CN113801238A - 表达nk抑制性分子的工程化免疫细胞及其用途 - Google Patents
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Abstract
本发明涉及一种NK抑制性分子,其包含一个或多个NK抑制性配体、跨膜结构域和共刺激结构域,其中所述NK抑制性配体特异性结合NK抑制性受体以抑制NK细胞对表达所述NK抑制性分子的工程化免疫细胞的杀伤。本发明还涉及一种工程化免疫细胞,其表达本发明的NK抑制性分子,且其中至少一种MHC相关基因的表达被抑制或沉默。本发明还提供了该工程化免疫细胞在治疗癌症、感染或自身免疫性疾病中的用途。与传统的工程化免疫细胞相比,本发明的工程化免疫细胞能够显著抑制受试者体内的NK细胞的杀伤作用,从而降低HvGD风险。
Description
技术领域
本发明属于免疫治疗领域。更具体地,本发明涉及一种NK抑制性分子,其包含一个或多个NK抑制性配体、跨膜结构域和共刺激结构域,其中所述NK抑制性配体特异性结合NK抑制性受体以抑制NK细胞对表达所述NK抑制性分子的工程化免疫细胞的杀伤。
背景技术
近几年,癌症免疫治疗技术发展迅速,尤其是嵌合抗原受体T细胞(CAR-T)相关的免疫疗法在血液瘤的治疗上获得了优异的临床效果。CAR-T细胞免疫疗法是将T细胞在体外进行基因改造,使其能够识别肿瘤抗原,在扩增到一定数量后回输至病人体内,进行癌细胞杀伤,从而达到治疗肿瘤的目的。
2017年,两款自体型CAR-T疗法获FDA批准在美国上市,一款针对B细胞急性白血病,另一款针对弥漫性B细胞非霍奇金氏淋巴瘤。虽然这两款CAR-T细胞在临床上治疗效果优异,但其定价十分高昂,制备周期较长,使得大规模推广变得非常困难。因此,有必要发展通用型CAR-T产品以解决上述问题。通用型CAR-T可以用健康供体外周血分离的T细胞进行制备,从而实现同种异体回输,大大缩短患者等待治疗的时间。此外,从健康供体获得的T细胞的活力和功能也优于患者来源的T细胞,这可以增加CAR感染率,提高治疗效果。
然而,通用型CAR-T细胞的开发仍然面临如下两个问题:(1)工程改造的CAR-T细胞进入患者体内并增殖到一定程度后,可能攻击患者的正常细胞或组织,从而产生移植物抗宿主病(GvHD);(2)患者体内的正常免疫系统可能会排斥异体来源的CAR-T细胞,从而产生宿主抗移植物病(HvGD)。目前,对于HvGD,主要通过敲除CD52或HLA的方式来降低或避免。具体地,敲除CD52可以使通用型CAR-T细胞对阿仑单抗(CD52抗体)产生抗性,从而避免在用阿伦单抗清除患者体内T细胞时对引入的CAR-T细胞产生杀伤。然而,使用阿仑单抗会增加通用型CAR-T产品的生产和治疗成本。另一方面,敲除HLA分子虽然可以保证在不使用抗体或者其他处理的情况下避免CAR-T细胞被患者T细胞清除,但敲除HLA分子的细胞会被病人的NK细胞识别而发生排斥反应。
因此,仍然需要对现有的通用型CAR细胞疗法进行改进,尤其是降低NK细胞对CAR细胞的杀伤作用,从而进一步降低或避免HvGD风险。
发明简述
在第一个方面,本发明提供一种NK抑制性分子,其包含一个或多个NK抑制性配体、跨膜结构域和共刺激结构域,其中所述NK抑制性配体特异性结合NK抑制性受体(NKinhibitory receptor,NKIR)以抑制NK细胞对表达所述NK抑制性分子的工程化免疫细胞的杀伤。
在一个实施方案中,NK抑制性配体是靶向NKIR的抗体或其功能性片段,或NKIR的天然配体或其包含的NKIR结合片段。在一个实施方案中,所述NKIR选自NKG2/CD94组分(例如NKG2A、NKG2B、CD94);杀伤细胞Ig样受体(KIR)家族成员(例如KIR2DL1、KIR2DL2/3、KIR2DL5A、KIR2DL5B、KIR3DL1、KIR3DL2和KIR3DL3);白细胞Ig样受体(LIR)家族成员(例如LIR1、LIR2、LIR3、LIR5和LIR8);NK细胞受体蛋白1(NKR-P1)家族成员(例如NKR-P1B和NKR-P1D);免疫检查点受体(如PD-1、TIGIT和CD96、TIM3、LAG3);癌胚抗原相关的细胞黏附分子1(CEACAM1);唾液酸结合性免疫球蛋白样凝集素(SIGLEC)家族成员(例如SIGLEC7和SIGLEC9);白细胞相关的免疫球蛋白样受体1(LAIR1);Ly49家族成员(例如Ly49A、Ly49C、Ly49F、Ly49G1和Ly49G4)和杀伤细胞凝集素样受体G1(KLRG1)。优选地,所述NKIR选自PD1、NKG2A、NKG2B、CD94、LIR1、LIR2、LIR3、KIR2DL1、KIR2DL2/3、KIR3DL1、CEACAM1、LAIR1、SIGLEC7、SIGLEC9和KLRG1。更优选地,所述NKIR选自PD1、NKG2A、CD94、KIR2DL1、KIR2DL2/3、KIR3DL1、LIR1、CEACAM1、LAIR1、SIGLEC7、SIGLEC9和KLRG1。
在一个实施方案中,NK抑制性配体是靶向NKIR的抗体,所述抗体是完整抗体、Fab、Fab’、F(ab’)2、Fv片段、scFv抗体片段、线性抗体、sdAb或纳米抗体。在一个优选的实施方案中,NK抑制性配体是靶向PD1、NKG2A、LIR1、KIR、SIGLEC7、SIGLEC9和/或KLRG1的抗体或其功能性片段。
在一个实施方案中,NK抑制性配体是NKIR的天然配体或其包含的NKIR结合片段。优选的,所述NK抑制性配体选自HLA-E、HLA-F、HLA-G、钙黏素、胶原蛋白、OCIL、唾液酸、免疫检查点配体(例如PD-L1/PD-L2、CD155、CD112、CD113、Gal-9、FGL1等),和它们包含的NKIR结合区。更优选的,所述NK抑制性配体是唾液酸、HLA-E、HLA-F、HLA-G、钙黏素、PD-L1、PD-L2,或它们包含的NKIR结合区。更优选的,所述NK抑制性配体选自唾液酸、HLA-E胞外区、HLA-G胞外区、E-钙黏素胞外区、PD-L1胞外区和PD-L2胞外区。更优选的,所述NK抑制性配体是E-钙黏素胞外区,其包含EC1和EC2,更优选包含EC1、EC2、EC3、EC4和EC5。
在一个实施方案中,NK抑制性分子包含的跨膜结构域选自以下蛋白质的跨膜结构域:TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137、CD154,和NKIR天然配体的跨膜结构域,例如HLA-E、HLA-F、HLA-G、钙黏素、胶原蛋白、OCIL的跨膜结构域。在一个优选的实施方案中,跨膜结构域选自CD8α、CD4、CD28和CD278的跨膜结构域。
在一个实施方案中,所述跨膜结构域与SEQ ID NO:9或11所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,NK抑制性分子包含的共刺激结构域选自以下蛋白质的共刺激信号传导结构域:LTB、CD94、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70以及它们的组合。优选地,本发明的共刺激结构域来自4-1BB、CD28、CD27、OX40、CD278或其组合。
在一个实施方案中,所述共刺激结构域与SEQ ID NO:13或15所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,NK抑制性分子进不包含胞内信号传导结构域。在另一个实施方案中,NK抑制性分子进一步包含胞内信号传导结构域。
在一个实施方案中,所述胞内信号传导结构域选自以下蛋白的信号传导结构域:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d。优选地,所述胞内信号传导结构域包含CD3ζ的信号传导结构域。
在一个实施方案中,所述胞内信号传导结构域与SEQ ID NO:17或19所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
本发明还提供编码上述NK抑制性分子的核酸,和包含所述核酸的载体。
在第二个方面,本发明提供一种工程化免疫细胞,其特征在于:(1)表达本发明的NK抑制性分子,和(2)至少一种MHC相关基因的表达被抑制或沉默。在一个实施方案中,本发明的工程化免疫细胞进一步表达嵌合抗原受体,所述嵌合抗原受体包含配体结合结构域、跨膜结构域、共刺激结构域和细胞内信号传导结构域。
在一个方面,本发明提供一种工程化免疫细胞,其特征在于:(1)表达本发明的NK抑制性分子和嵌合抗原受体的融合蛋白,所述融合蛋白包含NK抑制性配体、配体结合结构域、跨膜结构域、共刺激结构域和胞内信号传导结构域,和(2)至少一种MHC相关基因的表达被抑制或沉默。
在一个实施方案中,MHC相关基因选自HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA和它们的组合,优选HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
在一个实施方案中,所述工程化免疫细胞还包含至少一种TCR/CD3基因的表达被抑制或沉默,所述TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ和它们的组合。
在一个优选的实施方案中,所述工程化免疫细胞的至少一种TCR/CD3基因和至少一种MHC相关基因的表达被抑制或沉默,其中所述至少一种TCR/CD3基因选自TRAC、TRBC和它们的组合,所述至少一种MHC相关基因是B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。在一个实施方案中,所述工程化免疫细胞的TRAC或TRBC,和B2M的表达被抑制或沉默。在一个实施方案中,所述工程化免疫细胞的TRAC或TRBC,和CIITA的表达被抑制或沉默。在一个优选的实施方案中,所述工程化免疫细胞的TRAC或TRBC、B2M和CIITA的表达被抑制或沉默。在一个优选的实施方案中,所述工程化免疫细胞的TRAC或TRBC、B2M和RFX5的表达被抑制或沉默。
在一个实施方案中,本发明的工程化免疫细胞的特征还在于,其中选自以下的一个或多个基因的表达被抑制或沉默:CD52、GR、dCK和免疫检查点基因,如PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。优选地,所述工程化免疫细胞的CD52、dCK、PD1、LAG3、TIM3、CTLA4、TIGIT或其组合被抑制或沉默。
在一个实施方案中,所述配体结合结构域与选自以下的靶标结合:TSHR、CD2、CD3、CD4、CD5、CD7、CD8、CD14、CD15、CD19、CD20、CD21、CD23、CD24、CD25、CD37、CD38、CD40、CD40L、CD44、CD46、CD47、CD52、CD54、CD56、CD70、CD73、CD80、CD97、CD123、CD22、CD126、CD138、CD179a、DR4、DR5、TAC、TEM1/CD248、VEGF、GUCY2C、EGP40、EGP-2、EGP-4、CD133、IFNAR1、DLL3、kappa轻链、TIM3、tEGFR、IL-22Ra、IL-2、ErbB3、ErbB4、MUC16、MAGE-A3、MAGE-A6、NKG2DL、BAFF-R、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、GD2、GD3、BCMA、GPRC5D、Tn Ag、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、间皮素、IL-l lRa、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、AFP、Folate受体α、ERBB2(Her2/neu)、MUC1、EGFR、CS1、CD138、NCAM、Claudin18.2、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gploo、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、豆荚蛋白、HPV E6、E7、MAGE-A4、MART-1、WT-1、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin 8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG(TMPRSS2 ETS融合基因)、NA17、PAX3、雄激素受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D和它们的任意组合。
在一个实施方案中,所述工程化免疫细胞是B细胞、T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞或NKT细胞。优选的,所述工程化免疫细胞是T细胞,例如CD4+/CD8+T细胞、CD4+辅助T细胞(例如Th1和Th2细胞)、CD8+T细胞(例如,细胞毒性T细胞)、肿瘤浸润细胞、记忆T细胞、幼稚T细胞、γδ-T细胞、αβ-T细胞。
在一个方面,本发明还提供一种药物组合物,其包含本发明所述的NK抑制性分子、核酸分子、载体或工程化免疫细胞作为活性剂,和一种或多种药学上可接受的赋型剂。
在一个方面,本发明还提供一种治疗患有癌症、感染或自身免疫性疾病的受试者的方法,包括向所述受试者施用有效量的根据本发明所述的NK抑制性分子、核酸分子、载体、工程化免疫细胞或药物组合物。因此,本发明还涵盖NK抑制性分子、核酸分子、载体、工程化免疫细胞在制备治疗癌症、感染或自身免疫性疾病的药物中的用途。
在一个实施方案中,所述癌症是实体瘤或血液肿瘤。更具体地,所述癌症选自:脑神经胶质瘤、胚细胞瘤、肉瘤、白血病、基底细胞癌、胆道癌、膀胱癌、骨癌、脑和CNS癌症、乳腺癌、腹膜癌、宫颈癌、绒毛膜癌、结肠和直肠癌、结缔组织癌症、消化系统的癌症、子宫内膜癌、食管癌、眼癌、头颈癌、胃癌、胶质母细胞瘤(GBM)、肝癌、肝细胞瘤、上皮内肿瘤、肾癌、喉癌、肝肿瘤、肺癌、淋巴瘤、黑色素瘤、骨髓瘤、神经母细胞瘤、口腔癌、卵巢癌、胰腺癌、前列腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸系统的癌症、唾液腺癌、皮肤癌、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌、子宫或子宫内膜癌、泌尿系统的恶性肿瘤、外阴癌以及其它癌和肉瘤、以及B细胞淋巴瘤、T细胞淋巴瘤、套细胞淋巴瘤、AIDS相关淋巴瘤、以及Waldenstrom巨球蛋白血症、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、B细胞急性淋巴细胞白血病(B-ALL)、T细胞急性淋巴细胞白血病(T-ALL)、B细胞幼淋巴细胞白血病、母细胞性浆细胞样树突状细胞瘤、伯基特氏淋巴瘤、弥散性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性骨髓性白血病(CML)、恶性淋巴组织增生疾病、MALT淋巴瘤、毛细胞白血病、边缘区淋巴瘤、多发性骨髓瘤、骨髓发育不良、浆母细胞性淋巴瘤、白血病前期、浆细胞样树突状细胞瘤、以及移植后淋巴细胞增生性紊乱(PTLD)。
在一个实施方案中,所述感染包括但不限于由病毒、细菌、真菌和寄生虫引起的感染。
在一个实施方案中,所述自身免疫性疾病包括但不限于I型糖尿病、腹腔疾病、格雷夫斯病、炎症性肠病、多发性硬化症、银屑病、类风湿性关节炎、艾迪生病、干燥综合征、桥本甲状腺炎、重症肌无力、血管炎、恶性贫血与系统性红斑狼疮等。
本发明的优势之处在于,与仅表达NK抑制性配体相比,本发明的NK抑制性分子还包含共刺激结构域,这能够进一步降低/抑制受试者体内NK细胞对工程化免疫细胞的杀伤,甚至当NK抑制性分子包含胞内信号传导结构域时,其能够增强工程化免疫细胞对受试者体内NK细胞的杀伤,从而更好地降低HvGD风险,实现真正的同种异体回输。
发明详述
除非另有说明,否则本文中所使用的所有科学技术术语的含义与本发明所属领域的普通技术人员通常所了解的相同。
NK抑制性分子
据报道,其中一种或多种HLA-I类分子表达被减少或消除的细胞可以被NK细胞识别为非自我,从而被靶向杀伤。因此,一种或多种NK抑制性分子在所述细胞上的表达可以保护它免受NK细胞杀伤。
因此,在第一个方面,本发明提供一种NK抑制性分子,其包含一个或多个NK抑制性配体、跨膜结构域和共刺激结构域,其中所述NK抑制性配体特异性结合NK抑制性受体(NKinhibitory receptor,NKIR)以抑制NK细胞对表达所述NK抑制性分子的工程化免疫细胞的杀伤。
如本文所用,术语“NK抑制性配体”是指能够与NKIR结合并抑制NK细胞功能(例如杀伤功能)的分子。在一个实施方案中,NK抑制性配体是靶向NKIR的抗体或其功能性片段,或NKIR的天然配体或其包含的NKIR结合片段。NKIR的非限制性实例包括具有基于免疫受体酪氨酸的抑制性基序(Immunoreceptor tyrosine-based inhibitory motif,ITIM)或与之结合的NK细胞表面受体。这类受体包括但不限于NKG2/CD94组分(例如NKG2A、NKG2B、CD94);杀伤细胞Ig样受体(KIR)家族成员(例如KIR2DL1、KIR2DL2/3、KIR2DL5A、KIR2DL5B、KIR3DL1、KIR3DL2和KIR3DL3);白细胞Ig样受体(LIR)家族成员(例如LIR1、LIR2、LIR3、LIR5和LIR8);NK细胞受体蛋白1(NKR-P1)家族成员(例如NKR-P1B和NKR-P1D);免疫检查点受体(例如PD-1、TIGIT和CD96、TIM3、LAG3);癌胚抗原相关的细胞黏附分子1(CEACAM1);唾液酸结合性免疫球蛋白样凝集素(SIGLEC)家族成员(例如SIGLEC7和SIGLEC9);白细胞相关的免疫球蛋白样受体1(LAIR1);Ly49家族成员(例如Ly49A、Ly49C、Ly49F、Ly49G1和Ly49G4)和杀伤细胞凝集素样受体G1(KLRG1)。
在一个实施方案中,NK抑制性配体是靶向NKIR的抗体或其功能性片段,例如单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体、鼠源抗体、嵌合抗体及其功能性片段。抗体或其功能性片段的实例包括但不限于完整抗体、Fab、Fab’、F(ab’)2、Fv片段、scFv抗体片段、线性抗体、sdAb(VH或VL)、纳米抗体(Nanobody,Nb)等,优选选自Fab、scFv、sdAb和纳米抗体。
在一个实施方案中,NK抑制性配体是靶向NKG2A/CD94组分的抗体或其功能性片段。在一个优选的实施方案中,NK抑制性配体是靶向NKG2A、NKG2B或CD94的抗体。NKG2/CD94是由CD94通过二硫键与另一个NKG2亚单位结合组成的异二聚体。CD94胞质区只有7个氨基酸残基,不具备传递信号的结构。NKG2家族包括NKG2A、NKG2B、NKG2C、NKG2D、NKG2E、NKG2F等成员,其中NKG2A和NKG2B是同一基因的不同剪接物,具有高度同源性。NKG2A/2B的胞质区尾部包含2个ITIM,通过募集SHP1或SHP-2来传递抑制信号。NKG2A/2B的天然配体是HLA-E。由于NKG2A/2B与配体结合的亲和力高于活化性受体NKG2C,因此当NK细胞的抑制性受体和活化受体都可与表达HLA-E的靶细胞结合时,抑制性的NKG2A/CD94将占据主导,最终抑制NK细胞活性。本领域技术人员熟知的NKG2A抗体可用于本发明,例如Z270(可获自Immunotech,France)、Z199(可获得自Beckman Coulter,USA)、20D5(可获得自BD BiosciencesPharmingen,USA)、P25(可获自Morettaetal,Univ.Genova,Italy)等。
在一个实施方案中,NK抑制性配体是靶向NKG2A的抗体,其包含(1)如SEQ ID NO:72所示的CDR-L1、如SEQ ID NO:73所示的CDR-L2、如SEQ ID NO:74所示的CDR-L3、如SEQ IDNO:75所示的CDR-H1、如SEQ ID NO:76所示的CDR-H2和如SEQ ID NO:77所示的CDR-H3,或(2)如SEQ ID NO:78所示的CDR-L1、如SEQ ID NO:79所示的CDR-L2、如SEQ ID NO:80所示的CDR-L3、如SEQ ID NO:81所示的CDR-H1、如SEQ ID NO:82所示的CDR-H2和如SEQ ID NO:83所示的CDR-H3。在一个实施方案中,NK抑制性配体是靶向NKG2A的抗体,其包含轻链可变区和重链可变区,所述轻链可变区与SEQ ID NO:3、7或68所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,所述重链可变区与SEQ ID NO:1、5、67所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。在一个优选的实施方案中,NK抑制性配体是包含SEQ ID NO:1和3的抗NKG2A抗体、包含SEQ ID NO:5和7的抗NKG2A抗体,或是包含SEQ IDNO:67和68的抗NKG2A抗体。
在一个实施方案中,NK抑制性配体是靶向KIR的抗体或其功能性片段。KIR分子是I型跨膜蛋白,属于免疫球蛋白超家族,其结构包括膜外区、跨膜区和胞质区。根据膜外区包含的Ig样结构域的数量,KIR可以分为KIR2D和KIR3D亚家族。根据胞质区的长短,KIR还可以分为长型(L)和短型(S),例如KIR2DL、KIR2DS、KIR3DL、KIR3DS。其中,KIR2DL1、KIR2DL2、KIR2DL3、KIR3DL1、KIR3DL2、KIR3DL3的胞质区包含2个基于免疫受体酪氨酸的抑制基序(Immunoreceptor tyrosine-based inhibitory motif,ITIM),KIR2DL5的胞质区包含1个ITIM,属于抑制性KIR受体。具体地,抑制性KIR受体胞质区包含的ITIM发生磷酸化时可以募集磷酸酶SHP1和SHP2,导致细胞底物去磷酸化,最终抑制或终止NK细胞的效应功能,例如细胞毒性作用和细胞因子的分泌。KIR在绝大部分NK细胞上表达,尽管在不同个体上的表达水平有差异。甚至在同一个体中,不同的NK细胞表达的KIR种类也不尽相同,且同一个NK细胞可表达几种不同的KIR分子。KIR的识别配体是经典HLA-I类分子,包括HLA-A、HLA-B和HLA-C的某些多态性表位。例如,KIR3DL2识别HLA-A等位基因-A3和-A11,KIR3DL1识别HLA-Bw-4,KIR2DL1识别HLA-Cw2、HLA-Cw4和HLA-Cw6同种型。KIR的小鼠同源物是gp49B1,其长度为335个氨基酸,并且在胞质区含有2个ITIM结构。在一个优选的实施方案中,靶向KIR的抗体是靶向选自以下的一个或多个靶标的抗体:KIR2DL1、KIR2DL2、KIR2DL3、KIR3DL1、KIR3DL2、KIR3DL3、KIR2DL5和gp49B1。本领域技术人员熟知的KIR抗体可用于本发明,例如GL183(靶向KIR2DL2/L3,可获自Immunotech,France和Beckton Dickinson,USA)、EB6(靶向KIR2DL1,可获自Immunotech,France和Beckton Dickinson,USA)、AZ138(靶向KIR3DL1,可获自Morettaetal,Univ.Genova,Italy)、Q66(靶向KIR3DL2,可获自Immunotech,France)、Z27(靶向KIR3DL1,可获自Immunotech,France和Beckton Dickinson,USA)等。
在一个实施方案中,NK抑制性配体是靶向KIR的抗体,其包含如SEQ ID NO:84所示的CDR-L1、如SEQ ID NO:85所示的CDR-L2、如SEQ ID NO:86所示的CDR-L3、如SEQ ID NO:87所示的CDR-H1、如SEQ ID NO:88所示的CDR-H2和如SEQ ID NO:89所示的CDR-H3。在一个实施方案中,NK抑制性配体是靶向KIR的抗体,其包含轻链可变区和重链可变区,所述轻链可变区与SEQ ID NO:58所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,所述重链可变区与SEQ ID NO:59所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。在一个优选的实施方案中,NK抑制性配体是包含SEQ ID NO:58和SEQ ID NO:59的抗KIR抗体,其氨基酸序列例如如SEQ ID NO:57或60所示。
在一个实施方案中,NK抑制性配体是靶向LIR的抗体或其功能性片段。LIR也称为免疫球蛋白样转录物(Immunoglobulin-like transcripts,ILT)或单核细胞-巨噬细胞抑制性受体(Monocyte-macrophage inhibitory receptor,MIR)。LIR家族包含8个成员,其中LIR1(也称为ILT2)、LIR2(也称为ILT4)、LIR3(也称为ILT5)、LIR5(也称为ILT3)和LIR8的胞质区含有2-4个ITIM结构,其中至少一个为VXYXXL/V基序,属于抑制性LIR受体。已有报道证明LIR-1能够抑制NK细胞系NKL对表达HLA-I类分子的靶细胞的杀伤以及CD16介导的NKL的活化。小鼠中LIR的同源物是PIR(Paired Ig-like receptor),包括PIR-A和PIR-B,其中PIR-A在FcRγ同源二聚体的协助下传递活化信号,而PIR-B则通过其胞质区包含的4个ITIM结构传递抑制信号。在一个优选的实施方案中,NK抑制性配体是靶向LIR1、LIR2、LIR3、LIR5、LIR8或PIR-B的抗体。
在一个实施方案中,NK抑制性配体是靶向LIR1的抗体,其包含:(1)如SEQ ID NO:90所示的CDR-L1、如SEQ ID NO:91所示的CDR-L2、如SEQ ID NO:92所示的CDR-L3、如SEQ IDNO:93所示的CDR-H1、如SEQ ID NO:94所示的CDR-H2和如SEQ ID NO:95所示的CDR-H3,或(2)如SEQ ID NO:96所示的CDR-L1、如SEQ ID NO:97所示的CDR-L2、如SEQ ID NO:98所示的CDR-L3、如SEQ ID NO:99所示的CDR-H1、如SEQ ID NO:100所示的CDR-H2和如SEQ ID NO:101所示的CDR-H3。在一个实施方案中,NK抑制性配体是靶向LIR1的抗体,其包含轻链可变区和重链可变区,所述轻链可变区与SEQ ID NO:61或65所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,所述重链可变区与SEQ ID NO:62或64所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。在一个优选的实施方案中,NK抑制性配体是抗LIR1抗体,其氨基酸序列如SEQ ID NO:63或66所示。本领域已知的其他靶向LIR家族成员的抗体也可用于本发明。在一个实施方案中,NK抑制性配体是靶向免疫检查点受体(例如PD-1、TIGIT、CD96、TIM3、LAG3)的抗体或其功能性片段。在一个优选的实施方案中,NK的抑制性配体是靶向PD-1的抗体或其功能性片段。PD-1主要在激活的NK细胞中表达,属于CD28家族成员,是由268个氨基酸组成的I型跨膜糖蛋白。它的结构主要包括胞外免疫球蛋白可变区(IgV)样结构、疏水的跨膜区以及胞内区。胞内区尾部有2个独立的酪氨酸残基,氮端的酪氨酸残基参与构成一个ITIM,碳端酪氨酸残基则参与构成一个免疫受体酪氨酸转换基序(immunoreceptor tyrosine based switch motif,ITSM)。PD-1与其配体(例如PD-L1和PD-L2)结合后,促使PD-1的ITSM结构域中的酪氨酸发生磷酸化,进而引起下游蛋白激酶Syk和PI3K的去磷酸化,抑制下游AKT、ERK等通路的活化,最终抑制NK的活性。
在一个优选的实施方案实施方案中,NK抑制性配体是靶向TIGIT的抗体或功能性片段。TIGIT属于免疫球蛋白超家族成员,它由细胞外免疫球蛋白可变区(IgV)结构域、1型跨膜结构域和具有ITIM和免疫球蛋白酪氨酸尾(ITT)基序的细胞内结构域组成。当其与配体(例如CD155、CD112、CD113)结合后,可诱发胞内抑制信号的传递,从而抑制NK细胞的活性。
在一个优选的实施方案中,NK抑制性配体是靶向LAG3的抗体或功能性片段。LAG3是蛋白质Ig超家族的成员。它是1型跨膜蛋白,表达于活化的T细胞、NK细胞、B细胞和浆细胞样树突状细胞上。LAG3的四个IgG域与CD4分子具有高的结构同源性,但其氨基酸的同源性低于20%。研究表明,LAG3对T细胞和NK细胞的增殖及持久记忆具有负调控作用。一旦被其配体(例如FGL1)激活以后,可以促进肿瘤细胞等“坏细胞”逃脱免疫系统的追杀。
在一个优选的实施方案中,NK抑制性配体是靶向TIM3的抗体或功能性片段。TIM3是TIM家族的一个受体蛋白,在T细胞、Treg细胞、先天免疫细胞(树突细胞、自然杀伤细胞、单核细胞)表面表达。TIM家族成员由3个基因编码,具体为HAVCR1编码TIM1、HAVCR2编码TIM3以及TIMD4编码TIM4。TIM3有多种配体,如磷脂酰丝氨酸(phosphatidylserine)、半乳凝素9(galectin-9或Gal-9)、HMGB1和CEACAM-1等。在NK细胞中表达时,TIM3被认为可能是功能障碍的NK细胞的标志物,TIM3阻断已被证明可逆转NK细胞的功能障碍。
在一个实施方案中,NK抑制性配体是靶向NKR-P1的抗体或其功能性片段。NKR-P1属于II型跨膜糖蛋白,在人、小鼠和大鼠NK细胞中均有表达。目前已发现小鼠的6个NKR-P1成员,分别为NKR-P1A、NKR-P1B、NKR-P1C、NKR-P1D、NKR-P1E、NKR-P1F,而在人体中只发现了NKR-P1A(又称为CD161)。NKR-P1分子胞外区属于C型凝集素样超家族中NK受体结构域(NKD),在结构上与Ly49、Cd69、CD94/NKG2分子相似。虽然NKR-P1主要以同源二聚体形式存在,但人NKR-P1A可能存在单体形式。NKR-P1家族分子的胞质区在不同物种中结构有所差异,例如NKR-P1B和NKR-P1D的胞质区含有ITIM基序,其在酪氨酸磷酸化后募集SHP-1来传递抑制性信号,而NKR-P1C则通过跨膜区的带正电氨基酸与Fc受体结合,进而募集Syk传递活化信号。因此,在一个优选的实施方案中,NK抑制性配体是靶向NKR-P1B或NKR-P1D的抗体。
在一个实施方案中,NK抑制性配体是靶向CEACAM1的抗体或其功能性片段。CEACAM1也称为CD66a、胆汁糖蛋白(BGP)或C-CAM1,是癌胚抗原(CEA)基因家族的成员并属于免疫球蛋白(Ig)超家族。在活化的NK细胞中,CEACAM1表达被上调,且其嗜同性相互作用(homophilic interaction)导致淋巴细胞细胞毒性效应的抑制。CEACAM1与其他已知CEACAM蛋白包括CD66a(CEACAM1)、CD66c(CEACAM6)和CD66e(CEACAM5、CEA)蛋白相互作用。在人中,迄今为止已检测11个不同的CEACAM1剪接变体。CEACAM1同种型的命名与胞外免疫球蛋白-样结构域的数目(例如,具有4个胞外免疫球蛋白样结构域的CEACAM1被称为CEACAM1-4)、以及胞质尾区的长度(例如,具有长胞质尾区的CEACAM1-4被称为CEACAM1-4L,具有短胞质尾区的CEACAM1-4被称为CEACAM1-4S)有关。CEACAM1的N-末端结构域紧接在信号肽之后开始,并且其结构被认为是IgV-型。
在一个实施方案中,NK抑制性配体是靶向SIGLEC的抗体或其功能性片段。已经在人类中鉴定了16种SIGLEC蛋白并且在小鼠中鉴定了9种SIGLEC蛋白,所述SIGLEC蛋白由包括氨基末端V-型结构域的2-17个细胞外Ig结构域组成,所述V-型结构域含有唾液酸结合位点。Siglec通常被分为两组:由Siglec1、Siglec2、Siglec4和Siglec15组成的第一子集,以及包括Siglec3、Siglec5、Siglec6、Siglec7、Siglec8、Siglec9、Siglec10、Siglec11、Siglec12、Siglec14和Siglec16的CD33相关的第二子集。Siglec7,也称为p75、CD328或AIRM,含有细胞外N-末端Ig样V-型结构域、两个Ig样C2-型结构域以及含有一个ITIM基序和一个ITIM样基序的胞质内区域。Siglec7在NK细胞、树突细胞、单核细胞和嗜中性粒细胞上组成型表达。已经观察到Siglec7对NK细胞介导的肿瘤清除具有抑制作用。Siglec9的结构与Siglec7非常相似,它们的N-末端V-组Ig结构域具有约77%的总氨基酸序列同一性,并且显示不同的唾液酸结合特异性。鉴于对NK细胞的功能研究已经证明,表达Siglec9结合唾液酸配体的肿瘤细胞抑制NK细胞活化和肿瘤细胞杀伤。许多人肿瘤稳健地上调结合Siglec9的唾液酸配体,这使得肿瘤能够逃避免疫,发生癌症进展。
在一个优选的实施方案中,NK抑制性配体是靶向Siglec7或Siglec9的抗体,例如本领域已知的那些。举例而言,抗Siglec7抗体可以源自人Siglec7/CD328抗体(AF1138,R&DSystems)、克隆#194212(MAB1138,R&D Systems)、克隆#194211(MAB11381,R&D Systems)、克隆Z176(A22330,Beckman Coulter)、6-434(339202,Biolegend)、REA214(MiltenylBiotec)、S7.7(MCA5782GA,BioRad)、10B2201(MBS604764,MyBioSource)、8D8(MBS690562,MyBioSource)、10B2202(MBS608694,MyBioSource)、5-386(MBS214370,MyBioSource)。抗Siglec9抗体可以源自MAB1139(克隆#191240,R&D Systems)、AF1139(R&D Systems)、D18(SC-34936,Santa Cruz Biotechnology)、Y-12SC34938(SC3-4938,Santa CruzBiotechnology)、AB 197981(Abeam)、AB96545(Abeam)、AB89484(克隆#MM0552-6K12,Abeam)、AB 130493(Abeam)、AB117859(克隆#3G8,Abeam)、E10-286(Becton Dickinson)。鉴于Siglec7和Siglec9在细胞外结构的相似性,同时靶向这两者的抗体也可作用本发明的NK抑制性配体。
