccagaagaag aagaaggagg atgtgaactg 1830
<210> 18
<211> 1830
<212> DNA
<213> Artificial Sequence
<220>
<223> 40DCR4的核酸序列（含信号肽）
<400> 18
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccgagccagg tgcagctggt gcagtctggg gctgaggtga agaagcctgg ggcctcagtg 120
aaggtctcct gcaaggcttc tggatacacc ttcaccggct actatatgca ctgggtgcga 180
caggcccctg gacaagggct tgagtggatg ggatggatca accctgacag tggtggcaca 240
aactatgcac agaagtttca gggcagggtc accatgacca gggacacgtc catcagcaca 300
gcctacatgg agctgaacag gctgagatct gacgacacgg ccgtgtatta ctgtgcgaga 360
gatcagcccc taggatattg tactaatggt gtatgctcct actttgacta ctggggccag 420
ggaaccctgg tcaccgtctc ctcaggtgga ggcggttcag gcggaggtgg cagcggcggt 480
ggcgggtcgg acatccagat gacccagtct ccatcttccg tgtctgcatc tgtaggagac 540
agagtcacca tcacttgtcg ggcgagtcag ggtatttaca gctggttagc ctggtatcag 600
cagaaaccag ggaaagcccc taacctcctg atctatactg catccacttt acaaagtggg 660
gtcccatcaa ggttcagcgg cagtggatct gggacagatt tcactctcac catcagcagc 720
ctgcaacctg aagattttgc aacttactat tgtcaacagg ctaacatttt cccgctcact 780
ttcggcggag ggaccaaggt ggagatcaaa gagtccaaat atggtccccc atgcccacca 840
tgcccagcac ctgagttcct ggggggacca tcagtcttcc tgttcccccc aaaacccaag 900
gacactctca tgatctcccg gacccctgag gtcacgtgcg tggtggtgga cgtgagccag 960
gaagaccccg aggtccagtt caactggtac gtggatggcg tggaggtgca taatgccaag 1020
acaaagccgc gggaggagca gttcaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1080
ctgcaccagg actggctgaa cggcaaggag tacaagtgca aggtctccaa caaaggcctc 1140
ccgtcctcca tcgagaaaac catctccaaa gccaaagggc agccccgaga gccacaggtg 1200
tacaccctgc ccccatccca ggaggagatg accaagaacc aggtcagcct gacctgcctg 1260
gtcaaaggct tctaccccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1320
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1380
aggctaaccg tggacaagag caggtggcag gaggggaatg tcttctcatg ctccgtgatg 1440
catgaggctc tgcacaacca ctacacacag aagagcctct ccctgtctct gggtaaaccc 1500
ttttgggtgc tggtggtggt tggtggagtc ctggcttgct atagcttgct agtaacagtg 1560
gcctttatta ttttctgggt gaaacggggc agaaagaagc tcctgtatat attcaaacaa 1620
ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1680
gaagaagaag aaggaggatg tgaactgagg agtaagagga gcaggctcct gcacagtgac 1740
tacatgaaca tgactccccg ccgccccggg cccacccgca agcattacca gccctatgcc 1800
ccaccacgcg acttcgcagc ctatcgctcc 1830
<210> 19
<211> 1638
<212> DNA
<213> Artificial Sequence
<220>
<223> 40DCR1的核酸序列（不含信号肽）
<400> 19
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaaccctg acagtggtgg cacaaactat 180
gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga acaggctgag atctgacgac acggccgtgt attactgtgc gagagatcag 300
cccctaggat attgtactaa tggtgtatgc tcctactttg actactgggg ccagggaacc 360
ctggtcaccg tctcctcagg tggaggcggt tcaggcggag gtggcagcgg cggtggcggg 420
tcggacatcc agatgaccca gtctccatct tccgtgtctg catctgtagg agacagagtc 480
accatcactt gtcgggcgag tcagggtatt tacagctggt tagcctggta tcagcagaaa 540
ccagggaaag cccctaacct cctgatctat actgcatcca ctttacaaag tggggtccca 600
tcaaggttca gcggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcaa 660
