CN112480263A - 一种双特异t细胞激活器活化t细胞的设计及其应用 - Google Patents
一种双特异t细胞激活器活化t细胞的设计及其应用 Download PDFInfo
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Abstract
本发明提供了一种抑制肿瘤尤其是实体肿瘤的免疫治疗方案——将表达嵌合CD3e融合蛋白的T细胞与BiTA联用,其中嵌合CD3e融合蛋白与BiTA相互结合,发挥活化T细胞和靶向肿瘤细胞的功能。本发明还提供了一种CAB结构和CAB编辑T细胞(CAB‑T)。CAB‑T细胞分泌的BiTA在肿瘤组织中可以同时实现CAB‑T细胞激活和非编辑T细胞内源TCR的活化,并发挥CAB‑T自身抗肿瘤以及调动未编辑T细胞的抗肿瘤作用。CAB‑T表达的嵌合CD3e与BiTA相互协同发挥抗肿瘤效应:嵌合CD3e的活化依赖于CAB‑T分泌的BiTA,而BiTA的分泌会进一步通过激活嵌合CD3e而刺激CAB‑T释放更多的BiTA;肿瘤组织中CAB‑T释放的少量BiTA可以通过活化嵌合CD3e而刺激CAB‑T释放更多的BiTA,实现肿瘤组织倾向的免疫细胞活化及抗肿瘤效应,保证了CAB‑T临床应用的安全性优势。
Description
技术领域
本发明属于免疫治疗领域,具体地,本发明涉及一种双特异T细胞激活器活化T细胞的设计及其应用。
背景技术
近年来,免疫细胞疗法在血液肿瘤完全缓解率方面取得了前所未有的成功。2017年,已有两个靶向CD19的CAR-T产品已成功上市,分别被批准用于治疗儿童及青少年急性白血病和非霍奇金淋巴瘤。
但利用免疫疗法治疗实体肿瘤,还存在两大难题:一方面,与CAR-T疗法相伴随的严重、甚至致命的临床副作用仍是CAR-T疗法临床应用的巨大风险,这些副作用主要包括细胞因子释放综合征(cytokine release syndrome,CRS)、巨噬细胞活化综合征、嗜血淋巴组织细胞瘤病、神经毒性等。而另一方面,在实体肿瘤的临床治疗中,CAR-T疗法还未展现其显著的临床疗效。
因此本领域急需开发一种临床疗效好而临床副作用低的抑制实体肿瘤的治疗方案。
发明内容
本发明的目的是提供一种临床疗效好而临床副作用低的抑制实体肿瘤的治疗方案。
本发明第一方面提供一种融合蛋白,其特征在于,所述融合蛋白的结构如下式I所示:
L-EC-H-TM-C-CD3ζ (I)
式中,
L为无或信号肽序列;
EC为多肽结合域,所述多肽结合域可被CD3抗体识别并与CD3抗体结合;
所述的多肽结合域也称为CD3抗体的识别结合域;
H为无或铰链区;
TM为跨膜结构域;
C为无或共刺激信号分子;
CD3ζ为源于CD3ζ的胞浆信号传导序列;
各“-”独立地为连接肽或肽键。
在另一优选例中,所述的L为选自下组的蛋白的信号肽:CD8、GM-CSF、CD4、CD137、或其组合。
在另一优选例中,所述的多肽结合域来自或衍生自CD3e蛋白。
在另一优选例中,所述的多肽结合域为CD3e胞外区或其他可被CD3抗体识别的氨基酸序列。
在另一优选例中,所述的CD3抗体选自下组:scFV(单链抗体)、纳米抗体、双链抗体、或其变体、或其组合。
在另一优选例中,所述的CD3抗体包括BiTA分子的CD3抗体区段。
在另一优选例中,所述的多肽结合域特异性识别并结合于CD3抗体。
在另一优选例中,所述的EC为野生型或突变型的CD3e蛋白的第1位至104位,其氨基酸序列如SEQ ID NO.:1所示。
在另一优选例中,所述的H为选自下组的蛋白的铰链区:CD8、CD28、CD137、或其组合。
在另一优选例中,所述的TM为选自下组的蛋白的跨膜区:CD28、CD3epsilon、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、或其组合。
在另一优选例中,所述的C为选自下组的蛋白的共刺激信号分子:OX40、CD2、CD7、CD27、CD28、CD30、CD40、CD70、CD134、4-1BB(CD137)、PD1、Dap10、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、NKG2D、GITR、TLR2、或其组合。
在另一优选例中,C包括4-1BB来源的共刺激信号分子,和/或CD28来源的共刺激信号分子。
本发明第二方面提供一种的核酸分子,其特征在于,所述的核酸分子编码如第一方面所述的融合蛋白。
本发明第三方面提供一种载体,其特征在于,所述的载体含有如第二方面所述的核酸分子。
在另一优选例中,所述载体包括慢病毒载体、腺病毒、逆转录病毒。
本发明第四方面提供一种基因工程化的T细胞,其特征在于,所述的T细胞中表达如第一方面所述的嵌合融合蛋白。
在另一优选例中,所述的T细胞来自人或非人哺乳动物。
在另一优选例中,所述的T细胞还包括其他嵌合抗原。
本发明第五方面提供一种基因工程化的T细胞,其特征在于,所述T细胞表达(a)基于anti-CD3的双特异T细胞激活元件BiTA,和(b)如第一方面所述的融合蛋白。
在另一优选例中,所述的(a)基于anti-CD3的双特异T细胞激活元件BiTA结构如下式Ⅱ所示:
L’-T1-B1-B2-T2 (Ⅱ)
式中,
L’为无或信号肽序列;
T1为无或标签元件;
B1为肿瘤抗原识别区;
B2为CD3抗原识别区;
T2为无或标签元件;
各“-”独立地为连接肽或肽键。
在另一优选例中,所述的L’为选自下组的蛋白的信号肽:CD8、GM-CSFR、CD4、CD137、或其组合。
在另一优选例中,所述标签元件,包括标签蛋白、荧光素标记蛋白或酶标记蛋白。
在另一优选例中,所述标签蛋白包括FLAG蛋白、His蛋白。
在另一优选例中,所述的肿瘤抗原识别区B1包含单域抗体序列(VHH)、和/或单链抗体可变区序列(scFv)。
在另一优选例中,所述的肿瘤抗原选自下组:TSHR、CD19、CD123、CD22、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、GD2、GD3、BCMA、Tn Ag、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、间皮素(Mesothelin)、IL-11Ra、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、叶酸受体α、ERBB2(Her2/neu)、MUC1、EGFR、NCAM、Prostase、PAP、ELF2M、肝配蛋白B2、IGF-I受体、CAIX、LMP2、gp100、bcr-abl、酪氨酸酶、EphA2、岩藻糖基GM1、sLe、GM3、TGS5、HMWMAA、邻乙酰基-GD2、叶酸受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD179a、ALK、聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-1a、MAGE-A1、legumain、HPV E6、E7、MAGE A1、ETV6-AML、***蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、prostein、存活蛋白和端粒酶、PCTA-1/Galectin8、MelanA/MART1、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG(TMPRSS2ETS融合基因)、NA17、PAX3、雄激素受体、细胞周期蛋白B1、MYCN、RhoC、TRP-2、CYP1B1、BORIS、SART3、PAX5、OY-TES1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠羧基酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、DLL3或其组合。
在另一优选例中,所述的肿瘤抗原识别区B1靶向CAIX和/或HER2。
在另一优选例中,所述的肿瘤抗原识别区B1为靶向CAIX的纳米抗体。
在另一优选例中,所述的肿瘤抗原识别区B1为靶向HER2的单链抗体。
在另一优选例中,所述的CD3抗原识别区B2为靶向CD3的单域抗体序列(VHH)、和/或单链抗体可变区序列(scFv)。
在另一优选例中,所述的BiTA为分泌型BiTA。
在另一优选例中,所述的分泌型BiTA可以自分泌、和/或旁分泌。
在另一优选例中,所述的BiTA可与嵌合CD3e结合。
在另一优选例中,所述的BiTA可与T细胞受体TCR结合。
在另一优选例中,所述的TCR来自于如第五方面所述的T细胞、和/或未经工程化编辑的T细胞。
本发明第六方面提供一种组合物,其特征在于,所述组合物包括如第一方面所述的融合蛋白和BiTA。
在另一优选例中,所述的组合物中的融合蛋白的位于如第一方面所述的T细胞细胞膜胞外区。
在另一优选例中,所述的组合物中的BiTA为自分泌、旁分泌或外源性的BiTA。
在另一优选例中,所述组合物的表达形式为结构式Ⅰ和结构式Ⅱ融合蛋白与2A蛋白的融合表达,其结构式为:Ⅰ-2A-Ⅱ或Ⅱ-2A-Ⅰ,所述2A序列包括T2A,P2A,F2A或E2A中的一种或其组合形式。
在另一优选例中,所述组合物的表达形式为结构式Ⅰ和结构式Ⅱ融合蛋白与IRES序列的组合,其结构式为:Ⅰ-IRES-Ⅱ或Ⅱ-IRES-Ⅰ,所述IRES为核糖体进入位点核苷酸序列。
在另一优选例中,所述IRES作用为启动下游基因的氨基酸翻译。
本发明第七方面提供一种基因工程化的T细胞,其特征在于,所述T细胞表达第五方面中所述组合物。
本发明第八方面提供一种非天然存在的T细胞群,所述的T细胞群中存在第四方面和第五方面所述的T细胞的比例C1≥10%,按所述T细胞群中的T细胞总数计。
在另一优选例中,所述的C1≥10%,较佳地C1≥20%,更佳地C1≥30%。
在另一优选例中,所述的T细胞群。
在另一优选例中,所述的T细胞群中还存在BiTA、和/或分泌BiTA的T细胞C2。
本发明第九方面提供一种细胞制剂,所述的细胞制剂含有(a)如第四方面所述的T细胞、如第五方面所述的T细胞、如第七方面所述的T细胞、和/或含有如第八方面所述的T细胞群,以及(b)药学上可接受的载体、稀释剂或赋形剂。