在一个实施方案中,NK抑制性配体是靶向SIGLEC7、SIGLEC9或两者的抗体,其包含(1)如SEQ ID NO:102所示的CDR-L1、如SEQ ID NO:103所示的CDR-L2、如SEQ ID NO:104所示的CDR-L3、如SEQ ID NO:105所示的CDR-H1、如SEQ ID NO:106所示的CDR-H2和如SEQ IDNO:107所示的CDR-H3,(2)如SEQ ID NO:122所示的CDR-L1、如SEQ ID NO:123所示的CDR-L2、如SEQ ID NO:124所示的CDR-L3、如SEQ ID NO:125所示的CDR-H1、如SEQ ID NO:126所示的CDR-H2和如SEQ ID NO:1277所示的CDR-H3,(3)如SEQ ID NO:131所示的CDR-L1、如SEQID NO:132所示的CDR-L2、如SEQ ID NO:133所示的CDR-L3、如SEQ ID NO:134所示的CDR-H1、如SEQ ID NO:135所示的CDR-H2和如SEQ ID NO:136所示的CDR-H3,(4)如SEQ ID NO:140所示的CDR-L1、如SEQ ID NO:141所示的CDR-L2、如SEQ ID NO:142所示的CDR-L3、如SEQID NO:143所示的CDR-H1、如SEQ ID NO:144所示的CDR-H2和如SEQ ID NO:155所示的CDR-H3,(5)如SEQ ID NO:176所示的CDR-L1、如SEQ ID NO:177所示的CDR-L2、如SEQ ID NO:178所示的CDR-L3、如SEQ ID NO:179所示的CDR-H1、如SEQ ID NO:180所示的CDR-H2和如SEQID NO:181所示的CDR-H3,或(6)如SEQ ID NO:188所示的CDR-L1、如SEQ ID NO:189所示的CDR-L2、如SEQ ID NO:190所示的CDR-L3、如SEQ ID NO:191所示的CDR-H1、如SEQ ID NO:192所示的CDR-H2和如SEQ ID NO:193所示的CDR-H3。上述抗体(1)-(4)靶向SIGLEC7,抗体(5)-(6)同时靶向SIGLEC7和SIGLEC9两者。在一个实施方案中,NK抑制性配体是靶向SIGLEC7、SIGLEC9或两者的抗体,其包含轻链可变区和重链可变区,所述轻链可变区与SEQID NO:108、128、137、146、182、185或194所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,所述重链可变区与SEQ ID NO:109、129、138、147、183、186或195所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。在一个优选的实施方案中,NK抑制性配体是抗SIGLEC7、SIGLEC9或两者的抗体,其氨基酸序列如SEQ ID NO:110、130、139、148、184、187或196所示。在一个实施方案中,NK抑制性配体是靶向LAIR1的抗体或其功能性片段。LAIR1含有10个外显子,编码由287个氨基酸组成的I型跨膜糖蛋白,其包含单个细胞外C2型Ig样结构域,随后是与单个跨膜结构域连接的茎区域和2个传递抑制信号的ITIM基序。LAIR1在结构上与LIR和KIR家族成员有一定同源性,表明这些分子可能来源于同一祖先基因。LAIR1在T细胞、B细胞、自然杀伤(NK)细胞、巨噬细胞和树突状细胞以及包括人CD34+细胞的造血祖细胞中表达。由于ITIM基序的存在,目前为止在人和小鼠体内的研究均发现LAIR1发挥免疫抑制的作用。进一步的研究表明,LAIR1不仅可抑制静止NK细胞,还可抑制活化的NK细胞对靶细胞的杀伤。
在一个实施方案中,NK抑制性配体是靶向Ly49的抗体或其功能性片段。Ly49是II型跨膜糖蛋白,可以通过二硫键连接形成同源二聚体,发挥与人KIR相似的功能,即通过与MHC-I类分子配体的相互作用来传递信号,进而调整NK细胞的活性。至今发现小鼠Ly49家族包括11个成员,分别是Ly49A、Ly49B、Ly49C、Ly49D、Ly49E、Ly49F、Ly49G、Ly49H、Ly49I、Ly49P、Ly49Q。其中,Ly49A、Ly49C、Ly49F、Ly49G和Ly49Q均在胞质区含有ITIM基序,能与酪氨酸激酶SHP-1结合并使之活化,通过干扰磷酸化酪氨酸的生成来抑制NK细胞活化。因此,在一个优选的实施方案中,NK抑制性配体是靶向Ly49A、Ly49C、Ly49F、Ly49G或Ly49Q的抗体。
在一个实施方案中,NK抑制性配体是靶向KLRG1的抗体或其功能性片段。KLRG1是调节T细胞和NK细胞的活性的II型跨膜蛋白表面共抑制受体。其细胞外部分包含C型凝集素结构域,已知的配体是钙粘素,并且其细胞内部分包含基于免疫受体酪氨酸的抑制基序(ITIM)结构域。有文献报道在丙肝病人外周血NK细胞上的KLRG1受体表达会促进NK细胞数量减少和功能受损,其机制主要是抑制NK细胞的增殖、促进NK细胞的凋亡和减少NK细胞炎症细胞因子的释放。
在一个实施方案中,NK抑制性配体是靶向KLRG1的抗体,其包含:(1)如SEQ ID NO:111所示的CDR-L1、如SEQ ID NO:112所示的CDR-L2、如SEQ ID NO:113所示的CDR-L3、如SEQID NO:114所示的CDR-H1、如SEQ ID NO:115所示的CDR-H2和如SEQ ID NO:116所示的CDR-H3,(2)如SEQ ID NO:149所示的CDR-L1、如SEQ ID NO:150所示的CDR-L2、如SEQ ID NO:151所示的CDR-L3、如SEQ ID NO:152所示的CDR-H1、如SEQ ID NO:153所示的CDR-H2和如SEQID NO:154所示的CDR-H3,(3)如SEQ ID NO:158所示的CDR-L1、如SEQ ID NO:159所示的CDR-L2、如SEQ ID NO:160所示的CDR-L3、如SEQ ID NO:161所示的CDR-H1、如SEQ ID NO:162所示的CDR-H2和如SEQ ID NO:163所示的CDR-H3,或(4)如SEQ ID NO:167所示的CDR-L1、如SEQ ID NO:168所示的CDR-L2、如SEQ ID NO:169所示的CDR-L3、如SEQ ID NO:170所示的CDR-H1、如SEQ ID NO:171所示的CDR-H2和如SEQ ID NO:172所示的CDR-H3。在一个实施方案中,NK抑制性配体是靶向KLRG1的抗体,其包含轻链可变区和重链可变区,所述轻链可变区与SEQ ID NO:117、155、164或173所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,所述重链可变区与SEQ ID NO:118、156、165或174所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。在一个优选的实施方案中,NK抑制性配体是抗KLRG1抗体,其氨基酸序列如SEQ ID NO:119、157、166或175所示。
在一个实施方案中,NK抑制性配体是NKIR天然配体或其包含的NKIR结合区(例如胞外区),此类天然配体包括但不限于非经典HLA-I类分子(例如HLA-E、HLA-F和HLA-G)、钙黏素(Cadherin)、胶原蛋白、OCIL、唾液酸、免疫检查点配体(例如PD-L1/PD-L2、CD155、CD112、CD113、Gal-9、FGL1)等。
在一个实施方案中,NK抑制性配体是非经典HLA-I类分子或其胞外区,更优选非经典HLA-I类分子的α1和α2结构域。非经典HLA-I类分子位于相同的染色体区域6p21.3,第6号染色体短臂,由通过非共价键结合的重链(α链)和轻链(β链,由B2M基因编码)组成。α链包括胞外区(包括α1、α2、α3三个结构域)、跨膜结构域和胞质区三部分,其中α1和α2形成抗原结合槽,负责与进入槽内的抗原肽结合,α3与免疫球蛋白的恒定区结构域同源,与T细胞表面分子CD8结合。非经典HLA-I类分子包括三个成员:HLA-E、HLA-F和HLA-G。HLA-E通过与NK细胞表面的CD94/NKG2受体结合,调节NK细胞活性。HLA-E的功能是结合源自于I类HLA分子(HLA-A、-B、-C和-G)的前导序列的肽,并通过与抑制性受体CD94/NKG2A的相互作用将它们呈递给NK细胞,从而抑制NK细胞对表达正常水平的I类HLA分子的细胞的裂解。由于生理情况下HLA-E与抑制性受体CD94/NKG2A的亲和力明显高于其与活化性受体CD94/NKG2C之前的亲和力,因此HLA-E的表达水平上调可以保护靶细胞免受NK细胞的杀伤作用。HLA-F能够与NK抑制性受体ILT2和ILT4结合,并且这种结合能被ILT2和ILT4抗体有效抑制。目前对HLA-F功能仍在探索,但推测其与ILT2和ILT4的结合可能具有免疫抑制作用。HLA-G可识别多种NK抑制性受体,例如CD94/NKG2A、LIR-1、LIR-2、KIR2DL1等。研究发现,胎儿细胞表面的HLA-G分子可能通过与母体NK细胞表面的KIR结合,抑制NK细胞杀伤活性,从而导致母体对HLA半异源性胎儿产生免疫耐受。此外,在实体肿瘤,例如黑素瘤、肉瘤、淋巴瘤等细胞表面高表达的HLA-G分子还能使肿瘤细胞逃避NK细胞的杀伤、溶解作用。
在一个实施方案中,NK抑制性配体是HLA-E胞外区,其与SEQ ID NO:31所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:32所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。在另一个实施方案中,NK抑制性配体是HLA-E胞外区的突变体(包含Y84C突变),其与SEQ ID NO:33所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:34所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,NK抑制性配体是HLA-G胞外区,其与SEQ ID NO:35所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:36所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,当需要将工程化免疫细胞的内源性B2M敲除并且表达非经典HLA-I类分子作为NK抑制性配体时,需要引入同义突变(即,仅核苷酸序列改变而氨基酸序列不改变)的B2M基因以使其能与非经典HLA-I分子形成复合物从而发挥抑制功能,同时同义突变的B2M基因也能避免被靶向内源性B2M的基因编辑工具敲除。在该实施方案中,NK抑制性配体包含B2M和非经典HLA-I类分子的胞外区的融合分子。例如,NK抑制性配体包含B2M和HLA-E胞外区或HLA-G胞外区的融合分子。在一个具体的实施方案中,NK抑制性配体包含B2M和HLA-E胞外区的融合分子,优选的,所述HLA-E胞外区包含Y84C突变(SEQ ID NO:33)。在一个优选的实施方案中,NK抑制性配体包含提呈肽、以及B2M和HLA-E胞外区的融合分子,所述提呈肽选自SEQ ID NO:46-53。将B2M基因进行同义突变的方法是本领域技术人员熟知的。在一个优选的实施方案中,B2M与SEQ ID NO:37所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性;同义突变的B2M基因的核苷酸序列例如如SEQ ID NO:38所示。
在一个实施方案中,NK抑制性配体是破骨细胞抑制凝集素(Osteoclastinhibitory lectin,OCIL)或其NKIR结合区。小鼠OCIL包括三个成员:OCIL(也称为Clr-b)、OCILrP1(也称为Clr-d)和mOCILrP2(也称为Clr-g)。OCIL广泛表达在各组织中,其表达模式与MHC-I类分子相似。OCIL是NKR-P1B/D的配体。研究表明,在肿瘤细胞上表达OCL可以抑制NK细胞对肿瘤细胞的杀伤作用,而OCL特异性抗体则可以逆转这种抑制作用。
在一个实施方案中,NK抑制性配体是钙黏素或其胞外区,例如E-钙粘素(E-cad)、N-钙粘素(N-cad)或R-钙粘素(R-cad),优选E-钙粘素的胞外区。钙黏素是一类主要介导细胞间同质黏附的钙依赖性跨膜蛋白,其结合NK抑制性受体KLRG1。钙黏素分子是I型膜蛋白,由约723-748个氨基酸组成,结构上包括负责与配体结合的胞外区、跨膜区和高度保守的胞质区。其中,胞外区有数个钙黏蛋白重复结构域(EC),并含有由4~5个氨基酸残基组成的重复序列,负责与配体结合。人E-钙黏素由CDH 1基因编码,是目前研究最多的钙黏素家族成员。因此,在一个优选的实施方案中,NK抑制性配体是E-钙粘素的胞外区,其包含EC1和EC2。更优选的,NK抑制性配体是E-钙粘素的胞外区,其包含EC1、EC2、EC3、EC4和EC5。更优选地,NK抑制性配体是E-Cad,其与SEQ ID NO:39或41所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ IDNO:40或42所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,NK抑制性配体是胶原蛋白或其NKIR结合区,其结合LAIR 1。胶原分子是由3条α链组成的三聚体,每条α链都含有(甘氨酸-脯氨酸-羟脯氨酸)n重复序列。LAIR1识别Gly-Pro-Hyp重复序列并与其相互作用。由于该重复序列的广泛存在,已经证明LAIR1可与多种胶原分子广泛结合,包括但不限于跨膜胶原,例如胶原XVII、XIII、XXIII;和非跨膜胶原,例如胶原I、II、III等。肿瘤细胞或肿瘤间质细胞常常高表达多种胶原分子,这可能通过与免疫细胞表面的抑制性受体LAIR1结合来向免疫细胞内传递抑制性信号,从而达到免疫逃逸的目的。
在一个实施方案中,NK抑制性配体是唾液酸或其NKIR结合区,其结合SIGLEC家族成员(例如SIGLEC7和/或SIGLEC9)。唾液酸是脊椎动物先天性免疫系统的重要组成部分,NK细胞杀伤活性与肿瘤细胞表面的唾液酸化相关。肿瘤细胞的唾液酸化不仅可以阻碍肿瘤细胞与NK细胞之间的物理作用,而且可以遮蔽肿瘤细胞表面能够与之结合的活化性配体。此外,肿瘤细胞表面的唾液酸化会导致肿瘤细胞和NK细胞之间的免疫突触形成受阻,从而削弱NK细胞对肿瘤的杀伤毒性。研究发现,肿瘤细胞表面的唾液酸化还可以通过触发由Siglec介导的免疫抑制信号来抑制NK细胞的杀伤活性。Siglec7表达于大部分的NK细胞表面,而肿瘤细胞表面以α-2,8糖苷键连接的唾液酸与NK细胞表面的Siglec7结合后,会抑制NK细胞的活化,从而使肿瘤细胞逃逸NK细胞介导的杀伤功能。
在一个实施方案中,NK抑制性配体为PD-L1/PD-L2或其胞外区,其结合PD1。PD-L1组成性地低表达于抗原递呈细胞(APC)、以及非造血细胞如血管内皮细胞、胰岛细胞以及免疫豁免部位(如胎盘、睾丸和眼睛)。炎性细胞因子如I型和II型干扰素、TNF-α和VEGF等均可以诱导PD-L1的表达。PD-L2只在被激活的巨噬细胞和树突细胞中有表达。肿瘤细胞本身可上调PD-L1的表达,同时肿瘤微环境中的炎症因子同样可以诱导PD-L1和PDL2的表达。肿瘤细胞表面PD-L1和PD-L2的上调表达可触发由PD-1介导的免疫抑制信号的传递进而抑制NK细胞的杀伤活性。在一个优选的实施方案中,NK抑制性配体是PD-L1胞外区或PD-L2胞外区,其与SEQ ID NO:70或71所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,NK抑制性配体为CD155、CD112或CD113或其NKIR结合区,其均结合TIGIT。CD155是TIGIT的高亲和力配体。肿瘤表面高表达的CD155一旦与NK表面的TIGIT结合,NK细胞对肿瘤细胞的杀伤作用就会被抑制。CD112和CD113也与TIGIT结合,尽管亲和力相对较弱。
在一个实施方案中,NK抑制性配体是半乳凝素9(也称为Gal-9)或其NKIR结合区,其结合TIM3。Gal-9是一种由许多造血细胞广泛表达和分泌的C型凝集素,可与细胞表面蛋白上的碳水化合物部分结合。在TIM3上,Gal-9结合其IgV域上的碳水化合物基序,可诱导TIM3阳性NK细胞钙内流和细胞死亡。已有大量证明表明,TIM3/Gal-9相互作用在抑制免疫反应中发挥了作用。
在一个实施方案中,NK抑制性配体是FGL1或其NKIR结合区,其结合LAG3。FGL1属于纤维蛋白原家族,是新进发现的LAG3的配体,但它并没有特征性的血小板结合位点、凝血酶敏感位点等结构域。FGL1蛋白主要分布于肿瘤细胞中,肿瘤间质表达较低。FGL1/LAG3相互作用是独立于B7-H1/PD-1通路的另一条肿瘤免疫逃逸通路,阻断这条通路能和阻断PD-1通路起到协同作用。
如本文所用,术语“跨膜结构域”是指能够使嵌合抗原受体在免疫细胞(例如淋巴细胞或NKT细胞)表面上表达,并且引导免疫细胞针对靶细胞的细胞应答的多肽结构。跨膜结构域可以是天然或合成的,也可以源自任何膜结合蛋白或跨膜蛋白。当嵌合抗原受体与靶抗原结合时,跨膜结构域能够进行信号传导。特别适用于本发明中的跨膜结构域可以源自例如TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137、CD154,和NKIR天然配体的跨膜结构域,例如非经典HLA-I类分子(例如HLA-E、HLA-F和HLA-G)、钙黏素(Cadherin)、胶原蛋白、OCIL等的跨膜结构域。优选地,跨膜结构域选自CD8α、CD4、CD28和CD278的跨膜结构域。或者,跨膜结构域可以是合成的并且可以主要地包含疏水性残基如亮氨酸和缬氨酸。优选地,所述跨膜结构域源自CD8α或CD28,更优选与SEQ ID NO:9或11所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或所述跨膜结构域的编码序列与SEQ ID NO:10或12所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的NK抑制性分子还可以包含位于NK抑制性配体和跨膜结构域之间的铰链区。如本文所用,术语“铰链区”一般是指作用为连接跨膜结构域至配体结合结构域的任何寡肽或多肽。具体地,铰链区用来为配体结合结构域提供更大的灵活性和可及性。铰链区可以包含最多达300个氨基酸,优选10至100个氨基酸并且最优选25至50个氨基酸。铰链区可以全部或部分源自天然分子,如全部或部分源自CD8、CD4或CD28的胞外区,或全部或部分源自抗体恒定区。或者,铰链区可以是对应于天然存在的铰链序列的合成序列,或可以是完全合成的铰链序列。在优选的实施方式中,所述铰链区包含CD8α、CD28、FcγRIIIα受体、IgG4或IgG1的铰链区部分,更优选CD8α、CD28或IgG4铰链,其与SEQ ID NO:25、27或29所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或者CD28铰链的编码序列与SEQ ID NO:26、28或30所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
本发明的NK抑制性分子包括共刺激结构域。因此,当NK抑制性配体与NKIR结合时,一方面可以通过NKIR的信号传导区向NK细胞传递抑制信号,降低其对靶细胞(例如本发明的工程化免疫细胞)的杀伤;另一方面可以通过NK抑制性分子包含的共刺激结构域向靶细胞(例如本发明的工程化免疫细胞)内部传递刺激信号,刺激其增殖和存活,从而更好地抵抗NK细胞的杀伤。之前有研究发现,使用抗体靶向NK细胞NKG2A、KIR、ILT2等抑制性受体,可以竞争结合HLA-E、HLA-G等抑制分子的结合位点或中和其抑制效果,从而起到激活NK细胞的作用。与此相反,本发明首次发现,表达靶向NK抑制性受体的NK抑制性分子可以抑制NK细胞。本发明还发现,与不含共刺激结构域的NK抑制性分子相比,包含共刺激结构域的NK抑制性分子对NK细胞的杀伤作用抑制效果更好。
共刺激结构域可以是来自共刺激分子的细胞内功能性信号传导结构域,其包含所述共刺激分子的整个细胞内部分,或其功能片段。“共刺激分子”是指在T细胞上与共刺激配体特异性结合,由此介导T细胞的共刺激反应(例如增殖)的同源结合配偶体。共刺激分子包括但不限于I类MHC分子、BTLA和Toll配体受体。本发明的共刺激结构域的非限制性施例包括但不限于源自以下蛋白质的共刺激信号传导结构域:LTB、CD94、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70以及它们的组合。优选地,本发明的共刺激结构域来自4-1BB、CD28、CD27、OX40、CD278或其组合,更优选4-1BB、CD28或其组合。在一个实施方案中,本发明的共刺激结构域与SEQ ID NO:13或15所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或该共刺激结构域的编码序列与SEQ ID NO:14或16所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,NK抑制性分子不包含胞内信号传导结构域。在另一个实施方案中,NK抑制性分子进一步包含胞内信号传导结构域。即,NK抑制性分子包含NK抑制性配体、跨膜结构域、共刺激结构域和胞内信号传导结构域。在该实施方案中,NK抑制性配体与NKIR的结合会通过共刺激结构域和胞内信号传导结构域向靶细胞(例如本发明的工程化免疫细胞)传递活化信号,促使靶细胞对NK细胞的杀伤,从而进一步增强对NK细胞杀伤作用的抑制效果。
如本文所用,术语“胞内信号传导结构域”是指转导效应子功能信号并指导细胞进行指定功能的蛋白质部分。胞内信号传导结构域负责在配体结合结构域结合抗原以后的细胞内初级信号传递,从而导致免疫细胞和免疫反应的活化。换言之,胞内信号传导结构域负责活化其中表达NK抑制性分子的免疫细胞的正常的效应子功能的至少一种。例如,T细胞的效应子功能可以是细胞溶解活性或辅助活性,包括细胞因子的分泌。
在一个实施方案中,本发明的胞内信号传导结构域可以是T细胞受体和共受体的细胞质序列,其在抗原受体结合以后一同起作用以引发初级信号传导,以及这些序列的任何衍生物或变体和具有相同或相似功能的任何合成序列。胞内信号传导结构域可以包含许多免疫受体酪氨酸激活基序(Immunoreceptor Tyrosine-based Activation Motifs,ITAM)。本发明的胞内信号传导结构域的非限制性施例包括但不限于源自FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d的那些。在优选的实施方式中,本发明CAR的信号传导结构域可以包含CD3ζ信号传导结构域,该信号传导结构域与SEQ ID NO:17或19所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:18或20所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的NK抑制性分子还可以包含信号肽,使得当其在细胞例如T细胞中表达时,新生蛋白质被引导至内质网并随后引导至细胞表面。信号肽的核心可以含有长的疏水性氨基酸区段,其具有形成单个α-螺旋的倾向。在信号肽的末端,通常有被信号肽酶识别和切割的氨基酸区段。信号肽酶可以在移位期间或完成后切割,以产生游离信号肽和成熟蛋白。然后,游离信号肽被特定蛋白酶消化。可用于本发明的信号肽是本领域技术人员熟知的,例如衍生自B2M、CD8α、IgG1、GM-CSFRα等的信号肽。在一个实施方案中,可用于本发明的信号肽与SEQ ID NO:21或23所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或该信号肽的编码序列与SEQ ID NO:22或24所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
至少一种MHC相关基因的抑制或沉默
在一个实施方案中,所述表达NK抑制性分子的工程化免疫细胞进一步包括至少一种MHC相关基因表达被抑制或沉默,例如使至少一种MHC基因的表达被抑制或沉默,或使与至少一种MHC基因相互作用或调控其表达的基因的表达被抑制或沉默。
主要组织相容性复合物(major histocompatibility complex,MHC)最初被表征为在移植反应中起主要作用的蛋白,其在所有高等脊椎动物的表面上上表达,并且在小鼠中称为H-2,在人细胞中称为HLA。MHC主要有两类:I类和II类。I类MHC蛋白是两种蛋白质的异二聚体:一种是由MHCI基因编码的跨膜蛋白α链,另一种是由不位于MHC基因簇内的基因编码的细胞外蛋白质的β2微球蛋白链。α链包括三个结构域,外来肽与两个在N末端,也是最可变的结构域α1、α2结合。II类MHC蛋白也是异二聚体,包含两个由MHC复合物内的基因编码的跨膜蛋白质。I类MHC/抗原复合物与细胞毒性T细胞相互作用,而II类MHC向辅助T细胞呈递抗原。此外,I类MHC蛋白倾向于在几乎所有有核细胞和血小板(以及小鼠中的红血细胞)中表达,而II类MHC蛋白更具选择性地表达。通常,II类MHC蛋白在B细胞、一些巨噬细胞和单核细胞、郎格罕氏细胞(Langerhans cell)和树突细胞上表达。
人的I类HLA基因簇包含三个主要基因座B、C和A。HLA-A、HLA-B和HLA-C是I类HLA重链旁系同源物。I类分子是由MHCα重链(由HLA-A、HLA-B或HLA-C编码)和轻链(β-2微球蛋白,由B2M编码)组成的异二聚体。重链锚定在膜中,为约45kDa,并且含有8个外显子。外显子1编码前导肽,外显子2和3编码α1和α2结构域,其两者均结合肽,外显子4编码α3结构域,外显子5编码跨膜区域,外显子6和7编码细胞质尾部。外显子2和外显子3内的多态性导致每一类分子的肽结合特异性。因此,在一个实施方案中,使MHC相关基因表达被抑制或沉默是指使选自以下的一个或多个基因的表达被抑制或沉默:HLA-A、HLA-B、HLA-C和B2M。
人的II类HLA簇也包含三个主要基因座DP、DQ和DR,并且I类基因簇与II类基因簇两者均是多态性的。HLA-DPA1、HLA-DQA1和HLA-DRA属于II类HLAα链旁系同源物。II类分子通过呈递外源性肽而在免疫系统中起主要作用,主要在抗原呈递细胞(例如B淋巴细胞、树突细胞、巨噬细胞)中表达。II类分子是由均锚定在膜中的α链和β链组成的异二聚体,其中α链为约33-35kDa,并且含有5个外显子。外显子1编码前导肽,外显子2和3编码两个细胞外结构域,外显子4编码跨膜结构域,外显子5编码细胞质尾部。因此,在一个实施方案中,使MHC相关基因表达被抑制或沉默是指使选自以下的一个或多个基因的表达被抑制或沉默:HLA-DPA、HLA-DQ和HLA-DRA。
I类和II类MHC的表达还取决于多种辅助蛋白质。例如,Tap1和Tap2亚单位是将肽抗原装载于I类HLA复合物上所必需的TAP转运体复合物的部分。LMP2和LMP7蛋白体亚单位在使抗原蛋白水解降解成肽以在HLA上展示中起作用。已显示,降低LMP7会降低细胞表面处I类MHC的表达量。II类MHC表达则受到一些正调控因子的诱导和表达,例如RFX复合物、CIITA等。RFX复合物由三个亚基组成:RFXANK(也称为RFXB)、RFX5和RFX辅助蛋白(也称为RFXAP)。RFX复合物通过促进其他转录因子与II类MHC分子的启动子结合并增强启动子结合的特异性促进II类MHC分子的表达。CIITA是II类MHC表达的主控制因子。CIITA包括富含酸性氨基酸的N端,富含Pro、Ser、Thr的PST区域,中间的GTP结合区域以及富含Leu重复序列(LRR)的C端,其中N端酸性区域和PST区域是转录激活区域。因此,在一个实施方案中,使MHC相关基因表达被抑制或沉默是指使选自以下的一个或多个基因的表达被抑制或沉默:TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK和CIITA。
因此,在一个实施方案中,使MHC相关基因表达被抑制或沉默是指使选自以下的一个或多个基因的表达被抑制或沉默:HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA和它们的组合,优选选自HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
在一个实施方案中,所述表达NK抑制性分子的工程化免疫细胞进一步包括至少一种TCR/CD3基因的表达被抑制或沉默。
T细胞表面受体(T cell receptor,TCR)是所有T细胞表面的特征性标志,以非共价键与CD3结合形成TCR/CD3复合物,并通过与抗原呈递细胞表面的特异性MHC-抗原肽复合物结合,产生特异性抗原刺激信号,激活T细胞,发挥杀伤作用。TCR是由两条不同肽链构成的异二聚体,通常分为两类:α/β型和γ/δ型,其中95%以上的外周T淋巴细胞都表达TCRα/β。TCRα链由TRAC基因编码,β链由TRBC基因编码。TCR的每条肽链包括可变区(V区)、恒定区(C区)、跨膜区和胞质区,其中胞质区很短,不具备传递抗原刺激信号的能力。TCR分子属于免疫球蛋白超家族,其抗原特异性存在于V区;V区又各有三个高变区CDR1、CDR2、CDR3,其中以CDR3变异最大,直接决定了TCR的抗原结合特异性。在TCR识别MHC-抗原肽复合物时,CDR1、CDR2识别并结合MHC分子,而CDR3直接与抗原肽相结合。CD3包括四种亚基:γ、δ、ε、ζ,通常以二聚体εγ、εδ、ζζ的形式存在。这四种亚基均包含保守的免疫受体酪氨酸激活基序(Immunoreceptor tyrosine-based activation motif,ITAM),其中的2个酪氨酸残基被酪氨酸蛋白激酶磷酸化后,向T细胞传递活化信号。因此,在一个实施方案中,使至少一种TCR/CD3基因表达被抑制或沉默是指使选自以下的一个或多个基因的表达被抑制或沉默:TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ。
在一个优选的实施方案中,所述表达NK抑制性分子的工程化免疫细胞包括至少一种TCR/CD3基因和至少一种MHC相关基因的表达被抑制或沉默,其中所述至少一种TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ和它们的组合;所述至少一种MHC相关基因选自HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA和它们的组合,优选选自HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
在一个优选的实施方案中,所述至少一种TCR/CD3基因选自TRAC、TRBC和它们的组合,所述至少一种MHC相关基因选自B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。在一个实施方案中,所述工程化免疫细胞的TRAC或TRBC,和B2M的表达被抑制或沉默。在一个实施方案中,所述工程化免疫细胞的TRAC或TRBC,和CIITA的表达被抑制或沉默。在一个优选的实施方案中,所述工程化免疫细胞的TRAC或TRBC、B2M和CIITA的表达被抑制或沉默。在一个优选的实施方案中,所述工程化免疫细胞的TRAC或TRBC、B2M和RFX5的表达被抑制或沉默。
在一个实施方案中,除了MHC相关基因和任选的TCR/CD3基因,本发明的工程化免疫细胞还可以包含至少一种选自以下的基因的表达被抑制或沉默:CD52、GR、dCK和免疫检查点基因,如PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。
抑制基因表达或使基因沉默的方法是本领域技术人员熟知的,包括但不限于例如通过大范围核酸酶、锌指核酸酶、TALE核酸酶或CRISPR系统中的Cas酶介导DNA断裂、或通过反义寡核苷酸、RNAi、shRNA等技术使基因失活。
嵌合抗原受体
在另一个方面,本发明的表达NK抑制性分子的工程化免疫细胞还可以表达嵌合抗原受体。即,在该实施方案中,工程化免疫细胞表达NK抑制性分子和嵌合抗原受体,优选地,所述工程化免疫细胞的至少一种MHC相关基因的表达被抑制或沉默。在一个优选的实施方案中,所述工程化免疫细胞还包括至少一种TCR/CD3基因的表达被抑制或沉默。
如本文所用,术语“嵌合抗原受体”或“CAR”是指人工构建的杂合多肽,该杂合多肽一般包括一个或多个配体结合结构域(例如抗体的抗原结合部分)、跨膜结构域、共刺激结构域和细胞内信号传导结构域,各个结构域之间通过接头连接。CAR能够利用单克隆抗体的抗原结合特性以非MHC限制性的方式将T细胞和其它免疫细胞的特异性和反应性重定向至所选择的靶标。非MHC限制性的抗原识别给予CAR细胞与抗原处理无关的识别抗原的能力,因此绕过了肿瘤逃逸的主要机制。此外,当在T细胞内表达时,CAR有利地不与内源性T细胞受体(TCR)的α链和β链二聚化。
如本文所用,“配体结合结构域”是指可以与配体(例如抗原)结合的任何结构或其功能性变体。配体结合结构域可以是抗体结构,包括但不限于单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体、鼠源抗体、嵌合抗体及其功能性片段。例如,配体结合结构域包括但不限于完整抗体、Fab、Fab’、F(ab’)2、Fv片段、scFv抗体片段、线性抗体、sdAb(VH或VL)、纳米抗体(Nanobody,Nb)、重组纤连蛋白结构域、anticalin和DARPIN等,优选选自Fab、scFv、sdAb和纳米抗体。在本发明中,配体结合结构域可以是单价或二价,且可以是单特异性、双特异性或多特异性的抗体。
