CN117304294A - 一种β-catenin突变表位肽及其应用 - Google Patents
一种β-catenin突变表位肽及其应用 Download PDFInfo
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- CN117304294A CN117304294A CN202210704327.1A CN202210704327A CN117304294A CN 117304294 A CN117304294 A CN 117304294A CN 202210704327 A CN202210704327 A CN 202210704327A CN 117304294 A CN117304294 A CN 117304294A
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- catenin
- epitope peptide
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Abstract
本发明属于细胞免疫治疗技术领域，本发明首先公开了一种多肽，基于以上多肽，公开了一种特异性识别β‑catenin突变表位肽/HLA‑A11复合物、及其特异性TCR。本发明通过筛选得到所述多肽，得到β‑catenin突变表位肽特异性的TCR，成功构建了对应的TCR‑T细胞，确定了该TCR序列特异性的识别并结合β‑catenin突变表位肽/HLA‑A11复合物，且不能识别β‑catenin未突变表位肽/HLA‑A11复合物；同时在体外验证了TCR转基因阳性的人CD8细胞(TCR‑T)细胞具有β‑catenin突变肽表位依赖性的杀伤靶细胞人肝癌细胞的能力，并且不会对β‑catenin未突变肽表位负载靶细胞进行杀伤。本发明验证所述多肽及其特异性TCR在免疫细胞技术治疗肿瘤上具备重要的应用价值。
Description
技术领域
本发明涉及细胞免疫治疗技术领域，更具体地，涉及一种HLA-A11限制性β-catenin突变表位肽及其应用。
背景技术
免疫细胞治疗技术是生物医药领域中发展最为迅速的板块，其中最有效的治疗策略之一就是过继细胞转移疗法。嵌合抗原受体(CAR)和工程化T细胞受体(TCR)是近年来主要的过继性T细胞免疫疗法，在肿瘤临床治疗中展现出广阔的应用前景。2013年《科学·转化医学》杂志预测，细胞治疗将成为“未来医学第三大支柱”。2017年10月以来，美国FDA相继批准诺华与KITE公司的CAR-T药物上市，开创免疫细胞治疗癌症的新时代。近两年，国产CAR-T创新药也取得重大突破。2021年6月和2022年3月，复星凯特和传奇生物的CAR-T细胞治疗产品相继获得批准。
CAR-T疗法在血液肿瘤中取得了卓越的疗效，但在实体瘤中的治疗效果却差强人意。相较于CAR-T疗法，TCR-T细胞技术因可以识别细胞内表位，从而具有更广的靶标范围，在实体瘤治疗中具备独特优势和巨大的治疗潜力。此外，部分肿瘤是由病毒引起，靶向病毒抗原同样可获得相应治疗效果，而大部分病毒抗原属于胞内蛋白，因此TCR-T治疗也是病毒性肿瘤细胞治疗中的优选方案。2022年1月25日，全球首款TCR-T疗法获得美国食品药品监督管理局(FDA)批准上市，剑指实体瘤！FDA批准Immunocore公司的Kimmtrak产品用于无法切除或转移性葡萄膜黑色素瘤成人患者。Kimmtrak的获批成为TCR-T治疗领域具有里程碑意义的重大突破，令业界振奋。
肿瘤新抗原的发现是TCR-T治疗的关键，筛选鉴定相对应的TCR序列是TCR-T治疗的核心。肿瘤新抗原是肿瘤细胞在基因变异的基础上所产生的带有特异性突变氨基酸序列的蛋白，其只表达于肿瘤组织；由其引起的免疫应答作用于肿瘤组织，不影响正常的自身组织，可有效杀伤肿瘤细胞并大大降低由其引起自身免疫反应的危险性。目前已发现多种肿瘤相关突变热点，如P53、Kras等突变，这些突变在肿瘤发生发展中起到重要促进作用，针对这些突变的TCR筛选和药物开发是肿瘤TCR-T治疗的重要方向。
TCR-T细胞过继治疗的一个重要特征是有严格的HLA(human leukocyte antigen)限制性，不同人群具有不同的HLA表型。现有报道的治疗性T细胞的研究主要局限在HLA-A2人群的研究，而针对其它HLA人群的关注却明显不足。HLA-A3超家族(包含HLA-A11、HLA-A33、HLA-A68、HLA-A31等)在中国人群HLA分型中占着最大比例(约52.7％)。其中，HLA-A11是A3超家族中分布最广的，并且是某些癌症如肝癌患者的主要分型。目前，国内外尚无研究报道HLA-A11限制性TCR-T，开展HLA-A11限制性的免疫细胞治疗具有广阔的应用前景和重要社会意义。
β-catenin是一种重要的胞内蛋白，它具有双重功能。一是与上皮细胞钙黏附素(E-cadherin)结合，在细胞内形成E-cadherin/catenin复合体，介导细胞黏附；其异常改变在肿瘤浸润、转移过程中发挥重要作用。二是Wnt信号传导途径的关键信号分子。降解障碍致使细胞质内游离的β-catenin积累，通过与T细胞因子/淋巴细胞增强因子(TCF/LEF)结合进入细胞核，激活下游cyclin D1、c-Jun、c-myc等靶基因转录，引起细胞增殖和分化失控，从而导致肿瘤发生。β-catenin蛋白的S33、S37、T41和S45等4个丝/苏氨基酸残基，被认为是GSK-β磷酸化作用位点。它们都由β-catenin基因的第3外显子编码。如果β-catenin基因的第3外显子发生突变，GSK-3β将不能磷酸化β-catenin，未经磷酸化的β-catenin不能经泛素化途径降解，正常的Wnt/β-catenin通路被打破，引起肿瘤的发生。现已发现β-catenin的突变相关多种重要癌症的发生发展，涉及肝癌、胆管癌、胃癌、胰腺癌、肺癌、子宫内膜癌、结直肠癌、恶性黑素瘤、膀胱癌、前列腺癌、皮肤癌、食管癌、卵巢癌、甲状腺癌、肾癌、乳腺癌、宫颈癌等。因此，β-catenin突变点是肿瘤治疗的热门靶点。
