CN117304301A - 一种结合ssx2抗原的tcr分子及其应用 - Google Patents
一种结合ssx2抗原的tcr分子及其应用 Download PDFInfo
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Abstract
本发明提供了一种结合SSX2抗原的TCR分子及其应用,所述TCR分子能够与SSX2抗原短肽复合物AQIPEKIQK‑HLA A1101特异性结合。同时,转导所述TCR的效应细胞还具有很强的杀伤功能。所述TCR可以单独使用,也可与治疗剂联用,还可以用于过继性细胞免疫治疗,以靶向呈递AQIPEKIQK‑HLA A1101复合物肿瘤细胞。
Description
技术领域
本发明属于生物技术领域,涉及一种结合SSX2抗原的TCR分子及其应用,具体涉及一种能够识别衍生自SSX2蛋白多肽的T细胞受体(T cell receptor,TCR)及其制备方法和用途。
背景技术
仅仅有两种类型的分子能够以特异性的方式识别抗原。其中一种是免疫球蛋白或抗体;另一种是T细胞受体(TCR)。TCR是由α链/β链或者γ链/δ链以异二聚体形式存在的细胞膜表面的糖蛋白,在人类中,TCR中95%的T细胞受体由α链和β链组成,分别由TRA和 TRB编码。TCR对pMHC(抗原肽-主要组织相容性复合体)的识别涉及到两种结合:TCR 与MHC分子的结合以及TCR与多肽抗原的结合。
TCR上的结合面来自6个区域:TCRα、β链上各自的CDRl、CDR2以及CDR3。CDR1 与CDR2主要结合相对保守的MHC分子,CDR3则主要结合多变的抗原多肽。这种结合模式可以很好地保证TCR特异地结合MHC分子,并能识别多变的抗原。其中以CDR3的变异最大,直接决定了TCR的抗原结合特异性。
在免疫系统中,通过抗原特异性的TCR与pMHC复合物的结合引发T细胞与抗原呈递细胞(APC)直接的物理接触,然后T细胞及APC两者的其他细胞膜表面分子就发生相互作用,这就引起了一系列后续的细胞信号传递和其他生理反应,从而使得不同抗原特异性的T 细胞对其靶细胞发挥免疫效应。
SSX2是滑膜肉瘤X断点,也被称为HOM-MEL-40。SSX2是SSX家族十种高度同源的核酸蛋白之一。SSX蛋白是肿瘤睾丸抗原,只在肿瘤细胞以及没有MHC表达的睾丸胚细胞中表达。SSX2在多种人类癌细胞中表达,包括但不限于,肝癌、肺癌、纤维肉瘤、乳腺癌、结肠癌、前列腺癌。SSX2在细胞内生成后被降解成小分子多肽,并与MHC(主组织相容性复合体)分子结合形成复合物,被呈递到细胞表面,AQIPEKIQK是衍生自SSX2抗原的短肽。
本发明致力于开发能够结合AQIPEKIQK-HLA A1101复合物且对肿瘤的治疗具有很高的应用价值的TCR。例如,能够靶向该肿瘤细胞标记的TCR可用于将细胞毒性剂或免疫刺激剂递送到靶细胞,或被转化入T细胞,使表达该TCR的T细胞能够破坏肿瘤细胞,以便在被称为过继免疫治疗的治疗过程中给予患者。
发明内容
针对现有技术存在的不足,本发明的目的在于提供一种结合SSX2抗原的TCR分子及其应用。本发明提供了一种特异性识别并结合AQIPEKIQK-HLA A1101复合物的TCR分子,本发明还提供了提供一种所述TCR分子的制备方法及所述TCR分子的用途。
为达到此发明目的,本发明采用以下技术方案:
本发明的第一方面,提供了一种TCR分子,所述TCR分子包含TCRα链可变域和TCRβ链可变域,所述TCR分子具有结合AQIPEKIQK-HLA A1101复合物的活性,并且所述TCRα链可变域的氨基酸序列与SEQ ID NO:1所示的氨基酸序列有至少90%的序列同源性(例如可以是91%、92%、93%、94%、95%、96%、97%、98%、99%或100%);和所述TCRβ链可变域的3个CDR区的氨基酸序列为:
βCDR1-SGHVS (SEQ ID NO:16)
βCDR2-FQNEAQ (SEQ ID NO:17)
βCDR3-ASSLVGYEQY (SEQ ID NO:18)。
在另一优选例中,所述TCRα链可变域的氨基酸序列与SEQ ID NO:1所示的氨基酸序列有至少90%的序列同源性,和所述TCRβ链可变域的氨基酸序列与SEQ ID NO:7所示的氨基酸序列有至少90%的序列同源性(例如可以是91%、92%、93%、94%、95%、96%、97%、 98%、99%或100%)。
在本发明中,所述TCR分子的α链可变域相对于SEQ ID NO:1所示的序列,有1、2、3、4、5、6、7、8、9、10或11个氨基酸残基插入、缺失、替换或其组合。
在本发明中,所述TCR分子的β链可变域相对于SEQ ID NO:7所示的序列,有1、2、3、4、5、6、7、8、9、10或11个氨基酸残基插入、缺失、替换或其组合。
在另一优选例中,所述TCR分子为αβ异质二聚TCR。
优选地,所述TCR分子具有α链恒定区序列TRAC*01和β链恒定区序列TRBC1*01或TRBC2*01。
在另一优选例中,所述TCR分子包含α链恒定区与β链恒定区,所述α链恒定区为鼠的恒定区和/或所述β链恒定区为鼠的恒定区。
在另一优选例中,所述TCR分子的α与β链的恒定区分别为鼠源的α与β链的恒定区。
在另一优选例中,所述TCRα链可变域包含3个CDR区,和所述TCRβ链可变域包含3个CDR区,其中所述TCRβ链可变域的3个CDR区的氨基酸序列为:
βCDR1-SGHVS (SEQ ID NO:16)
βCDR2-FQNEAQ (SEQ ID NO:17)
βCDR3-ASSLVGYEQY (SEQ ID NO:18)。
在另一优选例中,所述TCR分子的α链可变域为与SEQ ID NO:1所示的氨基酸序列有至少95%的序列同源性的氨基酸序列,和所述TCR分子的β链可变域为与SEQ ID NO:7所示的氨基酸序列有至少95%的序列同源性的氨基酸序列。
在另一优选例中,所述TCR分子的β链可变域氨基酸序列为SEQ ID NO:7。
在另一优选例中,所述TCRα链可变域包含3个CDR区,和所述TCRβ链可变域包含3个CDR区,其中所述TCRα链可变域的3个CDR区的氨基酸序列为:
αCDR1-SSYSPS (SEQ ID NO:13)
αCDR2-YTSAATLV (SEQ ID NO:14)
αCDR3-VVSSGNTPLV (SEQ ID NO:15)。
在另一优选例中,所述TCR分子的α链可变域为与SEQ ID NO:1所示的氨基酸序列有至少95%的序列同源性的氨基酸序列;和所述TCRβ链可变域的3个CDR区的氨基酸序列为:
βCDR1-SGHVS (SEQ ID NO:16)
βCDR2-FQNEAQ (SEQ ID NO:17)
βCDR3-ASSLVGYEQY (SEQ ID NO:18)。
在另一优选例中,所述TCR分子的α链可变域为与SEQ ID NO:1所示的氨基酸序列有至少95%的序列同源性的氨基酸序列;和所述TCR分子的β链可变域氨基酸序列为SEQ IDNO:7。
在另一优选例中,所述TCR具有选自下组的CDR,如表1所示:
表1
作为本发明的优选技术方案,所述TCR分子的α链可变域的3个CDR区的氨基酸序列为:
αCDR1-SSYSPS (SEQ ID NO:13)
αCDR2-YTSAATLV (SEQ ID NO:14)
αCDR3-VVSSGNTPLV (SEQ ID NO:15);
所述TCR分子的β链可变域的3个CDR区的氨基酸序列为:
βCDR1-SGHVS (SEQ ID NO:16)
βCDR2-FQNEAQ (SEQ ID NO:17)
βCDR3-ASSLVGYEQY (SEQ ID NO:18)。
作为本发明的优选技术方案,所述TCR分子的α链可变域的3个CDR区的氨基酸序列为:
αCDR1-SSYSPY (SEQ ID NO:24)
αCDR2-YTSAATLV (SEQ ID NO:14)
αCDR3-VISLGNTPLV (SEQ ID NO:25);
所述TCR分子的β链可变域的3个CDR区的氨基酸序列为:
βCDR1-SGHVS (SEQ ID NO:16)
βCDR2-FQNEAQ (SEQ ID NO:17)
βCDR3-ASSLVGYEQY (SEQ ID NO:18)。