“Fab”是指免疫球蛋白分子被木瓜蛋白酶裂解后产生的两个相同片段中的任一个,由通过二硫键连接的完整轻链和重链N端部分组成,其中重链N端部分包括重链可变区和CH1。与完整的IgG相比,Fab没有Fc片段,流动性和组织穿透能力较高,并且无需介导抗体效应即可单价结合抗原。
“单链抗体”或“scFv”是由抗体重链可变区(VH)和轻链可变区(VL)通过接头连接而成的抗体。可以选择接头的最佳长度和/或氨基酸组成。接头的长度会明显影响scFv的可变区折叠和相互作用情况。事实上,如果使用较短的接头(例如在5-10个氨基酸之间),则可以防止链内折叠。关于接头的大小和组成的选择,参见例如,Hollinger等人,1993ProcNatl Acad.Sci.U.S.A.90:6444-6448;美国专利申请公布号2005/0100543、2005/0175606、2007/0014794;以及PCT公布号WO2006/020258和WO2007/024715,其全文通过引用并入本文。scFv可以包含以任何顺序连接的VH和VL,例如VH-接头-VL或VL-接头-VH。
“单结构域抗体”或“sdAb”是指一种天然缺失轻链的抗体,该抗体只包含一个重链可变区(VHH)和两个常规的CH2与CH3区,也称为“重链抗体”。
“纳米抗体”或“Nb”是指单独克隆并表达出来的VHH结构,其具有与原重链抗体相当的结构稳定性以及与抗原的结合活性,是目前已知的可结合目标抗原的最小单位。
术语“功能性变体”或“功能性片段”是指基本上包含亲本的氨基酸序列但与该亲本氨基酸序列相比含有至少一个氨基酸修饰(即取代、缺失或插入)的变体,条件是所述变体保留亲本氨基酸序列的生物活性。例如,对于抗体,其功能性片段是其抗原结合部分。在一个实施方案中,所述氨基酸修饰优选是保守型修饰。
如本文所用,术语“保守性修饰”是指不会明显影响或改变含有该氨基酸序列的抗体或抗体片段的结合特征的氨基酸修饰。这些保守修饰包括氨基酸取代、添加及缺失。修饰可以通过本领域中已知的标准技术,如定点诱变和PCR介导的诱变而引入本发明的嵌合抗原受体中。保守氨基酸取代是氨基酸残基被具有类似侧链的氨基酸残基置换的取代。具有类似侧链的氨基酸残基家族已在本领域中有定义,包括碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)及芳香族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。保守性修饰可以例如基于极性、电荷、溶解度、疏水性、亲水性和/或所涉及残基的两亲性质的相似性来进行选择。
因此,“功能性变体”或“功能性片段”与亲本氨基酸序列具有至少75%,优选至少76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性,并且保留亲本氨基酸的生物活性,例如结合活性。
如本文所用,术语“序列同一性”表示两个(核苷酸或氨基酸)序列在比对中在相同位置处具有相同残基的程度,并且通常表示为百分数。优选地,同一性在被比较的序列的整体长度上确定。因此,具有完全相同序列的两个拷贝具有100%同一性。本领域技术人员将认识到,一些算法可以用于使用标准参数来确定序列同一性,例如Blast(Altschul等(1997)Nucleic Acids Res.25:3389-3402)、Blast2(Altschul等(1990)J.Mol.Biol.215:403-410)、Smith-Waterman(Smith等(1981)J.Mol.Biol.147:195-197)和ClustalW。
配体结合结构域的选择取决于待识别的与具体疾病状态相关的靶细胞上的细胞表面标记,例如肿瘤特异性抗原或肿瘤相关抗原。因此,在一个实施方案中,本发明的配体结合结构域与选自以下的一个或多个靶标结合: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、IL-l lRa、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、Folate受体α、ERBB2(Her2/neu)、MUC1、EGFR、NCAM、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gplOO、bcr-abl、酪氨酸酶、EphA2、FucosylGMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD 179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、豆荚蛋白、HPVE6、E7、MAGE Al、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin 8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG(TMPRSS2 ETS融合基因)、NA17、PAX3、雄激素受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、Claudin18.2、NKG2D和它们的任意组合。优选地,所述靶标选自:CD19、CD20、CD22、BAFF-R、CD33、EGFRvIII、BCMA、GPRC5D、PSMA、ROR1、FAP、ERBB2(Her2/neu)、MUC1、EGFR、CAIX、WT1、NY-ESO-1、CD79a、CD79b、GPC3、Claudin18.2、NKG2D和它们的任意组合。根据待靶向的抗原,本发明的CAR可以被设计为包括对该抗原具有特异性的配体结合结构域。例如,如果CD19是待靶向的抗原,则CD19抗体可用作本发明的配体结合结构域。
可用于本发明的CAR包含的跨膜结构域、共刺激结构域、胞内信号传导结构域以及任选的铰链区、信号肽等结构的定义参见上文。
在一个实施方案中,本发明的CAR还可以包含开关结构,以调控CAR的表达时间。例如,开关结构可以是二聚化结构域的形式,通过与其相应配体的结合引起构象变化,暴露胞外结合结构域,使其与被靶向抗原结合,从而激活信号传导通路。或者,也可以使用开关结构域分别连接结合结构域和信号传导结构域,仅当开关结构域互相结合(例如在诱导化合物的存在下)时,结合结构域和信号传导结构域才能通过二聚体连接在一起,从而激活信号通路。开关结构还可以是掩蔽肽的形式。掩蔽肽可以遮蔽胞外结合结构域,阻止其与被靶向抗原的结合,当通过例如蛋白酶切割掩蔽肽后,就可以暴露胞外结合结构域,使其成为一个“普通”的CAR结构。本领域技术人员知晓的各种开关结构均可用于本发明。
在一个实施方案中,本发明的CAR还可以包含自杀基因,即,使其表达一个可通过外源物质诱导的细胞死亡信号,以在需要时(例如产生严重的毒副作用时)清除CAR细胞。例如,自杀基因可以是插入的表位的形式,例如CD20表位、RQR8等,当需要时,可以通过加入靶向这些表位的抗体或试剂来消除CAR细胞。自杀基因也可以是单纯疱疹病毒胸苷激酶(HSV-TK),该基因可使细胞在接受更昔洛韦治疗诱导下死亡。自杀基因还可以是iCaspase-9,可以通过化学诱导药物如AP1903、AP20187等诱导iCaspase-9发生二聚化,从而激活下游的Caspase3分子,导致细胞凋亡。本领域技术人员知晓的各种自杀基因均可用于本发明。
根据需要,当NK抑制性分子包含胞内信号传导结构域且细胞表达CAR时,本发明的NK抑制性分子和CAR可以共享除结合区之外的其他结构,例如共刺激结构域和胞内信号传导结构域。因此,在该实施方案中,本发明的工程化免疫细胞:(1)表达本发明的NK抑制性分子和嵌合抗原受体的融合蛋白,所述融合蛋白包含NK抑制性配体、配体结合结构域、跨膜结构域、共刺激结构域和胞内信号传导结构域,和(2)至少一种MHC相关基因的表达被抑制或沉默。
核酸和载体
本发明还提供一种核酸分子,其包含编码本发明的NK抑制性分子的核酸序列。任选地,所述核酸分子还可以包含编码嵌合抗原受体的核酸序列。
如本文所用,术语“核酸分子”包括核糖核苷酸和脱氧核糖核苷酸的序列,如经修饰的或未经修饰的RNA或DNA,各自为单链和/或双链形式的线性或环状,或它们的混合物(包括杂合分子)。因此,根据本发明的核酸包括DNA(比如dsDNA、ssDNA、cDNA)、RNA(比如dsRNA、ssRNA、mRNA、ivtRNA),它们的组合或衍生物(比如PNA)。优选地,所述核酸是DNA或RNA,更优选mRNA。
核酸可以包含常规的磷酸二酯键或非常规的键(如酰胺键,比如在肽核酸(PNA)中发现的)。本发明的核酸还可含有一种或多种经修饰的碱基,比如,例如三苯甲基化的碱基和不常见的碱基(比如肌苷)。也可以想到其它修饰,包括化学、酶促或代谢修饰,只要本发明的多链CAR可以从多核苷酸表达即可。核酸可以以分离的形式提供。在一个实施方案中,核酸也可以包括调节序列,比如转录控制元件(包括启动子、增强子、操纵子、抑制子和转录终止信号)、核糖体结合位点、内含子等。
可以对本发明的核酸序列进行密码子优化以在所需的宿主细胞(如,免疫细胞)中进行最佳表达;或者用于在细菌、酵母菌或昆虫细胞中表达。密码子优化是指将目标序列中存在的在给定物种的高度表达的基因中一般罕见的密码子替换为在这类物种的高度表达的基因中一般常见的密码子,而替换前后的密码子编码相同的氨基酸。因此,最佳密码子的选择取决于宿主基因组的密码子使用偏好。
本发明还提供一种载体,其包含本发明所述的核酸分子。任选地,编码NK抑制性分子的核酸序列和编码嵌合抗原受体的核酸序列可以位于相同载体或不同载体。
如本文所用,术语“载体”是用作将(外源)遗传材料转移到宿主细胞中的媒介核酸分子,在该宿主细胞中所述核酸分子可以例如复制和/或表达。
载体一般包括靶向载体和表达载体。“靶向载体”是通过例如同源重组或使用特异性靶向位点处序列的杂合重组酶将分离的核酸递送至细胞内部的介质。“表达载体”是用于异源核酸序列(例如编码本发明的嵌合抗原受体多肽的那些序列)在合适的宿主细胞中的转录以及它们的mRNA的翻译的载体。可用于本发明的合适载体是本领域已知的,并且许多可商购获得。在一个实施方案中,本发明的载体包括但不限于质粒、病毒(例如逆转录病毒、慢病毒、腺病毒、牛痘病毒、劳氏肉瘤病毒(RSV、多瘤病毒和腺相关病毒(AAV)等)、噬菌体、噬菌粒、粘粒和人工染色体(包括BAC和YAC)。载体本身通常是核苷酸序列,通常是包含插入物(转基因)的DNA序列和作为载体“骨架”的较大序列。工程化载体通常还包含在宿主细胞中自主复制的起点(如果需要多核苷酸的稳定表达)、选择标记和限制酶切割位点(如多克隆位点,MCS)。载体可另外包含启动子、多聚腺苷酸尾(polyA)、3’UTR、增强子、终止子、绝缘子、操纵子、选择标记、报告基因、靶向序列和/或蛋白质纯化标签等元件。在一个具体的实施方案中,所述载体是体外转录的载体。
工程化免疫细胞
本发明还提供一种工程化免疫细胞,其表达本发明的NK抑制性分子,且其中至少一种MHC相关基因的表达被抑制或沉默。在一个实施方案中,本发明的工程化免疫细胞进一步表达嵌合抗原受体,所述嵌合抗原受体包含一个或多个配体结合结构域、跨膜结构域、共刺激结构域和胞内信号传导结构域。在一个优选的实施方案中,本发明的工程化免疫细胞还包括至少一种TCR/CD3基因的表达被抑制或沉默。
在一个实施方案中,除了MHC相关基因和任选的TCR/CD3基因,本发明的工程化免疫细胞还可以包含至少一种选自以下的基因的表达被抑制或沉默:CD52、GR、dCK和免疫检查点基因,如PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。
根据需要,当NK抑制性分子包含胞内信号传导结构域且细胞表达CAR时,本发明的NK抑制性分子和CAR可以共享除结合区之外的其他结构,例如共刺激结构域和胞内信号传导结构域。因此,在该实施方案中,本发明的工程化免疫细胞:(1)表达本发明的NK抑制性分子和嵌合抗原受体的融合蛋白,所述融合蛋白包含NK抑制性配体、配体结合结构域、跨膜结构域、共刺激结构域和胞内信号传导结构域,和(2)至少一种MHC相关基因的表达被抑制或沉默。在一个优选的实施方案中,所述工程化免疫细胞还包括至少一种TCR/CD3基因的表达被抑制或沉默。
如本文所用,术语“免疫细胞”是指免疫系统的具有一种或多种效应子功能(例如,细胞毒性细胞杀伤活性、分泌细胞因子、诱导ADCC和/或CDC)的任何细胞。例如,免疫细胞可以是B细胞、T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞或NKT细胞,或者是从细胞脐带血等干细胞来源获得的免疫细胞。优选地,免疫细胞是T细胞。T细胞可以是任何T细胞,如体外培养的T细胞,例如原代T细胞,或者来自体外培养的T细胞系例如Jurkat、SupT1等的T细胞,或获得自受试者的T细胞。受试者的实例包括人、狗、猫、小鼠、大鼠及其转基因物种。T细胞可以从多种来源获得,包括外周血单核细胞、骨髓、淋巴结组织、脐血、胸腺组织、来自感染部位的组织、腹水、胸膜积液、脾组织及肿瘤。T细胞也可以被浓缩或纯化。T细胞可以处于任何发育阶段,包括但不限于,CD4+/CD8+T细胞、CD4+辅助T细胞(例如Th1和Th2细胞)、CD8+T细胞(例如,细胞毒性T细胞)、肿瘤浸润细胞、记忆T细胞、幼稚T细胞、γδ-T细胞、αβ-T细胞等。在一个优选的实施方案中,免疫细胞是人T细胞。可以使用本领域技术人员已知的多种技术,如Ficoll分离从受试者的血液获得T细胞。
采用本领域已知的常规方法(如通过转导、转染、转化等)可以NK抑制性分子和任选的嵌合抗原受体引入免疫细胞。“转染”是将核酸分子或多核苷酸(包括载体)引入靶细胞的过程。一个例子是RNA转染,即将RNA(比如体外转录的RNA,ivtRNA)引入宿主细胞的过程。该术语主要用于真核细胞中的非病毒方法。术语“转导”通常用于描述病毒介导的核酸分子或多核苷酸的转移。动物细胞的转染通常涉及在细胞膜中打开瞬时的孔或“洞”,以允许摄取材料。可以使用磷酸钙、通过电穿孔、通过细胞挤压或通过将阳离子脂质与材料混合以产生与细胞膜融合并将它们的运载物沉积入内部的脂质体,进行转染。用于转染真核宿主细胞的示例性技术包括脂质囊泡介导的摄取、热休克介导的摄取、磷酸钙介导的转染(磷酸钙/DNA共沉淀)、显微注射和电穿孔。术语“转化”用于描述核酸分子或多核苷酸(包括载体)向细菌中、也向非动物真核细胞(包括植物细胞)中的非病毒转移。因此,转化是细菌或非动物真核细胞的基因改变,其通过细胞膜从其周围直接摄取并随后并入外源遗传材料(核酸分子)而产生。转化可以通过人工手段实现。为了发生转化,细胞或细菌必须处于感受态的状态。对于原核转化,技术可包括热休克介导的摄取、与完整细胞的细菌原生质体融合、显微注射和电穿孔。
试剂盒和药物组合物
本发明该提供一种试剂盒,其包含本发明的NK抑制性分子、核酸分子、载体或工程化免疫细胞。
在一个优选的实施方案中,本发明的试剂盒还包含说明书。
本发明还提供一种药物组合物,其包含本发明所述的NK抑制性分子、工程化免疫细胞、核酸分子或载体作为活性剂,和一种多种药学上可接受的赋型剂。因此,本发明还涵盖所述NK抑制性分子、核酸分子、载体或工程化免疫细胞在制备药物组合物或药物中的用途。
如本文所用,术语“药学上可接受的赋型剂”是指在药理学和/或生理学上与受试者和活性成分相容(即,能够引发所需的治疗效果而不会引起任何不希望的局部或全身作用)的载体和/或赋形剂,其是本领域公知的(参见例如Remington's PharmaceuticalSciences.Edited by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995)。药学上可接受的赋型剂的实例包括但不限于填充剂、粘合剂、崩解剂、包衣剂、吸附剂、抗粘附剂、助流剂、抗氧化剂、调味剂、着色剂、甜味剂、溶剂、共溶剂、缓冲剂、螯合剂、表面活性剂、稀释剂、润湿剂、防腐剂、乳化剂、包覆剂、等渗剂、吸收延迟剂、稳定剂和张力调节剂。本领域技术人员已知选择合适的赋型剂以制备本发明期望的药物组合物。用于本发明的药物组合物中的示例性赋型剂包括盐水、缓冲盐水、葡萄糖和水。通常,合适的赋形剂的选择尤其取决于所使用的活性剂、待治疗的疾病和药物组合物的期望剂型。
根据本发明的药物组合物可适用于多种途径施用。通常,通过胃肠外完成施用。胃肠外递送方法包括局部、动脉内、肌内、皮下、髓内、鞘内、心室内、静脉内、腹膜内、子宫内、阴道内、舌下或鼻内施用。
根据本发明的药物组合物也可以制备成各种形式,如固态、液态、气态或冻干形式,特别可以是软膏、乳膏、透皮贴剂、凝胶、粉末、片剂、溶液、气雾剂、颗粒、丸剂、混悬剂、乳剂、胶囊、糖浆、酏剂、浸膏剂、酊剂或流浸膏提取物的形式,或者是特别适用于所需施用方法的形式。本发明已知的用于生产药物的过程可包括例如常规混合、溶解、制粒、制糖衣、研磨、乳化、包封、包埋或冻干过程。包含例如本文所述的免疫细胞的药物组合物通常以溶液形式提供,并且优选包含药学上可接受的缓冲剂。
根据本发明的药物组合物还可以与一种或多种适用于治疗和/或预防待治疗疾病的其它药剂组合施用。适用于组合的药剂的优选实例包括已知的抗癌药物,比如顺铂、美登素衍生物、雷查霉素(rachelmycin)、卡里奇霉素(calicheamicin)、多西紫杉醇、依托泊苷、吉西他滨、异环磷酰胺、伊立替康、美法仑、米托蒽醌、sorfimer卟啉钠II(sorfimersodiumphotofrin II)、替莫唑胺、拓扑替康、葡萄糖醛酸曲美沙特(trimetreateglucuronate)、奥利斯他汀E(auristatin E)、长春新碱和阿霉素;肽细胞毒素,比如蓖麻毒素、白喉毒素、假单胞菌细菌外毒素A、DNA酶和RNA酶;放射性核素,比如碘131、铼186、铟111、铱90、铋210和213、锕225和砹213;前药,比如抗体定向的酶前药;免疫刺激剂,比如血小板因子4、黑色素瘤生长刺激蛋白等;抗体或其片段,比如抗CD3抗体或其片段,补体活化剂,异种蛋白结构域,同种蛋白结构域,病毒/细菌蛋白结构域和病毒/细菌肽。此外,本发明的药物组合物也可以与其他一种或多种治疗方法,例如化疗、放疗组合使用。
治疗应用
本发明还提供一种治疗患有癌症、感染或自身免疫性疾病的受试者的方法,包括向所述受试者施用有效量的根据本发明所述的NK抑制性分子、核酸分子、载体、工程化免疫细胞或药物组合物。因此,本发明还涵盖所述NK抑制性分子、核酸分子、载体或工程化免疫细胞在制备治疗癌症、感染或自身免疫性疾病的药物中的用途。
在一个实施方案中,直接向受试者施用有效量的本发明的免疫细胞和/或药物组合物。
在另一个实施方案中,本发明的治疗方法是离体治疗。具体地,该方法包括以下步骤:(a)提供样品,所述样品包含免疫细胞;(b)在体外将所述免疫细胞的至少一种TCR/CD3基因和至少一种MHC相关基因的表达抑制或沉默,并将本发明的NK抑制性分子以及任选的嵌合抗原受体引入所述免疫细胞,获得经修饰的免疫细胞,(c)向有此需要的受试者施用所述经修饰的免疫细胞。优选地,步骤(a)中提供的免疫细胞选自B细胞、巨噬细胞、树突状细胞、单核细胞、T细胞、NK细胞或NKT细胞;并且所述免疫细胞可以通过本领域已知的常规方法从受试者的样品(特别是血液样品)中获得。然而,也可以使用能够表达本发明的嵌合抗原受体和NK抑制性分子并发挥如本文所述的所需生物效应功能的其它免疫细胞。此外,通常选择的免疫细胞与受试者的免疫系统相容,即优选所述免疫细胞不引发免疫原性响应。例如,可以使用“通用接受体细胞”,即发挥所需生物效应功能的普遍相容的可在体外生长和扩增的淋巴细胞。使用此类细胞将不需要获得和/或提供受试者自身淋巴细胞。步骤(c)的离体引入可以通过经由电穿孔将本文所述的核酸或载体引入免疫细胞或通过用病毒载体感染免疫细胞来实施,所述病毒载体为如前所述的慢病毒载体、腺病毒载体、腺相关病毒载体或逆转录病毒载体。其它可想到的方法包括使用转染试剂(比如脂质体)或瞬时RNA转染。
在一个实施方案中,所述免疫细胞是自体或同种异体的细胞,优选B细胞、T细胞、巨噬细胞、树突状细胞、单核细胞或、NK细胞NKT细胞,更优选T细胞、NK细胞或NKT细胞。
如本文所用,术语“自体”是指来源于个体的任何材料稍后将被再引入该相同个体中。
如本文所用,术语“同种异体”是指任何材料来源于与引入该材料的个体相同物种的不同动物或不同患者。当在一个或多个基因座处的基因不同时,认为两个或更多个体彼此为同种异体的。在一些情况下,来自同一物种的各个体的同种异体材料在基因上的不同可能足以发生抗原相互作用。
如本文所用,术语“受试者”是哺乳动物。哺乳动物可以是人、非人灵长类动物、小鼠、大鼠、狗、猫、马或牛,但不限于这些实例。除人以外的哺乳动物可以有利地用作代表癌症动物模型的受试者。优选地,所述受试者是人。
在一个实施方案中,所述癌症是与配体结合结构域结合的靶标表达有关的癌症。例如,所述癌症包括但不限于:脑神经胶质瘤、胚细胞瘤、肉瘤、白血病、基底细胞癌、胆道癌、膀胱癌、骨癌、脑和CNS癌症、乳腺癌、腹膜癌、宫颈癌、绒毛膜癌、结肠和直肠癌、结缔组织癌症、消化系统的癌症、子宫内膜癌、食管癌、眼癌、头颈癌、胃癌(包括胃肠癌)、胶质母细胞瘤(GBM)、肝癌、肝细胞瘤、上皮内肿瘤、肾癌、喉癌、肝肿瘤、肺癌(例如小细胞肺癌、非小细胞肺癌、腺状肺癌和鳞状肺癌)、淋巴瘤(包括霍奇金淋巴瘤和非霍奇金淋巴瘤)、黑色素瘤、骨髓瘤、神经母细胞瘤、口腔癌(例如唇、舌、口和咽)、卵巢癌、胰腺癌、前列腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸系统的癌症、唾液腺癌、皮肤癌、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌、子宫或子宫内膜癌、泌尿系统的恶性肿瘤、外阴癌以及其它癌和肉瘤、以及B细胞淋巴瘤(包括低级/滤泡性非霍奇金淋巴瘤(NHL)、小淋巴细胞性(SL)NHL、中间级/滤泡性NHL、中间级扩散性NHL、高级成免疫细胞性NHL、高级成淋巴细胞性NHL、高级小型非裂化细胞性NHL、大肿块病NHL)、套细胞淋巴瘤、AIDS相关淋巴瘤、以及Waldenstrom巨球蛋白血症、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、B细胞急性淋巴细胞白血病(B-ALL)、T细胞急性淋巴细胞白血病(T-ALL)、B细胞幼淋巴细胞白血病、母细胞性浆细胞样树突状细胞瘤、伯基特氏淋巴瘤、弥散性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性骨髓性白血病(CML)、恶性淋巴组织增生疾病、MALT淋巴瘤、毛细胞白血病、边缘区淋巴瘤、多发性骨髓瘤、骨髓发育不良、浆母细胞性淋巴瘤、白血病前期、浆细胞样树突状细胞瘤、以及移植后淋巴细胞增生性紊乱(PTLD);以及其他与靶标表达有关的疾病。优选地,可以用本发明的工程化免疫细胞或药物组合物治疗的疾病选自:白血病、淋巴瘤、多发性骨髓瘤、脑神经胶质瘤、胰腺癌、胃癌等。
在一个实施方案中,所述感染包括但不限于由病毒、细菌、真菌和寄生虫引起的感染。
在一个实施方案中,所述自身免疫性疾病包括但不限于I型糖尿病、腹腔疾病、格雷夫斯病、炎症性肠病、多发性硬化症、银屑病、类风湿性关节炎、艾迪生病、干燥综合征、桥本甲状腺炎、重症肌无力、血管炎、恶性贫血与系统性红斑狼疮等。
在一个实施方案中,所述方法还进一步包括向所述受试者施用一种或多种额外的化疗剂、生物制剂、药物或治疗。在该实施方案中,化疗剂、生物制剂、药物或治疗选自放射疗法、手术、抗体试剂和/或小分子和它们的任意组合。
下面将参考附图并结合实例来详细说明本发明。需要说明的是,本领域的技术人员应该理解本发明的附图及其实施例仅仅是为了例举的目的,并不能对本发明构成任何限制。在不矛盾的情况下,本申请中的实施例及实施例中的特征可以相互组合。
附图说明
图1:示出了E0-UNKi-T和E28-UNKi-T细胞中HLA-E的表达水平。
图2:示出了G0-UNKi-T和G28-UNKi-T细胞中HLA-G的表达水平。
图3:示出了ECad0-UNKi-T和ECad28-UNKi-T细胞中E-钙黏素的表达水平。
图4:示出了A28-UNKi-T细胞中NKG2A scFv的表达水平。
图5:示出了NK92-KLRG1细胞中KLRG1的表达水平。
图6:示出了本发明的UNKi-T细胞对NK细胞杀伤作用的抑制效果。用Two-wayANOVA分析,并用T test进行统计学分析。*表示P值小于0.05,**表示P值小于0.01,***表示P值小于0.001,达到显著水平。
图7:示出了A28z-UNKi-T细胞中NKG2A ScFv的表达水平。
图8:示出了E28z-UNKi-T细胞中HLA-E的表达水平。
图9:示出了本发明的UNKi-T细胞对NK细胞的杀伤效果。用Two-way ANOVA分析,并用T test进行统计学分析。*表示P值小于0.05,**表示P值小于0.01,***表示P值小于0.001,达到显著水平。
图10:示出了本发明的UNKi-T细胞与NK细胞共培养后的IFN-γ释放水平。用Two-way ANOVA分析,并用T test进行统计学分析。***表示P值小于0.001,达到显著水平。
图11:示出了本发明KIRG4-UNKi-T细胞中KIR scFv的表达水平。
图12:示出了本发明LIRG4-UNKi-1-T和LIRG4-UNKi-2-T细胞中LIR1 scFv的表达水平。
图13:示出了本发明的UNKi-T细胞对NK细胞杀伤作用的抑制效果。
图14:示出了SC7G4-T细胞、SC7/SC9G4-T细胞和K1G4-T细胞中scFv的表达水平。
图15:示出了SC7G4-T细胞、SC7/SC9G4-T细胞和K1G4-T细胞对NK细胞杀伤作用的抑制效果。
图16:示出了PDL1-T细胞中PDL1的表达水平。
图17:示出了PDL1-T细胞对NK细胞增殖的抑制效果。
图18:示出了NKi-B细胞和NKi-Huh7细胞中KIR scFv的表达水平。
图19:示出了NKi-B细胞和NKi-Huh7细胞对NK细胞杀伤作用的抑制效果。
具体实施方式
本发明所有实施例中使用的T细胞是通过Ficoll-PaqueTM PREMIUM(GEHealthcare,货号17-5442-02)采用白细胞分离术从健康供体分离的原代人CD4+CD8+T细胞。
实施例1:构建表达NK抑制性分子且敲除TCR/HLA-I/HLA-II的UNKi-T免疫细胞
合成以下的编码序列,并将其依次克隆至pGEM-T Easy载体(Promega,货号A1360):B2m信号肽(SEQ ID NO:21)、NK抑制性配体、CD28铰链区(SEQ ID NO:27)、CD28跨膜区(SEQ ID NO:11),其中NK抑制性配体是E-钙黏素的胞外区(SEQ ID NO:41,对应ECad0质粒)、B2M和HLA-E胞外区的融合分子(包含提呈肽SEQ ID NO:46、B2M SEQ ID NO:37和HLA-E胞外区突变体SEQ ID NO:33,其中B2M的核酸序列是同义突变的SEQ ID NO:38,对应E0质粒),或B2M和HLA-G胞外区的融合分子(包含B2M SEQ ID NO:37和HLA-G胞外区SEQ ID NO:35,其中B2M的核酸序列是同义突变的SEQ ID NO:38,对应G0质粒)。在ECad0、E0和G0质粒中进一步包括CD28共刺激结构域(SEQ ID NO:13),分别获得ECad28、E28和G28质粒。通过测序确认目标序列在质粒中的正确插入。
合成以下编码序列,并将其依次克隆至pGEM-T Easy载体(Promega,货号A1360):B2m信号肽(SEQ ID NO:21)、抗NKG2A-scFv(包含SEQ ID NO:5和7)、IgG4铰链区(SEQ IDNO:29)、CD28跨膜区(SEQ ID NO:11)、CD28共刺激结构域(SEQ ID NO:13),获得A28质粒,并通过测序确认目标序列在质粒中的正确插入。
在无菌管中加入3ml Opti-MEM(Gibco,货号31985-070)稀释上述质粒后,再根据质粒:病毒包装载体:病毒包膜载体=4:2:1的比例加入包装载体psPAX2(Addgene,货号12260)和包膜载体pMD2.G(Addgene,货号12259)。然后,加入120ul X-treme GENE HP DNA转染试剂(Roche,货号06366236001),立即混匀,于室温下孵育15min,然后将质粒/载体/转染试剂混合物逐滴加入到293T细胞的培养瓶中。在24小时和48小时收集病毒,将其合并后,超速离心(25000g,4℃,2.5小时)获得浓缩的慢病毒。
用DynaBeads CD3/CD28 CTSTM(Gibco,货号40203D)激活T细胞,并在37℃和5%CO2下培养1天。然后,加入浓缩的慢病毒,持续培养3天后,获得表达NK抑制性分子的T细胞。
然后采用CRISPR系统敲除所述表达NK抑制性分子的T细胞中的TCR/CD3组分(具体为TRAC基因)和MHC相关基因(具体为B2M和RFX5)。具体地,使用BTX Agile Pulse Max电穿孔仪(Harvard Apparatus BTX),以400V、0.7ms将10ug Cas9蛋白和10ug sgRNA(3.3ugTRAC sgRNA(SEQ ID NO:43)+3.3ug B2m sgRNA(SEQ ID NO:44)+3.3ug RFX5 sgRNA(SEQID NO:45))电转染进激活的NKi-T细胞。电转染之后,立即将NKi-T细胞放入1ml预热的培养基中,并在IL-2(300IU/ml)存在下,在37℃和5%CO2下培养,获得TCR/B2M/RFX5三敲除的UNKi-T细胞。用CRISPR系统敲除TCR/B2M/RFX5的野生型T细胞(即,Mock T细胞)和未敲除基因的野生型T细胞(即,NT细胞)作为对照。
本实施例中制备的UNKi-T细胞包含的NK抑制性分子的结构如下表1所示。
表1.包含NK抑制性分子的UNKi-T细胞
11天之后,使用FITC Mouse Anti-Human CD3(BD Pharmingen,货号555916)抗体、PE mouse anti-human HLA-I(R&D货号FAB7098P)和APC anti-human DR,DP,DQ(biolegend,货号361714)抗体,通过流式细胞仪检测UNKi-T细胞、Mock T细胞和NT细胞中的TCR/HLA-I/HLA-II的表达效率,结果如下表2所示。
表2.UNKi-T细胞中的基因表达效率
从表2可以看出,本发明制备的UNKi-T细胞以及Mock T细胞中的TCR/B2M/RFX5的表达被有效抑制或沉默。
此外,使用流式细胞仪,用PE mouse anti-human HLA-E(biolegend货号342604)检测UNKi-T细胞和Mock T细胞中的HLA-E表达(图1),用PE mouse anti-human HLA-G(biolegend货号335906)检测UNKi-T细胞和Mock T细胞中的HLA-G表达(图2),用E-cadherin monoclonal antibody(invitrogen货号13-5700)和Goat anti-Mouse IgG(H+L)Cross-Adsorbed Secondary Antibody,Alexa Fluor 488(Invitrogen,货号A-11001)检测UNKi-T细胞和Mock T细胞中的E-钙黏素表达(图3),用Biotin-SP(long spacer)AffiniPure Goat Anti-Human IgG,F(ab')fragment specific antibody(JacksonImmunoResearch,货号109-065-097)和APC Streptavidin(BD,货号554067)检测UNKi-T细胞和Mock T细胞中的anti-NKG2A scFv表达(图4)。
从图1-4可以看出,本发明制备的UNKi-T细胞中的NK抑制性分子均有效表达。
实施例2.UNKi-T细胞对NK细胞杀伤作用的抑制效果
本实施例中使用的效应细胞是NK92细胞。由于NK92细胞系不表达E-钙黏素的受体KLRG1,因此首先制备过表达KLRG1的NK92细胞。
合成编码KLRG1(SEQ ID NO:54)的核酸序列,并将其依次克隆至pGEM-T Easy载体(Promega,货号A1360),并通过测序确认目标序列的正确插入。用SpeI酶对该载体进行酶切,纯化回收后获得线性化载体。然后,根据制造商的建议,以线性化载体为模板,用mMESSAGET7 Ultra Kit试剂盒(Invitrogen,货号AM1345)制备mRNA,并用Fastpure cell/Tissue total RNA isolation kit试剂盒(Vazyme,货号RC101-01)进行纯化,获得纯化的mRNA。然后,使用BTX Agile Pulse Max电穿孔仪(Harvard ApparatusBTX),以200V、2ms将上述制备的20ug纯化mRNA电转染进NK92细胞内,获得NK92-KLRG1细胞。16h后,检测KLRG1的表达,结果如图5所示。未转染KLRG1的NK92细胞作为对照。
从图5可以看出,NK92-KLRG1细胞可有效表达KLRG1。
然后根据以下方法检测本发明制备的UNKi-T细胞对NK细胞杀伤作用的抑制效果:用Far-Red(invitrogen,货号C34564)标记本发明制备的UNKi-T细胞和Mock-T细胞。然后按照1x104个细胞/孔的浓度将标记好的UNKi-T细胞和Mock T细胞铺入96孔板,并以2:1的效靶比加入NK92细胞(用于表达HLA-E、HLA-G或NKG2A scFv的UNKi-T细胞和Mock T细胞)或NK92-KLRG1细胞(用于表达E-钙黏素的UNKi-T细胞)进行共培养。16-18小时后,用流式细胞仪检测培养物中T细胞的比例,进而计算NK细胞对T细胞的杀伤率,结果如图6所示。
从图6可以看出,与不表达NK抑制性分子的Mock T细胞相比,表达包含抑制性配体例如NKG2A scFv、HLA-G、HLA-E、E-钙黏素的NK抑制性分子的UNKi-T细胞均能显著降低NK细胞对T细胞的杀伤作用。并且,与仅表达抑制性配体和跨膜结构域的T细胞相比,共刺激结构域的加入可以进一步显著增强T细胞对NK细胞杀伤的抑制(参见G0 vs G28;E0 vs E28;ECad0 vs ECad28)。因此,本发明制备的包含抑制性配体、跨膜结构域和共刺激结构域的NK抑制性分子可以显著降低NK细胞对UNKi-T细胞的杀伤作用,从而能够有效降低HvGD风险。