免疫细胞技术已成为肿瘤治疗第三大支柱，显示出广阔的应用前景。在中国人群为主的HLA-A11限制性β-catenin突变表位肽特异性细胞治疗尚处于空白阶段，亟需进行深入的研究开发。
发明内容
本发明的首要目的是提供一种新的β-catenin突变表位肽。
本发明另一目的是提供上述β-catenin突变表位肽与HLA-A11形成复合物、与上述复合物结合的T细胞受体、抗体及细胞等，以及这些T细胞受体、抗体及细胞等的用途，例如以上物质在肿瘤治疗药物中的应用。
本发明的目的是通过以下技术方案实现的：
本发明首先提供了一种HLA-A11限制性β-catenin突变表位肽(简称β-catenin突变表位肽)或其片段、变体，所述β-catenin突变表位肽的氨基酸序列为如下的一种：SEQ IDNO：1～2。
上述“片段、变体”，或与这些序列具有99％以上、95％以上、90％以上、85％以上或者80％以上同一性且编码相同氨基酸残基的序列。
基于以上HLA-A11限制性β-catenin突变表位肽，制备成相应的诊断、预防和治疗性质的药物，所述药物还包括β-catenin突变表位肽的衍生物；所述衍生物为基于β-catenin突变表位肽而产生的抗体、T细胞受体、致敏淋巴细胞或效应因子，以产生相同或类似的特异性的免疫应答。
作为一种优选的处理，所述β-catenin突变表位肽能够与HLA-A11形成复合物。
进一步地，所述β-catenin突变表位肽与HLA-A11形成复合物后，能够被T细胞识别，且该识别是特异性的。
对应地，本发明的β-catenin突变表位肽与HLA-A11形成复合物后，可以用于筛选或检测与其结合的分子，如筛选TCR或抗体库。上述提及的结合分子是抗体时，术语“抗体”指免疫球蛋白分子和免疫球蛋白分子的免疫活性部分，即含有特异性结合位点的分子，其可以全天然、或部分人工合成、或全部人工合成；涵盖抗体片段、其衍生物、功能性等效物以及同源抗体、人源化抗体，所述抗体片段包括免疫球蛋白结合区，所述结合区是抗体结合区或与抗体结合区同源。其可以全天然、或部分人工合成、或全部人工合成。人源化抗体可以是修饰的抗体，其含有非人抗体的可变区(例如，小鼠)以及人抗体的恒定区。抗体可以是多抗或单抗，优选为单克隆抗体。
上述提及的“TCR”，即T细胞受体，是T细胞表面的特异性受体，负责识别由主要组织相容性复合体(MHC)所呈递的抗原，与B细胞受体不同，并不能识别游离的抗原。通常情况下，T细胞受体与抗原间拥有较低的亲和力，因而同一抗原可能被不同的T细胞受体所识别，某一受体也可能识别许多种抗原。
本发明保护上述β-catenin突变表位肽及其β-catenin突变表位肽与HLA-A11形成的复合物及其衍生物，所述衍生物为复合物产生的T细胞受体、抗体或效应分子，并要求保护基于以上复合物构建的核酸分子、载体、细胞等。
进一步地，HLA-A11为HLA-A*11:01。
上述任一所述的物质均可应用在制备预防和/或治疗由恶性肿瘤所致的疾病的药物上。以此在体内或体外实现杀伤靶细胞。例如，将包含所述复合物作为肿瘤疫苗。
作为一种具体的实施方式，本发明提供了一种特异性识别所述β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物，可包含α链和β链。所述α链可包含三个互补决定区，氨基酸序列分别如SEQ ID NO：5的第46-51位、第69-75位和第110-122位所示；或指具有至少一个氨基酸改变，但不超过两个、三个或四个改变(例如，置换、缺失或插入，例如，保守性置换)的序列变体。
所述β链可包含三个互补决定区，氨基酸序列分别如SEQ ID NO：7的第49-53位、第71-76位和第114-124位所示；或指具有至少一个氨基酸改变，但不超过两个、三个或四个改变(例如，置换、缺失或插入，例如，保守性置换)的序列变体。
上述互补决定区的序列如下：
αCDR1：STYSPF；
αCDR2：SFTDNKR；
αCDR3：ALSGPSSNTNKVV；
βCDR1：FNHDT；
βCDR2：SITEND；
βCDR3：ASSMRGLSDYT。
所述T细胞受体中，所述α链的可变区的氨基酸序列可如SEQ ID NO：5第20-112所示；或指具有至少一个氨基酸改变，但不超过两个、三个或四个改变(例如，置换、缺失或插入，例如，保守性置换)的序列变体。所述β链的可变区的氨基酸序列可如SEQ ID NO：7第23-116所示；或指具有至少一个氨基酸改变，但不超过两个、三个或四个改变(例如，置换、缺失或插入，例如，保守性置换)的序列变体。
所述T细胞受体中，所述α链的氨基酸序列可如SEQ ID NO：5所示。所述β链的氨基酸序列可如SEQ ID NO：7所示。
TCR的衍生物代表的是TCR的功能性变体，均指代基于所述TCR的相同功能，能够被T细胞特异性识别，在基因、蛋白等形式上做出的结构等效替代。