在另一优选例中,所述TCR分子的α链可变域氨基酸序列为:SEQ ID NO:1、SEQ IDNO:21之一;和/或所述TCR分子的β链可变域氨基酸序列选自:SEQ ID NO:7。
在另一优选例中,所述TCR分子选自下组:
(1)α链可变域序列为SEQ ID NO:1,和β链可变域序列为SEQ ID NO:7;
(2)α链可变域序列为SEQ ID NO:21,和β链可变域序列为SEQ ID NO:7。
在另一优选例中,所述TCR分子包含(ⅰ)除其跨膜结构域以外的全部或部分TCRα链,和(ⅱ)除其跨膜结构域以外的全部或部分TCRβ链,其中(ⅰ)和(ⅱ)均包含TCR链的可变域和至少一部分恒定域。
在另一优选例中,所述TCR分子的α链恒定区与β链恒定区之间含有人工链间二硫键。
优选地,所述形成人工链间二硫键的半胱氨酸残基取代了选自下列的一组或多组位点:
TRAC*01外显子1的Thr48和TRBC1*01或TRBC2*01外显子1的Ser57;
TRAC*01外显子1的Thr45和TRBC1*01或TRBC2*01外显子1的Ser77;
TRAC*01外显子1的Tyr10和TRBC1*01或TRBC2*01外显子1的Ser17;
TRAC*01外显子1的Thr45和TRBC1*01或TRBC2*01外显子1的Asp59;
TRAC*01外显子1的Ser15和TRBC1*01或TRBC2*01外显子1的Glu15;
TRAC*01外显子1的Arg53和TRBC1*01或TRBC2*01外显子1的Ser54;
TRAC*01外显子1的Pro89和TRBC1*01或TRBC2*01外显子1的Ala19;
或TRAC*01外显子1的Tyr10和TRBC1*01或TRBC2*01外显子1的Glu20。
在另一优选例中,本发明所述TCR分子是人源的。
在另一优选例中,本发明所述TCR分子是人源化的。
在另一优选例中,所述TCR分子是可溶的。
在另一优选例中,所述TCR分子为单链TCR。
优选地,所述单链TCR是α链可变域和β链可变域由一柔性短肽序列(linker)连接而成。
在另一优选例中,所述TCR分子的α链和/或β链的C-或N-末端结合有偶联物。
优选地,所述偶联物包括可检测标记物、治疗剂或PK修饰部分中任意一种或至少两种的组合。
最优选地,与所述TCR分子结合的治疗剂为连接于所述TCR分子的α或β链的C-或N-末端的抗-CD3抗体。
本发明的第二方面,提供了一种多价TCR复合物,所述多价TCR复合物包含至少两个 TCR分子,并且其中的至少一个TCR分子为本发明第一方面所述的TCR分子。
本发明的第三方面,提供了一种核酸分子,所述核酸分子包含编码本发明第一方面所述的TCR分子的核苷酸序列,或编码本发明第一方面所述的TCR分子的核苷酸序列的互补序列。
本发明的第四方面,提供了一种载体,所述载体含有本发明第三方面所述的核酸分子。
优选地,所述载体为病毒载体。
更优选地,所述载体为慢病毒载体。
本发明的第五方面,提供了一种宿主细胞,所述宿主细胞中含有本发明第四方面所述的载体,或所述宿主细胞的基因组中整合有外源的本发明第三方面所述的核酸分子。
本发明的第六方面,提供了一种分离的细胞,所述分离的细胞表达本发明第一方面所述的TCR分子。
优选地,所述分离的细胞包括T细胞、NK细胞或NKT细胞。
在另一优选例中,所述分离的细胞表达本发明第一方面所述的TCR分子,并且还表达外源的CD8受体。
优选地,所述CD8受体是CD8α。
本发明的第七方面,提供了一种药物组合物,所述药物组合物含有本发明第一方面所述的TCR分子、本发明第二方面所述的多价TCR复合物或本发明第六方面所述的分离的细胞中任意一种或至少两种的组合。
优选地,所述药物组合物还含有药学上可接受的载体。
本发明的第八方面,提供了一种治疗疾病的方法,所述治疗疾病的方法包括给需要治疗的对象施用适量的本发明第一方面所述的TCR分子、本发明第二方面所述的多价TCR复合物、本发明第六方面所述的分离的细胞或本发明第七方面所述的药物组合物中任意一种或至少两种的组合。
优选地,所述疾病包括SSX2阳性肿瘤。
本发明的第九方面,提供了本发明第一方面所述的TCR分子、本发明第二方面所述的多价TCR复合物、本发明第六方面所述的分离的细胞中任意一种或至少两种的组合在制备治疗肿瘤或自身免疫疾病的药物中的用途。
优选地,所述肿瘤包括SSX2阳性肿瘤。
本发明的第十方面,提供了本发明第一方面所述的TCR分子、本发明第二方面所述的多价TCR复合物或本发明第六方面所述的分离的细胞中任意一种或至少两种的组合用作治疗肿瘤或自身免疫疾病的药物。
优选地,所述肿瘤包括SSX2阳性肿瘤。
本发明的第十一方面,提供了一种细胞,所述细胞转导有本发明第三方面所述的核酸分子或本发明第四方面所述的载体。
优选地,所述细胞包括T细胞、NK细胞或NKT细胞。
本发明的第十二方面,提供了一种本发明第一方面所述的TCR分子的制备方法,所述制备方法包括如下步骤:
(i)培养本发明第五方面所述的宿主细胞,从而表达本发明第一方面所述的TCR分子;
(ii)分离或纯化出所述TCR分子。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明所述的数值范围不仅包括上述例举的点值,还包括没有例举出的上述数值范围之间的任意的点值,限于篇幅及出于简明的考虑,本发明不再穷尽列举所述范围包括的具体点值。
相对于现有技术,本发明具有以下有益效果:
(1)本发明的TCR分子能够与SSX2抗原短肽复合物AQIPEKIQK-HLA A1101特异性结合。
(2)针对阳性靶细胞,转导本发明TCR分子的效应细胞能够被特异性激活,同时,转导本发明TCR分子的效应细胞还具有很强的杀伤功能。
附图说明
图1为实施例1中单克隆细胞的CD8-APC及四聚体-PE双阳性染色结果。
图2为实施例1中T细胞克隆的ELISPOT激活功能验证结果。
图3a为实施例3中可溶性TCR1的SDS-PAGE电泳胶图,右侧泳道为非还原胶,左侧泳道为分子量标记(marker)。
图3b为实施例3中可溶性TCR1的SDS-PAGE电泳胶图,右侧泳道为还原胶,左侧泳道为分子量标记(marker)。
图3c为实施例3中可溶性TCR2的SDS-PAGE电泳胶图,左侧泳道非还原胶,右侧泳道为分子量标记(marker)。
图3d为实施例3中可溶性TCR2的SDS-PAGE电泳胶图,左侧泳道为还原胶,右侧泳道为分子量标记(marker)。
图4a为实施例4中TCR1与AQIPEKIQK-HLA A1101复合物结合的BIAcore动力学图谱。
图4b为实施例4中TCR2与AQIPEKIQK-HLA A1101复合物结合的BIAcore动力学图谱。
图5为实施例5中针对负载短肽的T2细胞,转染所述TCR2的效应细胞的激活功能实验结果。
图6a为实施例6中针对肿瘤细胞系,转染所述TCR1的效应细胞的激活功能实验结果。
图6b为实施例6中针对肿瘤细胞系,转染所述TCR2的效应细胞的激活功能实验结果。
图7为实施例7中针对肿瘤细胞系,转染所述TCR2的效应细胞的激活功能ELISA实验结果。
图8为实施例8中针对肿瘤细胞系,转染所述TCR2的效应细胞的杀伤功能LDH实验结果。
具体实施方式
在描述本发明之前,应当理解本发明不限于所述的具体方法和实验条件,因为这类方法和条件可以变动。还应当理解本文所用的术语其目的仅在于描述具体实施方案,并且其意图不是限制性的,本发明的范围将仅由所附的权利要求书限制。
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
虽然在本发明的实施或测试中可以使用与本发明中所述相似或等价的任何方法和材料,本文在此处例举优选的方法和材料。
术语
T细胞受体(T cell receptor,TCR)
可以采用国际免疫遗传学信息系统(IMGT)来描述TCR。天然αβ异源二聚TCR具有α链和β链。广义上讲,各链包含可变区(V区)、连接区(J区)和恒定区(C区),β链通常还在可变区和连接区之间含有短的多变区(D区),但所述多变区常视作连接区的一部分。通过独特的IMGT的TRAJ和TRBJ确定TCR的连接区,通过IMGT的TRAC和TRBC确定 TCR的恒定区。