本发明第十方面提供一种如第四方面所述的T细胞、如第五方面所述的T细胞、如第七方面所述的T细胞、和/或如第八方面所述的T细胞群、和/或如第九方面所述的细胞制剂的用途,用于制备预防和/或治疗癌症或肿瘤的药物。
在另一优选例中,所述肿瘤选自下组:血液肿瘤、实体瘤、或其组合。
在另一优选例中,所述血液肿瘤选自下组:急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性淋巴白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、或其组合。
在另一优选例中,所述实体瘤选自下组:胃癌、胃癌腹膜转移、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、***癌、结直肠癌、乳腺癌、大肠癌、***、卵巢癌、淋巴癌、鼻咽癌、肾上腺肿瘤、***、非小细胞肺癌(NSCLC)、脑胶质瘤、子宫内膜癌、睾丸癌、结直肠癌、尿路肿瘤、甲状腺癌、或其组合。
在另一优选例中,所述实体瘤选自下组:卵巢癌、间皮瘤、肺癌、胰腺癌、乳腺癌、肝癌、子宫内膜癌、或其组合。
本发明第十一方面提供一种治疗疾病的方法,包括:给需要治疗的对象施用适量的如第四方面所述的T细胞、如第五方面所述的T细胞、如第七方面所述的T细胞、和/或如第八方面所述的T细胞群、和/或如第九方面所述的细胞制剂。
在另一优选例中,所述疾病为癌症或肿瘤。
在另一优选例中,所述方法还包括施用适量的刺激细胞分泌的细胞因子或药物化合物及其组合物,以增强免疫细胞响应能力。
在另一优选例中,所述免疫细胞包括如第四方面所述的T细胞、如第五方面所述的T细胞、如第七方面所述的T细胞、和/或如第八方面所述的T细胞群、和/或如第九方面所述的细胞制剂,以及内源性的T细胞、NK细胞、巨噬细胞、B细胞。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了第一组实验CAB-T及其对照组结构。
图2显示了第二组实验CAB-T及其对照组结构。
图3显示了第三组实验CAB-T及其对照组结构。
图4显示了第一组结构编辑T细胞阳性率检测结果。
图5显示了第二组结构编辑T细胞阳性率检测结果。
图6显示了第三组结构编辑T细胞阳性率检测结果。
图7显示了CAIX-CAB-T细胞因子释放检测(第一组实验)。
图8显示了CAIX-CAB-T细胞因子释放检测(第二组实验)。
图9显示了CAIX-CAB-T细胞活化水平检测(第一组实验)。
图10显示了CAIX-CAB-T细胞活化水平检测(第二组实验)。
图11显示了HER2-CAB-T细胞活化水平检测(第三组实验)。
图12显示了CAIX-CAB-T旁分泌活化T细胞水平检测(第二组)。
图13显示了HER2-CAB-T旁分泌活化T细胞水平检测(第三组)。
图14显示了CAIX-CAB-T及其对照细胞免疫检查点表达水平和细胞分化表型分析(第二组)。
图15显示了HER2-CAB-T及其对照细胞免疫检查点表达水平和细胞分化表型分析(第三组实验)。
图16显示了CAIX-CAB-T及其对照组细胞介导的肿瘤杀伤能力检测(第一组实验)。
图17显示了CAIX-CAB-T及其对照组细胞介导的肿瘤杀伤能力检测(第二组实验)。
图18显示了HER2-CAB-T及其对照组细胞介导的肿瘤杀伤能力检测(第三组实验)。
图19显示了CAB-T作用机制模式图。
具体实施方式
本发明人经过广泛而深入的研究,提供了一种抑制肿瘤尤其是实体肿瘤的免疫治疗方案——将表达嵌合CD3e融合蛋白的T细胞与BiTA联用,其中嵌合CD3e融合蛋白与BiTA相互结合,发挥活化T细胞和靶向肿瘤细胞的功能。本发明还提供了一种CAB结构和CAB编辑T细胞(CAB-T),在所述的编辑T细胞表达嵌合CD3e和基于CD3抗体的双特异性T细胞激活器。CAB-T细胞分泌的BiTA在肿瘤组织中可以同时实现CAB-T细胞激活和非编辑T细胞内源TCR的活化,并发挥CAB-T自身抗肿瘤以及调动未编辑T细胞的抗肿瘤作用,这保证了CAB-T临床应用的有效性。CAB-T表达的嵌合CD3e与BiTA相互协同发挥抗肿瘤效应:嵌合CD3e的活化依赖于CAB-T分泌的BiTA,而BiTA的分泌会进一步通过激活嵌合CD3e而刺激CAB-T释放更多的BiTA;肿瘤组织中CAB-T释放的少量BiTA可以通过活化嵌合CD3e而刺激CAB-T释放更多的BiTA,实现肿瘤组织倾向的免疫细胞活化及抗肿瘤效应,保证了CAB-T临床应用的安全性优势。在此基础上,发明人完成了本发明。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
术语“给予”是指使用本领域技术人员已知的各种方法和递送***中的任一种将本发明的产品物理引入受试者,包括静脉内,肌内,皮下,腹膜内,脊髓或其它肠胃外给药途径,例如通过注射或输注。
术语“抗体”(Ab)应包括但不限于免疫球蛋白,其特异性结合抗原并包含通过二硫键互连的至少两条重(H)链和两条轻(L)链,或其抗原结合部分。每条H链包含重链可变区(本文缩写为VH)和重链恒定区。重链恒定区包含三个恒定结构域CH1、CH2和CH3。每条轻链包含轻链可变区(本文缩写为VL)和轻链恒定区。轻链恒定区包含一个恒定结构域CL。VH和VL区可以进一步细分为称为互补决定区(CDR)的高变区,其散布有更保守的称为框架区(FR)的区域。每个VH和VL包含三个CDR和四个FR,从氨基末端到羧基末端按照以下顺序排列:FR1,CDR1,FR2,CDR2,FR3,CDR3,FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。
应理解,本文中氨基酸名称采用国际通用的单英文字母标识,与其相对应的氨基酸名称三英文字母简写分别是:Ala(A)、Arg(R)、Asn(N)、Asp(D)、Cys(C)、Gln(Q)、Glu(E)、Gly(G)、His(H)、I1e(I)、Leu(L)、Lys(K)、Met(M)、Phe(F)、Pro(P)、Ser(S)、Thr(T)、Trp(W)、Tyr(Y)、Val(V)。
嵌合抗原受体(CAR)
嵌合抗原受体(CAR)的结构是以TCR复合体CD3ζ胞内段基域和来自共刺激信号CD28或4-1BB的胞内活化基域为基础的融合蛋白,克服了T细胞依赖MHC呈递抗原的缺点,被称为二代CAR结构,两个于2017年被批准的CAR-T药物均是属于此类结构。
T细胞受体(TCR)
T细胞受体(TCR)是人体中最复杂的受体,六个不同受体亚基的相互作用共同决定了其在T细胞内传导的广泛信号。TCRα和TCRβ两条链共同识别多肽-组织相容性复合体组成的复合物,传递TCR信号的亚基统称为CD3,包括:1个由CD3ε和CD3γ形成的异源二聚体,1个由CD3ε和CD3δ形成的异源二聚体,以及一个CDζ同源二聚体。TCR所有的亚基都是Ⅰ型跨膜蛋白,并且除CD3ζ之外都具有免疫球蛋白基域。TCR受体中四种不同的CD3亚基一共具有10个免疫受体酪氨酸激活基序(immune receptor tyrosine-based activation motifs,ITAM),在TCR受体活化时总共可以接受20个酪氨酸磷酸基。在转基因小鼠实验中显示,CD3ε胞内段脯氨酸富集区域或CD3ε的构想改变对于传递完整的TCR起到至关重要的调节作用。已经证明,TCR活性可以通过以下方式调节:配体与TCRαβ的结合并稳定CD3亚基的排列分布、配体非依赖的TCR寡聚化,以及与胆固醇的结合。
TRuC结构
TCR2自主开发的新型T细胞治疗平台-TRuCTM,由以抗体为基础的靶抗原识别序列与TCR受体亚基组成的嵌合抗原受体,TRuC结构可以重编程一个识别肿瘤抗原的完整的TCR复合体。与CAR结构不同,TRuC结构可以整合在TCR复合体中发挥作用。TRuC-T具有二代CAR-T同样的肿瘤杀伤活性;同时,由于不带有额外共刺激信号基域(CD28或4-1BB),TRuC-T细胞释放的细胞因子水平显著低于CAR-T细胞。TRuC-T在血液肿瘤和实体瘤移植模型中均显示了抗肿瘤活性。同时,在多个肿瘤模型中,TRuC-T均显示了相比于CAR-T更有效的抗肿瘤活性。
T细胞抗原耦连器(TAC)
Triumvira的TAC(T细胞抗原耦连器)技术平台,通过调节T细胞内源TCR,可以诱导比CAR-T更高效抗肿瘤反应,并且更低的毒性。TAC结构由三部分组成:1.胞外抗原结合区;2.CD3单链抗体的TCR-募集区;3.CD4/CD8共受体结合区。临床前实验表明,TAC-T技术能够特异性的结合肿瘤细胞并产生细胞毒性,而且TAC-T细胞的激活与正常T细胞的激活类似,避免了大量细胞因子的产生。在小鼠肿瘤移植模型中,不管是对实体瘤还是血液瘤,TAC-T都表现出比CAR-T更好的活性。此外,在实体瘤中,TAC-T浸润到肿瘤微环境的能力更强。
双特异性T细胞衔接器(BiTE)
Blinatumomab,是美国安进公司开发的一种靶向CD19的双特异性T细胞衔接器(BiTE)药物,已在2014年被FDA批准用于急性白血病的临床治疗,该抗体由识别CD19抗原的scFv和识别TCR(CD3e)的scFv两部分组成。BiTE抗体在识别肿瘤细胞靶抗原CD19后,可以利用CD3scFv部分诱导T细胞内源TCR寡聚化进而激活T细胞和触发肿瘤杀伤。利用BiTE***的方式与TRuC以及TAC技术类似,都是引起T细胞内源TCR活化。理论上讲,三者对内源TCR信号的活化能力相当,都对调动T细胞治疗实体肿瘤具有潜在的巨大价值。但是,由于BiTE药物的***给药方式导致安全性较差,并且BiTE药物在体内半衰期极短等原因,造成其在实体肿瘤的临床治疗中还未展现较好疗效。
双特异性T细胞激活器(BiTA)结构
本文所述“双特异性T细胞激活器结构”、“BiTA”、“双特异性T细胞激活器”、“-BiTA”,均代指CAB结构中的基于anti-CD3的双特异性T细胞激活器(BiTA)结构由包括识别肿瘤抗原的单域抗体序列(VHH)或单链抗体可变区序列(scFv),以及识别CD3单链抗体可变区序列两部分。
CD3e蛋白
本文所述的“CD3e蛋白”、“CD3e”均指代人源的CD3e蛋白。其氨基酸序列如SEQ IDNO.:1.
