CN113527464A - 识别mboat2的tcr - Google Patents
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- CN113527464A CN113527464A CN202110814401.0A CN202110814401A CN113527464A CN 113527464 A CN113527464 A CN 113527464A CN 202110814401 A CN202110814401 A CN 202110814401A CN 113527464 A CN113527464 A CN 113527464A
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Abstract
本发明公开了一种识别MBOAT2的TCR，其是首例能够识别MBOAT2p.R43Q突变产生的新生抗原的TCR。针对MBOAT2p.R43Q突变产生的新生抗原,正常氨基酸序列为AAIWFRTYL，新生抗原氨基酸序列为AAIWFQTYL，抗原呈递分子为HLA‑C03:04，发明了一种能够特异性识别MBOAT2p.R43Q突变的TCR，其可以用于基因编辑改造T细胞，改造过的T细胞能够特异性识别含有该突变的肿瘤新生抗原，进而可以用于TCR‑T疗法，杀死肿瘤细胞。
Description
技术领域
本发明涉及免疫疗法领域，更具体地说，它涉及识别MBOAT2突变产生的新生抗原的TCR。
背景技术
恶性肿瘤，作为中国居民死亡主要原因之一，发病率以每年3.9％的增幅增长，死亡率保持每年2.5％的增幅。全国每年有超300万人确诊患有癌症，平均每天确诊超过1万人。中国癌症高发病前十的恶性肿瘤，均为实体肿瘤。
过继性免疫细胞技术，以利用人体免疫系统杀伤癌细胞、病原体为目的，一般先采集病患自身T细胞，在体外扩增自体T细胞和/或优化该T细胞靶向性后，再向病患回输抗癌能力增强的T细胞；因为以自体T细胞为底物，所以相较传统疗法，过继性免疫细胞技术具有低毒副作用、低耐药性等优势。其中，针对肿瘤新生抗原的TCR-T疗法，被认为是能够攻克实体肿瘤最有效的治疗手段之一。
MBOAT2(膜结合O-酰基转运酶结构域2)基因编码一种催化将酰基辅酶中的酰基转运到水解磷脂的酰基转运酶，参与磷脂重构通路中的再酰化过程。在大鼠食道鳞状细胞癌模型中的研究发现，MBOAT2是miR-31的靶基因之一，而miR-31是在包括结直肠癌、食道癌等多种类型的肿瘤中最常见的过表达并致癌的microRNA之一。近年来有研究发现，MBOAT2基因位点同时转录一段环状RNA circMBOAT2，其在结直肠癌样本中及患者血清中高度表达并与肿瘤分期及预后相关，可以作为潜在的结直肠癌生物标志物。根据TCGA的数据，MBOAT2p.R43Q突变发生频率较高的肿瘤类型包括直肠癌(2.2％)和子宫内膜癌(1.1％)。
发明内容
应用基因编辑技术，改造的含有本发明的识别MBOAT2的TCR组合的T细胞，可以特异性杀伤通过HLA-C03:04呈递抗原肽AAIWFQTYL的细胞，其可以用于TCR-T疗法的开发应用。
为实现上述目的，本发明提供了如下技术方案：
在一个方面，本发明提供了识别MBOAT2的TCR，其包括TCRα链和TCRβ链；其中，TCRα链包括互补决定区CDR3，CDR3与选自SEQ ID NO:3的氨基酸序列具有至少70％的序列同一性，TCRβ链包括互补决定区CDR3，CDR3与选自SEQ ID NO:6的氨基酸序列具有至少70％的序列同一性。
至少70％的序列同一性：包括至少70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％的序列同一性。
在一些实施方案中，所述TCRα链包括三个互补决定区CDR1、CDR2和CDR3，其中CDR1选自SEQ ID NO:1，CDR2选自SEQ ID NO:2，CDR3选自SEQ ID NO:3。
在一些实施方案中，所述TCRα链还包括四个框架区FR1、FR2、FR3和FR4，其中FR1选自SEQ ID NO:7，FR2选自SEQ ID NO:8，FR3选自SEQ ID NO:9，FR4选自SEQ ID NO:10。
在一些实施方案中，所述的识别MBOAT2的TCR，所述TCRβ链包括三个互补决定区CDR1、CDR2和CDR3，其中CDR1选自SEQ ID NO:4，CDR2选自SEQ ID NO:5，CDR3选自SEQ IDNO:6
在一些实施方案中，所述TCRβ链还包括四个框架区FR1、FR2、FR3和FR4，其中FR1选自SEQ ID NO:11，FR2选自SEQ ID NO:12，FR3选自SEQ ID NO:13，FR4选自SEQ ID NO:14。