在IMGT命名法中,TRAV和TRBV的不同编号分别指代不同Vα类型和Vβ的类型。在IMGT系统中,α链恒定结构域具有以下的符号:TRAC*01,其中“TR”表示T细胞受体基因;“A”表示α链基因;C表示恒定区;“*01”表示等位基因1。β链恒定结构域具有以下的符号:TRBC1*01或TRBC2*01,其中“TR”表示T细胞受体基因;“B”表示β链基因; C表示恒定区;“*01”表示等位基因1。α链的恒定区是唯一确定的,在β链的形式中,存在两个可能的恒定区基因“C1”和“C2”。本领域技术人员通过公开的IMGT数据库可以获得 TCRα与β链的恒定区基因序列。
TCR的α和β链一般看作各有两个“结构域”即可变域和恒定结构域。可变域由连接的可变区和连接区构成。因此,在本申请的说明书和权利要求书中,“TCRα链可变域”指连接的TRAV和TRAJ区,同样地,“TCRβ链可变域”指连接的TRBV和TRBD/TRBJ区。
各可变区包含嵌合在框架序列中的3个CDR(互补决定区),CDR1、CDR2和CDR3。 TCRα链可变域的3个CDR分别为CDR1α、CDR2α和CDR3α;TCRβ链可变域的3个CDR 分别为CDR1β、CDR2β和CDR3β。本发明TCR可变域的框架序列可以为鼠源的或人源的,优选为人源的。TCR的恒定结构域包含胞内部分、跨膜区和胞外部分。
对AQIPEKIQK-HLA A1101复合物能够特异性结合的野生型TCRα链与β链的胞外氨基酸序列分别如SEQ ID NO:22和SEQ ID NO:23所示。
本发明中所用的TCR序列为人源的。在本发明中,术语“本发明多肽”、“本发明的TCR”、“本发明的T细胞受体”可互换使用。T细胞受体可简称为“TCR分子”或“TCR”。
天然链间二硫键与人工链间二硫键
在天然TCR的近膜区Cα与Cβ链间存在一组二硫键,本发明中称为“天然链间二硫键”。在本发明中,将人工引入的,位置与天然链间二硫键的位置不同的链间共价二硫键称为“人工链间二硫键”。
为方便描述,本发明中TRAC*01与TRBC1*01或TRBC2*01氨基酸序列的位置编号按从N端到C端依次的顺序进行位置编号,如TRBC1*01或TRBC2*01中,按从N端到C端依次的顺序第60个氨基酸为P(脯氨酸),则本发明中可将其描述为TRBC1*01或TRBC2*01 外显子1的Pro60,也可将其表述为TRBC1*01或TRBC2*01外显子1的第60位氨基酸,又如TRBC1*01或TRBC2*01中,按从N端到C端依次的顺序第61个氨基酸为Q(谷氨酰胺),则本发明中可将其描述为TRBC1*01或TRBC2*01外显子1的Gln61,也可将其表述为 TRBC1*01或TRBC2*01外显子1的第61位氨基酸,其他以此类推。本发明中,可变区TRAV 与TRBV的氨基酸序列的位置编号,按照IMGT中列出的位置编号。如TRAV中的某个氨基酸,IMGT中列出的位置编号为46,则本发明中将其描述为TRAV第46位氨基酸,其他以此类推。本发明中,其他氨基酸的序列位置编号有特殊说明的,则按特殊说明。
肿瘤
术语“肿瘤”指包括所有类型的癌细胞生长或致癌过程,转移性组织或恶性转化细胞、组织或器官,不管病理类型或侵染的阶段。肿瘤的实施例非限制性地包括:实体瘤、软组织瘤和转移性病灶。转导本发明的TCR的T细胞可用于治疗靶细胞呈递SSX2抗原短肽AQIPEKIQK-HLA A1101复合物的相关疾病,包括但不限于肿瘤,如结肠癌、乳腺癌等。
发明详述
在抗原加工过程中,抗原在细胞内被降解,然后通过MHC分子携带至细胞表面。T细胞受体能够识别抗原呈递细胞表面的肽-MHC复合物。因此,本发明的第一方面,提供了一种TCR,所述TCR具有结合AQIPEKIQK-HLA A1101复合物的活性,并且所述TCR的TCRα链可变域为与SEQ ID NO:1具有至少90%序列同源性的氨基酸序列(例如可以是至少91%、 92%、93%、94%、95%、96%、97%、98%、99%或100%等),优选为具有至少95%的序列同源性的氨基酸序列;和/或本发明TCRβ链可变域为与SEQ ID NO:7具有至少90%序列同源性的氨基酸序列(例如可以是至少91%、92%、93%、94%、95%、96%、97%、98%、99%或100%等),优选为具有至少95%的序列同源性的氨基酸序列。
在另一优选例中,本发明所述TCR是人源的。
在本发明的一个优选例中,本发明的TCR包含的α链可变域氨基酸序列为SEQ IDNO:1、 SEQ ID NO:21之一;和所述TCR的β链可变域氨基酸序列为SEQ ID NO:7。
TCR对pMHC(抗原肽-主要组织相容性复合体)的识别涉及到两种结合:TCR与MHC分子的结合以及TCR与多肽抗原的结合。TCR上的结合面来自6个区域:TCRα、β链上各自的CDRl、CDR2以及CDR3。CDR1与CDR2主要结合相对保守的MHC分子,CDR3则主要结合多变的抗原多肽。这种结合模式可以很好地保证TCR特异地结合MHC分子,并能识别多变的抗原。其中以CDR3的变异最大,直接决定了TCR的抗原结合特异性。本发明TCR 经测序确定的CDR区如表1所示。
可以将上述本发明的CDR区氨基酸序列嵌入到任何适合的框架结构中来制备嵌合TCR。在本领域中,用性能相近或相似的氨基酸进行取代时,通常不会改变蛋白质的功能。在C末端和/或N末端添加一个或数个氨基酸通常也不会改变蛋白质的结构和功能。因此,本发明 TCR还包括本发明TCR的至多5个,较佳地至多3个,更佳地至多2个,最佳地1个氨基酸(尤其是位于CDR区之外的氨基酸),被性质相似或相近的氨基酸所替换,并仍能够保持其功能性的TCR。
在本发明的一个优选例中,本发明的TCR分子的恒定域是人的恒定域。本领域技术人员知晓或可以通过查阅相关书籍或IMGT(国际免疫遗传学信息系统)的公开数据库来获得人的恒定域氨基酸序列。例如,本发明TCR分子α链的恒定域序列可以为“TRAC*01”,TCR分子β链的恒定域序列可以为“TRBC1*01”或“TRBC2*01”。IMGT的TRAC*01中给出的氨基酸序列的第53位为Arg,在此表示为:TRAC*01外显子1的Arg53,其他以此类推。
在另一优选例中,所述TCR为αβ异质二聚TCR;优选地,所述TCR具有α链恒定区序列TRAC*01和β链恒定区序列TRBC1*01或TRBC2*01。
在本发明的一个优选例中,本发明的TCR分子是由α链的部分或全部,和/或β链的部分或全部组成的单链TCR分子。有关单链TCR分子的描述可以参考文献Chung et al(1994) Proc.Natl.Acad.Sci.USA 91,12654-12658。根据文献中所述,本领域技术人员能够容易地构建包含本发明CDRs区的单链TCR分子。具体地,所述单链TCR分子包含Vα、Vβ和Cβ,优选地按照从N端到C端的顺序连接。
基于本发明的目的,本发明TCR是具有至少一个TCRα和/或TCRβ链可变域的部分。它们通常同时包含TCRα链可变域和TCRβ链可变域。它们可以是αβ异源二聚体或是单链形式或是其他任何能够稳定存在的形式。在过继性免疫治疗中,可将αβ异源二聚TCR的全长链(包含胞质和跨膜结构域)进行转染。本发明TCR可用作将治疗剂递送至抗原呈递细胞的靶向剂或与其他分子结合制备双功能多肽来定向效应细胞,此时TCR优选为可溶形式。
天然存在的TCR是一种膜蛋白,通过其跨膜区得以稳定。如同免疫球蛋白(抗体)作为抗原识别分子一样,TCR也可以被开发应用于诊断和治疗,这时需要获得可溶性的TCR分子。可溶性的TCR分子不包括其跨膜区。可溶性TCR有很广泛的用途,它不仅可用于研究TCR与pMHC的相互作用,也可用作检测感染的诊断工具或作为自身免疫病的标志物。类似地,可溶性TCR可以被用来将治疗剂(如细胞毒素化合物或免疫刺激性化合物)输送到呈递特异性抗原的细胞,另外,可溶性TCR还可与其他分子(如,抗-CD3抗体)结合来重新定向T 细胞,从而使其靶向呈递特定抗原的细胞。
为获得可溶性TCR,一方面,本发明TCR可以是在其α和β链恒定域的残基之间引入人工二硫键的TCR。半胱氨酸残基在所述TCR的α和β链恒定域间形成人工链间二硫键。半胱氨酸残基可以取代在天然TCR中合适位点的其他氨基酸残基以形成人工链间二硫键。例如,取代TRAC*01外显子1的Thr48和取代TRBC1*01或TRBC2*01外显子1的Ser57的半胱氨酸残基来形成二硫键。引入半胱氨酸残基以形成二硫键的其他位点还可以是:
TRAC*01外显子1的Thr45和TRBC1*01或TRBC2*01外显子1的Ser77;
