CN109467598B - 肿瘤相关基因notch1突变短肽及其应用 - Google Patents

肿瘤相关基因notch1突变短肽及其应用 Download PDF

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CN109467598B
CN109467598B CN201811430743.7A CN201811430743A CN109467598B CN 109467598 B CN109467598 B CN 109467598B CN 201811430743 A CN201811430743 A CN 201811430743A CN 109467598 B CN109467598 B CN 109467598B
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李许锋
罗尔夫·马丁
赵乙木
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Abstract

本发明公开了一种肿瘤相关基因NOTCH1突变多肽及其应用，多肽的序列为SEQ ID:2‑21中的一条。本发明的NOTCH1突变肽诱导建立的CTL对NOTCH1基因突变细胞能够靶向免疫清除，诱导得到的CTL克隆具有良好的特异杀伤效应。另外，在建立CTL过程中，发明人发现筛选出的NOTCH1突变肽抗原能够与DC细胞上MHC I类分子结合，并能够有效地刺激、诱导阐述特异性CTLs，说明具备良好的多肽疫苗及DC疫苗的潜力，能够预防NOTCH1突变相关疾病，尤其是肿瘤性疾病，具有良好的临床转化及实际应用前景。

Description

肿瘤相关基因NOTCH1突变短肽及其应用
技术领域
本发明涉及生物技术领域，具体涉及肿瘤相关基因突变抗原肽及其应用，特别涉及肿瘤相关基因NOTCH1突变短肽及其应用。
背景技术
2017年2月，国家癌症中心发布了中国最新癌症报告。报告显示：在中国，每年新发癌症病例达429万，也就是说全国每天约1万人确诊癌症，每1分钟约7人确诊患癌。若中国人均预期寿命是85岁，那么每个人的累计患癌风险高达36％。在世界范围内，大约22％的新增癌症病例和27％的癌症死亡发生在中国。大部分癌症疾病早期缺乏特异的临床症状，在确诊时往往处于中晚期，针对中晚期肿瘤的治疗目主要是延长患者生存期。因此，解决癌症问题的出路在于预防。
癌症发生的具体机理尚未研究清楚，但可以肯定的是癌症由基因突变引起，这里说的突变包括基因碱基的点突变、缺失、插入，基因的非正常扩增以及基因的异常融合。1990年，Eric Ft.Fearon和Bert Vogelstein在《Cell》上发表论文，提出肠癌癌变的模型，该过程显示基因突变远早于临床表现，可以作为癌症早期诊断标志物。斯特拉顿教授领导的研究小组，通过分析乳腺癌患者的基因组，解析了癌症发生发展的全过程。他们发现在癌变发生的过程中，多数乳腺癌患者在有临床症状之前，体内的癌变就已开始。如果以体细胞突变为起点算起，患者早在十余年前就已经患上癌症，而当时并无任何临床症状。因此，清除体内突变的体细胞是预防癌症的关键。
NOTCH基因最早于1917年在果蝇中发现,因其功能的部分缺失会在果蝇翅膀的边缘造成切迹而命名,1980年此基因首次被克隆出来。目前在哺乳动物中发现有4种Notch受体(Notch1-4)以及5种配体,这些配体分别命名为Delta-like-1、Deltalike-3、Delta-like-4(DLL1、3、4)和Jagg ed1、Jag ged2(JAG1、2)。Notch信号转导过程主要发生在细胞间,Notch受体是由异二聚体组成的单跨膜分子,其配体同样为跨膜分子。Notch受体胞外区含有连接于受体结合区的29～36个表皮生长因子样受体(EGFR)、可阻止非配体依赖性信号转导的3个富含半胱氨酸的LIN重复序列(Lin/Notch repeats,LNR)以及1个异二聚体区域。人类Notch-1和Notch-2各含有36个EGFR,Notch-3和No tch-4分别含有34和29个EGFR。胞外区是配体结合并激活Notch受体的部位。Notch受体通过LNR与跨膜区之间的二硫键形成异二聚体。N tch受体胞内区(Notch intracellular domain,NICD)含有以下区域:RAM(RBP-Jkappa associated molecular)结构域、6个锚蛋白重复序列(ANK,也称cdc10/ANK)、2个核定位信号区(nuclear localization signal,NLS；Notch-4只有1个NLS)、1个转录激活结构域(transactiva tion domains,TAD；Notch-3和-4中TAD尚未确定)以及1个PEST序列(praline-,glutamate-,serineandthreonine-rich domain)。NICD是Notch受体蛋白的活性形式,其中RAM结构域是C启动子结合因子-1/重组信号结合蛋白-Jκ(C promoterbinding factor-1/Recombination signal binding protein-J kappa,CBF1/RBPJκ)的主要结合部位,CBF1是存在于人或哺乳动物中的Su(H)蛋白的同源蛋白,也能与锚蛋白重复序列(anky rin repea ts,ANK)结构域相互作用；ANK重复序列结构域是Deltex、Mastermind等的结合部位,这些蛋白对Notch信号通路有调节作用；PEST结构域则与Notch受体蛋白的降解有关。许多研究表明,异常的Notch信号与一些肿瘤的发生密切相关,Notch信号的紊乱不仅能够直接引起肿瘤的发生,而且可通过与其他多条信号通路的交互作用,以直接或间接的方式最终诱导肿瘤形成。已发现Notch信号通路异常与食管癌、胃癌、宫颈癌、结肠癌等密切相关,其中Notch1是在肿瘤组织中最常被检测到的Notch受体家族成员。异常的Notch1在调控肿瘤细胞的生长、代谢、细胞周期及凋亡等过程中发挥重要作用。
免疫学研究证实，CD8阳性T淋巴细胞CTL发挥细胞免疫的原理为，CTL细胞通过识别与MHC-I分子结合的抗原肽被激活，被激活的CTL可以杀死相应的靶细胞，发挥免疫监视作用。
发明人通过T细胞表位预测综合平台NetCTL数据库(http://www.cbs.dtu.dk/services/NetCTL)在线分析，通过生物信息学预测，发现COSM12772、COSM13047、COSM13046、COSM13048的突变多肽能够与MHC-I类分子结合，说明该位点是免疫清除NOTCH1基因突变细胞的重要靶点。
发明内容
基于此，本发明提供肿瘤相关基因NOTCH1突变短肽及其应用。
本发明采取的技术方案是：
NOTCH1突变短肽，其序列为SEQ ID NO:2-SEQ ID NO:21中的一条。
如SEQ ID NO:2-SEQ ID NO:21所述的NOTCH1突变短肽能够诱导特异性细胞毒性T淋巴细胞的产生。
特异性细胞毒性T淋巴细胞的诱导方法，使用SEQ ID NO:2-SEQ ID NO:21的NOTCH1突变短肽中的至少一条经抗原提呈细胞与CD8+T细胞共培养，诱导得到NOTCH1突变特异性细胞毒性T细胞。
一种多肽疫苗，由活性抗原成分和辅剂组成，活性抗原成分为如SEQ ID NO:2-SEQID NO:21所述的NOTCH1突变短肽中的至少一条。
一种用于NOTCH1突变防治的DC疫苗，主要由SEQ ID NO:2-SEQ ID NO:21所述的NOTCH1突变短肽中的至少一条和树突状细胞加载得到。