cctgaagatt ttgcaactta ctattgtcaa caggctaaca ttttcccgct cactttcggc 720
ggagggacca aggtggagat caaagagtcc aaatatggtc ccccatgccc accatgccca 780
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 840
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 900
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 960
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1020
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 1080
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 1140
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 1200
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1260
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 1320
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 1380
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa acccttttgg 1440
gtgctggtgg tggttggtgg agtcctggct tgctatagct tgctagtaac agtggccttt 1500
attattttct gggtgaggag taagaggagc aggctcctgc acagtgacta catgaacatg 1560
actccccgcc gccccgggcc cacccgcaag cattaccagc cctatgcccc accacgcgac 1620
ttcgcagcct atcgctcc 1638
<210> 20
<211> 1638
<212> DNA
<213> Artificial Sequence
<220>
<223> 28DCR2的核酸序列（不含信号肽）
<400> 20
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaaccctg acagtggtgg cacaaactat 180
gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga acaggctgag atctgacgac acggccgtgt attactgtgc gagagatcag 300
cccctaggat attgtactaa tggtgtatgc tcctactttg actactgggg ccagggaacc 360
ctggtcaccg tctcctcagg tggaggcggt tcaggcggag gtggcagcgg cggtggcggg 420
tcggacatcc agatgaccca gtctccatct tccgtgtctg catctgtagg agacagagtc 480
accatcactt gtcgggcgag tcagggtatt tacagctggt tagcctggta tcagcagaaa 540
ccagggaaag cccctaacct cctgatctat actgcatcca ctttacaaag tggggtccca 600
tcaaggttca gcggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcaa 660
cctgaagatt ttgcaactta ctattgtcaa caggctaaca ttttcccgct cactttcggc 720
ggagggacca aggtggagat caaagagtcc aaatatggtc ccccatgccc accatgccca 780
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 840
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 900
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 960
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1020
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 1080
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 1140
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 1200
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1260
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 1320
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 1380
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa acccttttgg 1440
gtgctggtgg tggttggtgg agtcctggct tgctatagct tgctagtaac agtggccttt 1500
attattttct gggtgaggag taagaggagc aggctcctgc acagtgacta catgaacatg 1560
actccccgcc gccccgggcc cacccgcaag cattaccagc cctatgcccc accacgcgac 1620
ttcgcagcct atcgctcc 1638
<210> 21
<211> 1764
<212> DNA
<213> Artificial Sequence
<220>
<223> 40DCR3的核酸序列（不含信号肽）
<400> 21
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaaccctg acagtggtgg cacaaactat 180
gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga acaggctgag atctgacgac acggccgtgt attactgtgc gagagatcag 300
cccctaggat attgtactaa tggtgtatgc tcctactttg actactgggg ccagggaacc 360
ctggtcaccg tctcctcagg tggaggcggt tcaggcggag gtggcagcgg cggtggcggg 420
tcggacatcc agatgaccca gtctccatct tccgtgtctg catctgtagg agacagagtc 480
accatcactt gtcgggcgag tcagggtatt tacagctggt tagcctggta tcagcagaaa 540
ccagggaaag cccctaacct cctgatctat actgcatcca ctttacaaag tggggtccca 600
tcaaggttca gcggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcaa 660
cctgaagatt ttgcaactta ctattgtcaa caggctaaca ttttcccgct cactttcggc 720
ggagggacca aggtggagat caaagagtcc aaatatggtc ccccatgccc accatgccca 780
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 840
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 900
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 960
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1020
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 1080
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 1140
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 1200
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1260
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 1320
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 1380
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa acccttttgg 1440
gtgctggtgg tggttggtgg agtcctggct tgctatagct tgctagtaac agtggccttt 1500
attattttct gggtgaggag taagaggagc aggctcctgc acagtgacta catgaacatg 1560
actccccgcc gccccgggcc cacccgcaag cattaccagc cctatgcccc accacgcgac 1620
ttcgcagcct atcgctccaa acggggcaga aagaagctcc tgtatatatt caaacaacca 1680
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1740
gaagaagaag gaggatgtga actg 1764
<210> 22
<211> 1764
<212> DNA
<213> Artificial Sequence
<220>
<223> 40DCR4的核酸序列（不含信号肽）
<400> 22
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaaccctg acagtggtgg cacaaactat 180
gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga acaggctgag atctgacgac acggccgtgt attactgtgc gagagatcag 300
cccctaggat attgtactaa tggtgtatgc tcctactttg actactgggg ccagggaacc 360
ctggtcaccg tctcctcagg tggaggcggt tcaggcggag gtggcagcgg cggtggcggg 420
tcggacatcc agatgaccca gtctccatct tccgtgtctg catctgtagg agacagagtc 480
accatcactt gtcgggcgag tcagggtatt tacagctggt tagcctggta tcagcagaaa 540
ccagggaaag cccctaacct cctgatctat actgcatcca ctttacaaag tggggtccca 600
tcaaggttca gcggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcaa 660
cctgaagatt ttgcaactta ctattgtcaa caggctaaca ttttcccgct cactttcggc 720
ggagggacca aggtggagat caaagagtcc aaatatggtc ccccatgccc accatgccca 780
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 840
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 900
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 960
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1020
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 1080
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 1140
