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

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)

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

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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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。

Images