本发明通过生物信息学技术预测NOTCH1突变序列与T淋巴细胞受体(TCR)及MHC I类分子的结合能力，同时分析其表达定位于细胞膜外，筛选出多肽序列：SEQ:2-21，所筛选出的NOTCH1抗原肽具有与DC细胞上MHC I分子高度的亲和力并能有效地刺激、诱导产生特异性细胞毒性T淋巴细胞(CTLs)，说明其具备良好的多肽疫苗及DC疫苗的潜力，并且提示其具有良好的临床转化及疾病预防前景。
附图说明：
图1是NOTCH1 SEQ2特异性CTL IFN-γ释放实验；
图2是NOTCH1 SEQ5特异性CTL IFN-γ释放实验；
图3是NOTCH1 SEQ8特异性CTL IFN-γ释放实验；
图4是NOTCH1 SEQ12特异性CTL IFN-γ释放实验；
图5是NOTCH1 SEQ14特异性CTL IFN-γ释放实验。
具体实施方式
NOTCH1作为膜结合配体的一种受体，用来调节细胞命运的决定，其可以影响分化、增殖和凋亡的进程，参与血管生成，对内皮细胞的增殖、迁移和血管生成生长有负面的调节作用。在胸腺中，NOTCH1参与包括CD4+和CD8+细胞的成熟。NOTCH1对对卵泡的分化很重要，可能在卵泡内的细胞命运选择发挥作用。在小脑发育过程中，NOTCH1作为神经细胞受体的受体，并参与了Bergmann的分化，抑制神经元和肌原分化。在细胞的分化的某些方面扮演着重要的角色，NOTCH1与中胚层发育、躯体形成和神经发生有关。该基因(如SEQ ID NO.22所示)的突变与主动脉瓣膜病、亚当-奥利弗综合征、t细胞急性淋巴细胞白血病、慢性淋巴细胞白血病、头颈部鳞状细胞癌有关。
NOTCH1氨基酸序列为：(SEQ ID NO:1)
Figure BDA0001882644700000051
Figure BDA0001882644700000061
下面结合实验，进一步地说明本发明的技术方案。
NOTCH1基因突变肽的T细胞表位预测：
本发明通过T细胞表位预测数据综合平台(http://www.cbs.dtu.dk/services/NetCTL)，预测与T细胞表位及MHC I类分子高亲和力的多肽序列，所得候选肽由专业公司合成，具体多肽序列如表1：
表1
Figure BDA0001882644700000062
Figure BDA0001882644700000071
基于预测结果，本发明随机挑选其中5条进行实验，具体实验如下：
NOTCH1突变短肽特异性CTL克隆建立的操作如下:
同一健康捐献者的105个CD8+T细胞通过负载NOTCH1突变短肽的104个Mo-DCs间隔1周刺激2次后，再通过自体105个丝裂霉素C处理过的负载NOTCH1短肽的PBMC刺激1次后，经标准细胞毒试验筛选获得。
T2细胞加载5uM NOTCH1突变短肽作为靶细胞，CTL的NOTCH1短肽特异性细胞毒性通过LDH释放试验得以证实。
采用以上体外诱导建立NOTCH1基因突变短肽特异性CTL克隆的方法，本发明还建立了MHC-I限制性CTL克隆，通过IFN-γ释放试验证实其多肽特异性免疫应答效应。
如图1至图5，其中，
图1：1表示SEQ ID NO:2多肽,2表示PBS磷酸盐缓冲液，3表示Control peptide无关对照肽；
图2：1表示SEQ ID NO:5多肽,2表示PBS磷酸盐缓冲液，3表示Control peptide无关对照肽；
图3：1表示SEQ ID NO:8多肽,2表示PBS磷酸盐缓冲液，3表示Control peptide无关对照肽；
图4：1表示SEQ ID NO:12多肽,2表示PBS磷酸盐缓冲液，3表示Control peptide无关对照肽；
图5：1表示SEQ ID NO:14多肽,2表示PBS磷酸盐缓冲液，3表示Control peptide无关对照肽。
上述实验数据表明，本发明所建立的CTL表位是极其有效的，预测结果与实验结果符合性非常好。
可见，通过将上述NOTCH1突变短肽中的至少一条(SEQ NO:2-21)经抗原提呈细胞与细胞毒性淋巴T细胞共培养，可诱导筛选得到NOTCH1突变特异性细胞毒性T淋巴细胞。这种NOTCH1突变抗原特异性细胞毒性T淋巴细胞可用于NOTCH1基因突变细胞的免疫清除，预防相关疾病的发生，尤其是肿瘤疾病。
将上述NOTCH短肽中的至少一条(SEQ2-21)与树突状细胞(dendritic cell,DC)加载回输，可以作为DC疫苗用于疾病预防，刺激机体产生多肽特异性抗细胞毒性T细胞，进而实现NOTCH1基因突变相关疾病的预防，尤其是肿瘤的预防。
本发明的NOTCH1短肽长度较短，化学合成难度小，可以直接合成得到高纯的产物，应用成本大大降低，同时效果明确，具有很好的应用潜力。
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<110> 生命谷（海南）生物科技股份有限公司
<120> 肿瘤相关基因NOTCH1突变短肽及其应用
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Asp Lys Ile Asp Gly Tyr Glu Cys Ala Cys Glu Pro Gly Tyr Thr Gly
660 665 670
Ser Met Cys Asn Ile Asn Ile Asp Glu Cys Ala Gly Asn Pro Cys His
675 680 685
Asn Gly Gly Thr Cys Glu Asp Gly Ile Asn Gly Phe Thr Cys Arg Cys
690 695 700
Pro Glu Gly Tyr His Asp Pro Thr Cys Leu Ser Glu Val Asn Glu Cys
705 710 715 720
Asn Ser Asn Pro Cys Val His Gly Ala Cys Arg Asp Ser Leu Asn Gly
725 730 735
Tyr Lys Cys Asp Cys Asp Pro Gly Trp Ser Gly Thr Asn Cys Asp Ile
740 745 750
Asn Asn Asn Glu Cys Glu Ser Asn Pro Cys Val Asn Gly Gly Thr Cys
755 760 765
Lys Asp Met Thr Ser Gly Tyr Val Cys Thr Cys Arg Glu Gly Phe Ser
770 775 780
Gly Pro Asn Cys Gln Thr Asn Ile Asn Glu Cys Ala Ser Asn Pro Cys
785 790 795 800
Leu Asn Gln Gly Thr Cys Ile Asp Asp Val Ala Gly Tyr Lys Cys Asn
805 810 815
Cys Leu Leu Pro Tyr Thr Gly Ala Thr Cys Glu Val Val Leu Ala Pro
820 825 830
Cys Ala Pro Ser Pro Cys Arg Asn Gly Gly Glu Cys Arg Gln Ser Glu
835 840 845
Asp Tyr Glu Ser Phe Ser Cys Val Cys Pro Thr Gly Trp Gln Gly Gln
850 855 860
Thr Cys Glu Val Asp Ile Asn Glu Cys Val Leu Ser Pro Cys Arg His
865 870 875 880
Gly Ala Ser Cys Gln Asn Thr His Gly Gly Tyr Arg Cys His Cys Gln
885 890 895
Ala Gly Tyr Ser Gly Arg Asn Cys Glu Thr Asp Ile Asp Asp Cys Arg