编码上述任一所述T细胞受体的核酸分子也属于本发明的保护范围。进一步地，同时保护包含编码所述的特异性识别β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物的核苷酸序列或其互补序列形成的核酸分子。基于以上核苷酸序列或其互补序列上与上述序列具有99％以上、95％以上、90％以上、85％以上或者80％以上同一性且编码相同氨基酸残基的序列均在本申请保护范围内。
编码上述任一所述T细胞受体的核酸分子可包含编码所述T细胞受体的α链的核酸分子和编码所述T细胞受体的β链的核酸分子。
编码所述T细胞受体的α链中三个互补决定区的核苷酸序列分别可如SEQ ID NO：4的第136-153位、第205-225位和第328-366位所示；或与这些序列具有99％以上、95％以上、90％以上、85％以上或者80％以上同一性且编码相同氨基酸残基的序列。
编码所述T细胞受体的β链中三个互补决定区的核苷酸序列分别可如SEQ ID NO：6的第145-159位、第211-228位和第340-372位所示；或与这些序列具有99％以上、95％以上、90％以上、85％以上或者80％以上同一性且编码相同氨基酸残基的序列。
编码所述α链的可变区的核苷酸序列可如SEQ ID NO：4的第58-336位所示；或与这些序列具有99％以上、95％以上、90％以上、85％以上或者80％以上同一性且编码相同氨基酸残基的序列。
编码所述β链的可变区的核苷酸序列如SEQ ID NO：6的第67-348位所示；或与这些序列具有99％以上、95％以上、90％以上、85％以上或者80％以上同一性且编码相同氨基酸残基的序列。
编码所述α链的核酸分子的核苷酸序列如SEQ ID NO：4所示。
编码所述β链的核酸分子的核苷酸序列如SEQ ID NO：6所示。
所述T细胞受体的完整氨基酸序列如SEQ ID NO：13所示，完整核苷酸序列如SEQID NO：12所示。
含有上述任一所述核酸分子、及含有所述核酸分子构建的表达盒、载体或细胞也属于本发明的保护范围。
更进一步地，本申请要求保护一种药物组合物，所述药物组合物包所述特异性识别β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物作为活性成分，用于制备肿瘤免疫治疗药物。所述肿瘤免疫针对于HLA-A11人群中的肝癌治疗。同时，也涉及胆管癌、胃癌、胰腺癌、肺癌、子宫内膜癌、结直肠癌、恶性黑素瘤、膀胱癌、前列腺癌、皮肤癌、食管癌、卵巢癌、甲状腺癌、肾癌、乳腺癌、宫颈癌等治疗。优选为肝癌。优选地，所述药物组合物为疫苗。
本发明所述的药物组合物的给药途径较佳的为注射给药或口服给药。所述注射给药较佳的包括静脉注射、肌肉注射、腹腔注射、皮内注射或皮下注射等途径。所述的药物组合物为本领域常规的各种剂型，较佳的为液体、半固体、或固体的形式，可以为水溶液、非水溶液或混悬液，更佳的为输注剂、注射剂、片剂、胶囊、或颗粒剂等。本发明所述的药物组合物还包括药学上可接受的载体或赋形剂。所述的载体或赋形剂为本领域常规药用载体或赋形剂，所述的载体或赋形剂可以为任意合适的生理学或药学上可接受的药物辅料。所述的药物辅料为本领域常规的药物辅料，较佳的包括药学上可接受的赋形剂、填充剂或稀释剂等。
本发明药物组合物的应用，可以是基于疾病诊断、预防和/或治疗的药物组合物使用，例如，诊断方面，利用该特异性，使用特异性的免疫反应及其相应成分，结合现有的诊断辅助方法，检测出特异性的免疫反应物质、免疫信号等等。
如背景技术中提及：在肿瘤免疫治疗中，肿瘤新抗原特异性T细胞对新抗原多肽进行识别，特异性杀伤表达这些新抗原的肿瘤细胞。因此，基于本申请公开的内容，在肿瘤免疫治疗肿瘤，尤其是恶性肿瘤上具备较好的应用。恶性肿瘤，可以是肝癌、胆管癌、胃癌、胰腺癌、肺癌、子宫内膜癌、结直肠癌、恶性黑素瘤、膀胱癌、前列腺癌、皮肤癌、食管癌、卵巢癌、甲状腺癌、肾癌、乳腺癌、宫颈癌。
与现有技术相比，本发明具有以下有益效果：
本发明首先公开了一种多肽，基于以上多肽，公开了一种特异性识别β-catenin突变表位肽/HLA-A11复合物、及其构建的特异性TCR，并且成功构建了对应的TCR-T细胞，确定了TCR序列特异性的识别并结合β-catenin突变表位肽/HLA-A11复合物，不能识别β-catenin未突变表位肽/HLA-A11复合物。并且在体外验证了TCR转基因阳性的人CD8细胞(即人TCR-T细胞)具有β-catenin突变肽表位依赖性的杀伤靶细胞人肝癌细胞的能力，不会对β-catenin未突变肽表位负载靶细胞进行杀伤。表明该多肽及其特异性TCR具有重要的肿瘤治疗意义。
附图说明
图1为β-catenin突变表位肽诱导特异性CD8免疫反应的示意图。
图2为流式分选β-catenin突变表位肽特异性CD8细胞的示意图。
图3为表达TCR的Jurkat细胞抗原特异性染色结果。
图4为Human TCR-T细胞体外杀伤肿瘤靶细胞的结果。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是，对于这些实施方式的说明用于帮助理解本发明，但并不构成对本发明的限定。此外，下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实验例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
以下实施例中的定量试验，均设置三次重复实验，结果取平均值。