在一些实施方案中，所述的识别MBOAT2的TCRα链与选自SEQ ID NO:15的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％序列同一性；所述的识别MBOAT2的TCRβ链与选自SEQ ID NO:16的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％序列同一性。
本发明还提供了编码上述所述的识别MBOAT2的TCR的核酸分子。
在一些实施方案中，编码所述TCRα链的核酸分子与选自SEQ ID NO:17的核苷酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％序列同一性；编码所述TCRβ链的核酸分子与选自SEQ ID NO:18的核苷酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％序列同一性。
在另一个方面，本发明还提供了一种宿主细胞，其被工程改造成表达上述所述的识别MBOAT2的TCR。
在另一个方面，本发明还提供了一种药物组合物，其包括上述所述的识别MBOAT2的TCR和/或上述所述的核酸分子和/或上述所述的宿主细胞以及一种或多种药学上可接受的运载体或赋形剂。
在另一个方面，本发明还提供了上述所述的识别MBOAT2的TCR、权利要求8所述的宿主细胞，权利要求9所述的药物组合物，其用于治疗癌症的方法，所述方法包括过继性疗法。
在一些实施方案中，所述癌症包括直肠癌和子宫内膜癌，但不限于直肠癌和子宫内膜癌。
本发明所提供的识别被HLA-C03:04呈递的、由MBOAT2 p.R43Q突变产生的新生抗原AAIWFQTYL的TCR，其是首例能够识别MBOAT2 p.R43Q突变的新生抗原的TCR。针对MBOAT2p.R43Q突变的新生抗原,正常氨基酸序列为AAIWFRTYL，新生抗原氨基酸序列为AAIWFQTYL，抗原呈递分子为HLA-C03:04，发明了一种能够特异性识别MBOAT2 p.R43Q突变的TCR，其可以用于基因编辑改造T细胞，改造过的T细胞能够特异性地识别含有该突变的肿瘤新生抗原，进而可以用于TCR-T疗法，杀死肿瘤细胞。
附图说明
图1为过继性免疫细胞技术示意图；
图2为CAR-T与TCR-T细胞免疫技术示意图；
图3为CAR-T与TCR-T结构示意图；
图4为CAR-T与TCR-T细胞免疫技术原理示意图；
图5为该TCR特异性识别MBOAT2 p.R43Q突变抗原的示意图。
具体实施方式
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。
TCR(T cell receptor)是免疫球蛋白超家族的异二聚体细胞表面蛋白，其与参与介导信号转导的CD3复合体的不变蛋白关联。TCR以αβ和γδ形式存在，其在结构上是类似的，但有截然不同的结构位置和可能有截然不同的功能。天然的异二聚体αβTCR的α和β链是跨膜蛋白，其各自包含两个细胞外结构域，一个近膜恒定结构域，和一个远膜可变结构域。每个恒定和可变结构域包括链内二硫键。可变结构域包含类似于抗体的互补决定区(CDR)的高度多态环。
每个TCR链的可变区包含可变和连接段，对于β链还包含多样性段。每个可变区包含嵌入在框架区序列中的3个CDR(互补决定区)，一个是称为CDR3的高变区。存在由它们的框架，CDR1和CDR2序列，和由部分限定的CDR3序列鉴别的几种类型的α链可变(Vα)区和几种类型的β链可变(Vβ)区。独特的TRAV或TRBV号通过IMGT命名法给予Vα或Vβ。T细胞受体特异性主要由CDR3区决定。
术语“互补决定区”或“CDR”是本领域技术人员熟知的且可互换使用，是指抗体可变区内非连续的氨基酸序列，其赋予TCR抗原特异性和/或结合亲和力。术语“框架区”或“FR”也是本领域已知的，是指抗体可变区内的非CDR部分，其序列通常比较保守。
如本文所用的，术语“能够特异性地识别”，意指TCR可特异性地结合和在免疫学上识别所述表位，优选MBOAT2 p.R43Q。
如本文所用，术语“药学上可接受的赋形剂”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。
如本文所用的宿主细胞，宿主细胞可以是真核细胞，如植物、动物、真菌，或藻类，或可以是原核细胞，如细菌或原生动物。宿主细胞可以是培养的细胞或原代细胞，即直接从生物体，如人中分离的。宿主细胞可以是粘附细胞或悬浮的细胞，即在悬液中生长的细胞。为了产生重组TCR、多肽或蛋白的目的，宿主细胞优选地是哺乳动物细胞。最优选地，宿主细胞是人细胞。虽然宿主细胞可具有任何细胞类型，可源自任何类型的组织，并可具有任何发育阶段，宿主细胞优选地是外周血白细胞(PBL)或外周血单核细胞(PBMC)。更优选地，宿主细胞是T细胞或T细胞前体，特别是，人T细胞。T细胞可以是任何T细胞，例如培养的T细胞，例如原代T细胞，或来自培养的T细胞系的T细胞，例如Jurkat,SupTl等，或从哺乳动物获得的T细胞，优选地，它是来自人患者的T细胞或T细胞前体。T细胞可从许多来源，例如血、骨髓、淋巴结、胸腺，或其它组织或液体获得。T细胞也可被富集或纯化。优选地，T细胞是人T细胞。更优选地，T细胞是从人，如人患者分离的T细胞。T细胞可以是任何类型的T细胞并可具有任何发育阶段，包括但不限于，CD4+和/或CD8+、CD4+辅助T细胞，如Th1和Th2细胞、CD8+T细胞(如细胞毒性T细胞)、肿瘤浸润细胞(TILs)、效应细胞、中枢效应细胞、记忆T细胞、幼稚T细胞等，优选中枢-记忆T细胞。