TRAC*01外显子1的Tyr10和TRBC1*01或TRBC2*01外显子1的Ser17;
TRAC*01外显子1的Thr45和TRBC1*01或TRBC2*01外显子1的Asp59;
TRAC*01外显子1的Ser15和TRBC1*01或TRBC2*01外显子1的Glu15;
TRAC*01外显子1的Arg53和TRBC1*01或TRBC2*01外显子1的Ser54;
TRAC*01外显子1的Pro89和TRBC1*01或TRBC2*01外显子1的Ala19;
或TRAC*01外显子1的Tyr10和TRBC1*01或TRBC2*01外显子1的Glu20。
即半胱氨酸残基取代了上述α与β链恒定域中任一组位点。可在本发明TCR恒定域的一个或多个C末端截短最多50个、或最多30个、或最多15个、或最多10个、或最多8个或更少的氨基酸,以使其不包括半胱氨酸残基来达到缺失天然二硫键的目的,也可通过将形成天然二硫键的半胱氨酸残基突变为另一氨基酸来达到上述目的。本发明也获得了对SSX2抗原短肽具有特异性的可溶性TCR。如在本发明实施例3中构建的可溶性TCR,其α链可变域氨基酸序列为SEQ ID NO:19,和β链可变域氨基酸序列为SEQ ID NO:20。
如上所述,本发明的TCR可以包含在其α和β链恒定域的残基间引入的人工二硫键。应注意,恒定域间含或不含上文所述的引入的人工二硫键,本发明的TCR均可含有TRAC恒定域序列,和TRBC1或TRBC2恒定域序列。TCR的TRAC恒定域序列和TRBC1或TRBC2 恒定域序列可通过存在于TCR中的天然二硫键连接。
另外,对于稳定性而言,专利文献201680003540.2还公开了在TCR的α链可变区与β链恒定区之间引入人工链间二硫键能够使TCR的稳定性显著提高。因此,本发明的TCR的α链可变区与β链恒定区之间还可以含有人工链间二硫键。
具体地,在所述TCR的α链可变区与β链恒定区之间形成人工链间二硫键的半胱氨酸残基取代了:
TRAV的第46位氨基酸和TRBC1*01或TRBC2*01外显子1的第60位氨基酸;
TRAV的第47位氨基酸和TRBC1*01或TRBC2*01外显子1的61位氨基酸;
TRAV的第46位氨基酸和TRBC1*01或TRBC2*01外显子1的第61位氨基酸;
或TRAV的第47位氨基酸和TRBC1*01或TRBC2*01外显子1的第60位氨基酸。
优选地,这样的TCR可以包含(ⅰ)除其跨膜结构域以外的全部或部分TCRα链,和(ⅱ) 除其跨膜结构域以外的全部或部分TCRβ链,其中(ⅰ)和(ⅱ)均包含TCR链的可变域和至少一部分恒定域,α链与β链形成异质二聚体。
更优选地,这样的TCR可以包含α链可变域和β链可变域以及除跨膜结构域以外的全部或部分β链恒定域,但其不包含α链恒定域,所述TCR的α链可变域与β链形成异质二聚体。
突变可采用任何合适的方法进行,包括但不限于依据聚合酶链式反应(PCR)、依据限制性酶的克隆或不依赖连接的克隆(LIC)方法。许多标准分子生物学教材详述了这些方法。聚合酶链式反应(PCR)诱变和依据限制性酶的克隆的更多细节可参见Sambrook和Russell, (2001)分子克隆-实验室手册(Molecular Cloning-A Laboratory Manual)(第三版)CSHL出版社。 LIC方法的更多信息可见(Rashtchian,(1995)Curr Opin Biotechnol6(1):30-6)。
产生突变的方法可以是但不限于从展示此类TCR的噬菌体颗粒的多样性文库中筛选出对AQIPEKIQK-HLA A1101复合物特异性结合的TCR,如文献(Li,et al(2005)NatureBiotech 23(3):349-354)中所述。
本发明的TCR也可以多价复合体的形式提供。本发明的多价TCR复合体包含两个、三个、四个或更多个本发明TCR相结合而形成的多聚物,如可以用p53的四聚结构域来产生四聚体,或多个本发明TCR与另一分子结合而形成的复合物。本发明的TCR复合物可用于体外或体内追踪或靶向呈递特定抗原的细胞,也可用于产生具有此类应用的其他多价TCR复合物的中间体。
本发明的TCR可以单独使用,也可与偶联物以共价或其他方式结合,优选以共价方式结合。所述偶联物包括可检测标记物(为诊断目的,其中所述TCR用于检测呈递AQIPEKIQK-HLA A1101复合物的细胞的存在)、治疗剂、PK(蛋白激酶)修饰部分或任何以上这些物质的组合结合或偶联。
用于诊断目的的可检测标记物包括但不限于:荧光或发光标记物、放射性标记物、MRI (磁共振成像)或CT(电子计算机X射线断层扫描技术)造影剂、或能够产生可检测产物的酶。
可与本发明TCR结合或偶联的治疗剂包括但不限于:
1.放射性核素(Koppe等,2005,癌转移评论(Cancer metastasis reviews)24,539);
2.生物毒(Chaudhary等,1989,自然(Nature)339,394;Epel等,2002,癌症免疫学和免疫治疗(Cancer Immunology and Immunotherapy)51,565);
3.细胞因子如IL-2等(Gillies等,1992,美国国家科学院院刊(PNAS)89,1428;Card 等,2004,癌症免疫学和免疫治疗(Cancer Immunology and Immunotherapy)53,345;Halin等, 2003,癌症研究(Cancer Research)63,3202);
4.抗体Fc片段(Mosquera等,2005,免疫学杂志(The Journal Of Immunology)174,4381);
5.抗体scFv片段(Zhu等,1995,癌症国际期刊(International Journal ofCancer)62,319);
6.金纳米颗粒/纳米棒(Lapotko等,2005,癌症通信(Cancer letters)239,36;Huang等, 2006,美国化学学会杂志(Journal of the American Chemical Society)128,2115);
7.病毒颗粒(Peng等,2004,基因治疗(Gene therapy)11,1234);
8.脂质体(Mamot等,2005,癌症研究(Cancer research)65,11631);
9.纳米磁粒;
10.前药激活酶(例如,DT-心肌黄酶(DTD)或联苯基水解酶-样蛋白质(BPHL));
11.化疗剂(例如,顺铂)或任何形式的纳米颗粒等。
与本发明TCR结合的抗体或其片段包括抗-T细胞或NK-细胞决定抗体,如抗-CD3、抗 -CD28或抗-CD16抗体,上述抗体或其片段与TCR的结合能够对效应细胞进行定向来更好地靶向靶细胞。一个优选的实施方式是本发明TCR与抗-CD3抗体或所述抗-CD3抗体的功能片段或变体结合。具体地,本发明的TCR与抗CD3单链抗体的融合分子包括选自:(1)TCRα链可变域氨基酸序列为SEQ ID NO:1、SEQ ID NO:21之一,和所述TCR的β链可变域氨基酸序列为SEQ ID NO:7。
本发明还涉及编码本发明TCR的核酸分子。本发明的核酸分子可以是DNA形式或RNA 形式。DNA可以是编码链或非编码链。例如,编码本发明TCR的核酸序列可以与本发明序列表中所示的核酸序列相同或是简并的变异体。举例说明“简并的变异体”的含义,如本文所用,“简并的变异体”在本发明中是指编码具有SEQ ID NO:1的蛋白序列,但与SEQ ID NO:2 的序列有差别的核酸序列。
本发明的核酸分子全长序列或其片段通常可以用但不限于PCR扩增法、重组法或人工合成的方法获得。目前,已经可以完全通过化学合成来得到编码本发明TCR(或其片段,或其衍生物)的DNA序列。然后可将所述DNA序列引入本领域中已知的各种现有的DNA分子(或如载体)和细胞中。
本发明也涉及包含本发明的核酸分子的载体,以及用本发明的载体或编码序列经基因工程产生的宿主细胞。
所述包含本发明的核酸分子的载体,包括表达载体,即能够在体内或体外表达的构建体。常用的载体包括细菌质粒、噬菌体和动植物病毒。病毒递送系统包括但不限于腺病毒载体、腺相关病毒(AAV)载体、疱疹病毒载体、逆转录病毒载体、慢病毒载体或杆状病毒载体。优选地,所述载体可以将本发明的核苷酸转移至细胞中,例如T细胞中,使得所述细胞表达 HPV16E6抗原特异性的TCR。理想的情况下,所述载体应当能够在T细胞中持续高水平地表达。