900 905 910
Pro Asn Pro Cys His Asn Gly Gly Ser Cys Thr Asp Gly Ile Asn Thr
915 920 925
Ala Phe Cys Asp Cys Leu Pro Gly Phe Arg Gly Thr Phe Cys Glu Glu
930 935 940
Asp Ile Asn Glu Cys Ala Ser Asp Pro Cys Arg Asn Gly Ala Asn Cys
945 950 955 960
Thr Asp Cys Val Asp Ser Tyr Thr Cys Thr Cys Pro Ala Gly Phe Ser
965 970 975
Gly Ile His Cys Glu Asn Asn Thr Pro Asp Cys Thr Glu Ser Ser Cys
980 985 990
Phe Asn Gly Gly Thr Cys Val Asp Gly Ile Asn Ser Phe Thr Cys Leu
995 1000 1005
Cys Pro Pro Gly Phe Thr Gly Ser Tyr Cys Gln His Asp Val Asn Glu
1010 1015 1020
Cys Asp Ser Gln Pro Cys Leu His Gly Gly Thr Cys Gln Asp Gly Cys
1025 1030 1035 1040
Gly Ser Tyr Arg Cys Thr Cys Pro Gln Gly Tyr Thr Gly Pro Asn Cys
1045 1050 1055
Gln Asn Leu Val His Trp Cys Asp Ser Ser Pro Cys Lys Asn Gly Gly
1060 1065 1070
Lys Cys Trp Gln Thr His Thr Gln Tyr Arg Cys Glu Cys Pro Ser Gly
1075 1080 1085
Trp Thr Gly Leu Tyr Cys Asp Val Pro Ser Val Ser Cys Glu Val Ala
1090 1095 1100
Ala Gln Arg Gln Gly Val Asp Val Ala Arg Leu Cys Gln His Gly Gly
1105 1110 1115 1120
Leu Cys Val Asp Ala Gly Asn Thr His His Cys Arg Cys Gln Ala Gly
1125 1130 1135
Tyr Thr Gly Ser Tyr Cys Glu Asp Leu Val Asp Glu Cys Ser Pro Ser
1140 1145 1150
Pro Cys Gln Asn Gly Ala Thr Cys Thr Asp Tyr Leu Gly Gly Tyr Ser
1155 1160 1165
Cys Lys Cys Val Ala Gly Tyr His Gly Val Asn Cys Ser Glu Glu Ile
1170 1175 1180
Asp Glu Cys Leu Ser His Pro Cys Gln Asn Gly Gly Thr Cys Leu Asp
1185 1190 1195 1200
Leu Pro Asn Thr Tyr Lys Cys Ser Cys Pro Arg Gly Thr Gln Gly Val
1205 1210 1215
His Cys Glu Ile Asn Val Asp Asp Cys Asn Pro Pro Val Asp Pro Val
1220 1225 1230
Ser Arg Ser Pro Lys Cys Phe Asn Asn Gly Thr Cys Val Asp Gln Val
1235 1240 1245
Gly Gly Tyr Ser Cys Thr Cys Pro Pro Gly Phe Val Gly Glu Arg Cys
1250 1255 1260
Glu Gly Asp Val Asn Glu Cys Leu Ser Asn Pro Cys Asp Ala Arg Gly
1265 1270 1275 1280
Thr Gln Asn Cys Val Gln Arg Val Asn Asp Phe His Cys Glu Cys Arg
1285 1290 1295
Ala Gly His Thr Gly Arg Arg Cys Glu Ser Val Ile Asn Gly Cys Lys
1300 1305 1310
Gly Lys Pro Cys Lys Asn Gly Gly Thr Cys Ala Val Ala Ser Asn Thr
1315 1320 1325
Ala Arg Gly Phe Ile Cys Lys Cys Pro Ala Gly Phe Glu Gly Ala Thr
1330 1335 1340
Cys Glu Asn Asp Ala Arg Thr Cys Gly Ser Leu Arg Cys Leu Asn Gly
1345 1350 1355 1360
Gly Thr Cys Ile Ser Gly Pro Arg Ser Pro Thr Cys Leu Cys Leu Gly
1365 1370 1375
Pro Phe Thr Gly Pro Glu Cys Gln Phe Pro Ala Ser Ser Pro Cys Leu
1380 1385 1390
Gly Gly Asn Pro Cys Tyr Asn Gln Gly Thr Cys Glu Pro Thr Ser Glu
1395 1400 1405
Ser Pro Phe Tyr Arg Cys Leu Cys Pro Ala Lys Phe Asn Gly Leu Leu
1410 1415 1420
Cys His Ile Leu Asp Tyr Ser Phe Gly Gly Gly Ala Gly Arg Asp Ile
1425 1430 1435 1440
Pro Pro Pro Leu Ile Glu Glu Ala Cys Glu Leu Pro Glu Cys Gln Glu
1445 1450 1455
Asp Ala Gly Asn Lys Val Cys Ser Leu Gln Cys Asn Asn His Ala Cys
1460 1465 1470
Gly Trp Asp Gly Gly Asp Cys Ser Leu Asn Phe Asn Asp Pro Trp Lys
1475 1480 1485
Asn Cys Thr Gln Ser Leu Gln Cys Trp Lys Tyr Phe Ser Asp Gly His
1490 1495 1500
Cys Asp Ser Gln Cys Asn Ser Ala Gly Cys Leu Phe Asp Gly Phe Asp
1505 1510 1515 1520
Cys Gln Arg Ala Glu Gly Gln Cys Asn Pro Leu Tyr Asp Gln Tyr Cys
1525 1530 1535
Lys Asp His Phe Ser Asp Gly His Cys Asp Gln Gly Cys Asn Ser Ala
1540 1545 1550
Glu Cys Glu Trp Asp Gly Leu Asp Cys Ala Glu His Val Pro Glu Arg
1555 1560 1565