如本文所用，术语“核酸”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。
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。
纵观过往80年内医药行业发展历程与现状，不难发现，在小分子化学药和大分子生物药迭新换代的同时，现代药物研究热点开始迅速转向新近涌起的细胞治疗(CellTherapy)浪潮。乘着这轮浪潮，过继性免疫疗法(ACT，Adoptive Cell Therapy)技术屡屡突破创新，利用转基因抗原(Antigen)致敏T细胞杀伤肿瘤，逐步从科幻走进现实，人类也终于迎来彻底治愈癌症的曙光，如图1所示。
过继性免疫细胞技术，以利用人体免疫系统杀伤癌细胞、病原体为目的，一般先采集病患自身T细胞，在体外扩增自体T细胞和/或优化该T细胞靶向性后，再向病患回输抗癌能力增强的T细胞；因为以自体T细胞为底物，所以相较手术、化疗、放疗等传统疗法，过继性免疫细胞技术具有低毒副作用、低耐药性等优势。
过继性免疫细胞技术，分为非特异性和特异性两类。相比CIK(细胞因子介导的杀伤细胞，Cytokine Induced Killer)、DC、NK、LAK(淋巴因子激活的杀伤细胞，LymphokineActivated Killer)等非特异性免疫细胞技术，基于CAR-T(嵌合抗原受体-T细胞，ChimericAntigen Receptor T-Cell)或TCR-T(T细胞受体工程化-T细胞，T Cell Receptor-Engineered T Cell)细胞制品的特异性免疫细胞技术能够提高T细胞对肿瘤抗原的识别能力，具有明显靶向性，因此这类技术得到国际医学界广泛认可，成为未来细胞治疗发展方向之一(如图2所示)。
通常情况下，体外培养CAR-T需要向T细胞转染能够识别CD19、BCMA等肿瘤细胞膜表面抗原的嵌合蛋白(CAR，多由抗体抗原结合部与CD3-ζ链或FcεRIγ胞内部分偶联所得)。然而基因改造TCR-T，一般只是在T细胞表面修饰新的抗原受体(TCR)，从而识别MHC(主要组织相容性复合体，Major Histocompatibility Complex)呈递的NY-ESO、MAGE、HBV等癌细胞内部异常蛋白质“MHC-抗原肽(MHC-Peptide)复合物”(如图3所示)。
理论通说认为，CAR可识别的表达在癌细胞膜表面的抗原(靶点)数量约为101级，而CAR无法接触但是TCR可识别的肿瘤细胞内部靶点数量约为107级(如图4所示)；由于TCR-T具有广谱抗癌潜质，因此TCR-T细胞免疫技术现已被陆续应用于黑色素瘤、膀胱癌、肺癌、滑液细胞瘤等多种实体瘤的临床研究。
CAR-T和TCR-T，不仅两者结构上有区别，而且彼此“个性”也不尽相同。由于CAR能够直接与表达在肿瘤细胞膜表面的抗原结合，因此CAR-T同抗原间亲和力很强。然而，因为几乎所有细胞都包含MHC，所以为避免误导T细胞攻击正常细胞，TCR只有在MHC以及该MHC呈递到细胞膜表面的肿瘤细胞内MHC-抗原肽复合物都匹配时，才会与肿瘤细胞内部抗原特异性结合。
虽然TCR-T针对抗原的亲和力很弱，甚至只是CAR-T亲和力的0.1‰到1‰，但是TCR-T却可以异常灵敏地识别变异细胞。大量实验证明，即便在癌细胞表面只存在1个抗原的情况下，TCR-T依然可以响应，然而激活CAR-T杀伤癌细胞信号通路，至少需要癌细胞在膜表面表达300-400个抗原。
因为血液中存在多种白细胞表面天然表达特异性的白细胞分化抗原(CD分子)，而CD分子在白细胞发生癌变时，可以成为CAR-T疗法的理想靶点，所以目前在血液肿瘤临床应用中，特异性CAR-T细胞免疫技术表现优异、疗效显著。但是，由于肿瘤细胞通过正常体细胞变异而来，因此在实体瘤治疗领域内，CAR-T疗法的理想靶点非常少。然而，TCR-T细胞免疫技术直接以来自肿瘤细胞内部，经由肿瘤细胞内抗原呈递(Antigen-presenting)系统处理后，呈递到肿瘤细胞表面MHC分子上的肿瘤新生抗原(Neoantigen)作为靶点，于是TCR-T疗法可能治愈多种实体瘤，具有极其广阔的应用前景。CAR-T与TCR-T细胞免疫两者的比较如下表1所示。
表1 CAR-T与TCR-T细胞免疫技术特点对比