本文所述的“CD3e蛋白胞外区”指CD3e蛋白序列的第1-104位氨基酸,SEQ ID NO.:2。
所述蛋白序列包含与所述氨基酸序列的同源性不小于60%的氨基酸序列,例如,至少为65%,70%,75%,80%,85%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%。
嵌合融合蛋白
本文所述的“嵌合融合蛋白”、“融合蛋白”、“嵌合蛋白”、均代指本发明第一方面所述的在T细胞中表达的融合蛋白,其结构如下式I所示:
L-EC-H-TM-C-CD3ζ (I)
式中,
各“-”独立地为连接肽或肽键;
L为任选的信号肽序列;
EC为多肽结合域,所述多肽结合域可被CD3抗体识别并与CD3抗体结合;
所述的多肽结合域也称为CD3抗体的识别结合域;
H为任选的铰链区;
TM为跨膜结构域;
C为无或共刺激信号分子;
CD3ζ为源于CD3ζ的胞浆信号传导序列。
在另一优选例中,所述的多肽结合域来自或衍生自CD3e蛋白。
在另一优选例中,所述的多肽结合域为CD3e胞外区或其他可被CD3抗体识别的氨基酸序列。
在另一优选例中,所述的CD3抗体选自下组:scFV(单链抗体)、纳米抗体、双链抗体、或其变体、或其组合。
在另一优选例中,所述的CD3抗体包括BiTA分子的CD3抗体区段。
在另一优选例中,所述的多肽结合域特异性识别并结合于CD3抗体。
在另一优选例中,所述铰链区为CD8Hinge,其氨基酸序列为SEQ ID NO.:3。
在另一优选例中,所述跨膜区为CD8TM,其氨基酸序列为SEQ ID NO.:4
嵌合CD3e和基于CD3抗体的双特异性T细胞激活器编辑T细胞(chimeric CD3e andanti-CD3based Bispecific T cell activator engineered T cells,CAB-T)
本文所述的“嵌合CD3e和基于CD3抗体的双特异性T细胞激活器编辑T细胞”、“CAB-T细胞”、“CAB-T技术”、“CAB结构”、“CAB-T”、“-CAB-T”、“-CAB”均代指均有以下结构的编辑T细胞:CAB结构中的嵌合CD3e由CD3e胞外区、CD8铰链区和跨膜去、4-1BB胞内区和CD3ζ胞内区4个组件构成;CAB结构中基于anti-CD3的双特异性T细胞激活器(BiTA)结构由包括识别肿瘤抗原的单域抗体序列(VHH)或单链抗体可变区序列(scFv),以及识别CD3单链抗体可变区序列两部分。
所述CD3e胞外区的氨基酸序列如SEQ ID NO.:2所示。
所述4-1BB的氨基酸序列如SEQ ID NO.:5所示,
所述CD3ζ的氨基酸序列如SEQ ID NO.:6所示.
CAIX
CAIX是一种表达在多种实体肿瘤细胞中的跨膜蛋白。CAIX的主要功能是在实体肿瘤常见的低氧条件下维持胞内pH的稳态。CAIX在肿瘤细胞中的表达被认为是肿瘤环境的低氧标志蛋白和患者较差的预后。常见的表达CAIX的肿瘤类型包括子***、肾癌、脑癌、头颈癌、食管癌、肠癌、乳腺癌、卵巢癌、子宫内膜癌、膀胱癌等。正常组织中,CAIX主要表达在胆管和小肠的上皮细胞,以及胃上皮细胞等,但是与肿瘤细胞不同,正常组织中表达的CAIX主要定位在胞质中。因此,CAIX是包括细胞治疗在内靶向治疗非常理想的治疗靶点。
HER2
HER2是在肿瘤免疫治疗研究最多的靶点之一,常见在乳腺癌、胃癌、结直肠癌、***、子宫内膜癌、尿路上皮癌、卵巢癌、肺癌等组织中表达。尽管靶向HER2的单克隆抗体药物曲托株单抗已经大幅提高了HER2阳性乳腺癌患者的生存质量和生存期,但仍有大量的HER2阳性肿瘤患者对曲托株单抗无反应或产生抗药性。因此,开发靶向HER2的新的治疗方法仍有很大的市场需求。目前,也已有靶向HER2的CAR-T药物的报道。其中,Steven ARosenberg报道了靶向HER2三代CAR-T药物的临床实验中出现了严重的毒副作用,并由于造成患者呼吸窘迫和严重的肺部免疫细胞浸润导致患者死亡。所以,开发靶向HER2细胞药物的过程中,一定要在设计上凸显药物的安全性。
制剂
本发明提供了一种含有本发明第二方面所述的CAB-T细胞,以及药学上可接受的载体、稀释剂或赋形剂。在一个实施方式中,所述制剂为液态制剂。优选地,所述制剂为注射剂。优选地,所述制剂中所述CAB-T细胞的浓度为1×103-1×108个细胞/ml,更优地1×104-1×107个细胞/ml。
在一个实施方式中,所述制剂可包括缓冲液诸如中性缓冲盐水、硫酸盐缓冲盐水等等;碳水化合物诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸诸如甘氨酸;抗氧化剂;螯合剂诸如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。本发明的制剂优选配制用于静脉内施用。
治疗性应用
本发明包括用本发明第一方面所述的嵌合CD3e T细胞、本发明第二方面所述的CAB-T细胞进行的治疗性应用。转导的T细胞可靶向肿瘤细胞的标志物,同时自分泌、旁分泌或制剂中的BiTA能够协同激活T细胞,引起T细胞免疫应答,从而显著提高其对肿瘤细胞的杀伤效率。
因此,本发明也提供了刺激对哺乳动物的靶细胞群或组织的T细胞-介导的免疫应答的方法,其包括以下步骤:给哺乳动物施用本发明的嵌合CD3e T细胞、本发明第二方面所述的CAB-T细胞。
可治疗的癌症包括没有被血管化或基本上还没有被血管化的肿瘤,以及血管化的肿瘤。癌症可包括非实体瘤(诸如血液学肿瘤,例如白血病和淋巴瘤)或可包括实体瘤。用本发明的CAR治疗的癌症类型包括但不限于癌、胚细胞瘤和肉瘤,和某些白血病或淋巴恶性肿瘤、良性和恶性肿瘤、和恶性瘤,例如肉瘤、癌和黑素瘤。也包括成人肿瘤/癌症和儿童肿瘤/癌症。
血液学癌症为血液或骨髓的癌症。血液学(或血原性)癌症的例子包括白血病,包括急性白血病(诸如急性淋巴细胞白血病、急性髓细胞白血病、急性骨髓性白血病和成髓细胞性、前髓细胞性、粒-单核细胞型、单核细胞性和红白血病)、慢性白血病(诸如慢性髓细胞(粒细胞性)白血病、慢性骨髓性白血病和慢性淋巴细胞白血病)、真性红细胞增多症、淋巴瘤、霍奇金氏疾病、非霍奇金氏淋巴瘤(无痛和高等级形式)、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症、重链疾病、骨髓增生异常综合征、多毛细胞白血病和脊髓发育不良。
实体瘤为通常不包含囊肿或液体区的组织的异常肿块。实体瘤可为良性或恶性的。不同类型的实体瘤以形成它们的细胞类型命名(诸如肉瘤、癌和淋巴瘤)。实体瘤诸如肉瘤和癌的例子包括纤维肉瘤、粘液肉瘤、脂肪肉瘤间皮瘤、淋巴恶性肿瘤、胰腺癌卵巢癌、。
本发明的CAB-修饰T细胞也可用作对哺乳动物离体免疫和/或体内疗法的疫苗类型。优选地,哺乳动物为人。
对于离体免疫,以下中的至少一项在将细胞施用进入哺乳动物前在体外发生:i)扩增细胞,ii)将编码CAB的核酸引入细胞,和/或iii)冷冻保存细胞。
离体程序在本领域中是公知的,并在以下更完全地进行讨论。简单地说,细胞从哺乳动物(优选人)中分离并用表达本文公开的CAB的载体进行基因修饰(即,体外转导或转染)。CAB-修饰的细胞可被施用给哺乳动物接受者,以提供治疗益处。哺乳动物接受者可为人,和CAB-修饰的细胞可相对于接受者为自体的。可选地,细胞可相对于接受者为同种异基因的、同基因的(syngeneic)或异种的。
除了就离体免疫而言使用基于细胞的疫苗之外,本发明也提供了体内免疫以引起针对患者中抗原的免疫应答的组合物和方法。
本发明提供了***的方法,其包括施用给需要其的对象治疗有效量的本发明的CAB-修饰的T细胞。
本发明的CAB-修饰的T细胞可被单独施用或作为药物组合物与稀释剂和/或与其他组分诸如IL-2、IL-17或其他细胞因子或细胞群结合施用。简单地说,本发明的药物组合物可包括如本文所述的靶细胞群,与一种或多种药学或生理学上可接受载体、稀释剂或赋形剂结合。这样的组合物可包括缓冲液诸如中性缓冲盐水、硫酸盐缓冲盐水等等;碳水化合物诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸诸如甘氨酸;抗氧化剂;螯合剂诸如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。本发明的组合物优选配制用于静脉内施用。
本发明的药物组合物可以以适于待治疗(或预防)的疾病的方式施用。施用的数量和频率将由这样的因素确定,如患者的病症、和患者疾病的类型和严重度——尽管适当的剂量可由临床试验确定。
当指出“免疫学上有效量”、“抗肿瘤有效量”、“肿瘤-抑制有效量”或“治疗量”时,待施用的本发明组合物的精确量可由医师确定,其考虑患者(对象)的年龄、重量、肿瘤大小、感染或转移程度和病症的个体差异。可通常指出:包括本文描述的T细胞的药物组合物可以以104至109个细胞/kg体重的剂量,优选105至106个细胞/kg体重的剂量(包括那些范围内的所有整数值)施用。T细胞组合物也可以以这些剂量多次施用。细胞可通过使用免疫疗法中公知的注入技术(见例如Rosenberg等,NewEng.J.of Med.319:1676,1988)施用。对于具体患者的最佳剂量和治疗方案可通过监测患者的疾病迹象并因此调节治疗由医学领域技术人员容易地确定。
对象组合物的施用可以以任何方便的方式进行,包括通过喷雾法、注射、吞咽、输液、植入或移植。本文描述的组合物可被皮下、皮内、瘤内、结内、脊髓内、肌肉内、通过静脉内(i.v.)注射或腹膜内施用给患者。在一个实施方式中,本发明的T细胞组合物通过皮内或皮下注射被施用给患者。在另一个实施方式中,本发明的T细胞组合物优选通过i.v.注射施用。T细胞的组合物可被直接注入肿瘤,***或感染位置。
在本发明的某些实施方式中,利用本文描述的方法或本领域已知的其他将T细胞扩展至治疗性水平的方法活化和扩展的细胞,与任何数量的有关治疗形式结合(例如,之前、同时或之后)施用给患者,所述治疗形式包括但不限于用以下试剂进行治疗:所述试剂诸如抗病毒疗法、西多福韦和白细胞介素-2、阿糖胞苷(也已知为ARA-C)或对MS患者的那他珠单抗治疗或对牛皮癣患者的厄法珠单抗治疗或对PML患者的其他治疗。在进一步的实施方式中,本发明的T细胞可与以下结合使用:化疗、辐射、免疫抑制剂,诸如,环孢菌素、硫唑嘌呤、甲氨喋呤、麦考酚酯和FK506,抗体或其他免疫治疗剂。在进一步的实施方式中,本发明的细胞组合物与骨髓移植、利用化疗剂诸如氟达拉滨、外部光束放射疗法(XRT)、环磷酰胺结合(例如,之前、同时或之后)而施用给患者。例如,在一个实施方式中,对象可经历高剂量化疗的标准治疗,之后进行外周血干细胞移植。在一些实施方式中,在移植后,对象接受本发明的扩展的免疫细胞的注入。在一个额外的实施方式中,扩展的细胞在外科手术前或外科手术后施用。
施用给患者的以上治疗的剂量将随着治疗病症的精确属性和治疗的接受者而变化。人施用的剂量比例可根据本领域接受的实践实施。通常,每次治疗或每个疗程,可将1×106个至1×1010个本发明经修饰的T细胞(如,CAR-T20细胞),通过例如静脉回输的方式,施用于患者。
本发明的技术方案,具有如下有益效果:
1.本发明提供一种抑制肿瘤尤其是实体肿瘤的免疫治疗方案——将表达嵌合CD3e融合蛋白的T细胞与BiTA联用,其中嵌合CD3e融合蛋白与BiTA相互结合,发挥活化T细胞和靶向肿瘤细胞的功能。
2.本发明还提供的一种CAB技术,通过在T细胞中嵌合表达CD3e和BiTA,CAB-T细胞靶向肿瘤组织,其分泌的BiTA在肿瘤组织中可以同时实现CAB-T细胞激活和非编辑T细胞内源TCR的活化,并发挥CAB-T自身抗肿瘤以及调动未编辑T细胞的抗肿瘤作用,这保证了CAB-T临床应用的有效性。
3.由于嵌合CD3e的活化依赖于CAB-T分泌的BiTA,肿瘤组织中CAB-T释放的少量BiTA可以刺激CAB-T释放更多的BiTA,这保证了CAB-T临床应用的安全性优势。
4.CAB-T可以在实体肿瘤组织中可以实现更好地活化,实现在肿瘤部位发挥最大的抗肿瘤效果,达到近似肿瘤局部给药的安全性和有效性,在实体肿瘤的临床治疗中具有巨大的潜力。
下面结合具体实施,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1CAB及对照结构的设计
1.1对照组CD3e-BBζ、1st-CAIX-BiTA、1st-CAIX-CAB和CAIX-TRuC的结构设计
为验证CAB-T的抗肿瘤活性,在一组实验中我们利用靶向CAIX的纳米抗体首先设计了第一组结构:CD3e-BBζ(氨基酸序列为SEQ ID NO.:7),CAIX-BiTA(氨基酸序列为SEQID NO.:8),CAIX-CAB(氨基酸序列为SEQ ID NO.:9)和CAIX-TRuC(氨基酸序列为SEQ IDNO.:10)四种结构。为了后述第二组CAIX-CAB结构相区分,我们将此组的CAIX-BiTA和CAIX-CAB分别命名为1st-CAIX-BiTA和1st-CAIX-CAB。其中,1st-CAIX-BiTA为不带标签的BiTA,1st-CAIX-CAB为CD3e-BBζ和不带标签BiTA的CAB结构,CAIX-TRuC为利用TCR2公司的平台技术的对照结构。上述结构具体结构图如图1所示。
1.2靶向CAIX的纳米抗体试验组tERBB2、CD3e-BBζ、CAIX-BiTA、CAIX-CAB、CAIX-ζ、CAIX-BBζ和CAIX-28ζ的结构设计
在另一组实验中,我们利用靶向CAIX的纳米抗体设计了第二组结构,包括:截短的ERBB2(tERBB2,包含ERBB2胞外第四个基域、跨膜区和FLAG标签三部分结构)(氨基酸序列为SEQ ID NO.:11)、CD3e-BBζ、CAIX-BiTA、CAIX-CAB、CAIX-ζ(靶向CAIX的一代CAR结构)(氨基酸序列为SEQ ID NO.:12)、含4-1BB共刺激基域的二代CAR结构(CAIX-BBζ)(氨基酸序列为SEQ ID NO.:13)和含CD28共刺激基域的二代CAR结构(CAIX-28ζ)(氨基酸序列为SEQ IDNO.:14),共计7种结构。在此组结构中,所有结构都带有FLAG标签,并且所分泌的BiTA抗体都带有His标签。具体如图2所示。
1.3靶向HER2的单链抗体试验组tERBB2、CD3e-BBζ、HER2-BiTA、HER2-CAB、HER2-ζ、HER2-BBζ和HER2-28ζ的结构设计
第三组实验中,我们利用靶向HER2的单链抗体(scFv)测试了CAB平台的抗肿瘤活性。该单链抗体可变区序列来源为罗氏和基因泰克公司生产的抗体药Herceptin(trastuzumab),目前该药品药序列相关专利已经过期。在该实施例中,我们设计的第三组结构,包括:截短的ERBB2、CD3e-BBζ、HER2-BiTA、HER2-CAB(氨基酸序列为SEQ ID NO.:15)、HER2-ζ(氨基酸序列为SEQ ID NO.:16)、HER2-BBζ(氨基酸序列为SEQ ID NO.:17)和HER2-28ζ二代CAR结构(氨基酸序列为SEQ ID NO.:18),共计7种结构。在此组结构中,所有结构也都带有FLAG标签,所有分泌的BiTA抗体也都带有His标签。具体如图3所示。
实施例2 CAB及其对照结构慢病毒载体的包装
本发明中,我们利用慢病毒作为载体制备CAB-T细胞。首先,我们制备了携带CAB及其对照结构编码基因的慢病毒载体。慢病毒包装具体流程如下:
1)在10cm培养板中铺1×107HEK 293T细胞,加10mL的含10%FBS(Gibco,10099-141C)的DMEM(Hyclone,SH30243.01)培养基,充分混匀细胞,37度培养过夜;