Leu Ala Ala Gly Thr Leu Val Val Val Val Leu Met Pro Pro Glu Gln
1570 1575 1580
Leu Arg Asn Ser Ser Phe His Phe Leu Arg Glu Leu Ser Arg Val Leu
1585 1590 1595 1600
His Thr Asn Val Val Phe Lys Arg Asp Ala His Gly Gln Gln Met Ile
1605 1610 1615
Phe Pro Tyr Tyr Gly Arg Glu Glu Glu Leu Arg Lys His Pro Ile Lys
1620 1625 1630
Arg Ala Ala Glu Gly Trp Ala Ala Pro Asp Ala Leu Leu Gly Gln Val
1635 1640 1645
Lys Ala Ser Leu Leu Pro Gly Gly Ser Glu Gly Gly Arg Arg Arg Arg
1650 1655 1660
Glu Leu Asp Pro Met Asp Val Arg Gly Ser Ile Val Tyr Leu Glu Ile
1665 1670 1675 1680
Asp Asn Arg Gln Cys Val Gln Ala Ser Ser Gln Cys Phe Gln Ser Ala
1685 1690 1695
Thr Asp Val Ala Ala Phe Leu Gly Ala Leu Ala Ser Leu Gly Ser Leu
1700 1705 1710
Asn Ile Pro Tyr Lys Ile Glu Ala Val Gln Ser Glu Thr Val Glu Pro
1715 1720 1725
Pro Pro Pro Ala Gln Leu His Phe Met Tyr Val Ala Ala Ala Ala Phe
1730 1735 1740
Val Leu Leu Phe Phe Val Gly Cys Gly Val Leu Leu Ser Arg Lys Arg
1745 1750 1755 1760
Arg Arg Gln His Gly Gln Leu Trp Phe Pro Glu Gly Phe Lys Val Ser
1765 1770 1775
Glu Ala Ser Lys Lys Lys Arg Arg Glu Pro Leu Gly Glu Asp Ser Val
1780 1785 1790
Gly Leu Lys Pro Leu Lys Asn Ala Ser Asp Gly Ala Leu Met Asp Asp
1795 1800 1805
Asn Gln Asn Glu Trp Gly Asp Glu Asp Leu Glu Thr Lys Lys Phe Arg
1810 1815 1820
Phe Glu Glu Pro Val Val Leu Pro Asp Leu Asp Asp Gln Thr Asp His
1825 1830 1835 1840
Arg Gln Trp Thr Gln Gln His Leu Asp Ala Ala Asp Leu Arg Met Ser
1845 1850 1855
Ala Met Ala Pro Thr Pro Pro Gln Gly Glu Val Asp Ala Asp Cys Met
1860 1865 1870
Asp Val Asn Val Arg Gly Pro Asp Gly Phe Thr Pro Leu Met Ile Ala
1875 1880 1885
Ser Cys Ser Gly Gly Gly Leu Glu Thr Gly Asn Ser Glu Glu Glu Glu
1890 1895 1900
Asp Ala Pro Ala Val Ile Ser Asp Phe Ile Tyr Gln Gly Ala Ser Leu
1905 1910 1915 1920
His Asn Gln Thr Asp Arg Thr Gly Glu Thr Ala Leu His Leu Ala Ala
1925 1930 1935
Arg Tyr Ser Arg Ser Asp Ala Ala Lys Arg Leu Leu Glu Ala Ser Ala
1940 1945 1950
Asp Ala Asn Ile Gln Asp Asn Met Gly Arg Thr Pro Leu His Ala Ala
1955 1960 1965
Val Ser Ala Asp Ala Gln Gly Val Phe Gln Ile Leu Ile Arg Asn Arg
1970 1975 1980
Ala Thr Asp Leu Asp Ala Arg Met His Asp Gly Thr Thr Pro Leu Ile
1985 1990 1995 2000
Leu Ala Ala Arg Leu Ala Val Glu Gly Met Leu Glu Asp Leu Ile Asn
2005 2010 2015
Ser His Ala Asp Val Asn Ala Val Asp Asp Leu Gly Lys Ser Ala Leu
2020 2025 2030
His Trp Ala Ala Ala Val Asn Asn Val Asp Ala Ala Val Val Leu Leu
2035 2040 2045
Lys Asn Gly Ala Asn Lys Asp Met Gln Asn Asn Arg Glu Glu Thr Pro
2050 2055 2060
Leu Phe Leu Ala Ala Arg Glu Gly Ser Tyr Glu Thr Ala Lys Val Leu
2065 2070 2075 2080
Leu Asp His Phe Ala Asn Arg Asp Ile Thr Asp His Met Asp Arg Leu
2085 2090 2095
Pro Arg Asp Ile Ala Gln Glu Arg Met His His Asp Ile Val Arg Leu
2100 2105 2110
Leu Asp Glu Tyr Asn Leu Val Arg Ser Pro Gln Leu His Gly Ala Pro
2115 2120 2125
Leu Gly Gly Thr Pro Thr Leu Ser Pro Pro Leu Cys Ser Pro Asn Gly
2130 2135 2140
Tyr Leu Gly Ser Leu Lys Pro Gly Val Gln Gly Lys Lys Val Arg Lys
2145 2150 2155 2160
Pro Ser Ser Lys Gly Leu Ala Cys Gly Ser Lys Glu Ala Lys Asp Leu
2165 2170 2175
Lys Ala Arg Arg Lys Lys Ser Gln Asp Gly Lys Gly Cys Leu Leu Asp
2180 2185 2190
Ser Ser Gly Met Leu Ser Pro Val Asp Ser Leu Glu Ser Pro His Gly
2195 2200 2205
Tyr Leu Ser Asp Val Ala Ser Pro Pro Leu Leu Pro Ser Pro Phe Gln
2210 2215 2220