HLA-A11/hTAP-LMP转基因小鼠的处理参见文献：Man Huang，Wei Zhang，Jie Guo，Xundong Wei，Krung Phiwpan，Jianhua Zhang，Xuyu Zhou.Improved Transgenic MouseModel for Studying HLA Class I Antigen Presentation.Scientific Report.2016，doi:10.1038/srep33612.
实施例1、β-catenin 45位点氨基酸(S→P/F)突变多肽亲和力鉴定
本项目构建了兼顾抗原在胞内呈递和与胞外MHC分子结合的生物信息学预测模型。通过联用NetCTLpan和NetMHCpan两个生物信息学软件针对β-catenin 45位点常见氨基酸突变序列进行预测,NetMHCpan预测获得高亲和力的HLA-A11限制性表位多肽，结合NetCTLpan预测。NetMHCpan软件预测参数设置为：排序阈值≤2％，NetCTLpan软件预测参数设置为：排序阈值≤1％。得到本发明的多肽，氨基酸序列分别为：SEQ ID NO：1和SEQ IDNO：2，并用于后续功能验证。
实施例2、TCR-T细胞的获得及其应用
一、应用HLA-A11/hTAP-LMP转基因小鼠筛选获得A11限制性β-catenin突变表位肽特异性TCR序列
1、β-catenin突变表位肽免疫实验:
(1)使用MIX多肽免疫两次，中间间隔14天。MIX多肽：S45P、S45F各50μg/只，辅助多肽HBc128-140 100μg/只，将上述3种多肽混合后用PBS补足至体积100μL，然后加入等体积的IFA，乳化后得到200μL体积油包水混合物为1只小鼠皮下免疫用量，若免疫多只小鼠，按照上述参数×小鼠数量进行制备即可。多肽的信息如SEQ ID NO：1-3所示：
表1
| CTNNB1 S45P | TTAPPLSGK |
| CTNNB1 S45F | TTAPFLSGK |
| CTNNB1 S45S WT | TTAPSLSGK |
(2)第二次皮下免疫后7天进行质粒肌肉免疫，MIX质粒：β-catenin(S45P)、β-catenin(S45F)2种质粒各100μg/只，将上述2种质粒混合后用PBS补足至体积100μL，每只小腿注射50μL后电击，每只小鼠免疫2只小腿。
(3)质粒免疫后7天内进行胞内IFNg染色：取血，裂红后用单独多肽((S45P或S45F，10μg/μl)刺激4h，随后进行胞内染IFNg检测。由图1可知，β-catenin(S45P)能够刺激特异性CD8 T细胞产生CTL反应。
2、检测外周血Tetramer的比例
实验结果如图1所示，由图1可知，β-catenin(S45P)免疫的小鼠能够产生Tetramer阳性的CD8 T细胞并释放IFNg。并且，Tetramer阳性比例与IFNg释放比例有正相关关系。
3、对免疫小鼠的Tetramer阳性CD8细胞进行分选
Tetramerβ-catenin(S45P)阳性CD8T细胞分选流程如图2所示。分选效率以及纯度检测流程如图2所示。
利用β-catenin(S45P)阳性CD8 T细胞可分离1个TCR，其α链和β链的基因序列分别如SEQ ID NO：4、SEQ ID NO：6所示。其中α链CDR3的核苷酸列表和氨基酸序列分别如SEQ IDNO：8、SEQ ID NO：9所示；β链CDR3的核苷酸列表和氨基酸序列分别如SEQ ID NO：10、SEQ IDNO：11所示，序列见下表。
| chain | CDR3 aa | CDR3 nt |
| TRA | ALSGPSSNTNKVV | GCTTTGAGTGGACCTTCTTCCAATACCAACAAAGTCGTC |
| TRB | ASSMRGLSDYT | GCCAGCAGTATGAGGGGGCTCTCCGACTACACC |
二、表达TCR的Jurkat细胞的获得及鉴定
1、根据步骤一得到的α链可变区和β链可变区的序列，参考NCBI上小鼠基因组α链和α链的恒定区序列，获得并人工合成HLA-A11限制性β-catenin突变表位肽(S45P)特异性TCR受体α链和β链的完整编码基因。
α链的完整氨基酸序列如SEQ ID NO：5所示，编码该α链的核苷酸序列如SEQ IDNO：4所示。
β链的完整氨基酸序列如SEQ ID NO：7所示，编码该β链的核苷酸序列如SEQ IDNO：6所示。
2、将逆转录病毒载体MSCV-IRES-NGFR的限制性内切酶XhoI和EcoRI之间的DNA小片段替换为SEQ ID NO：12所示的DNA分子，其它序列均不变，得到重组质粒MSCV-TCR-IRES-NGFR(即重组质粒MSCV-TCR-NGFR)。
逆转录病毒载体MSCV-NGFR-GFP是将MO载体的限制性内切酶XhoI和EcoRI之间的DNA小片段替换为NGFR核苷酸序列(序列来源于addgene NGFR质粒,Plasmid#27489)，再将限制性内切酶EcoRI和ClaI之间的DNA小片段替换为IRES核苷酸序列(Genbank：MG550106.1)和荧光标记蛋白GFP核苷酸序列(Genbank：MH777595.1)，得到的重组质粒。
MO载体记载于如下文献：Tanyu Hu，Krung Phiwpan，Jitao Guo，et al.MicroRNA-142-3pNegatively Regulates Canonical Wnt Signaling Pathway.PLOS ONE.2016，DOI:10.1371/journal.pone.0158432.