2)第2天,待HEK 293T(ATCC,CRL-3216)细胞融合度达到90%左右更换无血清DMEM;
3)准备质粒复合物,各质粒的量分别为:8μg plasmid DNA,4μg psPAX2和2μgpMD2g,溶于1mL opti-MEM(Gibco,31985-070)中并加42μL PEI(Polysciences,24765-2);涡旋震荡20s。室温静置15分钟后轻柔地将混合物沿着边加入到HEK293T培养基中,37度继续培养;
4)培养4h后,去除培养基,PBS(Hyclone,SH30256.01)洗一遍,重新加入2%FBS预热的新鲜DMEM培养基;
5)转染48h和72h后分别收集上清,2000g离心5分钟后弃去沉淀,上清用0.25μm滤器(Sartorius,16541-K)过滤后加终浓度5%PEG8000(Sigma,89510-1KG-F)和终浓度0.15M的NaCl(Sigma,S5150-1L)剧烈混匀后于4℃过夜;
6)将病毒上清在2000g,4℃离心20分钟,去上清并将病毒沉淀溶于50-100μL PBS中,-80℃冻存。
实施例3 CAB及其对照结构工程化T细胞的制备
携带CAB结构的慢病毒载体制备完成后,即可利用此慢病毒载体感染免疫细胞,以完成CAB-T细胞的制备。CAB-T细胞的制备具体流程如下:
1)将商品化PBMC(赛笠生物,SLB-HP050B)细胞用含有5‰人血白蛋白(GRIFOLS,人血白蛋白20%)的X-VIVO 15(LONZA,04-418Q)培养,起始细胞密度为1×106/mL;
2)按细胞:Beads=3:1的比例加入anti-CD3/CD28beads(Miltenyi biotec,130-091-441),并加入1000IU/mL的IL-2(四环生物,国药准字S10970016)以激活T细胞扩增;
3)细胞激活48小时后加入适量病毒和12μg/mL鱼精蛋白(Sigma,P4005)感染T细胞;
4)慢病毒感染24h后,将细胞悬液吸出,并按1×106细胞/mL的浓度补加完全新鲜X-VIVO 15培养基;
5)每天观察细胞的密度,适时补加含IL-2 1000IU/ml的T细胞培养液,使T细胞的密度维持在1×106cell/mL左右,继续扩增5-10天,完成CAR-T细胞的制备。
实施例4 CAB-T细胞阳性率检测
CAB-T及其对照组细胞制备完成后,需要确定感染率以作为后续活性分析的依据。具体地,使用FLAG抗体检测CAB-T阳性率的方法如下:
1)取3-5×105细胞,每个流式管中加入200μL FACS buffer(含1%FBS的PBS),300g,5min离心;CAIX-Truc样本加入终浓度100nM的biotin-CAIX(sino biological,10107-H02H),4℃孵育20min;Her2-Truc样本加入终浓度100nM的biotin-HER-2(ACRO,HE2-H82E2),4℃孵育20min;弃掉上清,加入200μL Fixation/Permeabilization溶液(BDbioscience,554715),4℃孵育20min;
2)300g,离心5min;倒掉离心后的上清液,加200μL 1×Perm/Wash buffer(BDbioscience,554715)重悬,400g,离心5min;洗两遍;
3)倒掉离心后的上清液,每个样本中加入100μL 1:1000FACS buffer稀释后的anti-Flag抗体,混匀细胞,4℃孵育30min;
4)孵育后,向每个流式管中加入1mL FACS buffer,400g,5min离心;
5)倒掉离心后的上清液,加1mL FACS buffer重悬,400g,5min离心;
6)倒掉离心后的上清液,每个样本中加入100μL 1:250FACS buffer稀释后的SA-PE(Invitrogen,S866),混匀细胞,4℃避光孵育30min;孵育后,向每个流式管中加入1mLFACS buffer,300g,5min离心;倒掉离心后的上清液,重复洗两遍;
7)将样品置于流式细胞仪检测。
结果:
在第一组实验中,由于CD3e-BBζ结构和1st-CAIX-CAB结构中带有FLAG标签,可以利用FLAG抗体来检测相应结构编辑T细胞的阳性率,而CAIX-TRuC编辑T细胞可以利用生物素标记的CAIX蛋白检测T细胞转染的阳性率。但是,由于1st-CAIX-BiTA结构不到有合适的标签,因此无法检测其编辑T细胞的阳性率。但根据后续结果判断,1st-CAIX-BiTA编辑T细胞的阳性率水平可以满足实验分析的需求。检测结果如图4所示。
在第二组和第三组实验中,我们在每个结构中都设计了FLAG标签,相应编辑T细胞的阳性率检测可利用FLAG抗体标记并完成检测(HER2-ζ一代结构不带有FLAG标签,使用生物素化的HER2进行阳性率检测)。NT为non-transduced T cells(NT),为阴性对照组。检测结果如图5和图6所示,不同样品间的感染率差异在可接受范围内。
由上可知,使用本发明及现有技术公开的结构,设计得到的各组编辑T细胞转染的阳性率均满足实验分析的需求。
实施例5 CAB-T细胞因子释放水平的检测
CAB-T细胞与肿瘤细胞共培养时,CAB-T能够识别肿瘤细胞表面的靶抗原并发生活化,释放大量炎性细胞因子。基于此,本实施例中利用酶连免疫吸附实验(ELISA)检测活化CAB-T细胞释放细胞因子的水平。
ELISA检测流程如下:
1)效应细胞和靶细胞各1×105,200μL/孔。将共培养过夜的96孔细胞培养板,300g,5min离心,用多道移液器吸取150μL上清液/孔转移到新的96孔细胞培养板,细胞因子检测分别使用IFN-γ(invitrogen,88-7316-88)/IL-2(invitrogen,88-7025-88)/TNF-α(invitrogen,88-7346-88)检测试剂盒检测;
2)提前一天用Human IFN-γ/IL-2/TNF-αMab包被酶标板。将Human IFN-γ/IL-2/TNF-αMab用PBS稀释(1:250),每孔加入100μL抗体,用封板膜将酶标板密封,4℃过夜;
3)洗板:迅速倒掉板内液体,用多道移液器加入Wash Buffer,每孔200μL,重复洗板五次;
4)每孔加入200μL 1×ELISA/ELISASPOT diluent,盖上封板膜,室温封闭60分钟;
5)洗板:迅速倒掉板内液体,用多道移液器加入Wash Buffer,每孔200μL,重复洗板五次;
6)准备Human IFN-γELISA Standard,设置8个梯度(单位pg/mL):1000,500,250,125,62.5,31.25,15.625,7.8125;
7)将标准品和样品加入酶标板,100μL/孔,样品和标准品均用1×ELISA/ELISASPOT diluent稀释到所需浓度,盖上封板膜,室温孵育2h;
8)洗板:迅速倒掉板内液体,用多道移液器加入Wash Buffer,每孔200μL,重复洗板四次;
9)将Human IFN-γ/IL-2/TNF-α检测抗体用PBS稀释(1:250),每孔加入100μL抗体,用封板膜将酶标板密封室温孵育1h;
10)准备HRP-conjugated Streptavidin,用PBS稀释(1:250),每孔加入100μL到酶标板。盖上封板膜,室温孵育30分钟;
11)洗板:迅速倒掉板内液体,用多道移液器加入Wash Buffer,每孔200μL,重复洗板五次;
12)提前30min恢复TMB Substrate至室温,每孔加入100μL到酶标板。室温反应5-10分钟后,加入50μL/孔Stop solution;
13)酶标仪在检测波长OD=450nm处读取吸光度;
14)根据标准品的浓度和OD值计算标准曲线,根据标准曲线计算待测样品的浓度。GraphPad Prism作图软件作图。
结果:
在第一组实验中,当CAIX-CAB-T细胞或其对照组细胞分别与CAIX+HEK 293T细胞或CAIX-HEK293T共培养后检测上清液中炎性细胞因子IL-2、IFN-γ的释放水平。结果如图7所示,当CAIX-CAB-T及其对照分别与CAIX-HEK293T细胞共培养时,所有免疫细胞均没有明显细胞因子释放。而当CAIX-CAB-T及其对照与CAIX+HEK 293T细胞共培养时,1st-CAIX-BiTA、1st-CAIX-CAB和CAIX-TRuc编辑的T细胞都会呈现共培养时间依赖性的细胞因子释放水平,共培养48h累积的细胞因子明显高于共培养24h累积的细胞因子水平。而当未编辑T细胞和CD3e-BBζ编辑T细胞分别与CAIX+HEK 293T细胞共培养时,均未检测到IL-2和IFN-γ两种细胞因子的明显释放。同时,意外地发现共培养48h后,1st-CAIX-CAB-T细胞释放的细胞因子水平明显多于1st-CAIX-BiTA-T细胞的释放水平;当CD3e-BBζ和1st-CAIX-BiTA编辑的T细胞按1:1比例混合后再与CAIX+HEK 293T细胞共培养后,发现其释放的细胞因子水平与1st-CAIX-CAB-T细胞的释放水平相当。以上结果表明,CAIX-CAB-T细胞活化对CAIX抗原的依赖性,以及BiTA和CD3e-BBζ在促进T细胞活化方面的协同性;也证明了CAB-T细胞与对照组TRuC-T细胞具有相当的体外活化能力。
在第二组实验中,检测CAIX-CAB-T及其对照组细胞分别与CAIX+MB-231或CAIX-MB-231细胞(CAIX表达水平如图8.A所示)共培养后检测上清中炎性细胞因子IL-2、IFN-γ、TNF-α的释放水平。结果如图8所示,当CAIX-CAB-T细胞及其对照分别与CAIX-MB-231细胞共培养时,所有细胞均没有明显细胞因子释放。而当CAIX-CAB-T及其对照分别与CAIX+MB-231细胞共培养48h后,CAIX-BiTA、CAIX-CAB、CAIX-BBζ、CAIX-28ζ及CAIX-ζ编辑的T细胞均会有不同程度的活化水平。从数据可以发现,CAIX-CAB-T与CAIX-BiTA、一代和二代CAR结构修饰T细胞在IFN-γ和TNF-α的释放能力基本相当;而在IL-2释放方面,CAIX-CAB-T显著弱于二代CAR细胞,但略高于CAIX-BiTA及一代CAR修饰T细胞。第二组实验结果表明,CAIX-CAB-T细胞活化对CAIX抗原的依赖性,以及在细胞因子释放方面与二代CAR相比的差异性,即CAIX-BiTA-T和CAIX-CAB-T释放的IFN-γ和TNF-α与二代CAR基本相当,而在IL-2释放方面明显弱于二代CAR。
实施例6 CAB-T细胞活化水平检测结果
CAB-T细胞与肿瘤细胞共培养时,CAB-T能够识别肿瘤细胞表面的靶抗原并发生活化,T细胞活化标志蛋白包括CD137、CD25、CD27等的膜表面表达水平会显著上调,以Ki67表达水平为代表的细胞增殖能力会增加,以CD107a为代表的T细胞的杀伤能力也会增强。基于此,本实施例中利用上述染色方法和流式细胞技术检测活化CAB-T细胞中上述膜表面蛋白表达水平的变化。
具体的细胞染色流程如下:
1)效应细胞和靶细胞各1×105,200μL/孔。将共培养过夜的96孔细胞培养板,300g,5min离心,每孔加200μL FACS buffer,300g,5min离心;
2)倒掉离心后的上清液,加200μL FACS buffer重悬细胞,300g,5min离心;
3)用FACS buffer稀释抗体(100μL/孔)
BV421Mouse Anti-Human CD3(BD Bioscience,562426) 1:500稀释
PE Mouse Anti-Human CD137(BD Bioscience,555956) 1:200稀释
APC Mouse Anti-Human CD27(BD Bioscience,561786) 1:200稀释
PE-cy7Mouse Anti-Human CD25(BD Bioscience,557741) 1:200稀释
4)倒掉离心后的上清液,每孔加入100μL抗体mix,4℃避光孵育30min;
5)每孔加入200μL FACS buffer,300g,5min离心,倒掉上清;
6)倒掉离心后的上清液,重复步骤2.5;
7)弃掉上清,加入200μL Fixation/Permeabilization溶液(BD bioscience,554715),4℃孵育20min.;
8)300g,离心5min;倒掉离心后的上清液,加200μL 1×Perm/Wash buffer(BDbioscience,554715)重悬,400g,离心5min;
9)洗两遍,用FACS buffer稀释抗体FITC Mouse Anti-Flag(Biolegend,637318)1:1000稀释;
10)400g,离心5min;倒掉离心后的上清液,洗两遍;
11)流式细胞仪检测,以FSC,SSC画门,得到需要的淋巴细胞群(PBMCs),从中选取CD3BV421+,Flag FITC+细胞群即得到活的CAR-T细胞,再从中以未转染病毒的PBMCs为标准画门得到CAR-T细胞CD137PE+细胞的百分比。
结果:
在第一组实验中,当CAIX-CAB-T细胞或其对照组细胞分别与CAIX+HEK 293T细胞或CAIX-HEK293T共培养后检测T细胞膜表面CD137和CD107a的表达水平变化。结果如图9所示,当CAIX-CAB-T及其对照分别与CAIX-HEK293T细胞共培养时,CAB-T及其对照组免疫细胞的CD137和CD107a表达水平均没有明显变化。而当CAIX-CAB-T及其对照与CAIX+HEK 293T细胞共培养24后,1st-CAIX-BiTA、1st-CAIX-CAB和CAIX-TRuc编辑的T细胞的CD137和CD107a表达水平均显著上调,且1st-CAIX-CAB-T强于1st-CAIX-BiTA的上调水平。而当未编辑T细胞和CD3e-BBζ编辑T细胞分别与CAIX+HEK 293T细胞共培养时,均未检测到CD137和CD107a的明显上调。当CD3e-BBζ和1st-CAIX-BiTA编辑的T细胞按1:1比例混合后再与CAIX+HEK293T细胞共培养24h后,发现其CD137和CD107a的表达水平显著高于CD3e-BBζ-T和1st-CAIX-BiTA-T单独与CAIX+HEK 293T共培养的组别。以上结果表明,CAIX-CAB-T细胞活化对CAIX抗原的依赖性,以及BiTA和CD3e-BBζ在促进T细胞活化方面的协同性;也证明了CAB-T细胞与对照组TRuC-T细胞具有相当的体外活化能力。
在第二组实验中,当CAIX-CAB-T细胞及其对照组细胞分别与CAIX+HEK293T细胞或CAIX-HEK293T共培养48h后检测T细胞膜表面CD137、CD25、CD27和Ki67的表达水平变化。结果如图10所示,当CAIX-CAB-T及其对照分别与CAIX-HEK 293T细胞共培养时,CAIX-CAB-T及其对照组免疫细胞的CD137、CD25、CD27和Ki67表达水平均没有明显变化。而当CAIX-CAB-T及其对照与CAIX+HEK 293T细胞共培养后,CAIX-BiTA、CAIX-CAB和一代CAR及二代CAR编辑的T细胞的CD137、CD25、CD27和Ki67表达水平均显著上调。而当tERBB2和CD3e-BBζ编辑T细胞分别与CAIX+HEK 293T细胞共培养时,均未检测到CD137、CD25、CD27和Ki67的明显上调。以上结果表明,CAIX-CAB-T细胞活化对CAIX抗原的依赖性,也证明了CAB-T细胞与对照组BiTA-T,一代CAR及二代CAR细胞具有相当的体外活化能力。