实施例3.UNKi-T细胞对NK细胞的杀伤效果
根据实施例1所述的方法制备E28z-UNKi-T和A28z-UNKi-T细胞,其与E28-UNKi-T和A28-UNKi-T细胞的区别仅在于其进一步包含CD3ζ胞内信号传导结构域(SEQ ID NO:17)。
(1)检测NK抑制性分子的表达
用Biotin-SP(long spacer)AffiniPure Goat Anti-Human IgG,F(ab')fragmentspecific antibody(Jackson ImmunoResearch,货号109-065-097)和APC Streptavidin(BD,货号554067)检测A28z-UNKi-T细胞和Mock T细胞中的anti-NKG2A scFv表达(图7)。使用流式细胞仪,用PE mouse anti-human HLA-E(biolegend货号342604)检测E28z-UNKi-T细胞和Mock T细胞中的HLA-E表达(图8)。
可以看出,本发明制备的E28z-UNKi-T细胞和A28z-UNKi-T细胞中的NK抑制性分子能够有效表达。
(2)检测CD107a的表达
细胞毒性T淋巴细胞(CTL细胞)胞浆内含有高浓度以囊泡形式存在的细胞毒性颗粒,溶酶体相关膜蛋白I(CD107a)是囊泡膜蛋白的主要成分。CTL细胞杀伤靶细胞时,毒性颗粒将到达细胞膜并与细胞膜融合(此时CD107a分子被转运到细胞膜表面),引起颗粒内容物释放,最终导致靶细胞的死亡。因此,CD107a分子是CTL细胞脱颗粒的一种敏感标志,可反应细胞杀伤活性。
以1x105个细胞/孔的浓度将靶细胞(NK92细胞)铺于96孔板中,然后每孔以1:1的比例加入Mock T细胞、E28z-UNKi-T细胞和A28z-UNKi-T细胞,同时加入10μlPE-anti-humanCD107a(BD Pharmingen,货号555801),于37℃,5%CO2培养条件下共培养。1h后,加入Goigstop(BD Pharmingen,货号51-2092KZ)继续孵育2.5小时。然后向每孔加入5μl APC-anti human CD8(BD Pharmingen,货号:555369)和5μl FITC-anti human CD4(BDPharmingen,货号:561005),于37℃孵育30分钟后,用流式细胞仪检测CD107a的表达情况,结果如图9A(CD4+T细胞毒性)和图9B(CD8+T细胞毒性)所示。
可以看出,不表达NK抑制性分子的Mock T细胞对靶细胞几乎没有杀伤。与此相反,本发明制备的E28z-UNKi-T细胞和A28z-UNKi-T细胞与靶细胞共培养后,CD107a的表达率显著提高,表明本发明的UNKi-T细胞可显著杀伤NK细胞。
(3)检测IFN-γ的分泌
以1x105个细胞/孔将靶细胞(NK92细胞)铺于96孔板中,每孔以1:1的比例加入Mock T细胞、E28z-UNKi-T细胞和A28z-UNKi-T细胞,于37℃,5%CO2培养条件下共培养,18-24小时后收集细胞共培养上清液。
使用捕获抗体Purified anti-human IFN-γAntibody(Biolegend,货号506502)包被96孔板4℃孵育过夜,然后移除抗体溶液。加入250μL含有2%BSA(sigma,货号V900933-1kg)的PBST(含0.1%吐温的1XPBS)溶液,37℃孵育2小时。然后用250μLPBST(含0.1%吐温的1XPBS)清洗板3次。每孔加入50μL细胞共培养上清液或标准品,并在37℃孵育1小时,然后用250μL PBST(含0.1%吐温的1XPBS)清洗板3次。然后向各孔分别加入50μL检测抗体Anti-Interferon gamma抗体[MD-1](Biotin)(abcam,货号ab25017),在37℃孵育1小时后,用250μL PBST(含0.1%吐温的1XPBS)清洗板3次。再加入HRP Streptavidin(Biolegend,货号405210),在37℃孵育30分钟后,弃上清液,加入250μL PBST(含0.1%吐温的1XPBS),清洗5次。向各孔加入50μL TMB底物溶液。使反应在室温下于暗处发生30分钟,之后向各孔中加入50μL 1mol/L H2SO4以停止反应。在停止反应的30分钟内,使用酶标仪检测450nm处吸光度,并根据标准曲线(根据标准品的读值和浓度绘制)计算细胞因子的含量,结果如图10所示。
可以看出,本发明的E28z-UNKi-T细胞和A28z-UNKi-T细胞的细胞因子IFN-γ释放水平远远高于Mock T细胞,这也表明其对NK92靶细胞的杀伤显著增加。
实施例4.靶向KIR或LIR1的UNKi-T细胞及其对NK细胞杀伤作用的抑制效果
合成以下编码序列,并将其依次克隆至pLVX载体(Public Protein/PlasmidLibrary(PPL),货号:PPL00157-4a):B2m信号肽(SEQ ID NO:21)、抗KIR-scFv(包含SEQ IDNO:55和56)或抗LIR1 scFv(包含SEQ ID NO:57和58,或包含SEQ ID NO:59和60)、IgG4铰链区(SEQ ID NO:29)、CD8α跨膜区(SEQ ID NO:9)、CD28共刺激结构域(SEQ ID NO:13),获得KIRG4、LIRG4-1和LIRG4-2质粒,并通过测序确认目标序列在质粒中的正确插入。
根据实施例1中的敲除和感染方式制备UNKi-T细胞,并使用FITC Mouse Anti-Human CD3(BD Pharmingen,货号555916)抗体、PE mouse anti-human HLA-I(R&D货号FAB7098P)和APC anti-human DR,DP,DQ(biolegend,货号361714)抗体,通过流式细胞仪检测UNKi-T细胞、Mock T细胞和NT细胞中的CD3/HLA-I/HLA-II的表达效率,结果如下表3所示。
表3.UNKi-T细胞中的基因表达效率
细胞名称 | TCR/CD3 | B2M/HLA-I | RFX5/HLA-II |
KIRG4-UNKi-T | 4.5% | 16% | 10.8% |
LIRG4-UNKi-1-T | 3.5% | 17.6% | 10.9% |
LIRG4-UNKi-2-T | 4.3% | 16.9% | 10.3% |
Mock T | 2.6% | 15.8% | 9.3% |
NT | 98% | 98% | 83% |
从表3可以看出,本发明制备的UNKi-T细胞以及Mock T细胞中的CD3/HLA-I/HLA-II的表达被有效抑制或沉默。
用Biotin-SP(long spacer)AffiniPure Goat Anti-Human IgG,F(ab')fragmentspecific antibody(Jackson ImmunoResearch,货号109-065-097)和APC Streptavidin(BD,货号554067)检测KIRG4-UNKi-T细胞中的scFv表达,结果如图11所示。用recombinanthuman LILRB1 protein(sino biological,货号16014-H02H)作为一抗,APC anti-humanIgG Fc(biolegend,货号409306)作为二抗检测LIRG4-UNKi-1 T细胞和LIRG4-UNKi-2 T细胞中scFv的表达,结果如图12所示。从图11和图12中可以看出,本发明制备的UNKi-T细胞的scFv均有效表达。
根据实施例2中的方法将UNKi-T细胞和NK92细胞共培养,以检测UNKi-T细胞对NK细胞杀伤作用的抑制效果,结果如图13所示。可以看出,与Mock T相比,本实施例制备的靶向KIR(图13A)或LIR1(图13B)的UNKi-T细胞均能显著降低NK细胞对T细胞的杀伤作用。
实施例5.靶向SIGLC7、SIGLEC9或KLRG1的T细胞及其对NK细胞杀伤作用的抑制效果
合成以下编码序列,并将其依次克隆至pLVX载体(Public Protein/PlasmidLibrary(PPL),货号:PPL00157-4a):B2m信号肽(SEQ ID NO:21)、抗SIGLEC7-scFv(SEQ IDNO:130)、抗SIGLEC7/SIGLEC9-scFv(SEQ ID NO:184)或抗KLRG1-scFv(SEQ ID NO:119)、IgG4铰链区(SEQ ID NO:29)、CD8α跨膜区(SEQ ID NO:9)、CD28共刺激结构域(SEQ ID NO:13),获得SC7G4、SC7/SC9G4和K1G4质粒,并通过测序确认目标序列在质粒中的正确插入。
将上述质粒根据实施例1中的方法转入T细胞,并敲除其中的B2M基因,获得表达NK抑制性分子且B2M敲除的NKi-T细胞(即,SC7G4-T细胞、SC7/SC9G4-T细胞和K1G4-T细胞)。仅敲除B2M的T细胞用作阴性对照(NT)。
用Biotin-SP(long spacer)AffiniPure Goat Anti-mouse IgG,F(ab')fragmentspecific antibody(Jackson ImmunoResearch,货号115-066-072)和APC Streptavidin(BD,货号554067)检测SC7G4、SC7/SC9G4和K1G4 T细胞中的scFv表达,结果如图14所示。可以看出,本发明制备的NKi-T细胞的scFv均有效表达。
根据实施例2所述的方法,将上述NKi-T细胞与NK92-KLRG1细胞共培养,以检测其对NK细胞杀伤作用的抑制效果,结果如图15所示。可以看出,与NT相比,本实施例制备的靶向SIGLEC7、SIGLEC9或KLRG1的T细胞均能显著降低NK细胞对T细胞的杀伤作用。
实施例6.靶向PD-1的T细胞及其对NK细胞增殖的抑制效果
合成以下编码序列,并将其依次克隆至pLVX载体(Public Protein/PlasmidLibrary(PPL),货号:PPL00157-4a):PDL1信号肽(SEQ ID NO:121)、PDL1胞外区(SEQ IDNO:70)、PDL1跨膜区(SEQ ID NO:120)、CD28共刺激结构域(SEQ ID NO:13),获得PDL1质粒,并通过测序确认目标序列在质粒中的正确插入。
将上述质粒根据实施例1中的方法转入T细胞,获得表达NK抑制性分子的NKi-T细胞,即PDL1-T细胞。采用Anti-PD-L1 Antibody(厂家:索莱宝,货号:10084-R312-A)检测其表达,结果如图16所示。可以看出,PDL1被有效表达。未经处理的T细胞用作阴性对照(NT)。
将上述NKi-T细胞进行培养并经细胞丝裂霉素C处理,同时将两个异体来源的PBMC(donor1和donor2)采用Far-Red进行标记后,按照T细胞:PBMC=1:2的比例进行共培养。每2-3天进行半换液处理。8d后细胞计数并采用PE anti-human CD3(厂家biolegend,货号:317308)和FITC anti-human CD56(厂家:biolegend,货号:362546)染色,然后通过流式细胞术检测NK细胞群比例。通过细胞总量*NK细胞群比例来计算NK细胞数量,结果如图17所示。可以看出,靶向PD-1的NKi-T细胞可显著抑制NK细胞的增殖。
实施例7.靶向KIR的B细胞和Huh7细胞对NK细胞杀伤作用的抑制效果
将实施例4中制备的KIRG4质粒根据实施例1中的方法转入B细胞和Huh7细胞(肝癌细胞),并敲除其中的B2M基因,获得表达NK抑制性分子且B2M敲除的NKi-B细胞和NKi-Huh7细胞。仅敲除B2M基因的B细胞和Huh7细胞(NC细胞)用作阴性对照。
用Biotin-SP(long spacer)AffiniPure Goat Anti-Human IgG,F(ab')fragmentspecific antibody(Jackson ImmunoResearch,货号109-065-097)和APC Streptavidin(BD,货号554067)检测NKi-B细胞和NKi-Huh7细胞中的scFv表达,结果如图18所示。可以看出,NK抑制性分子在B细胞和Huh7细胞中均有效表达。
根据实施例2中的方法将上述制备的细胞和NK细胞共培养,以检测上述细胞对NK细胞杀伤作用的抑制效果,结果如图19所示。可以看出,与NC细胞相比,本实施例制备的NKi-B细胞和NKi-Huh7细胞均能显著降低NK细胞对其的杀伤作用。
要说明的是,以上仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。本领域技术人员理解的是,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
序列表
<110> 南京北恒生物科技有限公司
<120> 表达NK抑制性分子的工程化免疫细胞及其用途
<130> BHCN20V2
<150> 2020105275720
<151> 2020-06-11
<150> 2020112094202
<151> 2021-11-03
<160> 196
<170> SIPOSequenceListing 1.0
<210> 1
<211> 119
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> mNKG2A scFv-VH
<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ser Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Glu Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Ile Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Thr Arg His Gly Asp Tyr Pro Arg Phe Phe Asp Val Trp Gly Ala Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 2
<211> 357
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mNKG2A scFv-VH
<400> 2
gaagttcaac tggtagagtc agggggcgga ttggtaaagc cggggggctc tctgaagctg 60
tcatgcgccg catctgggtt taccttcagt tcttacgcta tgagttgggt tcgccagtct 120
cccgaaaaga gattggagtg ggtagcggaa attagttcag gcggaagcta cacgtattac 180
cccgatacag tcacgggacg gtttaccatt tcccgcgata atgccaagaa cacgctgtac 240
ctcgagatca gctctttgcg gagcgaggat actgcgatgt attactgcac ccgacacgga 300
gattatccga gattttttga tgtatgggga gcgggaacga cagttaccgt ctccagc 357
<210> 3
<211> 107
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mNKG2A scFv-VL
<400> 3
Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 4
<211> 321
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mNKG2A scFv-VL
<400> 4
cagatagtgc tgacacaaag cccagcactt atgtccgcat ccccaggaga aaaagtaacg 60
atgacttgta gcgctagttc tagtgtgagt tatatatact ggtatcagca gaaaccgaga 120
agtagtccga agccctggat ctatctcaca agcaatttgg ccagtggagt gcccgcgcgg 180
ttcagcggaa gtggcagcgg cacttcttac agcctcacta taagcagtat ggaagccgag 240
gacgcggcaa cgtattattg ccaacagtgg tccggcaatc cttatacttt tggtggcggt 300
acgaaactgg agatcaaacg c 321
<210> 5
<211> 119
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> hNKG2A scFv-VH
<400> 5
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Lys Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Glu Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Gly Asp Tyr Pro Arg Phe Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 6
<211> 357
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> hNKG2A scFv-VH
<400> 6
gaagtccaac ttgttgaaag cggagggggg cttgtaaagc caggtggttc tctccgcttg 60
agttgtgccg cttctggctt taccttctct tcttacgcta aatcttgggt tcgccaggct 120
cccggtaagg gtctggagtg ggtcagcgaa atctcttctg ggggctccta cacctactat 180
gccgattctg tgaaggggcg gttcaccata agccgcgaca acgcaaagaa cagcctctac 240
cttcagatga acagcctgcg cgcagaggac acagcagtct attactgcgc tcgacatggg 300
gattatccta gattttttga cgtctggggc caaggcacta ccgttaccgt aagcagc 357
<210> 7
<211> 107
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> hNKG2A scFv-VL
<400> 7
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Ser Tyr
20 25 30
Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Leu Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 8
<211> 321
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> hNKG2A scFv-VL
<400> 8
gaaatagttt tgacacaatc cccagcaacc ctttctctgt caccaggtga gagagctacg 60
ttgtcttgca gtgcgagttc cagcgtctct tcctacatct actggtacca gcagaagccc 120
gggcaggccc ctcgattgct catatacctg acatccaatc tggcatctgg aataccagca 180
cggttctctg gctcaggtag cggtacagac tttaccctga caatctcttc cctggaaccc 240
gaggactttg ccgtgtacta ctgccaacaa tggtctggga atccatatac tttcgggcag 300
gggacaaaac ttgaaatcaa g 321
<210> 9
<211> 25
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8α跨膜结构域
<400> 9
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys Lys
20 25
<210> 10
<211> 75
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8α跨膜结构域
<400> 10
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gcaaa 75
<210> 11
<211> 27
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28跨膜结构域
<400> 11
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 12
<211> 81
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28跨膜结构域
<400> 12
ttttgggtcc tcgtcgtagt tggaggggta cttgcctgtt atagcctcct ggttaccgta 60
gcatttatta tattctgggt g 81
<210> 13
<211> 41
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28公共刺激结构域
<400> 13
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 14
<211> 123
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28公共刺激结构域
<400> 14
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120
tcc 123
<210> 15
<211> 40
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 15
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
1 5 10 15
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
20 25 30
Glu Glu Glu Glu Gly Gly Cys Glu
35 40
<210> 16
<211> 120
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 16
cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 60
actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 120
<210> 17
<211> 113
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 17
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 18
<211> 339
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 18
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 180
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300
acctacgacg cccttcacat gcaggccctg ccccctcgc 339
<210> 19
<211> 114
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域突变体
<400> 19
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Phe Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
50 55 60
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
65 70 75 80
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser
85 90 95
Thr Ala Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro
100 105 110
Pro Arg
<210> 20
<211> 342
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域突变体
<400> 20
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctttaacg agctcaatct aggacgaaga gaggagttcg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg cagagaagga agaaccctca ggaaggcctg 180
tacaatgaac tgcagaaaga taagatggcg gaggcctaca gtgagattgg gatgaaaggc 240
gagcgccgga ggggcaaggg gcacgatggc cttttccagg gtctcagtac agccaccaag 300
gacacctttg acgcccttca catgcaggcc ctgccccctc gc 342
<210> 21
<211> 20
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> B2M信号肽
<400> 21
Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
1 5 10 15
Gly Leu Glu Ala
20
<210> 22
<211> 60
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> B2M信号肽
<400> 22
atgtcccgct ctgttgcttt ggctgtgctg gcccttttgt cccttagcgg actggaggcc 60
<210> 23
<211> 21
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8α信号肽
<400> 23
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 24
<211> 63
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8α信号肽
<400> 24
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 25
<211> 45
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8α铰链区
<400> 25
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 26
<211> 135
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8α铰链区
<400> 26
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 27
<211> 39
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28铰链区
<400> 27
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 28
<211> 117
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28铰链区
<400> 28
attgaagtta tgtatcctcc tccttaccta gacaatgaga agagcaatgg aaccattatc 60
catgtgaaag ggaaacacct ttgtccaagt cccctatttc ccggaccttc taagccc 117
<210> 29
<211> 12
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 29
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 30
<211> 36
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 30
gaaagcaaat acgggccgcc gtgtccaccc tgtccg 36
<210> 31
<211> 284
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> HLA-E胞外区
<400> 31
Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly
1 5 10 15
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
20 25 30
Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg
35 40 45
Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr
50 55 60
Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr
65 70 75 80
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
85 90 95
Trp Met His Gly Cys Glu Leu Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu
130 135 140
Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Arg Ala Tyr Leu
145 150 155 160
Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys
165 170 175
Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Val Thr Leu
260 265 270
Arg Trp Lys Pro Ala Ser Gln Pro Thr Ile Pro Ile
275 280
<210> 32
<211> 852
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> HLA-E胞外区
<400> 32
ggctcccact ctttgaagta cttccacacc agcgtgagca ggccgggcag gggtgaacca 60
agatttataa gtgttgggta tgtggacgat acacaatttg tgcgctttga taacgacgcg 120
gcttctcctc gaatggtgcc ccgcgcccct tggatggaac aagagggttc tgagtattgg 180
gatagggaaa cccgctccgc ccgagataca gcccagatct ttagagttaa cttgcgaaca 240
ctcagaggtt attataacca gagcgaggca ggttcacaca ccctccagtg gatgcacggg 300
tgtgagcttg gtcctgatgg ccgctttctc cggggttacg agcaatttgc ttatgatggg 360
aaggattatc ttacactcaa cgaggatctt cgatcctgga ccgcagtgga caccgcagcg 420
cagatttctg aacagaagtc caatgacgcg tcagaggcag aacaccaacg ggcgtatctg 480
gaagatacct gtgttgagtg gctgcataaa tacctcgaga aaggaaaaga gacgcttctc 540
catctcgaac cgcctaaaac tcacgtaact catcacccta taagtgacca cgaagccacg 600
ttgaggtgtt gggctctcgg tttttaccct gctgaaatca cactgacttg gcagcaggat 660
ggggagggcc acacccagga tacagaactc gttgaaactc gaccagcagg agacgggacg 720
tttcaaaagt gggccgcggt agtggttcct agtggtgagg aacagcggta cacttgccat 780
gttcaacacg aggggcttcc ggagccagtt accctccgat ggaaaccggc gtcacagcct 840
acaataccga tt 852