所述宿主细胞中含有本发明的载体或所述宿主细胞的染色体中整合有本发明的核酸分子。宿主细胞选自:原核细胞和真核细胞,例如大肠杆菌、酵母细胞或CHO细胞等。
另外,本发明还包括表达本发明的TCR的分离的细胞,可以为T细胞、NK细胞、NKT细胞等,优选为T细胞。所述T细胞可衍生自从受试者分离的T细胞,或者可以是从受试者中分离的混合细胞群,诸如外周血淋巴细胞(PBL)群的一部分。如,所述细胞可以分离自外周血单核细胞(PBMC),可以是CD4+辅助T细胞或CD8+细胞毒性T细胞。所述细胞可在 CD4+辅助T细胞/CD8+细胞毒性T细胞的混合群中。一般地,所述细胞可以用抗体(如,抗 -CD3或抗-CD28的抗体)活化,以便使它们能够更容易接受转染,例如用包含编码本发明 TCR分子的核苷酸序列的载体进行转染。
备选地,本发明的细胞还可以是或衍生自干细胞,如造血干细胞(HSC)。将基因转移至HSC不会导致在细胞表面表达TCR,因为干细胞表面不表达CD3分子。然而,当干细胞分化为迁移至胸腺的淋巴前体(lymphoid precursor)时,CD3分子的表达将启动在胸腺细胞的表面表达引入的TCR分子。
有许多方法适合于用编码本发明TCR的DNA或RNA进行T细胞转染(如,Robbins等.,(2008)J.Immunol.180:6116-6131)。表达本发明TCR的T细胞可以用于过继免疫治疗。本领域技术人员能够知晓进行过继性治疗的许多合适方法(如,Rosenberg等.,(2008)Nat RevCancer8(4):299-308)。
本发明还提供一种药物组合物,所述药物组合物含有药学上可接受的载体以及本发明 TCR、本发明TCR复合物或呈递本发明TCR的细胞。
本发明还提供了一种治疗疾病的方法,包括给需要治疗的对象施用适量的本发明TCR、本发明TCR复合物、呈递本发明TCR的细胞或本发明的药物组合物。
本发明的TCR、TCR复合物或本发明TCR转染的T细胞可与药学上可接受的载体一起在药物组合物中提供。本发明的TCR、多价TCR复合物或细胞通常作为无菌药物组合物的一部分提供,所述组合物通常包括药学上可接受的载体。所述药物组合物可以是任何合适的形式(取决于给予患者的所需方法)。其可采用单位剂型提供,通常在密封的容器中提供,可作为试剂盒的一部分提供。此类试剂盒(但非必需)包括使用说明书。其可包括多个所述单位剂型。
此外,本发明的TCR可以单用,也可与其他治疗剂结合或偶联在一起使用(如配制在同一药物组合物中)。
所述药物组合物还可含有药学上可接受的载体。术语“药学上可接受的载体”指用于治疗剂给药的载体。所述术语指这样一些药剂载体:它们本身不诱导产生对接受所述药物组合物的个体有害的抗体,且给药后没有过分的毒性。这些载体是本领域普通技术人员所熟知的。在雷明顿药物科学(Remington's Pharmaceutical Sciences(Mack Pub.Co.,N.J.1991))中可找到关于药学上可接受的赋形剂的充分讨论。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、佐剂及其组合。
治疗性组合物中药学上可接受的载体可含有液体,如水、盐水、甘油和乙醇。另外,所述载体中还可能存在辅助性的物质,如润湿剂或乳化剂、pH缓冲物质等。
通常,可将治疗性组合物制成可注射剂,例如液体溶液或悬液;还可制成在注射前适合配入溶液或悬液中、液体载体的固体形式。
一旦配成本发明的组合物,可将其通过常规途径进行给药,其中包括(但并不限于):眼内、肌内、静脉内、皮下、皮内或局部给药,优选为胃肠外包括皮下、肌肉内或静脉内。待预防或治疗的对象可以是动物;尤其是人。
当本发明的药物组合物被用于实际治疗时,可根据使用情况而采用各种不同剂型的药物组合物。较佳地,可以例举的有针剂、口服剂等。
所述药物组合物可根据常规方法通过混合、稀释或溶解而进行配制,并且偶尔添加合适的药物添加剂,如赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、等渗剂(isotonicities)、防腐剂、润湿剂、乳化剂、分散剂、稳定剂和助溶剂,而且配制过程可根据剂型用惯常方式进行。
本发明的药物组合物还可以缓释剂形式给药。例如,本发明TCR可被掺入以缓释聚合物为载体的药丸或微囊中,然后将该药丸或微囊通过手术植入待治疗的组织。作为缓释聚合物的例子,可例举的有乙烯-乙烯基乙酸酯共聚物、聚羟基甲基丙烯酸酯(polyhydrometaacrylate)、聚丙烯酰胺、聚乙烯吡咯烷酮、甲基纤维素、乳酸聚合物或乳酸-乙醇酸共聚物等,较佳地,可例举的是可生物降解的聚合物,如乳酸聚合物和乳酸-乙醇酸共聚物。
本发明提供了一种治疗SSX2相关疾病的方法,所述方法包括将分离的表达本发明TCR 的T细胞输入到病人体内;优选地,所述T细胞来源于病人本身。一般地,包括(1)分离病人的T细胞;(2)用本发明核酸分子或能够编码本发明TCR分子的核酸分子体外转导T 细胞;(3)将基因工程修饰的T细胞输入到病人体内。当本发明的药物组合物被用于实际治疗时,作为活性成分的本发明TCR或TCR复合物或呈递本发明TCR的细胞,可根据待治疗的每个病人的体重、年龄、性别、症状程度而合理地加以确定,最终由医师决定合理的用量。
另外,本发明的TCR还可以是包含衍生自超过一种物种序列的杂合TCR。例如,有研究显示鼠科TCR在人T细胞中比人TCR能够更有效地表达。因此,本发明TCR可包含人可变域和鼠的恒定域。这一方法的缺陷是可能引发免疫应答。因此,在其用于过继性T细胞治疗时应当有调节方案来进行免疫抑制,以允许表达鼠科的T细胞的植入。
应理解,本文中氨基酸名称采用国际通用的单英文字母或三英文字母表示,氨基酸名称的单英文字母与三英文字母的对应关系如下:Ala(A)、Arg(R)、Asn(N)、Asp(D)、Cys(C)、 Gln(Q)、Glu(E)、Gly(G)、His(H)、Ile(I)、Leu(L)、Lys(K)、Met(M)、Phe(F)、Pro(P)、Ser(S)、Thr(T)、Trp(W)、Tyr(Y)、Val(V)。
下面的具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。另外,下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的部分实施例,而不是全部。
下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如(Sambrook和Russell 等人,分子克隆:实验室手册(Molecular Cloning-A Laboratory Manual)(第三版)(2001)CSHL 出版社)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。其中, E.coli DH5α购自Tiangen、E.coli BL21(DE3)购自Tiangen、E.coliTuner(DE3)购自Novagen、质粒pET28a购自Novagen。
本发明的主要优点在于:
(1)本发明的TCR能够与SSX2抗原短肽复合物AQIPEKIQK-HLA A1101特异性结合。
(2)针对阳性靶细胞,转导本发明TCR的效应细胞能够被特异性激活,同时,转导本发明TCR的效应细胞还具有很强的杀伤功能。
本发明中所涉及的序列如下所示:
SEQ ID NO:1:
AQSVTQLDSHVSVSEGTPVLLRCNYSSSYSPSLFWYVQHPNKGLQLLLKYTSAATLVK GINGFEAEFKKSETSFHLTKPSAHMSDAAEYFCVVSSGNTPLVFGKGTRLSVIA。
SEQ ID NO:2:
gcccagtcggtgacccagcttgacagccacgtctctgtctctgaaggaaccccggtgctgctgaggtgcaactactcatcttcttattcac cgtctctcttctggtatgtgcaacaccccaacaaaggactccagcttctcctgaagtacacatcagcggccaccctggttaaaggcatcaacggtt ttgaggctgaatttaagaagagtgaaacctccttccacctgacgaaaccctcagcccatatgagcgacgcggctgagtacttctgtgttgtgagct caggaaacacacctcttgtctttggaaagggcacaagactttctgtgattgca。