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 1200
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1260
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 1320
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 1380
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa acccttttgg 1440
gtgctggtgg tggttggtgg agtcctggct tgctatagct tgctagtaac agtggccttt 1500
attattttct gggtgaaacg gggcagaaag aagctcctgt atatattcaa acaaccattt 1560
atgagaccag tacaaactac tcaagaggaa gatggctgta gctgccgatt tccagaagaa 1620
gaagaaggag gatgtgaact gaggagtaag aggagcaggc tcctgcacag tgactacatg 1680
aacatgactc cccgccgccc cgggcccacc cgcaagcatt accagcccta tgccccacca 1740
cgcgacttcg cagcctatcg ctcc 1764
<210> 23
<211> 499
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR G1 CAR的氨基酸序列
<400> 23
Ala Thr Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu
1 5 10 15
Leu Leu His Ala Ala Arg Pro Ser Asp Ile Leu Leu Thr Gln Ser Pro
20 25 30
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg
35 40 45
Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr
50 55 60
Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser
65 70 75 80
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys
100 105 110
Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu
115 120 125
Glu Leu Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro
145 150 155 160
Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr
165 170 175
Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu
180 185 190
Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro
195 200 205
Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val
210 215 220
Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr
225 230 235 240
Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly
245 250 255
Gln Gly Thr Leu Val Thr Val Ser Ser Phe Val Pro Val Phe Leu Pro
260 265 270
Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
275 280 285
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
290 295 300
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
305 310 315 320
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
325 330 335
Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Ser Lys Arg Ser Arg
340 345 350
Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro
355 360 365
Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala
370 375 380
Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 24
<211> 1503
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR G1 CAR的核酸序列
<400> 24
gccaccatgg ccttaccagt gaccgccttg ctcctgccgc tggccttgct gctccacgcc 60
gccaggccga gcgacatctt gctgactcag tctccagtca tcctgtctgt gagtccagga 120
gaaagagtca gtttctcctg cagggccagt cagagtattg gcacaaacat acactggtat 180
cagcaaagaa caaatggttc tccaaggctt ctcataaagt atgcttctga gtctatctct 240
gggatccctt ccaggtttag tggcagtgga tcagggacag attttactct tagcatcaac 300
agtgtggagt ctgaagatat tgcagattat tactgtcaac aaaataataa ctggccaacc 360
acgttcggtg ctgggaccaa gctggagctg aaaggtggag gcggttcagg cggaggtggc 420