在第三组实验中,我们检测了利用Trastuzumab来源scFv序列构建的HER2-CAB结构的体外活化能力。结果如图11所示,当HER2-CAB-T细胞及其对照组细胞分别与HER2阳性的SKBR3细胞株或HER2阴性的RAJI细胞株共培养48h后检测T细胞膜表面CD137、CD25、CD27和Ki67的表达水平变化。结果如图12所示,当HER2-CAB-T及其对照分别与RAJI细胞共培养时,HER2-CAB-T及其对照组免疫细胞的CD137、CD25、CD27和Ki67表达水平均没有明显变化。而当HER2-CAB-T及其对照与HER2阳性的SKBR3细胞共培养后,HER2-BiTA、HER2-CAB和一代CAR及二代CAR编辑的T细胞的CD137、CD25、CD27和Ki67表达水平均显著上调。而当tERBB2和CD3e-BBζ编辑T细胞分别与SKBR3细胞共培养时,均未检测到CD137、CD25、CD27和Ki67的明显上调。以上结果表明,HER2-CAB-T细胞活化对HER2抗原的依赖性,也证明了CAB-T细胞与对照组BiTA-T,一代CAR及二代CAR细胞具有相当的体外活化能力。
实施例7通过旁分泌CAB-T激活未编辑T细胞的分析
CAB结构的设计初衷,是为了实现在CAB-T碰到肿瘤细胞时不仅可以激活自身的抗肿瘤活性,而且其分泌的BiTA药物还可以活化CAB-T周围未编辑的T细胞,实现旁分泌的活化作用。未检测CAB-T的旁分泌活化T细胞功能,我们利用transwell实验做了验证。实验具体来讲是通过0.4μm的Transwell***,利用物理屏障将CAB-T和未编辑T细胞分隔开,CAB-T细胞置于上室,未编辑T细胞和肿瘤细胞置于下室。CAB-T分泌的可溶性BiTA可以自由穿过0.4μm的格网进入下室,来激活下层的未编辑T细胞通过识别肿瘤细胞来活化的能力。
具体实验流程如下:
1)将BiTA-T及CAB-T各1×106细胞数分别重悬于200μL X-VIVO 15培养基中,随后加入到0.4-μm Transwell(Coning,3413)的上室;
2)未编辑T细胞和靶细胞各1×106重悬于500μL的X-VIVO-15培养基加入到Transwell下室;
3)将上室小心放入下室,于培养箱中培养48小时;
4)取出共培养过夜的培养板,取出500μL下室细胞上清。300g,5min离心,用多道移液器吸取150μL上清液/孔转移到新的96孔细胞培养板,用于IFN-γ/IL-2/TNF-α的ELISA检测。
结果:
在第二组实验中(图12),CAIX-BiTA-T和CAIX-CAB-T分泌的BiTA均可以通过Transwell小孔激活下层未编辑T细胞识别CAIX阳性MB-231肿瘤细胞的能力,表现为IFN-γ和TNF-α的高水平释放。同时,我们发现IL-2释放水平未见明显变化,这与实施例9中的研究结果相一致。
由第三组实验(图13)所显示结果来看,HER2-CAB-T也显示了同样的旁分泌活化未编辑T细胞识别肿瘤抗原的能力。HER2-CAB-T细胞,而非对照的tERBB2-T细胞可以活化Transwell下层未编辑T细胞识别HER2阳性SKBR3肿瘤细胞。而HER2-CAB-T对未编辑T细胞识别HER2阴性的RAJI细胞没有帮助。
第二组和第三组实验均表明,CAB-T结构可以通过旁分泌BiTA活化未编辑T细胞识别肿瘤细胞的能力。
实施例8 CAB-T细胞免疫检查点表达水平及细胞分化表型的分析
由于免疫细胞上免疫检查点蛋白的表达水平及免疫细胞的分化表型对过继T细胞临床治疗的疗效有很大关系。较低的免疫检查点表达水平和记忆T细胞较高的比例均预示较好的临床反应率。我们利用流式细胞术检测了CAB结构对其编辑T细胞的免疫检查点表达水平和细胞表型的影响。
具体分析流程如下:
1)将共培养过夜的96孔细胞培养板,300g,5min离心,每孔加200μL FACS buffer,300g,5min离心;
2)倒掉离心后的上清液,加200μL FACS buffer重悬细胞,300g,5min离心;
3)用FACS buffer稀释抗体,配制抗体mix(100μL/孔)
4)倒掉离心后的上清液,每孔加入100μL抗体mix,4℃避光孵育30min;
5)每孔加入200μL FACS buffer,300g,5min离心,倒掉上清;
6)倒掉离心后的上清液,重复步骤2.5;
7)加入200μL Fixation/Permeabilization溶液(BD bioscience,554715),4℃孵育20min;
8)300g,离心5min;倒掉离心后的上清液,加200μL 1×Perm/Wash buffer(BDbioscience,554715)重悬,400g,离心5min;洗两遍;
9)用FACS buffer稀释抗体FITC Mouse Anti-Flag(Biolegend,637318)1:1000稀释;
10)400g,离心5min;倒掉离心后的上清液,洗两遍;
11)流式细胞仪检测,以FSC,SSC画门,得到需要的淋巴细胞群,从中选取CD3BV421+,Flag FITC+细胞群即得到活的CAR-T细胞,
结果:
由第二组实验结果可以看出(图14),在与CAIX阳性HEK 293T细胞共培养后,CAIX-CAB-T细胞表面免疫检查点蛋白表达水平,包括LAG-3、PD-1和TIM-3,相比于CAIX-28ζ二代CAR-T都处于较低的水平;CAB-T细胞上PD-1和TIM-3的表达水平与CAIX-BBζ编辑的二代CAR-T基本相当,CAB-T细胞中LAG-3的表达水平还表现出少许低于CAIX-BBζ编辑的二代CAR-T。较低的免疫检查点表达水平,显示出CAB-T细胞相比于二代CAR-T的临床应用优势。
此外,在第二组实验中我们还用CD45RA和CCR7来进行免疫细胞分化表型分析,其分化标志蛋白分别为:初始T细胞(CD45RA+,CCR7+),中央记忆T细胞(CD45RA-,CCR7+),效应记忆T细胞(CD45RA-,CCR7-),以及终末分化效应T细胞(CD45RA+,CCR7-)。由图14.D所示结果我们可以看出,相比于二代CAR-T,CAIX-CAB-T的初始分化T细胞表型和中央记忆T细胞表型的细胞比例明显高于二代CAR-T细胞,而二代CAR-T细胞效应记忆T细胞的比例明显多于CAB-T细胞。而较多中央记忆T细胞表型预示着更好的临床疗效,显示出CAB-T在分化状态中相较于二代CAR-T的优势。
由第三组实验(图15)所显示结果来看,HER2-CAB-T的免疫检查点表达状态及细胞表型的分化结果与CAIX-CAB-T的分析结果基本一致。即:HER2-CAB-T的免疫检查点表达水平相比于CAIX-28ζ二代CAR-T都处于较低的水平,表达水平与CAIX-BBζ编辑的二代CAR-T基本相当或稍低。HER2-CAB-T的分化状态与二代CAR-T相比,也有更高比例的中央记忆T细胞表型。
实施例9 CAB-T细胞的体外杀伤活性
CAB-T细胞是否具有体外杀伤活性是判断CAB-T潜在临床疗效的关键依据。为验证CAB-T的肿瘤杀伤活性及,我们利用LDH方法进行检测。
具体实验流程如下:
1)分别设置实验孔,效应细胞对照孔,靶细胞对照孔,靶细胞最大释放孔,培养基对照孔,体积对照孔;实验步骤按照CytoToxNon-Radioactive Cytotoxicity Assaykit(Promega,G1781)标准流程;
2)设置不同效靶比,即效应细胞数量:靶细胞数量=0:1,1:1,5:1,10:1,20:1
3)细胞数量:靶细胞1×104,50μL/孔;
4)实验孔,加不同稀释比例效应细胞:靶细胞=0:1,1:1,5:1,10:1,20:1的细胞共100ul(效应细胞50μL+靶细胞50μL)到细胞培养板,设置3个重复;
5)效应细胞对照孔,即效应细胞:靶细胞=0:0,1:0,5:0,10:0,20:0,设置2个重复;
6)靶细胞对照孔,加入靶细胞1×104/孔,50μL,+50μL培养基;
7)靶细胞最大释放孔,即加入靶细胞1×104,50μL,+50μL培养基,在收样前1h加入10μL裂解液;
8)培养基对照孔,即加入100μL培养基;
9)体积对照孔,即加入100μL培养基,在收样前1h向靶细胞最大释放孔中加入10ul裂解液的同时,加入10μL裂解液,37℃孵育。
10)根据设计好的版布局,加样,铺板放置37℃,5%CO2孵育24h,或36h,或48h;
11)从-20℃冰箱中取出检测缓冲液(assay buffer)置于4℃冰箱溶解,注意避光。使用时加12ml检测缓冲液(assay buffer)到一瓶底物混合物(substrate Mix)中混匀。
12)将培养板置于250g,4min离心,转移50μL/孔细胞上清到新的酶标版;
13)向新的酶标版中加入50μL/孔底物混合物(避光,12mL assay buffer加到一瓶substrate Mix中混匀);
14)室温避光孵育30min,加入50μL/孔终止液;
15)酶标仪在检测波长OD=490nm处读取吸光度,1h内完成。
16)根据OD值,计算细胞杀伤比例(百分比%)
实验孔=效靶比-培养基对照(均值)
靶细胞自发=靶细胞对照-培养基对照(均值)
效应细胞自发=效应细胞对照-培养基对照(均值)
靶细胞最大释放=靶细胞最大释放(均值)-体积对照(均值)
细胞杀伤比例(%)=(实验-靶细胞自发-效应细胞自发)/(靶细胞最大释放-靶细胞自发)
结果:
CAB-T分泌的BiTA可以实现靶抗原依赖性的CAB-T细胞自身及其周围未编辑T细胞的活化,并杀伤靶抗原阳性肿瘤细胞;同时,由于CAB-T细胞表达CD3e-BBζ,造成CAB-T不仅可以依赖内源TCR活化外,CD3e-BBζ也可以增强CAB-T细胞的活化水平,进而促进CAB-T释放更多的BiTA,彼此再互相增强。因此,理论上CAB-T相较于BiTA-T应该对肿瘤细胞有更强的杀伤效果。
在第一组实验中,为检测CAIX-CAB-T细胞对CAIX+HEK 293T靶细胞的杀伤作用,我们选择以CAIX-CAB-T细胞为实验组效应细胞进行了杀伤作用检测。按0:1、1:1、5:1、10:1、20:1的效靶比将效应细胞分别与靶胞共培养24和48小时,取上清测定在不同效靶比下的T细胞对靶细胞的杀伤能力。从图16的结果我们可以看出,1st-CAIX-CAB-T细胞及其对照组T细胞,对CAIX-HEK293T均不具有杀伤作用;而1st-BiTA-T细胞、1st-CAIX-CAB-T、CAIX-TRuC-T、以及CD3e-BBζ-T和1st-BiTA-T的混合T细胞对CAIX+HEK 293T细胞均展现了不同程度的杀伤能力,这种杀伤能力随着效靶比的升高而增强。并且,CAIX-CAB-T及其对照组T细胞对靶细胞的杀伤随着共培养时间的延长变得更加显著,共培养48h的杀伤效果明显强于共培养24h样品的杀伤效果。而CD3e-BBζ-T和未编辑T细胞对照组对CAIX+HEK 293T细胞未显示杀伤作用。此外,1st-CAIX-CAB-T、CAIX-TRuC-T、以及CD3e-BBζ-T和1st-BiTA-T的混合T细胞对CAIX+HEK 293T细胞的杀伤能力相当,且优于1st-BiTA-T的杀伤能力。由此,我们可以确定,CAIX-CAB-T对肿瘤细胞的杀伤能力依赖于其靶抗原的表达,且其杀伤能力与对照组CAXI-TRuC-T细胞的杀伤能力相当。此外,BiTA-T与CD3e-BBζ-T也显示出对靶细胞的杀伤具有协同效应。
第二组实验与第一组实验方法相同,我们检测了CAIX-CAB-T及其对照细胞对CAIX+MB-231或CAIX-MB-231肿瘤细胞的杀伤能力。按0:1、1:1、5:1、10:1、20:1的效靶比将效应细胞分别与靶胞共培养36h,取上清测定在不同效靶比下的T细胞对靶细胞的杀伤能力。从图17所示结果我们可以发现,CAIX-CAB-T及其对照细胞对CAIX-MB-231对照肿瘤细胞均不具有杀伤作用;而CAIX-CAB-T与靶向CAIX的一代和二代CAR-T细胞表现出对CAIX+MB-231细胞相当的杀伤能力。同时,tERBB2-T和CD3e-BBζ-T对照组细胞对CAIX+MB-231细胞不具有杀伤力。显示了CAIX-CAB-T对肿瘤细胞与一代和二代CAR-T相当的杀伤力,且该杀伤能力具有靶抗原依赖性。需要注意的是,由于转染了较高或供体细胞来源不同等原因,CAIX-CAB-T和CAIX-BiTA-T在此组实验中未显示出对靶细胞杀伤能力的差异。
第三组实验与第一组和第二组实验相同,我们检测了HER2-CAB-T及其对照细胞对HER2阳性肿瘤细胞SKBR3或HER2阴性肿瘤细胞RAJI杀伤能力。按0:1、1:1、5:1、10:1、20:1的效靶比将效应细胞分别与靶胞共培养36h,取上清测定在不同效靶比下的T细胞对靶细胞的杀伤能力。从图18所示结果我们可以看出,HER2-CAB-T及其对照细胞对HER2阴性的RAJI细胞均不具有杀伤作用;而HER2-CAB-T与靶向HER2的一代和二代CAR-T细胞表现出对SKBR3相当的杀伤能力。同时,tERBB2-T和CD3e-BBζ-T对照组细胞对SKBR3细胞不具有杀伤力。显示了HER2-CAB-T对肿瘤细胞与一代和二代CAR-T相当的杀伤力,且该杀伤能力具有靶抗原依赖性。同样需要注意的是,由于转染了较高或供体细胞来源不同等原因(第三组实验和第二组实验T细胞供体来源相同),HER2-CAB-T和HER2-BiTA-T在此组实验中未显示出对靶细胞杀伤能力的差异。
讨论:
CAB-T技术利用自身分泌的BiTA同时识别嵌合CD3e或肿瘤抗原和T细胞内源CD3,诱导肿瘤抗原依赖的内源TCR活化和嵌合CD3e活化。内源TCR和嵌合CD3e的活化都依赖于CAB-T细胞分泌的BiTA的表达和分泌水平。因而,BiTA可通过自分泌形式诱导CAB-T细胞和通过旁分泌形式诱导肿瘤微环境中的未编辑T细胞活化;同时,CAB-T细胞在肿瘤组织中活化后,可以在肿瘤组织中释放更高水平的BiTA,进而调动更多的肿瘤组织中未编辑T细胞的活化和抗肿瘤作用。
因此,相比于TRuC-T和TAC-T,CAB-T不仅具有活化内源TCR信号的优势,还可以调动肿瘤组织中浸润T细胞的抗肿瘤活性,理论上具有更好的实体肿瘤治疗潜力。另外,与BiTE药物不同,通过CAB-T细胞持续分泌的BiTA药物,解决了BiTE单药半衰期短的临床应用问题;此外,由于针对靶抗原的BiTA会在CAB-T细胞到达的肿瘤微环境部位发挥最大作用,不会在非肿瘤组织部位高浓度富集,相比于BiTE单药的***给药而言,具有更优的安全性和更大的临床应用潜力。
CAB-T的作用机制及临床应用潜力阐述如下:
1)在肿瘤组织中,CAB-T细胞中低表达的BiTA可以通过自分泌结合其自身内源TCR或CD3e-BBζ(图19B),从而刺激CAB-T释放更多的BiTA,继而BiTA与CAB-T的内源TCR和CD3e-BBζ实现充分的结合(图19C),引起CAB-T在肿瘤部位实现最大的活化水平,发挥最大的抗肿瘤效果,达到近似肿瘤局部给药的安全性和有效性。
2)通过自分泌BiTA结合并活化CAB-T中的嵌合CD3e(图19A),赋予了CAB-T相比于未编辑T细胞更强敏感的增殖和活化能力,进一步增强了CAB-T的抗肿瘤活性;
3)通过自分泌和旁分泌BiTA分别活化CAB-T(图19A,B,C)和未编辑T细胞(图19D),解决了CAR-T细胞无法活化内源TCR信号的问题,赋予了其治疗实体瘤的潜力;
4)CAB-T可以作为BiTA的药物合成工厂,解决了BiTA体内半衰期短的问题;并且CAB-T的活化依赖于BiTA的释放水平,二者彼此依赖,相互协同,共同决定了CAB-T临床应用的安全性和有效性。
CAB-T作用机制模式图如图19所示。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