3、培养Jurkat细胞至数量2×107以上，收集细胞，用不含抗生素的1640培养基清洗2遍，最后一遍洗后用不含抗生素1640培养基重悬至5×107/mL，将上述细胞分为400μL/份加至电转杯(BIO-RAD)，同时加入40μg重组质粒MSCV-TCR-NGFR，混匀，将电转杯放入电转仪(BIO-RAD，Gene Pulser XcellTM)中，电压250V，电容950μF电转，将重组质粒MSCV-TCR-NGFR导入Jurkat细胞，得到表达TCR的Jurkat细胞。
4、利用Tetramer(HLA-A11/S45P)对步骤3得到的表达TCR的Jurkat细胞或空白对照的Jurkat细胞进行染色。
染色结果见图3。结果表明，TCR对HLA-A11限制性表位具有较强的亲和力。
三、TCR-T细胞具有体外杀伤靶细胞的功能
为了体外验证TCR具有特异性的杀伤靶细胞的能力，进行体外杀伤实验。具体步骤如下：
1、慢病毒的包装与浓缩
(1)将慢病毒包装载体pCDH-MSCV-MCS-IRES-GFP(System Biosciences，编号：CD731B-1)的限制性内切酶EcoRI与BamHI之间的DNA小片段替换为TCR DNA片段(SEQ IDNO：12，对应的氨基酸序列如SEQ ID NO：13所示)，得到pCDH-MSCV-TCR-GFP质粒。
(2)将293T细胞吹打重悬成单细胞，计数，然后用含10％(v/v)FBS的DMEM培养基调节，得到浓度为5×105个/mL的细胞悬浮液。取培养皿(规格为10cm)，铺10mL细胞悬浮液，培养过夜。
(3)完成步骤(2)后，待293T细胞汇合度为75％时进行转染，转染前30min更换培养基为DMEM培养基。
(4)转染预混物准备
向500μL DMEM培养基中加入12μg pCDH-MSCV-TCR-GFP质粒、9μg psPAX2和6μgpMG2.D，涡旋充分混匀，得到质粒混合物。
psPAX2和pMG2.D均为北京天恩泽基因科技有限公司的产品。
向500μL DMEM培养基中加入27μg PEI，涡旋混匀，静置5min，得到PEI混合物。
(5)完成步骤(4)后，向500μL质粒混合物中加入500μL PEI混合物，涡旋充分混匀，室温孵育20min；然后将孵育完成的混合物轻柔沿培养皿侧壁加入293T细胞中，轻晃培养皿混匀，37℃培养箱培养。6-8h后将培养基更换为10mL含10％(v/v)FBS的DMEM培养基。
(6)完成步骤(5)后第48h，收集第一次病毒上清，补充新鲜DMEM培养基，病毒上清4℃保存。
(7)完成步骤(5)后第72h，收集第二次病毒上清。将第一次病毒上清和第二次病毒上清合并，800g、室温离心5min，收集上清。
(8)完成步骤(7)后，将所述上清使用0.45μm PES滤膜过滤除去细胞碎片，收集病毒上清。
(9)完成步骤(8)后，将所述病毒上清转移至超速离心管。4℃、70000g离心120min，小心弃上清，收集沉淀(白色病毒颗粒)。
(10)完成步骤(9)后，取所述沉淀，加入100倍浓缩体积的1640培养基重悬，4℃溶解过夜，得到浓缩慢病毒。将浓缩慢病毒分装保存于-80℃超低温冰箱，备用。
2、人外周淋巴细胞的分离
(1)抽取人外周静脉血5mL。
(2)完成步骤(1)后，取离心管(规格为50mL)，加入5mL外周血和5mL PBS缓冲液，充分混匀。
(3)完成步骤(2)后，向离心管中加入5mL人外周血淋巴细胞分离液(天津市灏洋生物制品科技有限公司)，使用一次性无菌滴管取稀释后外周血沿管壁小心叠加于分离液液面之上，注意保持清楚界面。
(4)完成步骤(3)后，将离心管置于离心机中，调节升速和降速为最低，800g离心20min。
(5)完成步骤(4)后，离心结束后管内分为四层，第一层为血浆和PBS，第二层为环状乳白色淋巴细胞层，第三层为透明分离液层，第四层为红细胞和粒细胞层。用移液器小心吸取第二层环状乳白色淋巴细胞层至无菌离心管(规格为50mL)，向离心管中加入40mL PBS缓冲液，混匀细胞，800g离心5min，弃上清，之后使用1640培养基重悬细胞，计数备用。
3、人外周T淋巴细胞的活化
(1)取24孔板，每孔加入500μL anti-CD3抗体稀释液和500μL anti-CD28抗体稀释液，4℃包被过夜。
anti-CD3抗体稀释液：用PBS缓冲液稀释anti-CD3抗体(BioXcell，克隆号：OKT3)至浓度为3μg/mL获得。
anti-CD28抗体稀释液：用PBS缓冲液稀释anti-CD28抗体(BioXcell，克隆号：CD28.2)至浓度为1μg/mL获得。
(2)完成步骤(1)后，取所述24孔板，移除液体，并用PBS缓冲液清洗一次。
(3)完成步骤(2)后，取所述24孔板，加入500μL人外周T淋巴细胞稀释液，37℃培养箱培养48h；之后400g离心5min，收集沉淀并使用1640培养基重悬，得到活化的人外周T淋巴细胞。活化的人外周T淋巴细胞用于感染慢病毒。
人外周T淋巴细胞稀释液：用1640培养基将步骤2获得的人外周T淋巴细胞稀释至4×106个/mL获得。
4、慢病毒感染人外周T淋巴细胞
(1)取24孔板，每孔加入5×105个活化的人外周T淋巴细胞和200μL浓缩慢病毒，然后用1640培养基补体积至500μL；最后加入polybrene和IL-2，并使polybrene和IL-2在体系中的浓度分别为8μg/mL和40U/mL。
(2)完成步骤(1)后，取24孔板，600g、32℃离心90min；然后将24孔板放入37℃培养箱感染24h。
(3)完成步骤(2)后，取所述24孔板，小心吸掉感染孔中350μL培养基，然后加入1640培养基补足至体积2mL并吹打混匀，37℃培养箱继续培养48h。