agcggcggtg gcgggtcgca ggtgcagctg aagcagtcag gacctggcct agtgcagccc 480
tcacagagcc tgtccatcac ctgcacagtc tctggtttct cattaactaa ctatggtgta 540
cactgggttc gccagtctcc aggaaagggt ctggagtggc tgggagtgat atggagtggt 600
ggaaacacag actataatac acctttcaca tccagactga gcatcaacaa ggacaattcc 660
aagagccaag ttttctttaa aatgaacagt ctgcaatcta atgacacagc catatattac 720
tgtgccagag ccctcaccta ctatgattac gagtttgctt actggggcca agggactctg 780
gtcactgtct cttcgttcgt gccggtcttc ctgccagcga agcccaccac gacgccagcg 840
ccgcgaccac caacaccggc gcccaccatc gcgtcgcagc ccctgtccct gcgcccagag 900
gcgtgccggc cagcggcggg gggcgcagtg cacacgaggg ggctggactt cgcctgtgat 960
atctacatct gggcgcccct ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaccacag gagtaagagg agcaggctcc tgcacagtga ctacatgaac 1080
atgactcccc gccgccccgg gcccacccgc aagcattacc agccctatgc cccaccacgc 1140
gacttcgcag cctatcgctc cagagtgaag ttcagcagga gcgcagacgc ccccgcgtac 1200
cagcagggcc agaaccagct ctataacgag ctcaatctag gacgaagaga ggagtacgat 1260
gttttggaca agagacgtgg ccgggaccct gagatggggg gaaagccgag aaggaagaac 1320
cctcaggaag gcctgtacaa tgaactgcag aaagataaga tggcggaggc ctacagtgag 1380
attgggatga aaggcgagcg ccggaggggc aaggggcacg atggccttta ccagggtctc 1440
agtacagcca ccaaggacac ctacgacgcc cttcacatgc aggccctgcc ccctcgctga 1500
taa 1503
<210> 25
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> CD3ζ的酪氨酸活化基序
<400> 25
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> 26
<211> 1503
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR G2 CAR的核苷酸序列
<400> 26
gccaccatgg ccttaccagt gaccgccttg ctcctgccgc tggccttgct gctccacgcc 60
gccaggccga gcgacatctt gctgactcag tctccagtca tcctgtctgt gagtccagga 120
gaaagagtca gtttctcctg cagggccagt cagagtattg gcacaaacat acactggtat 180
cagcaaagaa caaatggttc tccaaggctt ctcataaagt atgcttctga gtctatctct 240
gggatccctt ccaggtttag tggcagtgga tcagggacag attttactct tagcatcaac 300
agtgtggagt ctgaagatat tgcagattat tactgtcaac aaaataataa ctggccaacc 360
acgttcggtg ctgggaccaa gctggagctg aaaggtggag gcggttcagg cggaggtggc 420
agcggcggtg gcgggtcgca ggtgcagctg aagcagtcag gacctggcct agtgcagccc 480
tcacagagcc tgtccatcac ctgcacagtc tctggtttct cattaactaa ctatggtgta 540
cactgggttc gccagtctcc aggaaagggt ctggagtggc tgggagtgat atggagtggt 600
ggaaacacag actataatac acctttcaca tccagactga gcatcaacaa ggacaattcc 660
aagagccaag ttttctttaa aatgaacagt ctgcaatcta atgacacagc catatattac 720
tgtgccagag ccctcaccta ctatgattac gagtttgctt actggggcca agggactctg 780
gtcactgtct cttcgttcgt gccggtcttc ctgccagcga agcccaccac gacgccagcg 840
ccgcgaccac caacaccggc gcccaccatc gcgtcgcagc ccctgtccct gcgcccagag 900
gcgtgccggc cagcggcggg gggcgcagtg cacacgaggg ggctggactt cgcctgtgat 960
atctacatct gggcgcccct ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaccacag gagtaagagg agcaggctcc tgcacagtga ctacatgaac 1080
atgactcccc gccgccccgg gcccacccgc aagcattacc agccctatgc cccaccacgc 1140
gacttcgcag cctatcgctc cagagtgaag ttcagcagga gcgcagacgc ccccgcgtac 1200
cagcagggcc agaaccagct ctataacgag ctcaatctag gacgaagaga ggagtacgat 1260