首先用PE标记的链霉亲和素(Invitrogen公司)组合成PE标记的pHLA(短肽序列为AAIWFQTYL，HLA为HLA-C03:04)的四聚体，然后用APC标记的链霉亲和素(Invitrogen公司)组合成APC标记的pHLA(短肽序列为AAIWFQTYL，HLA为HLA-C03:04)的四聚体，通过以上两种四聚体刺激来自于健康志愿者的外周血单核淋巴细胞(PBMC)，分选该四聚体双阳性细胞。利用单细胞逆转录PCR技术，对双阳性的T细胞的T细胞受体(TCR)mRNA序列进行扩增、修饰、二代测序，最终得到抗原特异性TCR的alpha、beta链成对的CDR3序列。alpha、beta链的氨基酸和核苷酸序列如下表2所述：
表2 alpha、beta链的氨基酸和核苷酸序列
针对抗原特异性的TCR，利用CRISPR基因编辑技术，对健康志愿者的外周血的T细胞进行TCR基因编辑。首先，用CRISPR基因编辑技术敲除T细胞原有的TCR alpha和TCRbeta，然后将新发现的抗原特异性TCR导入T细胞中，通过扩增培养后，与抗原四聚体进行共孵育，通过流式细胞术进行表征。结果显示，CD4和CD8 T细胞均可以被特异性抗原四聚体染色(Q2)，而非特异性抗原四聚体无法染色CD4或CD8 T细胞。此结果表明此TCR序列组可以特异性识别MBOAT2 p.R43Q突变抗原，如图5所示。
本具体实施例中的指定方向仅仅是为了便于表述各部件之间位置关系以及相互配合的关系。以上所述仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 新景智源生物科技(苏州)有限公司
<120> 识别MBOAT2的TCR
<160> 18
<170> SIPOSequenceListing 1.0
<210> 1
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 1
Ser Ser Val Ser Val Tyr
1 5
<210> 2
<211> 8
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 2
Tyr Leu Ser Gly Ser Thr Leu Val
1 5
<210> 3
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 3
Cys Ala Val Ser Asp Leu Thr Asn Asn Leu Phe Phe
1 5 10
<210> 4
<211> 5
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 4
Ser Asn His Leu Tyr
1 5
<210> 5
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 5
Phe Tyr Asn Asn Glu Ile
1 5
<210> 6
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 6
Ala Ser Ser Glu Pro Pro Thr Tyr Glu Gln Tyr Phe
1 5 10
<210> 7
<211> 26
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 7
Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val Phe Glu Glu
1 5 10 15
Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser
20 25
<210> 8
<211> 17
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 8
Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln Leu Leu Leu
1 5 10 15
Lys
<210> 9
<211> 33
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 9
Lys Gly Ile Asn Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser
1 5 10 15
Phe His Leu Arg Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr
20 25 30
Phe
<210> 10
<211> 10
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 10
Gly Thr Gly Thr Arg Leu Thr Val Ile Pro
1 5 10
<210> 11
<211> 26
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 11