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<110> 普米斯生物技术(苏州)有限公司
<120> 一种双特异T细胞激活器活化T细胞的设计及其应用
<130> P2019-1414
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<170> PatentIn version 3.5
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Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
165 170 175
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
180 185 190
Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
195 200 205
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
210 215 220
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
225 230 235 240
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
245 250 255
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
260 265 270
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
275 280 285
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
290 295 300
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
305 310 315 320
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
325 330 335
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Asp Tyr Lys
340 345 350
Asp Asp Asp Asp Lys Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr
355 360 365
Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met Leu Leu Leu Val Thr
370 375 380
Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala Phe Leu Leu Ile Pro
385 390 395 400
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
405 410 415
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ser Ala Asn Ile Phe
420 425 430
Ser Phe Ala Ser Val Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg
435 440 445
Glu Leu Val Ala Val Ile Thr Ser Ala Gly Gly Thr Lys Tyr Ser Asp
450 455 460
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
465 470 475 480
Ile Leu Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
485 490 495
Tyr Cys Asn Val Asp Tyr Leu Gln Asp Tyr Trp Gly Gln Gly Thr Gln
500 505 510
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln
515 520 525
Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys
530 535 540
Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys
545 550 555 560
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser
565 570 575
Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu
580 585 590
Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu
595 600 605
Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp
610 615 620
His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
625 630 635 640
Ser Val Glu Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly
645 650 655
Gly Val Asp Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala
660 665 670
Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val
675 680 685
Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg
690 695 700
Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe
705 710 715 720
Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met
725 730 735
Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn
740 745 750
Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
755 760 765
<210> 10
<211> 339
<212> PRT
<213> 智人(Homo sapiens)
<400> 10
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Asn Ser Ala Asn Ile Phe Ser Phe Ala Ser Val Ala Trp Tyr Arg Gln
50 55 60
Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Val Ile Thr Ser Ala Gly
65 70 75 80
Gly Thr Lys Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
85 90 95
Asp Asn Ala Lys Asn Thr Ile Leu Leu Gln Met Asn Ser Leu Lys Pro
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asp Tyr Leu Gln Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Gly Asn Glu Glu Met
145 150 155 160
Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr
165 170 175
Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln
180 185 190
His Asn Asp Lys Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly
195 200 205
Ser Asp Glu Asp His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln
210 215 220
Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala
225 230 235 240
Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu
245 250 255
Met Asp Val Met Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile
260 265 270
Thr Gly Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys
275 280 285
Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln
290 295 300
Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr
305 310 315 320
Glu Pro Ile Arg Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln
325 330 335
Arg Arg Ile
<210> 11
<211> 212
<212> PRT
<213> 智人(Homo sapiens)
<400> 11
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Ala Cys His Gln Leu Cys Ala Arg Gly His
20 25 30
Cys Trp Gly Pro Gly Pro Thr Gln Cys Val Asn Cys Ser Gln Phe Leu
35 40 45
Arg Gly Gln Glu Cys Val Glu Glu Cys Arg Val Leu Gln Gly Leu Pro
50 55 60
Arg Glu Tyr Val Asn Ala Arg His Cys Leu Pro Cys His Pro Glu Cys
65 70 75 80
Gln Pro Gln Asn Gly Ser Val Thr Cys Phe Gly Pro Glu Ala Asp Gln
85 90 95
Cys Val Ala Cys Ala His Tyr Lys Asp Pro Pro Phe Cys Val Ala Arg
100 105 110
Cys Pro Ser Gly Val Lys Pro Asp Leu Ser Tyr Met Pro Ile Trp Lys
115 120 125
Phe Pro Asp Glu Glu Gly Ala Cys Gln Pro Cys Pro Ile Asn Cys Thr
130 135 140
His Ser Cys Val Asp Leu Asp Asp Lys Gly Cys Pro Ala Glu Gln Arg
145 150 155 160
Ala Ser Pro Leu Thr Ser Ile Ile Ser Ala Val Val Gly Ile Leu Leu
165 170 175
Val Val Val Leu Gly Val Val Phe Gly Ile Leu Ile Lys Arg Arg Gln
180 185 190
Gln Lys Ile Arg Lys Tyr Thr Met Arg Arg Leu Leu Asp Tyr Lys Asp
195 200 205
Asp Asp Asp Lys
210
<210> 12
<211> 328
<212> PRT
<213> 智人(Homo sapiens)
<400> 12
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Asn Ser Ala Asn Ile Phe Ser Phe Ala Ser Val Ala Trp Tyr Arg Gln
50 55 60
Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Val Ile Thr Ser Ala Gly
65 70 75 80
Gly Thr Lys Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
85 90 95
Asp Asn Ala Lys Asn Thr Ile Leu Leu Gln Met Asn Ser Leu Lys Pro
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asp Tyr Leu Gln Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr Pro Ala
130 135 140
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
145 150 155 160
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
165 170 175
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
180 185 190
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
195 200 205
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
210 215 220
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
225 230 235 240
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
245 250 255
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
260 265 270
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
275 280 285
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
290 295 300
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
305 310 315 320