(4)完成步骤(3)后，先取适量感染后T细胞进行流式检测感染效率；然后使用anti-mouse CD8a抗体(Biolegend，克隆号：53-6.7)和anti-mouse TCRVβ10抗体(BDBioscience，克隆号：B21.5)对感染后T细胞进行染色，4℃染色30min后进行上机检测，感染效率(TCRVβ10阳性率)大于15％，阳性细胞即为成功转入TCR的Human TCR-T细胞，用于后续杀伤实验。
5、Human TCR-T体外具有杀伤靶细胞的功能
底物、终止液和细胞裂解液均为CytoToxNon-Radioactive CytotoxicityAssay试剂盒(Promega公司)中的组件。
(1)通过慢病毒方法将HLA-A11导入人肝癌细胞系HepG2.2.15细胞，流式细胞术、RT-PCR和Western Blot检测HLA-11表达情况，建立高表达抗原提呈复合物HLA-11的肝癌细胞株(HepG2.2.15-A11)做为特异性HLA-A11限制性TCR-T细胞在体外特异性免疫识别与杀伤实验的肿瘤靶细胞。
(2)完成步骤(1)后，用1640培养基将HepG2.2.15-A11细胞稀释至浓度为1×107个/mL，然后加入多肽β-catenin(S45P)或β-catenin(S45S WT)并使其在体系中的浓度为10μg/mL，37℃、5％CO2培养1h，之后1640培养基洗涤两次，细胞计数，得到负载多肽β-catenin(S45P)或β-catenin(S45S WT)的靶细胞。
(3)将步骤(2)得到的负载多肽的靶细胞加入96孔板中，2×104个/孔；随后按效靶比例为2:1或1:1加入Human TCR-T细胞，37℃、5％CO2培养5h。
(4)取96孔板，250g离心4min；然后将50μL上清转移至新的96孔板，每孔加入底物50μL，室温、避光孵育30min；之后每孔加入50μL终止液，使用酶标仪(波长490nm)读取数值，即实验组数值。
(5)杀伤实验本底数值检测
①按照上述步骤(1)～(4)，将步骤(3)替换为步骤3A)，其它步骤均不变，得到T细胞自释放值。步骤3A)为：取96孔板，加入与实验组同等数量的Human TCR-T细胞，37℃、5％CO2培养5h。
②按照上述步骤(1)-(4)，将步骤(3)替换为步骤3B)，其它步骤均不变，得到靶细胞自释放值。步骤3B)为：取96孔板，加入与实验组同等数量的负载多肽β-catenin(S45P)的靶细胞，37℃、5％CO2培养5h。
③按照上述步骤(1)-(4)，将步骤(3)替换为步骤3C)，其它步骤均不变，得到靶细胞最大释放值。步骤3C)为：取96孔板，加入与实验组同等数量的负载多肽β-catenin(S45P)的靶细胞和10μL细胞裂解液，37℃、5％CO2培养5h。
6、计算杀伤活性
杀伤活性＝(实验组数值-T细胞自释放值-靶细胞自释放值)/(靶细胞最大释放值-靶细胞自释放值)
将上述方法中的多肽β-catenin(S45P)替换为β-catenin(S45S WT)，其它步骤均不变，作为对照。
将上述方法中的Human TCR-T替换为未转染TCR的Human T细胞，其它步骤均不变，作为对照。
检测结果见图4(A为Human TCR-T细胞的获得；B为Human TCR-T细胞体外杀伤靶细胞实验，其中E：T表示Human TCR-T细胞和靶细胞的比例，WT peptide为β-catenin(S45SWT)负载的靶细胞，Mut peptide为β-catenin(S45P)负载的靶细胞，control T为未转染TCR的Human T细胞，TCR-T为转染TCR的Human T细胞。结果表明，基于Mut peptide(S45P)构建的Human TCR-T细胞在体外可以有效的杀伤靶细胞。
综上所述，本发明首先鉴定了HLA-A11限制性的β-catenin突变抗原多肽，分离并获得了一对β-catenin突变表位肽特异性的TCR序列，成功构建了对应的TCR-T细胞，通过四聚体染色技术确定了我们筛选到的TCR序列特异性的识别并结合β-catenin突变表位肽/HLA-A11复合物，不能识别β-catenin未突变表位肽/HLA-A11复合物。并且在体外验证了TCR转基因阳性的人CD8细胞(即TCR-T细胞)具有β-catenin突变肽表位依赖性的杀伤靶细胞人肝癌细胞的能力，不会对β-catenin未突变肽表位负载靶细胞进行杀伤。
以上对本发明的实施方式作了详细说明，但本发明不限于所描述的实施方式。对于本领域的技术人员而言，在不脱离本发明原理和精神的情况下，对这些实施方式进行多种变化、修改、替换和变型，仍落入本发明的保护范围内。
序列表
<110> 中科启源（深圳）生物科技有限公司
<120> 一种β-catenin突变表位肽及其应用
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atgcgtcctg acacctgctc agttcttgtg ctcctcttaa tgctcagaag gaacaatgga 60
gactctgtga cccagacaga aggcctggtc actctcaccg aggggttgcc tgtgatgctg 120
aactgcacct atcagagtac ttactcacct ttccttttct ggtatgtgca acatctcaac 180