Glu Pro Glu Val Thr Gln Thr Pro Ser His Gln Val Thr Gln Met Gly
1 5 10 15
Gln Glu Val Ile Leu Arg Cys Val Pro Ile
20 25
<210> 12
<211> 17
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 12
Phe Tyr Trp Tyr Arg Gln Ile Leu Gly Gln Lys Val Glu Phe Leu Val
1 5 10 15
Ser
<210> 13
<211> 38
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 13
Ser Glu Lys Ser Glu Ile Phe Asp Asp Gln Phe Ser Val Glu Arg Pro
1 5 10 15
Asp Gly Ser Asn Phe Thr Leu Lys Ile Arg Ser Thr Lys Leu Glu Asp
20 25 30
Ser Ala Met Tyr Phe Cys
35
<210> 14
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 14
Gly Pro Gly Thr Arg Leu Thr Val Thr
1 5
<210> 15
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 15
Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val Phe Glu Glu
1 5 10 15
Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val Ser Val Tyr
20 25 30
Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln Leu Leu Leu
35 40 45
Lys Tyr Leu Ser Gly Ser Thr Leu Val Lys Gly Ile Asn Gly Phe Glu
50 55 60
Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg Lys Pro Ser
65 70 75 80
Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val Ser Asp Leu
85 90 95
Thr Asn Asn Leu Phe Phe Gly Thr Gly Thr Arg Leu Thr Val Ile Pro
100 105 110
<210> 16
<211> 113
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<400> 16
Glu Pro Glu Val Thr Gln Thr Pro Ser His Gln Val Thr Gln Met Gly
1 5 10 15
Gln Glu Val Ile Leu Arg Cys Val Pro Ile Ser Asn His Leu Tyr Phe
20 25 30
Tyr Trp Tyr Arg Gln Ile Leu Gly Gln Lys Val Glu Phe Leu Val Ser
35 40 45
Phe Tyr Asn Asn Glu Ile Ser Glu Lys Ser Glu Ile Phe Asp Asp Gln
50 55 60
Phe Ser Val Glu Arg Pro Asp Gly Ser Asn Phe Thr Leu Lys Ile Arg
65 70 75 80
Ser Thr Lys Leu Glu Asp Ser Ala Met Tyr Phe Cys Ala Ser Ser Glu
85 90 95
Pro Pro Thr Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val
100 105 110
Thr
<210> 17
<211> 337
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<400> 17
gcccagtctg tgacccagct tgacagccaa gtccctgtct ttgaagaagc ccctgtggag 60
ctgaggtgca actactcatc gtctgtttca gtgtatctct tctggtatgt gcaatacccc 120
aaccaaggac tccagcttct cctgaagtat ttatcaggat ccaccctggt taaaggcatc 180