Asp Tyr Lys Asp Asp Asp Asp Lys
325
<210> 13
<211> 369
<212> PRT
<213> 智人(Homo sapiens)
<400> 13
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn
35 40 45
Ser Ala Asn Ile Phe Ser Phe Ala Ser Val Ala Trp Tyr Arg Gln Ala
50 55 60
Pro Gly Lys Gln Arg Glu Leu Val Ala Val Ile Thr Ser Ala Gly Gly
65 70 75 80
Thr Lys Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asn Ala Lys Asn Thr Ile Leu Leu Gln Met Asn Ser Leu Lys Pro Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Asn Val Asp Tyr Leu Gln Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
195 200 205
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
210 215 220
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
225 230 235 240
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
245 250 255
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
260 265 270
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
275 280 285
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
290 295 300
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
305 310 315 320
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
325 330 335
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
340 345 350
Leu His Met Gln Ala Leu Pro Pro Arg Asp Tyr Lys Asp Asp Asp Asp
355 360 365
Lys
<210> 14
<211> 366
<212> PRT
<213> 智人(Homo sapiens)
<400> 14
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn
35 40 45
Ser Ala Asn Ile Phe Ser Phe Ala Ser Val Ala Trp Tyr Arg Gln Ala
50 55 60
Pro Gly Lys Gln Arg Glu Leu Val Ala Val Ile Thr Ser Ala Gly Gly
65 70 75 80
Thr Lys Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asn Ala Lys Asn Thr Ile Leu Leu Gln Met Asn Ser Leu Lys Pro Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Asn Val Asp Tyr Leu Gln Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ile Glu Val Met Tyr
130 135 140
Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His
145 150 155 160
Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser
165 170 175
Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr
180 185 190
Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys
195 200 205
Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg
210 215 220
Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp
225 230 235 240
Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
245 250 255
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
260 265 270
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
275 280 285
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
290 295 300
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
305 310 315 320
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
325 330 335
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
340 345 350
Gln Ala Leu Pro Pro Arg Asp Tyr Lys Asp Asp Asp Asp Lys
355 360 365
<210> 15
<211> 899
<212> PRT
<213> 智人(Homo sapiens)
<400> 15
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Asp Gly Asn Glu Glu Met Gly Gly Ile Thr
20 25 30
Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr
35 40 45
Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys
50 55 60
Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp
65 70 75 80
His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr
85 90 95
Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu
100 105 110
Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Thr Thr
115 120 125
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
130 135 140
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
145 150 155 160
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
165 170 175
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
180 185 190
Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
195 200 205
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
210 215 220
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
225 230 235 240
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
245 250 255
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
260 265 270
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
275 280 285
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
290 295 300
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
305 310 315 320
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
325 330 335
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Asp Tyr Lys
340 345 350
Asp Asp Asp Asp Lys Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr
355 360 365
Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met Leu Leu Leu Val Thr
370 375 380
Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala Phe Leu Leu Ile Pro
385 390 395 400
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
405 410 415
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
420 425 430
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
435 440 445
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
450 455 460
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
465 470 475 480
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
485 490 495
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Ser Thr Ser Gly
500 505 510
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Gln
515 520 525
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
530 535 540
Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His
545 550 555 560
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
565 570 575
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg
580 585 590
Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met
595 600 605
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp
610 615 620
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
625 630 635 640
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln
645 650 655
Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys
660 665 670
Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys
675 680 685
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser
690 695 700
Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu
705 710 715 720
Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu
725 730 735
Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp
740 745 750
His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
755 760 765
Ser Val Glu Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly
770 775 780
Gly Val Asp Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala
785 790 795 800
Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val
805 810 815
Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg
820 825 830
Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe
835 840 845
Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met
850 855 860
Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn
865 870 875 880
Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys His His His
885 890 895