Gln Ser Pro Ser Val Pro Leu Asn His Leu Pro Gly Met Pro Asp Thr
2225 2230 2235 2240
His Leu Gly Ile Gly His Leu Asn Val Ala Ala Lys Pro Glu Met Ala
2245 2250 2255
Ala Leu Gly Gly Gly Gly Arg Leu Ala Phe Glu Thr Gly Pro Pro Arg
2260 2265 2270
Leu Ser His Leu Pro Val Ala Ser Gly Thr Ser Thr Val Leu Gly Ser
2275 2280 2285
Ser Ser Gly Gly Ala Leu Asn Phe Thr Val Gly Gly Ser Thr Ser Leu
2290 2295 2300
Asn Gly Gln Cys Glu Trp Leu Ser Arg Leu Gln Ser Gly Met Val Pro
2305 2310 2315 2320
Asn Gln Tyr Asn Pro Leu Arg Gly Ser Val Ala Pro Gly Pro Leu Ser
2325 2330 2335
Thr Gln Ala Pro Ser Leu Gln His Gly Met Val Gly Pro Leu His Ser
2340 2345 2350
Ser Leu Ala Ala Ser Ala Leu Ser Gln Met Met Ser Tyr Gln Gly Leu
2355 2360 2365
Pro Ser Thr Arg Leu Ala Thr Gln Pro His Leu Val Gln Thr Gln Gln
2370 2375 2380
Val Gln Pro Gln Asn Leu Gln Met Gln Gln Gln Asn Leu Gln Pro Ala
2385 2390 2395 2400
Asn Ile Gln Gln Gln Gln Ser Leu Gln Pro Pro Pro Pro Pro Pro Gln
2405 2410 2415
Pro His Leu Gly Val Ser Ser Ala Ala Ser Gly His Leu Gly Arg Ser
2420 2425 2430
Phe Leu Ser Gly Glu Pro Ser Gln Ala Asp Val Gln Pro Leu Gly Pro
2435 2440 2445
Ser Ser Leu Ala Val His Thr Ile Leu Pro Gln Glu Ser Pro Ala Leu
2450 2455 2460
Pro Thr Ser Leu Pro Ser Ser Leu Val Pro Pro Val Thr Ala Ala Gln
2465 2470 2475 2480
Phe Leu Thr Pro Pro Ser Gln His Ser Tyr Ser Ser Pro Val Asp Asn
2485 2490 2495
Thr Pro Ser His Gln Leu Gln Val Pro Glu His Pro Phe Leu Thr Pro
2500 2505 2510
Ser Pro Glu Ser Pro Asp Gln Trp Ser Ser Ser Ser Pro His Ser Asn
2515 2520 2525
Val Ser Asp Trp Ser Glu Gly Val Ser Ser Pro Pro Thr Ser Met Gln
2530 2535 2540
Ser Gln Ile Ala Arg Ile Pro Glu Ala Phe Lys
2545 2550 2555
<210> 2
<211> 13
<212> PRT
<213> 人(Homo sapiens)
<400> 2
Leu Ala Ala Gly Thr Leu Val Val Val Val Leu Met Pro
1 5 10
<210> 3
<211> 12
<212> PRT
<213> 人(Homo sapiens)
<400> 3
Ala Ala Gly Thr Leu Val Val Val Val Leu Met Pro
1 5 10
<210> 4
<211> 11
<212> PRT
<213> 人(Homo sapiens)
<400> 4
Ala Gly Thr Leu Val Val Val Val Leu Met Pro
1 5 10
<210> 5
<211> 10
<212> PRT
<213> 人(Homo sapiens)
<400> 5
Gly Thr Leu Val Val Val Val Leu Met Pro
1 5 10
<210> 6
<211> 12
<212> PRT
<213> 人(Homo sapiens)
<400> 6
Leu Ala Ala Gly Thr Leu Val Val Val Val Leu Met
1 5 10
<210> 7
<211> 11
<212> PRT
<213> 人(Homo sapiens)
<400> 7
Leu Ala Ala Gly Thr Leu Val Val Val Val Leu
1 5 10
<210> 8
<211> 10
<212> PRT
<213> 人(Homo sapiens)
<400> 8
Leu Ala Ala Gly Thr Leu Val Val Val Val
1 5 10
<210> 9
<211> 11
<212> PRT
<213> 人(Homo sapiens)
<400> 9
Thr Leu Val Val Val Leu Met Pro Pro Glu Gln
1 5 10
<210> 10
<211> 10
<212> PRT
<213> 人(Homo sapiens)
<400> 10
Leu Val Val Val Leu Met Pro Pro Glu Gln
1 5 10
<210> 11
<211> 10
<212> PRT
<213> 人(Homo sapiens)
<400> 11
Thr Leu Val Val Val Leu Met Pro Pro Glu
1 5 10
<210> 12
<211> 12
<212> PRT
<213> 人(Homo sapiens)
<400> 12
Val Met Pro Pro Glu Gln Leu Arg Asn Ser Ser Phe
1 5 10
<210> 13
<211> 11
<212> PRT
<213> 人(Homo sapiens)
<400> 13
Val Met Pro Pro Glu Gln Leu Arg Asn Ser Ser
1 5 10
<210> 14
<211> 10
<212> PRT
<213> 人(Homo sapiens)
<400> 14
Val Met Pro Pro Glu Gln Leu Arg Asn Ser
1 5 10
<210> 15
<211> 11
<212> PRT
<213> 人(Homo sapiens)
<400> 15
Met Pro Pro Glu Gln Leu Arg Asn Ser Ser Phe
1 5 10
<210> 16
<211> 10
<212> PRT
<213> 人(Homo sapiens)
<400> 16
Pro Pro Glu Gln Leu Arg Asn Ser Ser Phe
1 5 10
<210> 17
<211> 11
<212> PRT