<210> 33
<211> 284
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> HLA-E胞外区突变体
<400> 33
Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly
1 5 10 15
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
20 25 30
Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg
35 40 45
Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr
50 55 60
Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr
65 70 75 80
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
85 90 95
Trp Met His Gly Cys Glu Leu Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu
130 135 140
Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Arg Ala Tyr Leu
145 150 155 160
Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys
165 170 175
Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Val Thr Leu
260 265 270
Arg Trp Lys Pro Ala Ser Gln Pro Thr Ile Pro Ile
275 280
<210> 34
<211> 852
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> HLA-E胞外区突变体
<400> 34
ggctcccact ccttgaagta tttccacact tccgtgtccc ggcccggccg cggggagccc 60
cgcttcatct ctgtgggcta cgtggacgac acccagttcg tgcgcttcga caacgacgcc 120
gcgagtccga ggatggtgcc gcgggcgccg tggatggagc aggaggggtc agagtattgg 180
gaccgggaga cacggagcgc cagggacacc gcacagattt tccgagtgaa tctgcggacg 240
ctgcgcggct gctacaatca gagcgaggcc gggtctcaca ccctgcagtg gatgcatggc 300
tgcgagctgg ggcccgacgg gcgcttcctc cgcgggtatg aacagttcgc ctacgacggc 360
aaggattatc tcaccctgaa tgaggacctg cgctcctgga ccgcggtgga cacggcggct 420
cagatctccg agcaaaagtc aaatgatgcc tctgaggcgg agcaccagag agcctacctg 480
gaagacacat gcgtggagtg gctccacaaa tacctggaga aggggaagga gacgctgctt 540
cacctggagc ccccaaagac acacgtgact caccacccca tctctgacca tgaggccacc 600
ctgaggtgct gggccctggg cttctaccct gcggagatca cactgacctg gcagcaggat 660
ggggagggcc atacccagga cacggagctc gtggagacca ggcctgcagg ggatggaacc 720
ttccagaagt gggcagctgt ggtggtgcct tctggagagg agcagagata cacgtgccat 780
gtgcagcatg aggggctacc cgagcccgtc accctgagat ggaagccggc ttcccagccc 840
accatcccca tc 852
<210> 35
<211> 283
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> HLA-G胞外区
<400> 35
Gly Ser His Ser Met Arg Tyr Phe Ser Ala Ala Val Ser Arg Pro Gly
1 5 10 15
Arg Gly Glu Pro Arg Phe Ile Ala Met Gly Tyr Val Asp Asp Thr Gln
20 25 30
Phe Val Arg Phe Asp Ser Asp Ser Ala Cys Pro Arg Met Glu Pro Arg
35 40 45
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Glu Glu Glu Thr
50 55 60
Arg Asn Thr Lys Ala His Ala Gln Thr Asp Arg Met Asn Leu Gln Thr
65 70 75 80
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Ser Ser His Thr Leu Gln
85 90 95
Trp Met Ile Gly Cys Asp Leu Gly Ser Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Glu Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Leu Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Ser Lys
130 135 140
Arg Lys Cys Glu Ala Ala Asn Val Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu His Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Met Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Phe Asp Tyr Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Ile Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Val Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Met Leu
260 265 270
Arg Trp Lys Gln Ser Ser Leu Pro Thr Ile Pro
275 280
<210> 36
<211> 849
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> HLA-G胞外区
<400> 36
ggctcccact ccatgaggta tttcagcgcc gccgtgtccc ggcccggccg cggggagccc 60
cgcttcatcg ccatgggcta cgtggacgac acgcagttcg tgcggttcga cagcgactcg 120
gcgtgtccga ggatggagcc gcgggcgccg tgggtggagc aggaggggcc ggagtattgg 180
gaagaggaga cacggaacac caaggcccac gcacagactg acagaatgaa cctgcagacc 240
ctgcgcggct actacaacca gagcgaggcc agttctcaca ccctccagtg gatgattggc 300
tgcgacctgg ggtccgacgg acgcctcctc cgcgggtatg aacagtatgc ctacgatggc 360
aaggattacc tcgccctgaa cgaggacctg cgctcctgga ccgcagcgga cactgcggct 420
cagatctcca agcgcaagtg tgaggcggcc aatgtggctg aacaaaggag agcctacctg 480
gagggcacgt gcgtggagtg gctccacaga tacctggaga acgggaagga gatgctgcag 540
cgcgcggacc cccccaagac acacgtgacc caccaccctg tctttgacta tgaggccacc 600
ctgaggtgct gggccctggg cttctaccct gcggagatca tactgacctg gcagcgggat 660
ggggaggacc agacccagga cgtggagctc gtggagacca ggcctgcagg ggatggaacc 720
ttccagaagt gggcagctgt ggtggtgcct tctggagagg agcagagata cacgtgccat 780
gtgcagcatg aggggctgcc ggagcccctc atgctgagat ggaagcagtc ttccctgccc 840
accatcccc 849
<210> 37
<211> 99
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> B2M
<400> 37
Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu
1 5 10 15
Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro
20 25 30
Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys
35 40 45
Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu
50 55 60
Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys
65 70 75 80
Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp
85 90 95
Arg Asp Met
<210> 38
<211> 297
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 同义突变的B2M
<400> 38
atccagagga ccccgaagat ccaggtttat tctcggcatc ctgccgaaaa tggaaaaagc 60
aattttctca actgttatgt gtctggattt cacccatctg acatagaggt tgaccttctt 120
aagaatggcg agagaatcga gaaggtcgaa cattcagact tgagcttcag caaggattgg 180
agcttttatc ttctttatta tactgaattt actcccactg aaaaggatga atacgcctgc 240
agggtaaacc atgtaacact cagtcagcca aagatcgtaa aatgggaccg agacatg 297
<210> 39
<211> 689
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> E-钙黏素 EC1-EC5
<400> 39
Trp Leu Cys Gln Glu Pro Glu Pro Cys His Pro Gly Phe Asp Ala Glu
1 5 10 15
Ser Tyr Thr Phe Thr Val Pro Arg Arg His Leu Glu Arg Gly Arg Val
20 25 30
Leu Gly Arg Val Asn Phe Glu Asp Cys Thr Gly Arg Gln Arg Thr Ala
35 40 45
Tyr Phe Ser Leu Asp Thr Arg Phe Lys Val Gly Thr Asp Gly Val Ile
50 55 60
Thr Val Lys Arg Pro Leu Arg Phe His Asn Pro Gln Ile His Phe Leu
65 70 75 80
Val Tyr Ala Trp Asp Ser Thr Tyr Arg Lys Phe Ser Thr Lys Val Thr
85 90 95
Leu Asn Thr Val Gly His His His Arg Pro Pro Pro His Gln Ala Ser
100 105 110
Val Ser Gly Ile Gln Ala Glu Leu Leu Thr Phe Pro Asn Ser Ser Pro
115 120 125
Gly Leu Arg Arg Gln Lys Arg Asp Trp Val Ile Pro Pro Ile Ser Cys
130 135 140
Pro Glu Asn Glu Lys Gly Pro Phe Pro Lys Asn Leu Val Gln Ile Lys
145 150 155 160
Ser Asn Lys Asp Lys Glu Gly Lys Val Phe Tyr Ser Ile Thr Gly Gln
165 170 175
Gly Ala Asp Thr Pro Pro Val Gly Val Phe Ile Ile Glu Arg Glu Thr
180 185 190
Gly Trp Leu Lys Val Thr Glu Pro Leu Asp Arg Glu Arg Ile Ala Thr
195 200 205
Tyr Thr Leu Phe Ser His Ala Val Ser Ser Asn Gly Asn Ala Val Glu
210 215 220
Asp Pro Met Glu Ile Leu Ile Thr Val Thr Asp Gln Asn Asp Asn Lys
225 230 235 240
Pro Glu Phe Thr Gln Glu Val Phe Lys Gly Ser Val Met Glu Gly Ala
245 250 255
Leu Pro Gly Thr Ser Val Met Glu Val Thr Ala Thr Asp Ala Asp Asp
260 265 270
Asp Val Asn Thr Tyr Asn Ala Ala Ile Ala Tyr Thr Ile Leu Ser Gln
275 280 285
Asp Pro Glu Leu Pro Asp Lys Asn Met Phe Thr Ile Asn Arg Asn Thr
290 295 300
Gly Val Ile Ser Val Val Thr Thr Gly Leu Asp Arg Glu Ser Phe Pro
305 310 315 320
Thr Tyr Thr Leu Val Val Gln Ala Ala Asp Leu Gln Gly Glu Gly Leu
325 330 335
Ser Thr Thr Ala Thr Ala Val Ile Thr Val Thr Asp Thr Asn Asp Asn
340 345 350
Pro Pro Ile Phe Asn Pro Thr Thr Tyr Lys Gly Gln Val Pro Glu Asn
355 360 365
Glu Ala Asn Val Val Ile Thr Thr Leu Lys Val Thr Asp Ala Asp Ala
370 375 380
Pro Asn Thr Pro Ala Trp Glu Ala Val Tyr Thr Ile Leu Asn Asp Asp
385 390 395 400
Gly Gly Gln Phe Val Val Thr Thr Asn Pro Val Asn Asn Asp Gly Ile
405 410 415
Leu Lys Thr Ala Lys Gly Leu Asp Phe Glu Ala Lys Gln Gln Tyr Ile
420 425 430
Leu His Val Ala Val Thr Asn Val Val Pro Phe Glu Val Ser Leu Thr
435 440 445
Thr Ser Thr Ala Thr Val Thr Val Asp Val Leu Asp Val Asn Glu Ala
450 455 460
Pro Ile Phe Val Pro Pro Glu Lys Arg Val Glu Val Ser Glu Asp Phe
465 470 475 480
Gly Val Gly Gln Glu Ile Thr Ser Tyr Thr Ala Gln Glu Pro Asp Thr
485 490 495
Phe Met Glu Gln Lys Ile Thr Tyr Arg Ile Trp Arg Asp Thr Ala Asn
500 505 510
Trp Leu Glu Ile Asn Pro Asp Thr Gly Ala Ile Ser Thr Arg Ala Glu
515 520 525
Leu Asp Arg Glu Asp Phe Glu His Val Lys Asn Ser Thr Tyr Thr Ala
530 535 540
Leu Ile Ile Ala Thr Asp Asn Gly Ser Pro Val Ala Thr Gly Thr Gly
545 550 555 560
Thr Leu Leu Leu Ile Leu Ser Asp Val Asn Asp Asn Ala Pro Ile Pro
565 570 575
Glu Pro Arg Thr Ile Phe Phe Cys Glu Arg Asn Pro Lys Pro Gln Val
580 585 590
Ile Asn Ile Ile Asp Ala Asp Leu Pro Pro Asn Thr Ser Pro Phe Thr
595 600 605
Ala Glu Leu Thr His Gly Ala Ser Ala Asn Trp Thr Ile Gln Tyr Asn
610 615 620
Asp Pro Thr Gln Glu Ser Ile Ile Leu Lys Pro Lys Met Ala Leu Glu
625 630 635 640
Val Gly Asp Tyr Lys Ile Asn Leu Lys Leu Met Asp Asn Gln Asn Lys
645 650 655
Asp Gln Val Thr Thr Leu Glu Val Ser Val Cys Asp Cys Glu Gly Ala
660 665 670
Ala Gly Val Cys Arg Lys Ala Gln Pro Val Glu Ala Gly Leu Gln Ile
675 680 685
Pro
<210> 40
<211> 2067
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> E-钙黏素 EC1-EC5
<400> 40
tggctttgcc aggagccaga accctgtcat cctggcttcg atgcggagtc atacacgttt 60
accgtgccac gaagacatct cgagagggga agagtcctcg ggcgcgtgaa ctttgaagac 120
tgtacggggc gccaacggac tgcatatttc tccctcgaca cgagattcaa ggtcggcaca 180
gacggcgtaa ttacagtaaa acgcccgctt agattccata accctcagat acatttcttg 240
gtctatgcgt gggatagtac ctatcggaag ttttcaacaa aggtaacact taataccgta 300
ggtcatcatc atagaccccc tccgcaccaa gcgtctgtgt ctggcattca ggcggaattg 360
ttgaccttcc caaactcttc accggggctg aggcgccaaa aacgagactg ggtcatcccg 420
cctattagct gtccagagaa tgaaaaagga cccttcccta aaaaccttgt acagattaaa 480
tctaataagg acaaagaggg taaggttttt tacagtatta cgggccaggg tgctgacacc 540
ccaccggtag gcgtattcat catcgagaga gaaaccggtt ggctcaaagt gactgagcca 600
ctcgacagag agagaattgc aacttacacc cttttcagtc acgcggtttc aagcaacgga 660
aatgcagtgg aagaccccat ggagattctc atcaccgtga cagatcaaaa tgataacaaa 720
cctgaattta cccaggaggt gtttaaaggg agcgtaatgg aaggtgcact tcctggtacg 780
tctgttatgg aagtaactgc cacagatgct gatgatgacg taaacaccta taatgctgcc 840
atagcctaca cgatcctgag tcaagatccc gaactgcccg acaaaaatat gttcacaata 900
aatcgcaaca caggggtgat atccgttgtt acgaccggct tggatcggga gtcttttcca 960
acttatacgc tcgttgtaca agcggcggac ttgcaagggg aaggactcag tacgaccgcc 1020
acagcagtaa taaccgttac cgatacaaat gacaaccctc caatcttcaa tccaactacg 1080
tacaaaggac aggtgcctga gaacgaggca aacgttgtca ttacaacgct taaagtcacc 1140
gatgctgatg ctccgaatac cccggcatgg gaggctgtgt acactattct gaatgatgat 1200
ggcggtcagt ttgtggtaac tacgaacccc gtcaacaacg acggaatcct caaaacagct 1260
aagggattgg atttcgaggc taagcaacaa tatatccttc atgtggcagt aacgaacgtg 1320
gtaccctttg aagtatccct tactacttca accgctacag tcactgttga cgtcctcgat 1380
gttaacgagg cacctatctt cgttcctcca gagaaacgcg tggaagtaag tgaggacttc 1440
ggcgttgggc aagaaattac gtcttataca gctcaagagc ctgatacatt tatggagcaa 1500
aagatcacat accgcatttg gagagatacg gcaaactggc tcgaaataaa tcctgatacg 1560
ggagcaataa gcacacgggc tgagttggac cgagaggatt ttgaacacgt caagaactcc 1620
acgtatacgg ccttgatcat cgcgactgat aatgggagtc ctgtggcaac aggaacgggc 1680
accctcttgt tgatcttgtc tgatgttaat gacaacgcgc caatcccaga accgaggacc 1740
atcttctttt gtgaaagaaa cccaaagccc caagtgataa acatcattga cgccgatctg 1800
ccaccaaaca cgtccccctt tacagccgag cttacacatg gggcgtcagc aaattggacg 1860
attcaataca acgaccctac gcaagaatca ataattctta agccaaaaat ggcgttggaa 1920
gtcggggact ataagatcaa cctgaagctc atggacaacc agaataaaga ccaagtaacg 1980
acacttgaag tctcagtttg tgattgcgag ggggcggctg gagtttgtcg gaaggcccaa 2040
cctgttgaag ccggcttgca gataccg 2067
<210> 41
<211> 356
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> E-钙黏素 EC1-EC2
<400> 41
Trp Leu Cys Gln Glu Pro Glu Pro Cys His Pro Gly Phe Asp Ala Glu
1 5 10 15
Ser Tyr Thr Phe Thr Val Pro Arg Arg His Leu Glu Arg Gly Arg Val
20 25 30
Leu Gly Arg Val Asn Phe Glu Asp Cys Thr Gly Arg Gln Arg Thr Ala
35 40 45
Tyr Phe Ser Leu Asp Thr Arg Phe Lys Val Gly Thr Asp Gly Val Ile
50 55 60
Thr Val Lys Arg Pro Leu Arg Phe His Asn Pro Gln Ile His Phe Leu
65 70 75 80
Val Tyr Ala Trp Asp Ser Thr Tyr Arg Lys Phe Ser Thr Lys Val Thr
85 90 95
Leu Asn Thr Val Gly His His His Arg Pro Pro Pro His Gln Ala Ser
100 105 110
Val Ser Gly Ile Gln Ala Glu Leu Leu Thr Phe Pro Asn Ser Ser Pro
115 120 125
Gly Leu Arg Arg Gln Lys Arg Asp Trp Val Ile Pro Pro Ile Ser Cys
130 135 140
Pro Glu Asn Glu Lys Gly Pro Phe Pro Lys Asn Leu Val Gln Ile Lys
145 150 155 160
Ser Asn Lys Asp Lys Glu Gly Lys Val Phe Tyr Ser Ile Thr Gly Gln
165 170 175
Gly Ala Asp Thr Pro Pro Val Gly Val Phe Ile Ile Glu Arg Glu Thr
180 185 190
Gly Trp Leu Lys Val Thr Glu Pro Leu Asp Arg Glu Arg Ile Ala Thr
195 200 205
Tyr Thr Leu Phe Ser His Ala Val Ser Ser Asn Gly Asn Ala Val Glu
210 215 220
Asp Pro Met Glu Ile Leu Ile Thr Val Thr Asp Gln Asn Asp Asn Lys
225 230 235 240
Pro Glu Phe Thr Gln Glu Val Phe Lys Gly Ser Val Met Glu Gly Ala
245 250 255
Leu Pro Gly Thr Ser Val Met Glu Val Thr Ala Thr Asp Ala Asp Asp
260 265 270
Asp Val Asn Thr Tyr Asn Ala Ala Ile Ala Tyr Thr Ile Leu Ser Gln
275 280 285
Asp Pro Glu Leu Pro Asp Lys Asn Met Phe Thr Ile Asn Arg Asn Thr
290 295 300
Gly Val Ile Ser Val Val Thr Thr Gly Leu Asp Arg Glu Ser Phe Pro
305 310 315 320
Thr Tyr Thr Leu Val Val Gln Ala Ala Asp Leu Gln Gly Glu Gly Leu
325 330 335
Ser Thr Thr Ala Thr Ala Val Ile Thr Val Thr Asp Thr Asn Asp Asn
340 345 350
Pro Pro Ile Phe
355
<210> 42
<211> 1068
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> E-钙黏素 EC1-EC2
<400> 42
tggttgtgcc aggaacccga gccttgccat cccggattcg atgcagagtc atatacattt 60
acggtacccc gccgacatct ggagcgaggg cgggttctcg ggagagttaa ctttgaagac 120
tgcaccggca ggcagcggac cgcctacttt tcattggata cgcgattcaa agtcggcacc 180
gatggcgtca taaccgttaa acggccactg cgcttccata atccacaaat tcatttcctc 240
gtatacgcat gggacagtac ttatcgcaag ttcagcacaa aagttacact taatacggta 300
gggcatcacc acaggcctcc accccaccag gcttcagtga gtggcataca ggctgaactc 360
ctgacatttc caaattcttc acccggactc agaagacaaa agcgcgactg ggtcattcca 420
cctatttcct gtccagagaa cgaaaaaggg ccgttcccga aaaatctggt tcaaattaaa 480
agtaacaaag ataaagaggg taaagtgttt tacagtataa ccggccaggg cgccgatact 540
cctcccgtcg gggtctttat catcgaacgg gaaactggtt ggcttaaagt aacagaaccc 600
ctcgataggg aacggatagc aacgtataca ctgttcagtc atgcagttag cagcaatggc 660
aacgcagtag aagaccctat ggaaatcctc attactgtta ctgaccaaaa tgataacaag 720
cccgagttta cacaggaggt attcaagggc tcagtaatgg agggcgcgct tccagggacc 780
agtgttatgg aggtaactgc gaccgatgcg gatgacgatg tgaacacgta caacgctgcg 840
atagcctata ccattttgtc acaggatcct gaactcccgg acaaaaacat gttcacaata 900
aaccggaaca caggagtcat atcagtggtg actacaggcc ttgaccgcga atcctttcct 960
acgtatactc tcgtggtcca agcggcagat ctgcaaggtg aagggctgag tacaacggcc 1020
actgccgtaa ttactgtcac cgacactaat gacaatccac ccatattc 1068
<210> 43
<211> 20
<212> RNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> TRAC sgRNA
<400> 43
agagucucuc agcugguaca 20
<210> 44
<211> 20
<212> RNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> B2M sgRNA
<400> 44
ggguagcgcg agcacagcua 20
<210> 45
<211> 19
<212> RNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> RFX5 sgRNA
<400> 45
ggguugcgga uccaccuau 19
<210> 46
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 46
Val Met Ala Pro Arg Thr Leu Ile Leu
1 5
<210> 47
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 47
Val Met Ala Pro Arg Thr Leu Phe Leu
1 5
<210> 48
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 48