SEQ ID NO:3:
AQSVTQLDSHVSVSEGTPVLLRCNYSSSYSPSLFWYVQHPNKGLQLLLKYTSAATLVK GINGFEAEFKKSETSFHLTKPSAHMSDAAEYFCVVSSGNTPLVFGKGTRLSVIANIQNPDPAV YQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKS DFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLL MTLRLWSS。
SEQ ID NO:4:
gcccagtcggtgacccagcttgacagccacgtctctgtctctgaaggaaccccggtgctgctgaggtgcaactactcatcttcttattcac cgtctctcttctggtatgtgcaacaccccaacaaaggactccagcttctcctgaagtacacatcagcggccaccctggttaaaggcatcaacggtt ttgaggctgaatttaagaagagtgaaacctccttccacctgacgaaaccctcagcccatatgagcgacgcggctgagtacttctgtgttgtgagct caggaaacacacctcttgtctttggaaagggcacaagactttctgtgattgcaaatAtccagaaccctgaccctgccgtgtaccagctgagagac tctaaatccagtgacaagtctgtctgcctattcaccgattttgattctcaaacaaatgtgtcacaaagtaaggattctgatgtgtatatcacagacaaa actgtgctagacatgaggtctatggacttcaagagcaacagtgctgtggcctggagcaacaaatctgactttgcatgtgcaaacgccttcaacaa cagcattattccagaagacaccttcttccccagcccagaaagttcctgtgatgtcaagctggtcgagaaaagctttgaaacagatacgaacctaaa ctttcaaaacctgtcagtgattgggttccgaatcctcctcctgaaagtggccgggtttaatctgctcatgacgctgcggctgtggtccagc。
SEQ ID NO:5:
LLLLVPVLEVIFTLGGTRAQSVTQLDSHVSVSEGTPVLLRCNYSSSYSPSLFWYVQHPN KGLQLLLKYTSAATLVKGINGFEAEFKKSETSFHLTKPSAHMSDAAEYFCVVSSGNTPLVFG KGTRLSVIANIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDM RSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNL SVIGFRILLLKVAGFNLLMTLRLWSS。
SEQ ID NO:6:
ctcctgctgctcgtcccagtgctcgaggtgatttttaccctgggaggaaccagagcccagtcggtgacccagcttgacagccacgtctct gtctctgaaggaaccccggtgctgctgaggtgcaactactcatcttcttattcaccgtctctcttctggtatgtgcaacaccccaacaaaggactcc agcttctcctgaagtacacatcagcggccaccctggttaaaggcatcaacggttttgaggctgaatttaagaagagtgaaacctccttccacctga cgaaaccctcagcccatatgagcgacgcggctgagtacttctgtgttgtgagctcaggaaacacacctcttgtctttggaaagggcacaagacttt ctgtgattgcaaatAtccagaaccctgaccctgccgtgtaccagctgagagactctaaatccagtgacaagtctgtctgcctattcaccgattttga ttctcaaacaaatgtgtcacaaagtaaggattctgatgtgtatatcacagacaaaactgtgctagacatgaggtctatggacttcaagagcaacagt gctgtggcctggagcaacaaatctgactttgcatgtgcaaacgccttcaacaacagcattattccagaagacaccttcttccccagcccagaaagttcctgtgatgtcaagctggtcgagaaaagctttgaaacagatacgaacctaaactttcaaaacctgtcagtgattgggttccgaatcctcctcctga aagtggccgggtttaatctgctcatgacgctgcggctgtggtccagc。
SEQ ID NO:7:
GAGVSQSPRYKVAKRGQDVALRCDPISGHVSLFWYQQALGQGPEFLTYFQNEAQLDK SGLPSDRFFAERPEGSVSTLKIQRTQQEDSAVYLCASSLVGYEQYFGPGTRLTVT。
SEQ ID NO:8:
ggtgctggagtctcccagtcccctaggtacaaagtcgcaaagagaggacaggatgtagctctcaggtgtgatccaatttcgggtcatgta tcccttttttggtaccaacaggccctggggcaggggccagagtttctgacttatttccagaatgaagctcaactagacaaatcggggctgcccagt gatcgcttctttgcagaaaggcctgagggatccgtctccactctgaagatccagcgcacacagcaggaggactccgccgtgtatctctgtgcca gcagcttagtcggctacgagcagtacttcgggccgggcaccaggctcacggtcaca。
SEQ ID NO:9:
GAGVSQSPRYKVAKRGQDVALRCDPISGHVSLFWYQQALGQGPEFLTYFQNEAQLDK SGLPSDRFFAERPEGSVSTLKIQRTQQEDSAVYLCASSLVGYEQYFGPGTRLTVTEDLKNVFP PEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPAL NDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRA DCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG。
SEQ ID NO:10:
ggtgctggagtctcccagtcccctaggtacaaagtcgcaaagagaggacaggatgtagctctcaggtgtgatccaatttcgggtcatgta tcccttttttggtaccaacaggccctggggcaggggccagagtttctgacttatttccagaatgaagctcaactagacaaatcggggctgcccagt gatcgcttctttgcagaaaggcctgagggatccgtctccactctgaagatccagcgcacacagcaggaggactccgccgtgtatctctgtgcca gcagcttagtcggctacgagcagtacttcgggccgggcaccaggctcacggtcacaGaggacctgaaaaacgtgttcccacccgaggtcgct gtgtttgagccatcagaagcagagatctcccacacccaaaaggccacactggtgtgcctggccacaggcttctaccccgaccacgtggagctg agctggtgggtgaatgggaaggaggtgcacagtggggtcagcacagacccgcagcccctcaaggagcagcccgccctcaatgactccagat actgcctgagcagccgcctgagggtctcggccaccttctggcagaacccccgcaaccacttccgctgtcaagtccagttctacgggctctcgga gaatgacgagtggacccaggatagggccaaacctgtcacccagatcgtcagcgccgaggcctggggtagagcagactgtggcttcacctcc gagtcttaccagcaaggggtcctgtctgccaccatcctctatgagatcttgctagggaaggccaccttgtatgccgtgctggtcagtgccctcgtg ctgatggccatggtcaagagaaaggattccagaggc。