<213> 人(Homo sapiens)
<400> 17
Gly Ser Ile Val Tyr Leu Glu Ile Asp Asn Arg
1 5 10
<210> 18
<211> 10
<212> PRT
<213> 人(Homo sapiens)
<400> 18
Gly Ser Ile Val Tyr Leu Glu Ile Asp Asn
1 5 10
<210> 19
<211> 9
<212> PRT
<213> 人(Homo sapiens)
<400> 19
Gly Ser Ile Val Tyr Leu Glu Ile Asp
1 5
<210> 20
<211> 10
<212> PRT
<213> 人(Homo sapiens)
<400> 20
Ser Ile Val Tyr Leu Glu Ile Asp Asn Arg
1 5 10
<210> 21
<211> 9
<212> PRT
<213> 人(Homo sapiens)
<400> 21
Ile Val Tyr Leu Glu Ile Asp Asn Arg
1 5
<210> 22
<211> 7668
<212> DNA
<213> 人(Homo sapiens)
<400> 22
atgccgccgc tcctggcgcc cctgctctgc ctggcgctgc tgcccgcgct cgccgcacga 60
ggcccgcgat gctcccagcc cggtgagacc tgcctgaatg gcgggaagtg tgaagcggcc 120
aatggcacgg aggcctgcgt ctgtggcggg gccttcgtgg gcccgcgatg ccaggacccc 180
aacccgtgcc tcagcacccc ctgcaagaac gccgggacat gccacgtggt ggaccgcaga 240
ggcgtggcag actatgcctg cagctgtgcc ctgggcttct ctgggcccct ctgcctgaca 300
cccctggaca atgcctgcct caccaacccc tgccgcaacg ggggcacctg cgacctgctc 360
acgctgacgg agtacaagtg ccgctgcccg cccggctggt cagggaaatc gtgccagcag 420
gctgacccgt gcgcctccaa cccctgcgcc aacggtggcc agtgcctgcc cttcgaggcc 480
tcctacatct gccactgccc acccagcttc catggcccca cctgccggca ggatgtcaac 540
gagtgtggcc agaagcccgg gctttgccgc cacggaggca cctgccacaa cgaggtcggc 600
tcctaccgct gcgtctgccg cgccacccac actggcccca actgcgagcg gccctacgtg 660
ccctgcagcc cctcgccctg ccagaacggg ggcacctgcc gccccacggg cgacgtcacc 720
cacgagtgtg cctgcctgcc aggcttcacc ggccagaact gtgaggaaaa tatcgacgat 780
tgtccaggaa acaactgcaa gaacgggggt gcctgtgtgg acggcgtgaa cacctacaac 840
tgccgctgcc cgccagagtg gacaggtcag tactgtaccg aggatgtgga cgagtgccag 900
ctgatgccaa atgcctgcca gaacggcggg acctgccaca acacccacgg tggctacaac 960
tgcgtgtgtg tcaacggctg gactggtgag gactgcagcg agaacattga tgactgtgcc 1020
agcgccgcct gcttccacgg cgccacctgc catgaccgtg tggcctcctt ctactgcgag 1080
tgtccccatg gccgcacagg tctgctgtgc cacctcaacg acgcatgcat cagcaacccc 1140
tgtaacgagg gctccaactg cgacaccaac cctgtcaatg gcaaggccat ctgcacctgc 1200
ccctcggggt acacgggccc ggcctgcagc caggacgtgg atgagtgctc gctgggtgcc 1260
aacccctgcg agcatgcggg caagtgcatc aacacgctgg gctccttcga gtgccagtgt 1320
ctgcagggct acacgggccc ccgatgcgag atcgacgtca acgagtgcgt ctcgaacccg 1380
tgccagaacg acgccacctg cctggaccag attggggagt tccagtgcat ctgcatgccc 1440
ggctacgagg gtgtgcactg cgaggtcaac acagacgagt gtgccagcag cccctgcctg 1500
cacaatggcc gctgcctgga caagatcaat gagttccagt gcgagtgccc cacgggcttc 1560
actgggcatc tgtgccagta cgatgtggac gagtgtgcca gcaccccctg caagaatggt 1620
gccaagtgcc tggacggacc caacacttac acctgtgtgt gcacggaagg gtacacgggg 1680
acgcactgcg aggtggacat cgatgagtgc gaccccgacc cctgccacta cggctcctgc 1740
aaggacggcg tcgccacctt cacctgcctc tgccgcccag gctacacggg ccaccactgc 1800
gagaccaaca tcaacgagtg ctccagccag ccctgccgcc acgggggcac ctgccaggac 1860
cgcgacaacg cctacctctg cttctgcctg aaggggacca caggacccaa ctgcgagatc 1920
aacctggatg actgtgccag cagcccctgc gactcgggca cctgtctgga caagatcgat 1980
ggctacgagt gtgcctgtga gccgggctac acagggagca tgtgtaacat caacatcgat 2040
gagtgtgcgg gcaacccctg ccacaacggg ggcacctgcg aggacggcat caatggcttc 2100
acctgccgct gccccgaggg ctaccacgac cccacctgcc tgtctgaggt caatgagtgc 2160
aacagcaacc cctgcgtcca cggggcctgc cgggacagcc tcaacgggta caagtgcgac 2220
tgtgaccctg ggtggagtgg gaccaactgt gacatcaaca acaatgagtg tgaatccaac 2280
ccttgtgtca acggcggcac ctgcaaagac atgaccagtg gctacgtgtg cacctgccgg 2340