Val Met Ala Pro Leu Thr Leu Ile Leu
1 5
<210> 49
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 49
Val Met Ala Pro Arg Ile Leu Ile Leu
1 5
<210> 50
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 50
Val Met Ala Pro Gln Ser Leu Leu Leu
1 5
<210> 51
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 51
Gln Met Arg Pro Val Ser Arg Val Leu
1 5
<210> 52
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 52
Gly Met Lys Phe Asp Arg Gly Tyr Ile
1 5
<210> 53
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 提呈肽
<400> 53
Ala Ile Ser Pro Arg Thr Leu Asn Ala
1 5
<210> 54
<211> 195
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1
<400> 54
Met Thr Asp Ser Val Ile Tyr Ser Met Leu Glu Leu Pro Thr Ala Thr
1 5 10 15
Gln Ala Gln Asn Asp Tyr Gly Pro Gln Gln Lys Ser Ser Ser Ser Arg
20 25 30
Pro Ser Cys Ser Cys Leu Val Ala Ile Ala Leu Gly Leu Leu Thr Ala
35 40 45
Val Leu Leu Ser Val Leu Leu Tyr Gln Trp Ile Leu Cys Gln Gly Ser
50 55 60
Asn Tyr Ser Thr Cys Ala Ser Cys Pro Ser Cys Pro Asp Arg Trp Met
65 70 75 80
Lys Tyr Gly Asn His Cys Tyr Tyr Phe Ser Val Glu Glu Lys Asp Trp
85 90 95
Asn Ser Ser Leu Glu Phe Cys Leu Ala Arg Asp Ser His Leu Leu Val
100 105 110
Ile Thr Asp Asn Gln Glu Met Ser Leu Leu Gln Val Phe Leu Ser Glu
115 120 125
Ala Phe Cys Trp Ile Gly Leu Arg Asn Asn Ser Gly Trp Arg Trp Glu
130 135 140
Asp Gly Ser Pro Leu Asn Phe Ser Arg Ile Ser Ser Asn Ser Phe Val
145 150 155 160
Gln Thr Cys Gly Ala Ile Asn Lys Asn Gly Leu Gln Ala Ser Ser Cys
165 170 175
Glu Val Pro Leu His Trp Val Cys Lys Lys Cys Pro Phe Ala Asp Gln
180 185 190
Ala Leu Phe
195
<210> 55
<211> 108
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv VL
<400> 55
Glu Ile Val Leu Thr Gln Ser Pro Val Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Met Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 56
<211> 123
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv VH
<400> 56
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Ile Pro Ile Phe Gly Ala Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Pro Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 57
<211> 246
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv
<400> 57
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Ile Pro Ile Phe Gly Ala Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Pro Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Val Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser
145 150 155 160
Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg
180 185 190
Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr
210 215 220
Tyr Cys Gln Gln Arg Ser Asn Trp Met Tyr Thr Phe Gly Gln Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys Arg
245
<210> 58
<211> 109
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv VL
<400> 58
Glu Ile Val Leu Thr Gln Ser Pro Val Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Met Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr
100 105
<210> 59
<211> 123
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv VH
<400> 59
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Ile Pro Ile Phe Gly Ala Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Pro Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 60
<211> 247
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv
<400> 60
Glu Ile Val Leu Thr Gln Ser Pro Val Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Met Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu
115 120 125
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
130 135 140
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr Ala Ile Ser Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Phe Ile
165 170 175
Pro Ile Phe Gly Ala Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val
180 185 190
Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
195 200 205
Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ile Pro
210 215 220
Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val Trp Gly Gln Gly
225 230 235 240
Thr Thr Val Thr Val Ser Ser
245
<210> 61
<211> 107
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1 VL
<400> 61
Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 62
<211> 118
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1 VH
<400> 62
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Leu Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Leu Pro Ser
50 55 60
Leu Lys Ser Gln Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Thr Glu Leu Gly Arg Gly Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Ala Val Ser Ser
115
<210> 63
<211> 243
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2
<400> 63
Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Val Thr
115 120 125
Leu Lys Glu Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln Thr Leu Ser
130 135 140
Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Leu Gly
145 150 155 160
Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu Ala
165 170 175
His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Leu Pro Ser Leu Lys Ser
180 185 190
Gln Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val Phe Leu Lys
195 200 205
Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
210 215 220
Thr Glu Leu Gly Arg Gly Asp Tyr Trp Gly Gln Gly Thr Ser Val Ala
225 230 235 240
Val Ser Ser
<210> 64
<211> 121
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2 VL
<400> 64
Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Pro Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Glu Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Tyr Asp Gly Tyr Tyr Ser Ala Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Ala
115 120
<210> 65
<211> 108
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2 VH
<400> 65
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 66
<211> 244
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2
<400> 66
Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Pro Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Glu Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Tyr Asp Gly Tyr Tyr Ser Ala Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser His
130 135 140
Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr
180 185 190
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr Tyr Cys
210 215 220
Gln Gln His Tyr Ser Pro Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Arg
<210> 67
<211> 124
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv VH
<400> 67
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 Ser Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Tyr Asp Ser Glu Thr His Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Asp Phe Asp Val Gly Thr Leu Tyr Trp Phe Phe
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120
<210> 68
<211> 107
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv VL
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 69
<211> 246
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv
<400> 69
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln
115 120 125
Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys
130 135 140
Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met Asn Trp Val Arg
145 150 155 160
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Asp Pro Tyr
165 170 175
Asp Ser Glu Thr His Tyr Ala Gln Lys Leu Gln Gly Arg Val Thr Met
180 185 190
Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu
195 200 205
Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Asp
210 215 220
Phe Asp Val Gly Thr Leu Tyr Trp Phe Phe Asp Val Trp Gly Gln Gly
225 230 235 240
Thr Thr Val Thr Val Ser
245
<210> 70
<211> 223
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> PDL1胞外区
<400> 70
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
50 55 60
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His Leu
210 215 220
<210> 71
<211> 201
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> PDL2胞外区
<400> 71
Leu Phe Thr Val Thr Val Pro Lys Glu Leu Tyr Ile Ile Glu His Gly
1 5 10 15
Ser Asn Val Thr Leu Glu Cys Asn Phe Asp Thr Gly Ser His Val Asn
20 25 30
Leu Gly Ala Ile Thr Ala Ser Leu Gln Lys Val Glu Asn Asp Thr Ser
35 40 45
Pro His Arg Glu Arg Ala Thr Leu Leu Glu Glu Gln Leu Pro Leu Gly
50 55 60
Lys Ala Ser Phe His Ile Pro Gln Val Gln Val Arg Asp Glu Gly Gln
65 70 75 80
Tyr Gln Cys Ile Ile Ile Tyr Gly Val Ala Trp Asp Tyr Lys Tyr Leu
85 90 95
Thr Leu Lys Val Lys Ala Ser Tyr Arg Lys Ile Asn Thr His Ile Leu
100 105 110
Lys Val Pro Glu Thr Asp Glu Val Glu Leu Thr Cys Gln Ala Thr Gly
115 120 125
Tyr Pro Leu Ala Glu Val Ser Trp Pro Asn Val Ser Val Pro Ala Asn
130 135 140
Thr Ser His Ser Arg Thr Pro Glu Gly Leu Tyr Gln Val Thr Ser Val
145 150 155 160
Leu Arg Leu Lys Pro Pro Pro Gly Arg Asn Phe Ser Cys Val Phe Trp
165 170 175
Asn Thr His Val Arg Glu Leu Thr Leu Ala Ser Ile Asp Leu Gln Ser
180 185 190
Gln Met Glu Pro Arg Thr His Pro Thr
195 200
<210> 72
<211> 11
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-L1
<400> 72
Ser Ala Ser Ser Ser Val Ser Ser Tyr Ile Tyr
1 5 10
<210> 73
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-L2
<400> 73
Leu Thr Ser Asn Leu Ala Ser
1 5
<210> 74
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-L3
<400> 74
Gln Gln Trp Ser Gly Asn Pro Tyr Thr
1 5
<210> 75
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-H1
<400> 75
Gly Phe Thr Phe Ser Ser Tyr
1 5
<210> 76
<211> 6
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-H2
<400> 76
Ser Ser Gly Gly Ser Tyr
1 5
<210> 77
<211> 10
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-H3
<400> 77
His Gly Asp Tyr Pro Arg Phe Phe Asp Val
1 5 10
<210> 78
<211> 11
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-L1
<400> 78
Arg Ala Ser Glu Asn Ile Tyr Ser Tyr Leu Ala
1 5 10
<210> 79
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-L2
<400> 79
Asn Ala Lys Thr Leu Ala Glu
1 5
<210> 80
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-L3
<400> 80
Gln His His Tyr Gly Thr Pro Arg Thr
1 5
<210> 81
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-H1
<400> 81
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 82
<211> 6
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-H2
<400> 82
Asp Pro Tyr Asp Ser Glu
1 5
<210> 83
<211> 16
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> NKG2A scFv CDR-H3
<400> 83
Gly Gly Tyr Asp Phe Asp Val Gly Thr Leu Tyr Trp Phe Phe Asp Val
1 5 10 15
<210> 84
<211> 11
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv CDR-L1
<400> 84
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 85
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv CDR-L2
<400> 85
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 86
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv CDR-L3
<400> 86
Gln Gln Arg Ser Asn Trp Met Tyr Thr
1 5
<210> 87
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv CDR-H1
<400> 87
Gly Gly Thr Phe Ser Phe Tyr
1 5
<210> 88
<211> 6
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv CDR-H2
<400> 88
Ile Pro Ile Phe Gly Ala
1 5
<210> 89
<211> 14
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KIR scFv CDR-H3
<400> 89
Ile Pro Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val
1 5 10
<210> 90
<211> 11
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1 CDR-L1
<400> 90
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
1 5 10
<210> 91
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1 CDR-L2
<400> 91
Tyr Ala Ser Glu Ser Ile Ser
1 5
<210> 92
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1 CDR-L3
<400> 92
Gln Gln Ser Tyr Ser Trp Pro Tyr Thr
1 5
<210> 93
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1 CDR-H1
<400> 93
Gly Phe Ser Leu Ser Thr Ser Gly Leu
1 5
<210> 94
<211> 5
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1 CDR-H2
<400> 94
Trp Trp Asp Asp Asp
1 5
<210> 95
<211> 8
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-1 CDR-H3
<400> 95
Thr Glu Leu Gly Arg Gly Asp Tyr
1 5
<210> 96
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2 CDR-L1
<400> 96
Gly Tyr Ser Phe Thr Asn Tyr
1 5
<210> 97
<211> 6
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2 CDR-L2
<400> 97
Tyr Pro Gly Asn Ser Asp
1 5
<210> 98
<211> 11
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2 CDR-L3
<400> 98
Tyr Asp Gly Tyr Tyr Ser Ala Trp Phe Ala Tyr
1 5 10
<210> 99
<211> 11
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2 CDR-H1
<400> 99
Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 100
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2 CDR-H2
<400> 100
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 101
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> LIR1 scFv-2 CDR-H3
<400> 101
Gln Gln His Tyr Ser Pro Pro Trp Thr
1 5
<210> 102
<211> 15
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1 CDR-L1
<400> 102
Arg Ala Ser Gln Ser Val Ser Thr Ser Ser His Ser Tyr Leu His
1 5 10 15
<210> 103
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1 CDR-L2
<400> 103
Tyr Ala Ser Asn Leu Ala Ser
1 5
<210> 104
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1 CDR-L3
<400> 104
Gln His Ser Trp Glu Ile Pro Tyr Thr
1 5
<210> 105
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1 CDR-H1
<400> 105
Gly Phe Asn Phe Lys Asp Thr
1 5
<210> 106
<211> 6
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1 CDR-H2
<400> 106
Asp Pro Ala Asn Gly Asn
1 5
<210> 107
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1 CDR-H3
<400> 107
Gly Trp Asp Gly Tyr Tyr Phe Asp Cys
1 5
<210> 108
<211> 111
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1 VL
<400> 108
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Val Val Ser Leu Gly
1 5 10 15
Leu Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser His Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Ala Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 109
<211> 118
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1 VH
<400> 109
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Val Ser Gly Phe Asn Phe Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Ala Ser Lys Phe
50 55 60
Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Val Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Trp Asp Gly Tyr Tyr Phe Asp Cys Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 110
<211> 244
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-1
<400> 110
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Val Val Ser Leu Gly
1 5 10 15
Leu Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser His Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Ala Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val
130 135 140
Lys Leu Ser Cys Thr Val Ser Gly Phe Asn Phe Lys Asp Thr Tyr Ile
145 150 155 160
His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg
165 170 175
Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Ala Ser Lys Phe Gln Asp
180 185 190
Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Val Tyr Met Gln
195 200 205
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg
210 215 220
Gly Trp Asp Gly Tyr Tyr Phe Asp Cys Trp Gly Gln Gly Thr Thr Leu
225 230 235 240
Thr Val Ser Ser
<210> 111
<211> 12