SEQ ID NO:11:
GTRLLCWVVLGFLGTDHTGAGVSQSPRYKVAKRGQDVALRCDPISGHVSLFWYQQAL GQGPEFLTYFQNEAQLDKSGLPSDRFFAERPEGSVSTLKIQRTQQEDSAVYLCASSLVGYEQ YFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKE VHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQ DRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMV KRKDSRG。
SEQ ID NO:12:
ggcaccaggctcctctgctgggtggtcctgggtttcctagggacagatcacacaggtgctggagtctcccagtcccctaggtacaaagtc gcaaagagaggacaggatgtagctctcaggtgtgatccaatttcgggtcatgtatcccttttttggtaccaacaggccctggggcaggggccag agtttctgacttatttccagaatgaagctcaactagacaaatcggggctgcccagtgatcgcttctttgcagaaaggcctgagggatccgtctcca ctctgaagatccagcgcacacagcaggaggactccgccgtgtatctctgtgccagcagcttagtcggctacgagcagtacttcgggccgggca ccaggctcacggtcacaGaggacctgaaaaacgtgttcccacccgaggtcgctgtgtttgagccatcagaagcagagatctcccacacccaa aaggccacactggtgtgcctggccacaggcttctaccccgaccacgtggagctgagctggtgggtgaatgggaaggaggtgcacagtgggg tcagcacagacccgcagcccctcaaggagcagcccgccctcaatgactccagatactgcctgagcagccgcctgagggtctcggccaccttc tggcagaacccccgcaaccacttccgctgtcaagtccagttctacgggctctcggagaatgacgagtggacccaggatagggccaaacctgtc acccagatcgtcagcgccgaggcctggggtagagcagactgtggcttcacctccgagtcttaccagcaaggggtcctgtctgccaccatcctct atgagatcttgctagggaaggccaccttgtatgccgtgctggtcagtgccctcgtgctgatggccatggtcaagagaaaggattccagaggc。
SEQ ID NO:13:
SSYSPS。
SEQ ID NO:14:
YTSAATLV。
SEQ ID NO:15:
VVSSGNTPLV。
SEQ ID NO:16:
SGHVS。
SEQ ID NO:17:
FQNEAQ。
SEQ ID NO:18:
ASSLVGYEQY。
SEQ ID NO:19:
AQSVTQLDSHVSVSEGTPVLLRCNYSSSYSPSLFWYVQHPNKGLQLLLKYTSAATLVK GINGFEAEFKKSETSFHLTKPSAHMSDAAEYFCVVSSGNTPLVFGKGTRLSVIANIQNPDPAV YQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKS DFACANAFNNSIIPEDTFFCSPESS。
SEQ ID NO:20:
GAGVSQSPRYKVAKRGQDVALRCDPISGHVSLFWYQQALGQGPEFLTYFQNEAQLDK SGLPSDRFFAERPEGSVSTLKIQRTQQEDSAVYLCASSLVGYEQYFGPGTRLTVTEDLKNVFP PEVAVFEPSECEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPAL NDSRYALSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRA D。
SEQ ID NO:21:
AQSVTQLDSHVSVSEGTPVLLRCNYSSSYSPYLFWYVQHPNKGLQLLLKYTSAATLVK GINGFEAEFKKSETSFHLTKPSAHMSDAAEYFCVISLGNTPLVFGKGTRLSVIA。
SEQ ID NO:22:
AQSVTQLDSHVSVSEGTPVLLRCNYSSSYSPSLFWYVQHPNKGLQLLLKYTSAATLVK GINGFEAEFKKSETSFHLTKPSAHMSDAAEYFCVVSSGNTPLVFGKGTRLSVIANIQNPDPAV YQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKS DFACANAFNNSIIPEDTFFPSPESS。
SEQ ID NO:23:
GAGVSQSPRYKVAKRGQDVALRCDPISGHVSLFWYQQALGQGPEFLTYFQNEAQLDK SGLPSDRFFAERPEGSVSTLKIQRTQQEDSAVYLCASSLVGYEQYFGPGTRLTVTEDLKNVFP PEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPAL NDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRA D。
SEQ ID NO:24:
SSYSPY。
SEQ ID NO:25:
VISLGNTPLV。
实施例1克隆SSX2抗原短肽特异性T细胞
利用合成短肽AQIPEKIQK(由江苏金斯瑞生物科技有限公司合成)刺激来自于基因型为HLA-A1101的健康志愿者的外周血淋巴细胞(PBL)。将AQIPEKIQK短肽与带有生物素标记的HLA-A1101复性,制备pMHC单倍体。这些单倍体与用PE标记的链霉亲和素(BD 公司)组合成PE标记的四聚体,分选所述四聚体及抗-CD8-APC双阳性细胞。扩增分选的细胞,并按上述方法进行二次分选,随后用有限稀释法进行单克隆。单克隆细胞用四聚体染色,筛选到的双阳性克隆,单克隆细胞的CD8-APC及四聚体-PE双阳性染色结果如图1所示。经过层层筛选得到的双阳性克隆,还需要满足进一步的功能测试。
IFN-γ是活化T淋巴细胞产生的一种强有力的免疫调节因子,因此本实施例通过本领域技术人员熟知的ELISPOT实验检测IFN-γ数以验证转染本发明TCR的细胞的激活功能及抗原特异性。通过ELISPOT实验进一步检测所述T细胞克隆的功能及特异性。本实施例IFN-γ ELISPOT实验中所用的效应细胞为本实施例中获得的T细胞克隆,靶细胞为负载了AQIPEKIQK短肽的T2-A11(指转染HLA-A1101的T2细胞)、K562-A11-SSX2(指转染 HLA-A1101及SSX2的K562细胞),对照组为负载了其他抗原短肽的T2-A11和SW1088(人脑星型胶质瘤细胞)。其中,T2细胞和K562细胞均购自ATCC,SW1088购自广州赛库生物技术有限公司。