His His His
<210> 16
<211> 449
<212> PRT
<213> 智人(Homo sapiens)
<400> 16
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
20 25 30
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
35 40 45
Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His
100 105 110
Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
130 135 140
Lys Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys
165 170 175
Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
180 185 190
Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp
195 200 205
Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr
210 215 220
Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
225 230 235 240
Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp
245 250 255
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Arg Thr Thr Thr Pro
260 265 270
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
275 280 285
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
290 295 300
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
305 310 315 320
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
325 330 335
Cys Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
340 345 350
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
355 360 365
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
370 375 380
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
385 390 395 400
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
405 410 415
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
420 425 430
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
435 440 445
Arg
<210> 17
<211> 366
<212> PRT
<213> 智人(Homo sapiens)
<400> 17
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn
35 40 45
Ser Ala Asn Ile Phe Ser Phe Ala Ser Val Ala Trp Tyr Arg Gln Ala
50 55 60
Pro Gly Lys Gln Arg Glu Leu Val Ala Val Ile Thr Ser Ala Gly Gly
65 70 75 80
Thr Lys Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asn Ala Lys Asn Thr Ile Leu Leu Gln Met Asn Ser Leu Lys Pro Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Asn Val Asp Tyr Leu Gln Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ile Glu Val Met Tyr
130 135 140
Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His
145 150 155 160
Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser
165 170 175
Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr
180 185 190
Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys
195 200 205
Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg
210 215 220
Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp
225 230 235 240
Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
245 250 255
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
260 265 270
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
275 280 285
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
290 295 300
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
305 310 315 320
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
325 330 335
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
340 345 350
Gln Ala Leu Pro Pro Arg Asp Tyr Lys Asp Asp Asp Asp Lys
355 360 365
<210> 18
<211> 494
<212> PRT
<213> 智人(Homo sapiens)
<400> 18
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
20 25 30
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
35 40 45
Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His
100 105 110
Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
130 135 140
Lys Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys
165 170 175
Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
180 185 190
Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp
195 200 205
Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr
210 215 220
Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
225 230 235 240
Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp
245 250 255
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ile Glu Val Met Tyr
260 265 270
Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His
275 280 285
Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser
290 295 300
Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr
305 310 315 320
Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys
325 330 335
Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg
340 345 350
Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp
355 360 365
Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
370 375 380
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
385 390 395 400
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
405 410 415
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
420 425 430
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
435 440 445
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
450 455 460
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
465 470 475 480
Gln Ala Leu Pro Pro Arg Asp Tyr Lys Asp Asp Asp Asp Lys
485 490
Claims (10)
1.一种融合蛋白,其特征在于,所述融合蛋白的结构如下式I所示:
L-EC-H-TM-C-CD3ζ (I)
式中,
L为无或信号肽序列;
EC为多肽结合域,所述多肽结合域可被CD3抗体识别并与CD3抗体结合;
所述的多肽结合域也称为CD3抗体的识别结合域;
H为无或铰链区;
TM为跨膜结构域;
C为无或共刺激信号分子;
CD3ζ为源于CD3ζ的胞浆信号传导序列;
各“-”独立地为连接肽或肽键。
2.一种的核酸分子,其特征在于,所述的核酸分子编码如权利要求1所示的融合蛋白。
3.一种载体,其特征在于,所述的载体含有如权利要求2所述的核酸分子。
4.一种基因工程化的T细胞,其特征在于,所述的T细胞中表达如权利要求1所述的嵌合融合蛋白。
5.一种基因工程化的T细胞,其特征在于,所述T细胞表达(a)基于anti-CD3的双特异T细胞激活元件BiTA,和(b)如权利要求1所述的融合蛋白。
6.一种组合物,其特征在于,所述组合物包括如权利要求1所述的嵌合CD3e融合蛋白和BiTA。
7.一种基因工程化的T细胞,其特征在于,所述T细胞表达权利要求6中所述组合物。
8.一种非天然存在的T细胞群,所述的T细胞群中存在权利要求4和权利要求5所述的T细胞的比例C1≥10%,按所述T细胞群中的T细胞总数计。
9.一种细胞制剂,所述的细胞制剂含有(a)如权利要求4所述的T细胞、如权利要求5所述的T细胞、如权利要求7述的T细胞、和/或含有如权利要求8所述的T细胞群,以及(b)药学上可接受的载体、稀释剂或赋形剂。
10.一种如权利要求4所述的T细胞、如权利要求5所述的T细胞、如权利要求7所述的T细胞、和/或如权利要求8所述的细胞制剂的用途,用于制备预防和/或治疗癌症或肿瘤的药物。
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US17/642,570 US20220331416A1 (en) | 2019-09-12 | 2020-09-07 | Combined expression of a chimeric cd3 fusion protein and an anti-cd3-based bispecific t cell activating element |
CN202080064132.4A CN114616337A (zh) | 2019-09-12 | 2020-09-07 | 嵌合CD3融合蛋白与基于anti-CD3的双特异性T细胞激活元件的联合表达 |
PCT/IB2020/058302 WO2021048724A1 (en) | 2019-09-12 | 2020-09-07 | Combined expression of a chimeric cd3 fusion protein and an anti-cd3-based bispecific t cell activating element |
CA3150839A CA3150839A1 (en) | 2019-09-12 | 2020-09-07 | Combined expression of a chimeric cd3 fusion protein and an anti-cd3-based bispecific t cell activating element |
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AU2020345133A AU2020345133A1 (en) | 2019-09-12 | 2020-09-07 | Combined expression of a chimeric CD3 fusion protein and an anti-CD3-based bispecific T cell activating element |
EP20863564.9A EP4028525A4 (en) | 2019-09-12 | 2020-09-07 | COMBINED EXPRESSION OF A CHIMERIC CD3 FUSION PROTEIN AND AN ANTI-CD3 BISPECIFIC T CELL ACTIVATING ELEMENT |
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