gttttggaca agagacgtgg ccgggaccct gagatggggg gaaagccgag aaggaagaac 1320
cctcaggaag gcctgtacaa tgaactgcag aaagataaga tggcggaggc ctacagtgag 1380
attgggatga aaggcgagcg ccggaggggc aaggggcacg atggccttta ccagggtctc 1440
agtacagcca ccaaggacac ctacgacgcc cttcacatgc aggccctgcc ccctcgctga 1500
taa 1503
<210> 27
<211> 2718
<212> DNA
<213> Artificial Sequence
<220>
<223> PS328b载体的核酸序列
<400> 27
ggcgcgcctt aaccctagaa agataatcat attgtgacgt acgttaaaga taatcatgcg 60
taaaattgac gcatgtctag aggtgtggaa agtccccagg ctccccagca ggcagaagta 120
tgcaaagcat gcatctcaat tagtcagcaa ccaggtgtgg aaagtcccca ggctccccag 180
caggcagaag tatgcaaagc atgcatctca attagtcagc aaccaaggat ctgcgatcgc 240
tccggtgccc gtcagtgggc agagcgcaca tcgcccacag tccccgagaa gttgggggga 300
ggggtcggca attgaacggg tgcctagaga aggtggcgcg gggtaaactg ggaaagtgat 360
gtcgtgtact ggctccgcct ttttcccgag ggtgggggag aaccgtatat aagtgcagta 420
gtcgccgtga acgttctttt tcgcaacggg tttgccgcca gaacacagct gaagcttcga 480
ggggctcgca tctctccttc acgcgcccgc cgccctacct gaggccgcca tccacgccgg 540
ttgagtcgcg ttctgccgcc tcccgcctgt ggtgcctcct gaactgcgtc cgccgtctag 600
gtaagtttaa agctcaggtc gagaccgggc ctttgtccgg cgctcccttg gagcctacct 660
agactcagcc ggctctccac gctttgcctg accctgcttg ctcaactcta cgtctttgtt 720
tcgttttctg ttctgcgccg ttacagatcc aagctgtgac cggcgcctac gaattcggat 780
cctgcactag tgctgtcgac cagacatgat aagatacatt gatgagtttg gacaaaccac 840
aactagaatg cagtgaaaaa aatgctttat ttgtgaaatt tgtgatgcta ttgctttatt 900
tgtaaccatt ataagctgca ataaacaagt taacaacaac aattgcattc attttatgtt 960
tcaggttcag ggggaggtgt gggaggtttt ttaaagcaag taaaacctct acaaatgtgg 1020
tagcatgcgt caattttacg cagactatct ttctagggtt aaatcgatcc cgctagcccc 1080
gatatcccct taattaagag ggggagacca aagggcgaga cgttaaggcc tcacgtgaca 1140
tgtgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg ctggcgtttt 1200
tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt cagaggtggc 1260
gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc ctcgtgcgct 1320
ctcctgttcc gaccctgccg cttacgggat acctgtccgc ctttctccct tcgggaagcg 1380
tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc gttcgctcca 1440
agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta tccggtaact 1500
atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca gccactggta 1560
acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag tggtggccta 1620
actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag ccagttacct 1680
tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt agcggtggtt 1740
tttttgtttg caagcagcag attacgcgca gaaaaaaagg atctcaagaa gatcctttga 1800
tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg attttggtca 1860
tgccgtctca gaagaactcg tcaagaaggc gatagaaggc gatgcgctgc gaatcgggag 1920
cggcgatacc gtaaagcacg aggaagcggt cagcccattc gccgccaagc tcttcagcaa 1980
tatcacgggt agccaacgct atgtcctgat agcggtccgc cacacccagc cggccacagt 2040
cgatgaatcc agaaaagcgg ccattttcca ccatgatatt cggcaagcag gcatcgccat 2100
gggtcacgac gagatcctcg ccgtcgggca tgctcgcctt gagcctggcg aacagttcgg 2160
ctggcgcgag cccctgatgc tcttcgtcca gatcatcctg atcgacaaga ccggcttcca 2220