gagggcttca gcggtcccaa ctgccagacc aacatcaacg agtgtgcgtc caacccatgt 2400
ctgaaccagg gcacgtgtat tgacgacgtt gccgggtaca agtgcaactg cctgctgccc 2460
tacacaggtg ccacgtgtga ggtggtgctg gccccgtgtg cccccagccc ctgcagaaac 2520
ggcggggagt gcaggcaatc cgaggactat gagagcttct cctgtgtctg ccccacgggc 2580
tggcaagggc agacctgtga ggtcgacatc aacgagtgcg ttctgagccc gtgccggcac 2640
ggcgcatcct gccagaacac ccacggcggc taccgctgcc actgccaggc cggctacagt 2700
gggcgcaact gcgagaccga catcgacgac tgccggccca acccgtgtca caacgggggc 2760
tcctgcacag acggcatcaa cacggccttc tgcgactgcc tgcccggctt ccggggcact 2820
ttctgtgagg aggacatcaa cgagtgtgcc agtgacccct gccgcaacgg ggccaactgc 2880
acggactgcg tggacagcta cacgtgcacc tgccccgcag gcttcagcgg gatccactgt 2940
gagaacaaca cgcctgactg cacagagagc tcctgcttca acggtggcac ctgcgtggac 3000
ggcatcaact cgttcacctg cctgtgtcca cccggcttca cgggcagcta ctgccagcac 3060
gatgtcaatg agtgcgactc acagccctgc ctgcatggcg gcacctgtca ggacggctgc 3120
ggctcctaca ggtgcacctg cccccagggc tacactggcc ccaactgcca gaaccttgtg 3180
cactggtgtg actcctcgcc ctgcaagaac ggcggcaaat gctggcagac ccacacccag 3240
taccgctgcg agtgccccag cggctggacc ggcctttact gcgacgtgcc cagcgtgtcc 3300
tgtgaggtgg ctgcgcagcg acaaggtgtt gacgttgccc gcctgtgcca gcatggaggg 3360
ctctgtgtgg acgcgggcaa cacgcaccac tgccgctgcc aggcgggcta cacaggcagc 3420
tactgtgagg acctggtgga cgagtgctca cccagcccct gccagaacgg ggccacctgc 3480
acggactacc tgggcggcta ctcctgcaag tgcgtggccg gctaccacgg ggtgaactgc 3540
tctgaggaga tcgacgagtg cctctcccac ccctgccaga acgggggcac ctgcctcgac 3600
ctccccaaca cctacaagtg ctcctgccca cggggcactc agggtgtgca ctgtgagatc 3660
aacgtggacg actgcaatcc ccccgttgac cccgtgtccc ggagccccaa gtgctttaac 3720
aacggcacct gcgtggacca ggtgggcggc tacagctgca cctgcccgcc gggcttcgtg 3780
ggtgagcgct gtgaggggga tgtcaacgag tgcctgtcca atccctgcga cgcccgtggc 3840
acccagaact gcgtgcagcg cgtcaatgac ttccactgcg agtgccgtgc tggtcacacc 3900
gggcgccgct gcgagtccgt catcaatggc tgcaaaggca agccctgcaa gaatgggggc 3960
acctgcgccg tggcctccaa caccgcccgc gggttcatct gcaagtgccc tgcgggcttc 4020
gagggcgcca cgtgtgagaa tgacgctcgt acctgcggca gcctgcgctg cctcaacggc 4080
ggcacatgca tctccggccc gcgcagcccc acctgcctgt gcctgggccc cttcacgggc 4140
cccgaatgcc agttcccggc cagcagcccc tgcctgggcg gcaacccctg ctacaaccag 4200
gggacctgtg agcccacatc cgagagcccc ttctaccgtt gcctgtgccc cgccaaattc 4260
aacgggctct tgtgccacat cctggactac agcttcgggg gtggggccgg gcgcgacatc 4320
cccccgccgc tgatcgagga ggcgtgcgag ctgcccgagt gccaggagga cgcgggcaac 4380
aaggtctgca gcctgcagtg caacaaccac gcgtgcggct gggacggcgg tgactgctcc 4440
ctcaacttca atgacccctg gaagaactgc acgcagtctc tgcagtgctg gaagtacttc 4500
agtgacggcc actgtgacag ccagtgcaac tcagccggct gcctcttcga cggctttgac 4560
tgccagcgtg cggaaggcca gtgcaacccc ctgtacgacc agtactgcaa ggaccacttc 4620
agcgacgggc actgcgacca gggctgcaac agcgcggagt gcgagtggga cgggctggac 4680
tgtgcggagc atgtacccga gaggctggcg gccggcacgc tggtggtggt ggtgctgatg 4740
ccgccggagc agctgcgcaa cagctccttc cacttcctgc gggagctcag ccgcgtgctg 4800
cacaccaacg tggtcttcaa gcgtgacgca cacggccagc agatgatctt cccctactac 4860
ggccgcgagg aggagctgcg caagcacccc atcaagcgtg ccgccgaggg ctgggccgca 4920
cctgacgccc tgctgggcca ggtgaaggcc tcgctgctcc ctggtggcag cgagggtggg 4980
cggcggcgga gggagctgga ccccatggac gtccgcggct ccatcgtcta cctggagatt 5040
gacaaccggc agtgtgtgca ggcctcctcg cagtgcttcc agagtgccac cgacgtggcc 5100
gcattcctgg gagcgctcgc ctcgctgggc agcctcaaca tcccctacaa gatcgaggcc 5160