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ttccacgcca ctctccataa gagcagcagc tccttccatc tgcagaagtc ctcagcgcag 300
ctgtcagact ctgccctgta ctactgtgct ttgagtggac cttcttccaa taccaacaaa 360
gtcgtctttg gaacagggac cagattacaa gtattaccaa acatccagaa cccagaacct 420
gctgtgtacc agttaaaaga tcctcggtct caggacagca ccctctgcct gttcaccgac 480
tttgactccc aaatcaatgt gccgaaaacc atggaatctg gaacgttcat cactgacaaa 540
actgtgctgg acatggaagc tatggattcc aagagcaatg gggccattgc ctggagcaac 600
cagacaagct tcacctgcca agatatcttc aaagagacca acgccaccta ccccagttca 660
gacgttccct gtgatgccac gttgactgag aaaagctttg aaacagatat gaacctaaac 720
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gaacctgctg tgtaccagtt aaaagatcct cggtctcagg acagcaccct ctgcctgttc 480
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cagacaccca aattcctgat tggtcaggaa gggcaaaaac tgaccttgaa atgtcaacag 1020
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gcgtctcgag agaagaagtc atctttttct ctcactgtga catctgccca gaagaacgag 1200
atggccgttt ttctctgtgc cagcagtatg agggggctct ccgactacac cttcggctca 1260
gggaccaggc ttttggtaat agaggatctg agaaatgtga ctccacccaa ggtctccttg 1320
tttgagccat caaaagcaga gattgcaaac aaacaaaagg ctaccctcgt gtgcttggcc 1380
aggggcttct tccctgacca cgtggagctg agctggtggg tgaatggcaa ggaggtccac 1440
agtggggtca gcacggaccc tcaggcctac aaggagagca attatagcta ctgcctgagc 1500
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gtgcagttcc atgggctttc agaggaggac aagtggccag agggctcacc caaacctgtc 1620
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tga 1803
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Val Phe Leu Cys Ala Ser Ser Met Arg Gly Leu Ser Asp Tyr Thr Phe
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Gly Ser Gly Thr Arg Leu Leu Val Ile Glu Asp Leu Arg Asn Val Thr
420 425 430
Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn
435 440 445
Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp
450 455 460
His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly
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Val Ser Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys
485 490 495
Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg
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Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp
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Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala
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Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His