tccgagtacg tgctctctcg atgcgatgtt tcgcttggtg gtcgaatggg caggtagccg 2280
gatcaagcgt atgcagccgc cgcattgcat cagccatgat ggatactttc tcggcaggag 2340
caaggtgaga tgacaggaga tcctgccccg gcacttcgcc caatagcagc cagtcccttc 2400
ccgcttcagt gacaacgtcg agtacagctg cgcaaggaac gcccgtcgtg gccagccacg 2460
atagccgcgc tgcctcgtct tgcagttcat tcagggcacc ggacaggtcg gtcttgacaa 2520
aaagaaccgg gcgcccctgc gctgacagcc ggaacacggc ggcatcagag cagccgattg 2580
tctgttgtgc ccagtcatag ccgaatagcc tctccaccca agcggccgga gaacctgcgt 2640
gcaatccatc ttgttcaatc ataatattat tgaagcattt atcagggttc gtctcgtccc 2700
ggtctcctcc catgcatg 2718
<210> 28
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物CD40-F的碱基序列
<400> 28
acctcctgat ctatactg 18
<210> 29
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物CD40-R的碱基序列
<400> 29
gatggtgaga gtgaaatc 18
<210> 30
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> 探针Taqman中的碱基序列
<400> 30
cactgccgct gaaccttgat g 21
Claims (38)
1.一种分离的多肽，其从N端到C端依次包括下述元件：
信号肽、CD40激活型单链抗体、胞外铰链区、跨膜区和胞内共刺激信号分子；
其中，
所述信号肽为膜蛋白信号肽，
所述CD40激活型单链抗体的氨基酸序列如SEQ ID NO:2所示。
2.根据权利要求1所述的分离的多肽，其特征在于如下的(1)－(3)项中的任意1项、2项或3项：
(1)所述胞外铰链区选自IgG4Fc CH2CH3铰链区、CD28铰链区和CD8铰链区；
(2)所述跨膜区选自CD28跨膜区、CD8跨膜区、CD3ζ跨膜区、CD134跨膜区、CD137跨膜区、ICOS跨膜区和DAP10跨膜区；
(3)所述胞内共刺激信号分子选自CD28胞内结构域、CD134/OX40胞内结构域、CD137/4-1BB胞内结构域、LCK胞内结构域、ICOS胞内结构域和DAP10胞内结构域。
3.根据权利要求1所述的分离的多肽，其中，所述信号肽选自CD8信号肽、CD28信号肽和CD4信号肽。
4.根据权利要求3所述的分离的多肽，其中，所述信号肽是CD8信号肽，并且CD8信号肽的氨基酸序列如SEQ ID NO:1所示。
5.根据权利要求2所述的分离的多肽，其中，第(1)项中，所述胞外铰链区为IgG4FcCH2CH3铰链区，并且所述IgG4Fc CH2CH3铰链区的氨基酸序列如SEQ ID NO:3所示。
6.根据权利要求2所述的分离的多肽，其中，第(2)项中，所述跨膜区为CD28跨膜区，并且所述CD28跨膜区的氨基酸序列如SEQ ID NO:4所示。
7.根据权利要求2所述的分离的多肽，其中，第(3)项中，所述胞内共刺激信号分子为CD28胞内结构域和/或CD137胞内结构域。
8.根据权利要求7所述的分离的多肽，其中，所述CD28胞内结构域的氨基酸序列如SEQID NO:5所示。
9.根据权利要求7所述的分离的多肽，其中，所述CD137胞内结构域的氨基酸序列如SEQID NO:6所示。
10.根据权利要求1至9中任一权利要求所述的分离的多肽，其从N端到C端依次包括下述元件：
CD8信号肽、CD40激活型单链抗体、IgG4Fc CH2CH3铰链区、CD28跨膜区、以及CD28胞内结构域和/或CD137胞内结构域。
11.根据权利要求1至9中任一权利要求所述的分离的多肽，其氨基酸序列如SEQ IDNO:7至SEQ ID NO:10中任一序列所示。
12.一种分离的多核苷酸，其编码权利要求1至11中任一权利要求所述的分离的多肽。
13.根据权利要求12所述的分离的多核苷酸，其序列如SEQ ID NO:15至SEQ ID NO:18中任一序列所示。
14.一种重组载体，其含有权利要求12至13中任一权利要求所述的多核苷酸。
15.根据权利要求14所述的重组载体，其中，所述重组载体为重组克隆载体。
16.根据权利要求14所述的重组载体，其中，所述重组载体为重组病毒载体。
17.根据权利要求14所述的重组载体，其中，所述重组载体为重组真核表达载体。
18.根据权利要求17所述的重组载体，其中，所述重组真核表达载体为重组的转座子载体。
19.根据权利要求18所述的重组载体，其中，所述转座子载体含有选自piggybac、sleeping beauty、frog prince、Tn5或Ty的转座元件。
20.根据权利要求17所述的重组载体，其中，所述重组真核表达载体为权利要求12至13中任一权利要求所述的多核苷酸与PS328b载体经重组得到的重组载体。
21.一种重组载体组合，其包含重组载体1和重组载体2，其中：
所述重组载体1为权利要求14至20中任一权利要求所述的重组载体，
所述重组载体2含有第一代嵌合抗原受体的编码序列；
其中，所述第一代嵌合抗原受体为靶向EGFR的第一代嵌合抗原受体。
22.根据权利要求21所述的重组载体组合，其中，所述第一代嵌合抗原受体的氨基酸序列如SEQ ID NO:23所示。
23.根据权利要求21所述的重组载体组合，其中，所述第一代嵌合抗原受体的核酸序列如SEQ ID NO:24所示。
24.根据权利要求21至23中任一权利要求所述的重组载体组合，其中，所述重组载体2为重组的PNB328B载体。
25.一种重组宿主细胞，其中，所述细胞含有权利要求12至13中任一权利要求所述的多核苷酸、权利要求14至20中任一权利要求所述的重组载体或者权利要求21至24中任一权利要求所述的重组载体组合。
26.根据权利要求25所述的重组宿主细胞，其中，所述重组宿主细胞为重组哺乳动物细胞。
27.根据权利要求25所述的重组宿主细胞，其中，所述重组宿主细胞为重组T细胞。
28.根据权利要求25所述的重组宿主细胞，其中，所述重组T细胞为重组的外周血单核细胞。