aacggttttg aggctgaatt taacaagagt caaacttcct tccacttgag gaaaccctca 240
gtccatataa gcgacacggc tgagtacttc tgtgctgtga gtgatcttac aaacaacctc 300
ttctttggga ctggaacgag actcaccgtt attccct 337
<210> 18
<211> 340
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<400> 18
gaacctgaag tcacccagac tcccagccat caggtcacac agatgggaca ggaagtgatc 60
ttgcgctgtg tccccatctc taatcactta tacttctatt ggtacagaca aatcttgggg 120
cagaaagtcg agtttctggt ttccttttat aataatgaaa tctcagagaa gtctgaaata 180
ttcgatgatc aattctcagt tgaaaggcct gatggatcaa atttcactct gaagatccgg 240
tccacaaagc tggaggactc agccatgtac ttctgtgcca gcagtgagcc tcctacctac 300
gagcagtact tcgggccggg caccaggctc acggtcacag 340
Claims (12)
1.识别MBOAT2的TCR，其包括TCRα链和TCRβ链；其中，TCRα链包括互补决定区CDR3，CDR3与选自SEQ ID NO:3的氨基酸序列具有至少70％的序列同一性，TCRβ链包括互补决定区CDR3，CDR3与选自SEQ ID NO:6的氨基酸序列具有至少70％的序列同一性。
2.权利要求1所述的识别MBOAT2的TCR，所述TCRα链包括三个互补决定区CDR1、CDR2和CDR3，其中CDR1选自SEQ ID NO:1，CDR2选自SEQ ID NO:2，CDR3选自SEQ ID NO:3。
3.权利要求2所述的识别MBOAT2的TCR，所述TCRα链还包括四个框架区FR1、FR2、FR3和FR4，其中FR1选自SEQ ID NO:7，FR2选自SEQ ID NO:8，FR3选自SEQ ID NO:9，FR4选自SEQID NO:10。
4.权利要求2或3所述的识别MBOAT2的TCR，所述TCRβ链包括三个互补决定区CDR1、CDR2和CDR3，其中CDR1选自SEQ ID NO:4，CDR2选自SEQ ID NO:5，CDR3选自SEQ ID NO:6。
5.权利要求4中任一项所述的识别MBOAT2的TCR，所述TCRβ链还包括四个框架区FR1、FR2、FR3和FR4，其中FR1选自SEQ ID NO:11，FR2选自SEQ ID NO:12，FR3选自SEQ ID NO:13，FR4选自SEQ ID NO:14。
6.权利要求1～5中任一项所述的识别MBOAT2的TCR，其中所述的识别MBOAT2的TCRα链与选自SEQ ID NO:15的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％序列同一性；所述的识别MBOAT2的TCRβ链与选自SEQ ID NO:16的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％序列同一性。
7.编码权利要求1～6中任一项所述的识别MBOAT2的TCR的核酸分子。
8.权利要求7所述的核酸分子，其特征是：编码所述TCRα链的核酸分子与选自SEQ IDNO:17的核苷酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％序列同一性；编码所述TCRβ链的核酸分子与选自SEQ ID NO:18的核苷酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％序列同一性。
9.宿主细胞，其被工程改造成表达权利要求1～6中任一项所述的识别MBOAT2的TCR。
10.药物组合物，其包括权利要求1～6中任一项所述的识别MBOAT2的TCR和/或权利要求7～8中任一项所述的核酸分子和/或权利要求9所述的宿主细胞以及一种或多种药学上可接受的运载体或赋形剂。
11.权利要求1～6中任一项所述的识别MBOAT2的TCR、权利要求9所述的宿主细胞，权利要求10所述的药物组合物，其用于治疗癌症的方法，所述方法包括过继性疗法。
12.权利要求11所述的识别MBOAT2的TCR、权利要求9所述的宿主细胞，权利要求10所述的药物组合物，所述癌症包括直肠癌和子宫内膜癌。
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