545 550 555 560
Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
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Ala Thr Leu Tyr Ala Val Leu Val Ser Gly Leu Val Leu Met Ala Met
580 585 590
Val Lys Lys Lys Asn Ser
595
Claims (19)
1.一种β-catenin突变表位肽或其片段、变体，其特征在于，所述β-catenin突变表位肽的氨基酸序列为如下的一种：SEQ ID NO：1～2。
2.权利要求1所述β-catenin突变表位肽或其片段、变体在制备预防和/或治疗癌症药物中的应用，其特征在于，所述药物还包括β-catenin突变表位肽的衍生物；所述衍生物为基于β-catenin突变表位肽而产生的抗体、T细胞受体、致敏淋巴细胞或效应因子。
3.一种β-catenin突变表位肽/HLA-A11复合物，其特征在于，所述复合物包含权利要求1所述β-catenin突变表位肽或其片段、变体。
4.一种药物组合物，其特征在于，所述的药物组合物包括权利要求3所述复合物及其衍生物；复合物的衍生物为基于所述复合物产生的抗体、T细胞受体、致敏淋巴细胞或效应因子。
5.权利要求3所述复合物在制备治疗癌症的药物中的应用，其特征在于，所述应用包括将所述复合物及其衍生物作为肿瘤疫苗。
6.一种细胞，其特征在于，所述细胞表面呈递如权利要求3所述β-catenin突变表位肽/HLA-A11复合物。
7.一种核酸分子，其特征在于，所述核酸分子包含编码权利要求1所述的β-catenin突变表位肽的核苷酸序列或其互补序列。
8.一种载体或细胞或试剂盒，其特征在于，所述载体或细胞或试剂盒含有权利要求7所述的核酸分子。
9.一种特异性识别权利要求3所述β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物，其特征在于，所述TCR包括α链和β链；
所述α链包含三个互补决定区，氨基酸序列分别如SEQ ID NO：5的第46-51位、第69-75位和第110-122位所示；
所述β链包含三个互补决定区，氨基酸序列分别如SEQ ID NO：7的第49-53位、第71-76位和第114-124位所示。
10.根据权利要求9所述特异性识别β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物，其特征在于，
所述α链的可变区的氨基酸序列如SEQ ID NO：5第20-112所示；
所述β链的可变区的氨基酸序列如SEQ ID NO：7第23-116所示；
TCR的衍生物为TCR的功能性变体。
11.根据权利要求9或10所述特异性识别β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物，其特征在于，
所述α链的氨基酸序列如SEQ ID NO：5所示；
所述β链的氨基酸序列如SEQ ID NO：7所示。
12.编码权利要求9至11任一所述TCR及其衍生物的核酸分子，其特征在于，所述核酸分子包含编码权利要求9至11任一所述的特异性识别β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物的核苷酸序列或其互补序列。
13.如权利要求12所述的核酸分子，其特征在于，编码所述TCR的核酸分子包含编码所述TCR的α链的核酸分子和编码所述TCR的β链的核酸分子；
编码所述TCR的α链中三个互补决定区的核苷酸序列分别如SEQ ID NO：4的第136-153位、第205-225位和第328-366位所示；
编码所述TCR的β链中三个互补决定区的核苷酸序列分别如SEQ ID NO：6的第145-159位、第211-228位和第340-372位所示。
14.如权利要求12或13所述的核酸分子，其特征在于，
编码所述α链的可变区的核苷酸序列如SEQ ID NO：4的第58-336位所示；
编码所述β链的可变区的核苷酸序列如SEQ ID NO：6的第67-348位所示。
15.如权利要求12所述的核酸分子，其特征在于，
编码所述α链的核酸分子的核苷酸序列如SEQ ID NO：4所示；
编码所述β链的核酸分子的核苷酸序列如SEQ ID NO：6所示。
16.一种DNA分子，其特征在于，所述DNA的核苷酸序列如SEQ ID NO：12所示。
17.一种药物组合物，其特征在于，所述药物组合物包含权利要求9至11任一所述特异性识别β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物或13至15任一所述核酸分子作为活性成分。
18.权利要求9至11任一所述特异性识别β-catenin突变表位肽/HLA-A11复合物的TCR及其衍生物或13至15任一所述核酸分子在制备用于肿瘤免疫治疗药物中的应用。
19.根据权利要求16或17所述的应用，其特征在于，所述肿瘤免疫针对HLA-A11人群中的肝癌治疗，也可以是胆管癌、胃癌、胰腺癌、肺癌、子宫内膜癌、结直肠癌、恶性黑素瘤、膀胱癌、前列腺癌、皮肤癌、食管癌、卵巢癌、甲状腺癌、肾癌、乳腺癌、宫颈癌。
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