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1 CDR-L1
<400> 111
Arg Ala Ser Ser Ser Val Ser Ser Asn Tyr Leu His
1 5 10
<210> 112
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1 CDR-L2
<400> 112
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 113
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1 CDR-L3
<400> 113
Gln Gln Tyr Ser Gly Tyr Pro Leu Thr
1 5
<210> 114
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1 CDR-H1
<400> 114
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 115
<211> 6
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1 CDR-H2
<400> 115
Tyr Pro Gly Arg Ser Asn
1 5
<210> 116
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1 CDR-H3
<400> 116
Asp Ala Thr Val Glu Pro Leu Pro Tyr
1 5
<210> 117
<211> 108
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1 VL
<400> 117
Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Asn
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Lys Ile Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Ala Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 118
<211> 118
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1 VH
<400> 118
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Phe Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Arg Ser Asn Asn Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Phe Arg Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Thr Val Glu Pro Leu Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 119
<211> 241
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-1
<400> 119
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Phe Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Arg Ser Asn Asn Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Phe Arg Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Thr Val Glu Pro Leu Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met
130 135 140
Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser
145 150 155 160
Ser Val Ser Ser Asn Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala
165 170 175
Ser Pro Lys Ile Trp Ile Tyr Ser Thr Ser Asn Leu Ala Ser Ala Val
180 185 190
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr
195 200 205
Ile Ser Ser Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Tyr Ser Gly Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys
<210> 120
<211> 20
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> PDL1跨膜结构域
<400> 120
Val Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr Phe
1 5 10 15
Ile Phe Arg Leu
20
<210> 121
<211> 18
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> PDL1信号肽
<400> 121
Met Arg Ile Phe Ala Val Phe Ile Phe Met Thr Tyr Trp His Leu Leu
1 5 10 15
Asn Ala
<210> 122
<211> 11
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2 CDR-L1
<400> 122
Ser Ala Ser Gln Gly Ile Thr Asn Tyr Leu Asn
1 5 10
<210> 123
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2 CDR-L2
<400> 123
Tyr Thr Ser Ile Leu His Ser
1 5
<210> 124
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2 CDR-L3
<400> 124
Gln Gln Tyr Ser Lys Pro Pro Tyr Thr
1 5
<210> 125
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2 CDR-H1
<400> 125
Gly Phe Thr Phe Ser Asn Tyr
1 5
<210> 126
<211> 8
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2 CDR-H2
<400> 126
Arg Leu Lys Ser Asp Asn Tyr Ala
1 5
<210> 127
<211> 8
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2 CDR-H3
<400> 127
Gly Asp Tyr Asp Ile Phe Ala Tyr
1 5
<210> 128
<211> 107
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2 VL
<400> 128
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Lys Pro Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 129
<211> 119
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2 VH
<400> 129
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Val Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Thr Glu Gly Asp Tyr Asp Ile Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 130
<211> 241
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-2
<400> 130
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Lys Pro Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Glu Glu
115 120 125
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Met Lys Val Ser Cys
130 135 140
Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr Trp Met Asn Trp Val Arg
145 150 155 160
Gln Ser Pro Glu Lys Gly Leu Glu Trp Val Ala Gln Ile Arg Leu Lys
165 170 175
Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser Val Tyr Leu Gln Met Asn
195 200 205
Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr Tyr Cys Thr Glu Gly Asp
210 215 220
Tyr Asp Ile Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ala
<210> 131
<211> 15
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3 CDR-L1
<400> 131
Arg Ala Ser Gln Ser Val Ser Ser Ser Ser Tyr Ser Tyr Met His
1 5 10 15
<210> 132
<211> 7
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3 CDR-L2
<400> 132
Tyr Ala Ser Asn Leu Lys Ser
1 5
<210> 133
<211> 9
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3 CDR-L3
<400> 133
Gln His Ser Trp Glu Ile Pro Pro Thr
1 5
<210> 134
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3 CDR-H1
<400> 134
Gly Phe Ser Leu Ser Thr Phe Gly Met
1 5
<210> 135
<211> 5
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3 CDR-H2
<400> 135
Trp Trp Asp Asp Asp
1 5
<210> 136
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3 CDR-H3
<400> 136
Val Glu Arg Gly Tyr Pro Leu Asp His
1 5
<210> 137
<211> 111
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3 VL
<400> 137
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Lys Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 138
<211> 119
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3 VH
<400> 138
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr His Pro Ala
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Glu Thr Ala Thr Phe Tyr
85 90 95
Cys Ala Arg Val Glu Arg Gly Tyr Pro Leu Asp His Trp Gly Gln Gly
100 105 110
Thr Thr Leu Arg Val Ser Ser
115
<210> 139
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-3
<400> 139
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Lys Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
115 120 125
Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr Leu
130 135 140
Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Phe Gly Met
145 150 155 160
Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu
165 170 175
Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr His Pro Ala Leu Lys
180 185 190
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Asn Gln Val Phe Leu
195 200 205
Lys Ile Ala Asn Val Asp Thr Ala Glu Thr Ala Thr Phe Tyr Cys Ala
210 215 220
Arg Val Glu Arg Gly Tyr Pro Leu Asp His Trp Gly Gln Gly Thr Thr
225 230 235 240
Leu Arg Val Ser Ser
245
<210> 140
<211> 10
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4 CDR-L1
<400> 140
Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 141
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4 CDR-L2
<400> 141
Trp Thr Ser Thr Arg His Thr
1 5
<210> 142
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4 CDR-L3
<400> 142
His Gln Gln Tyr Ser Thr Pro Pro Thr
1 5
<210> 143
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4 CDR-H1
<400> 143
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 144
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4 CDR-H2
<400> 144
Asp Pro Ser Val Ser Tyr
1 5
<210> 145
<211> 10
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4 CDR-H3
<400> 145
Trp Ser Lys Asp Tyr Tyr Gly Met Asp Tyr
1 5 10
<210> 146
<211> 107
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4 VL
<400> 146
Asp Ile Val Leu Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Thr Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp His Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys His Gln Gln Tyr Ser Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 147
<211> 119
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4 VH
<400> 147
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Val Ser Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Lys Asp Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 148
<211> 241
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7 scFv-4
<400> 148
Asp Ile Val Leu Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Thr Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp His Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys His Gln Gln Tyr Ser Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln
115 120 125
Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys
130 135 140
Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met Gln Trp Val Lys
145 150 155 160
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Asp Pro Ser
165 170 175
Val Ser Tyr Thr Glu Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu
180 185 190
Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu
195 200 205
Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp Ser Lys Asp
210 215 220
Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser
225 230 235 240
Ser
<210> 149
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2 CDR-L1
<400> 149
Ser Val Ser Ser Ser Ile Ser Ser Ser Asn Leu His
1 5 10
<210> 150
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2 CDR-L2
<400> 150
Gly Thr Ser Asn Leu Ala Ser
1 5
<210> 151
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2 CDR-L3
<400> 151
Gln Gln Trp Ser Ser Tyr Pro Leu Thr
1 5
<210> 152
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2 CDR-H1
<400> 152
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 153
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2 CDR-H2
<400> 153
Tyr Pro Gly Ser Ser Ser
1 5
<210> 154
<211> 14
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2 CDR-H3
<400> 154
Gly Arg Leu Leu Arg Leu Arg Arg Gly Gly Tyr Phe Asp Tyr
1 5 10
<210> 155
<211> 108
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2 VL
<400> 155
Glu Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ala Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Val Ser Ser Ser Ile Ser Ser Ser
20 25 30
Asn Leu His Trp Tyr Gln Gln Lys Ser Glu Thr Ser Pro Lys Pro Trp
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro
85 90 95
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 156
<211> 123
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2 VH
<400> 156
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Tyr Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Asn
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Leu Leu Arg Leu Arg Arg Gly Gly Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 157
<211> 246
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-2
<400> 157
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Tyr Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Asn
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Leu Leu Arg Leu Arg Arg Gly Gly Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ala Leu Met Ala Ala Ser Pro Gly Glu Lys Val Thr Ile Thr
145 150 155 160
Cys Ser Val Ser Ser Ser Ile Ser Ser Ser Asn Leu His Trp Tyr Gln
165 170 175
Gln Lys Ser Glu Thr Ser Pro Lys Pro Trp Ile Tyr Gly Thr Ser Asn
180 185 190
Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr
210 215 220
Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro Leu Thr Phe Gly Ala Gly
225 230 235 240
Thr Lys Leu Glu Leu Lys
245
<210> 158
<211> 11
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3 CDR-L1
<400> 158
Arg Ala Ser Gln Asp Ile Tyr Gly Ser Leu Asn
1 5 10
<210> 159
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3 CDR-L2
<400> 159
Gly Thr Ser Ser Leu Asp Ser
1 5
<210> 160
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3 CDR-L3
<400> 160
Leu Gln Tyr Ala Ser Phe Pro Leu Thr
1 5
<210> 161
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3 CDR-H1
<400> 161
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 162
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3 CDR-H2
<400> 162
Asp Pro Ser Asp Ser Glu
1 5
<210> 163
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3 CDR-H3
<400> 163
Gly Arg Leu Leu Arg Leu Arg Asp Trp Phe Pro Tyr
1 5 10
<210> 164
<211> 107
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3 VL
<400> 164
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Ile Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Tyr Gly Ser
20 25 30
Leu Asn Trp Phe Gln Gln Lys Pro Asp Gly Thr Ile Lys Leu Leu Ile
35 40 45
Tyr Gly Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Ala Ser Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 165
<211> 121
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3 VH
<400> 165
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Met Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Ile Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Leu Leu Arg Leu Arg Asp Trp Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 166
<211> 243
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-3
<400> 166
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Met Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Ile Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Leu Leu Arg Leu Arg Asp Trp Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Leu Gly Glu Arg Ile Ser Leu Thr Cys Arg
145 150 155 160
Ala Ser Gln Asp Ile Tyr Gly Ser Leu Asn Trp Phe Gln Gln Lys Pro
165 170 175
Asp Gly Thr Ile Lys Leu Leu Ile Tyr Gly Thr Ser Ser Leu Asp Ser
180 185 190
Gly Val Pro Lys Arg Phe Ser Gly Ser Arg Ser Gly Ser Asp Tyr Ser
195 200 205
Leu Thr Ile Ser Ser Leu Glu Ser Glu Asp Phe Ala Asp Tyr Tyr Cys
210 215 220
Leu Gln Tyr Ala Ser Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
225 230 235 240
Glu Leu Lys
<210> 167
<211> 16
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4 CDR-L1
<400> 167
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 168
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4 CDR-L2
<400> 168
Leu Val Ser Glu Leu Glu Ser
1 5
<210> 169
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4 CDR-L3
<400> 169
Val Gln Gly Thr His Phe Pro Trp Thr
1 5
<210> 170
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4 CDR-H1
<400> 170
Gly Tyr Thr Phe Thr Asn Tyr
1 5
<210> 171
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4 CDR-H2
<400> 171
Tyr Pro Gly Asn Ser Asp
1 5
<210> 172
<211> 10
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4 CDR-H3
<400> 172
Glu Gly Asp Tyr Val Tyr Ala Met Asp Tyr
1 5 10
<210> 173
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4 VL
<400> 173
Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Ser Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Leu Val Ser Glu Leu Glu Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Val Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 174
<211> 119
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4 VH
<400> 174
Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Asn Glu Gly Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Glu Gly Asp Tyr Val Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 175
<211> 246
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> KLRG1 scFv-4
<400> 175
Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Asn Glu Gly Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Glu Gly Asp Tyr Val Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Thr Pro Leu Thr
130 135 140
Leu Ser Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser
145 150 155 160
Gln Ser Leu Leu Tyr Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu
165 170 175
Gln Ser Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Leu Val Ser Glu
180 185 190
Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val
210 215 220
Tyr Tyr Cys Val Gln Gly Thr His Phe Pro Trp Thr Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys
245
<210> 176
<211> 11
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1 CDR-L1
<400> 176
Lys Ala Ser Gln Asp Val Asn Thr Ala Val Ala
1 5 10
<210> 177
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1 CDR-L2
<400> 177
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 178
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1 CDR-L3
<400> 178
Gln Gln His Tyr Ser Thr Pro Arg Thr
1 5
<210> 179
<211> 8
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1 CDR-H1
<400> 179
Gly Tyr Ser Ile Thr Gly Gly Phe
1 5
<210> 180
<211> 5
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1 CDR-H2
<400> 180
Gly Tyr Gly Gly Ser
1 5
<210> 181
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1 CDR-H3
<400> 181
Gly Asp Tyr Leu Phe Ala Tyr
1 5
<210> 182
<211> 107
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1 VL
<400> 182
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 183
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1 VH
<400> 183
Asp Val Gln Leu Gln Glu Ser Gly Pro Leu Val Lys Pro Ser Gln Ser
1 5 10 15
Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Gly Gly Phe
20 25 30
Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Thr Leu Glu Trp Met
35 40 45
Gly Tyr Ile Gly Tyr Gly Gly Ser Thr Ser Tyr Asn Pro Ser Leu Asn
50 55 60
Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn His Phe Phe Leu
65 70 75 80
Gln Phe Asn Ser Val Thr Thr Asp Asp Ser Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Gly Asp Tyr Leu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 184
<211> 237
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1
<400> 184
Asp Val Gln Leu Gln Glu Ser Gly Pro Leu Val Lys Pro Ser Gln Ser
1 5 10 15
Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Gly Gly Phe
20 25 30
Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Thr Leu Glu Trp Met
35 40 45
Gly Tyr Ile Gly Tyr Gly Gly Ser Thr Ser Tyr Asn Pro Ser Leu Asn
50 55 60
Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn His Phe Phe Leu
65 70 75 80
Gln Phe Asn Ser Val Thr Thr Asp Asp Ser Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Gly Asp Tyr Leu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser
130 135 140
Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn
145 150 155 160
Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu
165 170 175
Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe
180 185 190
Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val
195 200 205
Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr
210 215 220
Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 185
<211> 107
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1-2 VL
<400> 185
Asp Thr Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 186
<211> 116
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1-2 VH
<400> 186
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Gly Gly
20 25 30
Phe Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Thr Leu Glu Trp
35 40 45
Met Gly Tyr Ile Gly Tyr Gly Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Asn Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn His Phe Phe
65 70 75 80
Leu Gln Phe Asn Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Tyr Leu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 187
<211> 238
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-1-2
<400> 187
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Gly Gly
20 25 30
Phe Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Thr Leu Glu Trp
35 40 45
Met Gly Tyr Ile Gly Tyr Gly Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Asn Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn His Phe Phe
65 70 75 80
Leu Gln Phe Asn Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Tyr Leu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Asp Thr Val Met Thr Gln Ser His Lys Phe Met Ser Thr
130 135 140
Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val
145 150 155 160
Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys
165 170 175
Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg
180 185 190
Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser
195 200 205
Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser
210 215 220
Thr Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 188
<211> 11
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2 CDR-L1
<400> 188
Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala
1 5 10
<210> 189
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2 CDR-L2
<400> 189
Ser Ala Ser Ser Arg Tyr Ser
1 5
<210> 190
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2 CDR-L3
<400> 190
Gln Gln Tyr Ile Thr Tyr Pro Tyr Thr
1 5
<210> 191
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2 CDR-H1
<400> 191
Gly Tyr Ser Phe Ser Asp Tyr
1 5
<210> 192
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2 CDR-H2
<400> 192
Asp Pro Tyr Tyr Gly Ala
1 5
<210> 193
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2 CDR-H3
<400> 193
Gly Asp Ser Leu Phe Ala Tyr
1 5
<210> 194
<211> 107
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2 VL
<400> 194
Asp Ile Val Met Thr Gln Ser Gln Glu Phe Met Ser Thr Ser Leu Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Leu
35 40 45
Tyr Ser Ala Ser Ser Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Ile Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 195
<211> 116
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2 VH
<400> 195
Glu Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Ser Asp Tyr
20 25 30
Asn Met Asn Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Ala Thr Ser Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Ser Leu Phe Ala Tyr Trp Gly His Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 196
<211> 238
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> SIGLEC7/9 scFv-2
<400> 196
Glu Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Ser Asp Tyr
20 25 30
Asn Met Asn Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Ala Thr Ser Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Ser Leu Phe Ala Tyr Trp Gly His Gly Thr Leu Val
100 105 110
Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Asp Ile Val Met Thr Gln Ser Gln Glu Phe Met Ser Thr
130 135 140
Ser Leu Gly Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val
145 150 155 160
Gly Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys
165 170 175
Ala Leu Leu Tyr Ser Ala Ser Ser Arg Tyr Ser Gly Val Pro Asp Arg
180 185 190
Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn
195 200 205
Val Gln Ser Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Ile Thr
210 215 220
Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
Claims (35)
1.一种NK抑制性分子,其包含一个或多个NK抑制性配体、跨膜结构域和共刺激结构域,其中所述NK抑制性配体特异性结合NK抑制性受体(NK inhibitory receptor,NKIR)以抑制NK细胞对表达所述NK抑制性分子的工程化免疫细胞的杀伤。
2.权利要求1所述的NK抑制性分子,其中所述NK抑制性配体是靶向NKIR的抗体,或NKIR的天然配体或其包含的NKIR结合区。
3.权利要求1或2所述的NK抑制性分子,其中所述NKIR选自:NKG2/CD94组分;杀伤细胞Ig样受体(KIR)家族成员;白细胞Ig样受体(LIR)家族成员;NK细胞受体蛋白1(NKR-P1)家族成员;免疫检查点受体;癌胚抗原相关的细胞黏附分子1(CEACAM1);唾液酸结合性免疫球蛋白样凝集素(SIGLEC)家族成员;白细胞相关的免疫球蛋白样受体1(LAIR1);Ly49家族成员和杀伤细胞凝集素样受体G1(KLRG1)。
4.权利要求3所述的NK抑制性分子,其中所述NKG2/CD94组分选自NKG2A、NKG2B和CD94;所述KIR家族成员选自KIR2DL1、KIR2DL2/3、KIR2DL5A、KIR2DL5B、KIR3DL1、KIR3DL2和KIR3DL3;所述LIR家族成员选自LIR1、LIR2、LIR3、LIR5和LIR8;所述NKR-P1家族成员选自NKR-P1B和NKR-P1D;所述免疫检查点受体选自PD-1、TIGIT、CD96、TIM3和LAG3;所述SIGLEC家族成员选自SIGLEC7和SIGLEC9;所述Ly49家族成员选自Ly49A、Ly49C、Ly49F、Ly49G1和Ly49G4。
5.权利要求3或4所述的NK抑制性分子,其中所述NKIR选自:NKG2A、NKG2B、CD94、LIR1、LIR2、LIR3、KIR2DL1、KIR2DL2/3、KIR3DL1、CEACAM1、PD1、LAIR1、SIGLEC7、SIGLEC9和KLRG1。
6.权利要求1-5任一项所述的NK抑制性分子,其中所述NK抑制性配体是靶向NKIR的抗体或其功能性片段,所述抗体或其功能性片段选自完整抗体、Fab、Fab’、F(ab’)2、Fv片段、scFv抗体片段、线性抗体、sdAb或纳米抗体。
7.权利要求1-5任一项所述的NK抑制性分子,其中所述NK抑制性配体是靶向PD1、NKG2A、LIR1、KIR、SIGLEC7、SIGLEC9和/或KLRG1的抗体。
8.权利要求7所述的NK抑制性分子,其中:
(i)所述靶向NKG2A的抗体包含(1)如SEQ ID NO:72所示的CDR-L1、如SEQ ID NO:73所示的CDR-L2、如SEQ ID NO:74所示的CDR-L3、如SEQ ID NO:75所示的CDR-H1、如SEQ ID NO:76所示的CDR-H2和如SEQ ID NO:77所示的CDR-H3,或(2)如SEQ ID NO:78所示的CDR-L1、如SEQ ID NO:79所示的CDR-L2、如SEQ ID NO:80所示的CDR-L3、如SEQ ID NO:81所示的CDR-H1、如SEQ ID NO:82所示的CDR-H2和如SEQ ID NO:83所示的CDR-H3;
(ii)所述靶向LIR1的抗体包含(1)如SEQ ID NO:90所示的CDR-L1、如SEQ ID NO:91所示的CDR-L2、如SEQ ID NO:92所示的CDR-L3、如SEQ ID NO:93所示的CDR-H1、如SEQ ID NO:94所示的CDR-H2和如SEQ ID NO:95所示的CDR-H3,或(2)如SEQ ID NO:96所示的CDR-L1、如SEQ ID NO:97所示的CDR-L2、如SEQ ID NO:98所示的CDR-L3、如SEQ ID NO:99所示的CDR-H1、如SEQ ID NO:100所示的CDR-H2和如SEQ ID NO:101所示的CDR-H3;
(iii)所述靶向KIR的抗体包含如SEQ ID NO:84所示的CDR-L1、如SEQ ID NO:85所示的CDR-L2、如SEQ ID NO:86所示的CDR-L3、如SEQ ID NO:87所示的CDR-H1、如SEQ ID NO:88所示的CDR-H2和如SEQ ID NO:89所示的CDR-H3;
(iv)所述靶向SIGLEC7、SIGLEC9或两者的抗体包含(1)如SEQ ID NO:102所示的CDR-L1、如SEQ ID NO:103所示的CDR-L2、如SEQ ID NO:104所示的CDR-L3、如SEQ ID NO:105所示的CDR-H1、如SEQ ID NO:106所示的CDR-H2和如SEQ ID NO:107所示的CDR-H3,(2)如SEQID NO:122所示的CDR-L1、如SEQ ID NO:123所示的CDR-L2、如SEQ ID NO:124所示的CDR-L3、如SEQ ID NO:125所示的CDR-H1、如SEQ ID NO:126所示的CDR-H2和如SEQ ID NO:1277所示的CDR-H3,(3)如SEQ ID NO:131所示的CDR-L1、如SEQ ID NO:132所示的CDR-L2、如SEQID NO:133所示的CDR-L3、如SEQ ID NO:134所示的CDR-H1、如SEQ ID NO:135所示的CDR-H2和如SEQ ID NO:136所示的CDR-H3,(4)如SEQ ID NO:140所示的CDR-L1、如SEQ ID NO:141所示的CDR-L2、如SEQ ID NO:142所示的CDR-L3、如SEQ ID NO:143所示的CDR-H1、如SEQ IDNO:144所示的CDR-H2和如SEQ ID NO:155所示的CDR-H3,(5)如SEQ ID NO:176所示的CDR-L1、如SEQ ID NO:177所示的CDR-L2、如SEQ ID NO:178所示的CDR-L3、如SEQ ID NO:179所示的CDR-H1、如SEQ ID NO:180所示的CDR-H2和如SEQ ID NO:181所示的CDR-H3,或(6)如SEQ ID NO:188所示的CDR-L1、如SEQ ID NO:189所示的CDR-L2、如SEQ ID NO:190所示的CDR-L3、如SEQ ID NO:191所示的CDR-H1、如SEQ ID NO:192所示的CDR-H2和如SEQ ID NO:193所示的CDR-H3;和/或
(v)所述靶向KLRG1的抗体包含(1)如SEQ ID NO:111所示的CDR-L1、如SEQ ID NO:112所示的CDR-L2、如SEQ ID NO:113所示的CDR-L3、如SEQ ID NO:114所示的CDR-H1、如SEQ IDNO:115所示的CDR-H2和如SEQ ID NO:116所示的CDR-H3,(2)如SEQ ID NO:149所示的CDR-L1、如SEQ ID NO:150所示的CDR-L2、如SEQ ID NO:151所示的CDR-L3、如SEQ ID NO:152所示的CDR-H1、如SEQ ID NO:153所示的CDR-H2和如SEQ ID NO:154所示的CDR-H3,(3)如SEQID NO:158所示的CDR-L1、如SEQ ID NO:159所示的CDR-L2、如SEQ ID NO:160所示的CDR-L3、如SEQ ID NO:161所示的CDR-H1、如SEQ ID NO:162所示的CDR-H2和如SEQ ID NO:163所示的CDR-H3,或(4)如SEQ ID NO:167所示的CDR-L1、如SEQ ID NO:168所示的CDR-L2、如SEQID NO:169所示的CDR-L3、如SEQ ID NO:170所示的CDR-H1、如SEQ ID NO:171所示的CDR-H2和如SEQ ID NO:172所示的CDR-H3。
9.权利要求1-5任一项所述的NK抑制性分子,其中所述NK抑制性配体选自HLA-E、HLA-F、HLA-G、钙黏素、胶原蛋白、OCIL、唾液酸、PD-L1/PD-L2、CD155、CD112、CD113、Gal-9、FGL1,和它们包含的NKIR结合区。
10.权利要求9所述的NK抑制性分子,其中所述NK抑制性配体选自唾液酸、HLA-E胞外区、HLA-F胞外区、HLA-G胞外区、E-钙黏素胞外区、PD-L1胞外区和PD-L2胞外区。
11.权利要求10所述的NK抑制性分子,其中:
(i)所述HLA-E的胞外区与SEQ ID NO:31或33所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性;
(ii)所述HLA-G的胞外区与SEQ ID NO:35所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性;
(iii)E-钙黏素胞外区与SEQ ID NO:39或41所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性;
(iv)PD-L1胞外区与SEQ ID NO:70所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性;
(v)PD-L2胞外区与SEQ ID NO:71所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
12.权利要求1所述的NK抑制性分子,其中所述跨膜结构域选自以下蛋白质的跨膜结构域:TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137、CD154、HLA-E、HLA-F、HLA-G、钙黏素、胶原蛋白、OCIL。
13.权利要求1所述的NK抑制性分子,其中所述共刺激结构域选自以下蛋白质的共刺激信号传导结构域:LTB、CD94、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70以及它们的组合。
14.权利要求1所述的NK抑制性分子,其中所述NK抑制性分子不包含胞内信号传导结构域。
15.权利要求1所述的NK抑制性分子,其中所述NK抑制性分子进一步包含胞内信号传导结构域。
16.权利要求14或15所述的NK抑制性分子,其中所述胞内信号传导结构域选自以下蛋白的信号传导结构域:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d。
17.权利要求14或15所述的NK抑制性分子,其中所述胞内信号传导结构域包含CD3ζ信号传导结构域。
18.一种核酸分子,其编码权利要求1-17任一项所述的NK抑制性分子。
19.一种载体,其包含权利要求18所述的核酸分子。
20.一种工程化免疫细胞,其特征在于:(1)表达权利要求1-17任一项所述的NK抑制性分子,和(2)至少一种MHC相关基因的表达被抑制或沉默。
21.权利要求20所述的工程化免疫细胞,其特征还在于,所述工程化免疫细胞还表达嵌合抗原受体,所述嵌合抗原受体包含配体结合结构域、跨膜结构域、共刺激结构域和细胞内信号传导结构域。
22.一种工程化免疫细胞,其特征在于:(1)表达NK抑制性分子和嵌合抗原受体的融合蛋白,所述融合蛋白包含NK抑制性配体、配体结合结构域、跨膜结构域、共刺激结构域和胞内信号传导结构域,和(2)至少一种MHC相关基因的表达被抑制或沉默。
23.权利要求20-22任一项所述的工程化免疫细胞,其中所述至少一种MHC相关基因选自HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
24.权利要求23所述的工程化免疫细胞,其中所述至少一种MHC相关基因选自B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
25.权利要求24所述的工程化免疫细胞,其中所述MHC相关基因包含B2M,其中所述NK抑制性配体是B2M和非经典HLA-I类分子的胞外区的融合分子。
26.权利要求25所述的工程化免疫细胞,其中所述非经典HLA-I类分子是HLA-E或HLA-G。
27.权利要求25所述的工程化免疫细胞,其中所述NK抑制性分子还包含提呈肽,其选自SEQ ID NO:46-53。
28.权利要求20-27任一项所述的工程化免疫细胞,其中所述工程化免疫细胞的至少一种TCR/CD3基因的表达被抑制或沉默,所述TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ和它们的组合。
29.权利要求20-28任一项所述的工程化免疫细胞,其特征还在于,其中选自以下的一个或多个基因的表达被抑制或沉默:CD52、GR、dCK、PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。
30.权利要求20-29任一项所述的工程化免疫细胞,其中所述配体结合结构域与选自以下的靶标结合:TSHR、CD2、CD3、CD4、CD5、CD7、CD8、CD14、CD15、CD19、CD20、CD21、CD23、CD24、CD25、CD37、CD38、CD40、CD40L、CD44、CD46、CD47、CD52、CD54、CD56、CD70、CD73、CD80、CD97、CD123、CD22、CD126、CD138、CD 179a、DR4、DR5、TAC、TEM1/CD248、VEGF、GUCY2C、EGP40、EGP-2、EGP-4、CD133、IFNAR1、DLL3、kappa轻链、TIM3、BAFF-R、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、tEGFR、GD2、GD3、BCMA、GPRC5D、Tn抗原、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、IL-22Ra、IL-2、间皮素、IL-llRa、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、AFP、Folate受体α、ERBB2(Her2/neu)、ErbB3、ErbB4、MUC1、MUC16、EGFR、CS1、CD138、NCAM、Claudin18.2、Prostase、PAP、ELF2M、EphrinB2、IGF-I受体、CAIX、LMP2、gploo、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、MAGE-A3、MAGE-A6、豆荚蛋白、HPV E6、E7、MAGE-A4、MART-1、WT-1、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin 8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG(TMPRSS2 ETS融合基因)、NA17、PAX3、雄激素受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D、NKG2DL和它们的任意组合。
31.权利要求30所述的工程化免疫细胞,其中所述靶标选自CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD123、CD138、CD171、MUC1、AFP、Folate受体α、CEA、PSCA、PSMA、Her2、EGFR、IL13Ra2、GD2、NKG2D、EGFRvIII、CS1、BCMA、间皮素、Cluadin18.2、ROR1、NY-ESO-1、MAGE-A4和它们的任意组合。
32.权利要求20-31任一项所述的工程化免疫细胞,其中所述工程化免疫细胞是B细胞、T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞或NKT细胞。
33.权利要求32所述的工程化免疫细胞,其中所述工程化免疫细胞是CD4+/CD8+T细胞、CD4+辅助T细胞、CD8+T细胞、肿瘤浸润细胞、记忆T细胞、幼稚T细胞、γδ-T细胞或αβ-T细胞。
34.一种药物组合物,其包含权利要求1-17任一项所述的NK抑制性分子、权利要求18所述的核酸分子、权利要求19所述的载体或权利要求20-33任一项所述的工程化免疫细胞,和一种多种药学上可接受的赋型剂。
35.权利要求1-17任一项所述的NK抑制性分子、权利要求18所述的核酸分子、权利要求19所述的载体或权利要求20-33任一项所述的工程化免疫细胞在制备治疗癌症、感染或自身免疫性疾病的药物中的用途。
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- 2021-06-10 JP JP2022549899A patent/JP2023514386A/ja active Pending
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- 2021-06-10 CN CN202110647514.6A patent/CN113801238A/zh active Pending
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JP2023514386A (ja) | 2023-04-05 |
US20230242661A1 (en) | 2023-08-03 |
AU2021286676A1 (en) | 2022-09-08 |
KR20220166837A (ko) | 2022-12-19 |
WO2021249462A1 (zh) | 2021-12-16 |
EP4112721A1 (en) | 2023-01-04 |
EP4112721A4 (en) | 2024-02-28 |
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