gtgcagagtg agaccgtgga gccgcccccg ccggcgcagc tgcacttcat gtacgtggcg 5220
gcggccgcct ttgtgcttct gttcttcgtg ggctgcgggg tgctgctgtc ccgcaagcgc 5280
cggcggcagc atggccagct ctggttccct gagggcttca aagtgtctga ggccagcaag 5340
aagaagcggc gggagcccct cggcgaggac tccgtgggcc tcaagcccct gaagaacgct 5400
tcagacggtg ccctcatgga cgacaaccag aatgagtggg gggacgagga cctggagacc 5460
aagaagttcc ggttcgagga gcccgtggtt ctgcctgacc tggacgacca gacagaccac 5520
cggcagtgga ctcagcagca cctggatgcc gctgacctgc gcatgtctgc catggccccc 5580
acaccgcccc agggtgaggt tgacgccgac tgcatggacg tcaatgtccg cgggcctgat 5640
ggcttcaccc cgctcatgat cgcctcctgc agcgggggcg gcctggagac gggcaacagc 5700
gaggaagagg aggacgcgcc ggccgtcatc tccgacttca tctaccaggg cgccagcctg 5760
cacaaccaga cagaccgcac gggcgagacc gccttgcacc tggccgcccg ctactcacgc 5820
tctgatgccg ccaagcgcct gctggaggcc agcgcagatg ccaacatcca ggacaacatg 5880
ggccgcaccc cgctgcatgc ggctgtgtct gccgacgcac aaggtgtctt ccagatcctg 5940
atccggaacc gagccacaga cctggatgcc cgcatgcatg atggcacgac gccactgatc 6000
ctggctgccc gcctggccgt ggagggcatg ctggaggacc tcatcaactc acacgccgac 6060
gtcaacgccg tagatgacct gggcaagtcc gccctgcact gggccgccgc cgtgaacaat 6120
gtggatgccg cagttgtgct cctgaagaac ggggctaaca aagatatgca gaacaacagg 6180
gaggagacac ccctgtttct ggccgcccgg gagggcagct acgagaccgc caaggtgctg 6240
ctggaccact ttgccaaccg ggacatcacg gatcatatgg accgcctgcc gcgcgacatc 6300
gcacaggagc gcatgcatca cgacatcgtg aggctgctgg acgagtacaa cctggtgcgc 6360
agcccgcagc tgcacggagc cccgctgggg ggcacgccca ccctgtcgcc cccgctctgc 6420
tcgcccaacg gctacctggg cagcctcaag cccggcgtgc agggcaagaa ggtccgcaag 6480
cccagcagca aaggcctggc ctgtggaagc aaggaggcca aggacctcaa ggcacggagg 6540
aagaagtccc aggacggcaa gggctgcctg ctggacagct ccggcatgct ctcgcccgtg 6600
gactccctgg agtcacccca tggctacctg tcagacgtgg cctcgccgcc actgctgccc 6660
tccccgttcc agcagtctcc gtccgtgccc ctcaaccacc tgcctgggat gcccgacacc 6720
cacctgggca tcgggcacct gaacgtggcg gccaagcccg agatggcggc gctgggtggg 6780
ggcggccggc tggcctttga gactggccca cctcgtctct cccacctgcc tgtggcctct 6840
ggcaccagca ccgtcctggg ctccagcagc ggaggggccc tgaatttcac tgtgggcggg 6900
tccaccagtt tgaatggtca atgcgagtgg ctgtcccggc tgcagagcgg catggtgccg 6960
aaccaataca accctctgcg ggggagtgtg gcaccaggcc ccctgagcac acaggccccc 7020
tccctgcagc atggcatggt aggcccgctg cacagtagcc ttgctgccag cgccctgtcc 7080
cagatgatga gctaccaggg cctgcccagc acccggctgg ccacccagcc tcacctggtg 7140
cagacccagc aggtgcagcc acaaaactta cagatgcagc agcagaacct gcagccagca 7200
aacatccagc agcagcaaag cctgcagccg ccaccaccac caccacagcc gcaccttggc 7260
gtgagctcag cagccagcgg ccacctgggc cggagcttcc tgagtggaga gccgagccag 7320
gcagacgtgc agccactggg ccccagcagc ctggcggtgc acactattct gccccaggag 7380
agccccgccc tgcccacgtc gctgccatcc tcgctggtcc cacccgtgac cgcagcccag 7440
ttcctgacgc ccccctcgca gcacagctac tcctcgcctg tggacaacac ccccagccac 7500
cagctacagg tgcctgagca ccccttcctc accccgtccc ctgagtcccc tgaccagtgg 7560
tccagctcgt ccccgcattc caacgtctcc gactggtccg agggcgtctc cagccctccc 7620
accagcatgc agtcccagat cgcccgcatt ccggaggcct tcaagtaa 7668

Claims (3)

1.一种肿瘤相关基因NOTCH1突变短肽，其特征在于，其序列为SEQ ID NO:2、SEQ IDNO:5、SEQ ID NO:8、SEQ ID NO:12、SEQ ID NO:14中的一条。
2.一种多肽人体免疫活性调节剂，由活性抗原成分和辅剂组成，其特征在于，所述活性抗原成分为如权利要求1所述的NOTCH1突变短肽中的至少一条。
3.一种用于NOTCH1突变防治的DC疫苗，其特征在于，该DC疫苗由权利要求1所述的NOTCH1突变短肽中的至少一条和树突状细胞加载得到。
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