29.一种T细胞，其表达有权利要求1至11中任一权利要求所述的多肽，以及第一代嵌合抗原受体；
其中，所述第一代嵌合抗原受体为靶向EGFR的第一代嵌合抗原受体。
30.根据权利要求29所述的T细胞，其中，所述T细胞为重组的外周血单核细胞。
31.根据权利要求29所述的T细胞，其中，所述第一代嵌合抗原受体的氨基酸序列如SEQID NO:23所示。
32.一种药用组合物，其包含权利要求1至11中任一权利要求所述的多肽、权利要求12至13中任一权利要求所述的多核苷酸、权利要求14至20中任一权利要求所述的重组载体、权利要求21至24中任一权利要求所述的重组载体组合、权利要求25至28中任一权利要求所述的重组宿主细胞或者权利要求29至31中任一权利要求所述的T细胞。
33.根据权利要求32所述的药物组合物，其还包含药学上可接受的辅料。
34.权利要求1至11中任一权利要求所述的多肽、权利要求12至13中任一权利要求所述的多核苷酸、权利要求14至20中任一权利要求所述的重组载体、权利要求21至24中任一权利要求所述的重组载体组合、权利要求25至28中任一权利要求所述的重组宿主细胞或者权利要求29至31中任一权利要求所述的T细胞在制备治疗癌症的药物中的用途；
其中，所述癌症为其癌细胞表面异常表达EGFR的癌症。
35.根据权利要求34所述的用途，其中，所述癌症选自：腺癌、肺癌、结肠癌、大肠癌、乳腺癌、卵巢癌、***、胃癌、胆管癌、胆囊癌、食管癌、胰腺癌或***癌。
36.权利要求1至11中任一权利要求所述的多肽、权利要求12至13中任一权利要求所述的多核苷酸、权利要求14至20中任一权利要求所述的重组载体、权利要求21至24中任一权利要求所述的重组载体组合、权利要求25至28中任一权利要求所述的重组宿主细胞或者权利要求29至31中任一权利要求所述的T细胞在制备抑制癌细胞的药物中的用途；
其中，所述癌细胞为细胞表面异常表达EGFR的癌细胞。
37.根据权利要求36所述的用途，其中，所述癌细胞选自如下癌症的癌细胞：腺癌、肺癌、结肠癌、大肠癌、乳腺癌、卵巢癌、***、胃癌、胆管癌、胆囊癌、食管癌、胰腺癌或***癌。
38.权利要求1至11中任一权利要求所述的多肽、权利要求12至13中任一权利要求所述的多核苷酸、权利要求14至20中任一权利要求所述的重组载体、权利要求21至24中任一权利要求所述的重组载体组合、权利要求25至28中任一权利要求所述的重组宿主细胞或者权利要求29至31中任一权利要求所述的T细胞在制备促进细胞因子分泌的药物中的用途，其中，所述细胞因子选自IL-2、IL-4、IL-6、IL-10、TNF-α和IFN-γ中的一种或多种。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711466912.8A CN109970867B (zh) | 2017-12-28 | 2017-12-28 | 一种cd40双向激活共刺激分子受体及其用途 |
| PCT/CN2018/123859 WO2019129047A1 (zh) | 2017-12-28 | 2018-12-26 | 一种cd40双向激活共刺激分子受体及其用途 |
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|---|---|---|---|
| CN201711466912.8A CN109970867B (zh) | 2017-12-28 | 2017-12-28 | 一种cd40双向激活共刺激分子受体及其用途 |
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| CN111378046B (zh) * | 2018-12-27 | 2024-03-15 | 上海细胞治疗集团有限公司 | 一种免疫效应细胞转换受体 |
| WO2022036495A1 (en) | 2020-08-17 | 2022-02-24 | Utc Therapeutics Inc. | Lymphocytes-antigen presenting cells co-stimulators and uses thereof |
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| WO2004009789A2 (en) * | 2002-07-22 | 2004-01-29 | Vectorlogics, Inc. | Targeted adenoviral vector displaying immunoglobulin-binding domain and uses thereof |
| CN103483453A (zh) * | 2012-06-12 | 2014-01-01 | 上海吴孟超医学科技基金会 | 结合egfr家族蛋白的嵌合抗原受体、其组合物及用途 |
| CN105177031A (zh) * | 2015-06-12 | 2015-12-23 | 北京艺妙神州医疗科技有限公司 | 嵌合抗原受体修饰的t细胞及其用途 |
| WO2017027291A1 (en) * | 2015-08-07 | 2017-02-16 | Seattle Children's Hospital (dba Seattle Children's Research Institute) | Bispecific car t-cells for solid tumor targeting |
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| WO2004009789A2 (en) * | 2002-07-22 | 2004-01-29 | Vectorlogics, Inc. | Targeted adenoviral vector displaying immunoglobulin-binding domain and uses thereof |
| CN103483453A (zh) * | 2012-06-12 | 2014-01-01 | 上海吴孟超医学科技基金会 | 结合egfr家族蛋白的嵌合抗原受体、其组合物及用途 |
| CN105177031A (zh) * | 2015-06-12 | 2015-12-23 | 北京艺妙神州医疗科技有限公司 | 嵌合抗原受体修饰的t细胞及其用途 |
| WO2017027291A1 (en) * | 2015-08-07 | 2017-02-16 | Seattle Children's Hospital (dba Seattle Children's Research Institute) | Bispecific car t-cells for solid tumor targeting |
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