首先准备ELISPOT平板,ELISPOT实验步骤如下:按以下顺序将试验的各个组分加入 ELISPOT平板:靶细胞20000个/孔、效应细胞2000个/孔后,在实验组和对照组加入20μL相应的短肽,T2-A11负载的短肽终浓度为10-5M,空白组加入20μL培养基(试验培养基),并设置2复孔。然后温育过夜(37℃,5%CO2)。随后洗涤平板并进行二级检测和显色,干燥平板1h,再利用免疫斑点平板读数计(ELISPOT READER system;AID公司)计数膜上形成的斑点。T细胞克隆的ELISPOT激活功能验证结果如图2所示,得到的T细胞克隆对负载了AQIPEKIQK短肽的T2-A11和K562-A11-SSX2高释放IFN-γ,而对负载了其他抗原短肽的T2-A11及SW1088基本无反应。
实施例2获取SSX2抗原短肽特异性TCR
用Quick-RNATM MiniPrep(ZYMO research)抽提实施例1中筛选到的抗原短肽AQIPEKIQK特异性、HLA-A1101限制性的T细胞克隆(双阳性克隆)的总RNA。cDNA的合成采用clontech的SMART RACE cDNA扩增试剂盒,采用的引物是设计在人类TCR基因的C端保守区。将序列克隆至T载体(TAKARA)上进行测序。应注意,所述序列为互补序列,不包含内含子。
经测序,所述双阳性克隆表达的TCR的α链和β链序列如下所示:
TCRα链可变域氨基酸序列 (SEQ ID NO:1)
TCRα链可变域核苷酸序列 (SEQ ID NO:2)
TCRα链氨基酸序列 (SEQ ID NO:3)
TCRα链核苷酸序列 (SEQ ID NO:4)
具有前导序列的TCRα链氨基酸序列 (SEQ ID NO:5)
具有前导序列的TCRα链核苷酸序列 (SEQ ID NO:6);
TCRβ链可变域氨基酸序列 (SEQ ID NO:7)
TCRβ链可变域核苷酸序列 (SEQ ID NO:8)
TCRβ链氨基酸序列 (SEQ ID NO:9)
TCRβ链核苷酸序列 (SEQ ID NO:10)
具有前导序列的TCRβ链氨基酸序列 (SEQ ID NO:11)
具有前导序列的TCRβ链核苷酸序列 (SEQ ID NO:12)。
为方便描述,将其命名为TCR1。经鉴定,TCR1的α链包含具有以下氨基酸序列的CDR:
αCDR1-SSYSPS (SEQ ID NO:13)
αCDR2-YTSAATLV (SEQ ID NO:14)
αCDR3-VVSSGNTPLV (SEQ ID NO:15)
TCR1的β链包含具有以下氨基酸序列的CDR:
βCDR1-SGHVS (SEQ ID NO:16)
βCDR2-FQNEAQ (SEQ ID NO:17)
βCDR3-ASSLVGYEQY (SEQ ID NO:18)。
本实施例进一步采用本领域技术人员熟知的定点突变的方法将Li等((2005)Nature Biotech 23(3):349-354)描述的TCR噬菌体展示和筛选方法应用于TCR1,突变后获得TCR2。利用BIAcore的结合表征可知,上述TCR2同样能够与复合物AQIPEKIQK-HLA A1101特异性结合。另外,本发明还意外地发现,针对SSX2阳性靶细胞系,转导了TCR2的效应细胞同样能够被特异性激活并具有很强的杀伤功能。TCR2的α链与TCR1的α链有至少95%的序列同源性。
具体地,相较于TCR1,TCR2在α链的CDR区中有3个突变,突变以双下划线标注,具体的CDR如表2所示:
表2
更具体地,本实施例的TCR的α和β链的可变域序列如下:
(1)TCR1:α链可变域序列为SEQ ID NO:1,β可变域序列为SEQ ID NO:7,解离平衡常数KD为2.41E-03M;
(2)TCR2:α链可变域序列为SEQ ID NO:21(其中突变的残基以加下划线表示),β可变域序列为SEQ ID NO:7,解离平衡常数KD为1.94E-05M。
实施例3SSX2抗原短肽特异性可溶TCR的表达、重折叠和纯化
本实施例在TCR的α和β链的恒定域中分别引入了一个半胱氨酸残基以形成人工链间二硫键,从而获得稳定的可溶的TCR分子(包括可溶的TCR1分子和可溶的TCR2分子),以便评估TCR与复合物AQIPEKIQK-HLA A1101之间的相互作用。所述可溶的TCR1分子的α链的氨基酸序列为SEQ ID NO:19,其中突变后的半胱氨酸残基以加粗字母表示;β链的氨基酸序列为SEQ ID NO:20,其中突变后的半胱氨酸残基以加粗字母表示。所述可溶的TCR2分子的α链的氨基酸序列为SEQ ID NO:24,其中突变后的半胱氨酸残基以加粗字母表示;β链的氨基酸序列为SEQ ID NO:25,其中突变后的半胱氨酸残基以加粗字母表示。
通过《分子克隆实验室手册》(Molecular Cloning a Laboratory Manual)(第三版,Sambrook 和Russell)中描述的标准方法将上述TCRα和β链的目的基因序列经合成后分别插入到表达载体pET28a+(Novagene),上下游的克隆位点分别是Nco I和Not I。插入片段经过测序确认无误。
将TCRα链和TCRβ链的表达载体分别通过化学转化法转化进入表达细菌BL21(DE3),细菌用LB培养基培养,于OD600=0.6时用终浓度0.5mM IPTG诱导,TCR的α和β链表达后形成的包涵体通过BugBuster Mix(Novagene)进行提取,并且经BugBuster溶液反复多次洗涤,包涵体最后溶解于缓冲液中(6M盐酸胍,10mM二硫苏糖醇(DTT),10mM乙二胺四乙酸(EDTA),20mM Tris,pH8.1)。
溶解后的TCRα链和TCRβ链以1:1的质量比快速混合于缓冲液中(5M尿素,0.4M精氨酸,20mM Tris(pH8.1),3.7mM cystamine,6.6mMβ-mercapoethylamine,4℃),终浓度为60mg/mL。混合后将溶液置于10倍体积的去离子水中透析(4℃),12h后将去离子水换成缓冲液(20mM Tris,pH8.0)继续于4℃透析12h。透析完成后的溶液经0.45μm的滤膜过滤后,通过阴离子交换柱(HiTrap Q HP,5mL,GE Healthcare)纯化。洗脱峰含有复性成功的α和β二聚体的TCR通过SDS-PAGE胶确认。TCR随后通过凝胶过滤层析(HiPrep 16/60, Sephacryl S-100HR,GE Healthcare)进一步纯化。纯化后的TCR纯度经过SDS-PAGE测定大于90%,浓度由BCA法确定。
本实施例得到的可溶性TCR1的SDS-PAGE电泳胶图如图3a和图3b所示,其中,图3a的右侧泳道为非还原胶,图3b的右侧泳道为还原胶,图3a和图3b的左侧泳道都为分子量标记(marker);可溶性TCR2的SDS-PAGE电泳胶图如图3c和图3d所示,图3c的左侧泳道非还原胶,图3d的左侧泳道为还原胶,图3c和图3d的右侧泳道都为分子量标记(marker)。
实施例4结合表征
本实施例使用BIAcore T200实时分析系统检测根据实施例3获得的可溶TCR分子与 AQIPEKIQK-HLA A1101复合物的结合活性。利用本领域技术人员所熟知的方法制备AQIPEKIQK-HLA A1101复合物,主要过程包括纯化、复性、再纯化和生物素化。
将抗链霉亲和素的抗体(GenScript)加入偶联缓冲液(10mM醋酸钠缓冲液,pH4.77),然后将抗体流过预先用EDC和NHS活化过的CM5芯片,使抗体固定在芯片表面,最后用乙醇胺的盐酸溶液封闭未反应的活化表面,完成偶联过程,偶联水平约为15000RU。使低浓度的链霉亲和素流过已包被抗体的芯片表面,然后将AQIPEKIQK-HLA A1101复合物流过检测通道,另一通道作为参比通道,再将0.05mM的生物素以10μL/min的流速流过芯片2min,封闭链霉亲和素剩余的结合位点。
利用BIAcore Evaluation软件计算动力学参数,得到本发明可溶性的TCR分子与AQIPEKIQK-HLA A1101复合物结合的动力学图谱,图谱分别如图4a和图4b所示,图4a为TCR1与AQIPEKIQK-HLA A1101复合物结合的BIAcore动力学图谱,图4b为TCR2与AQIPEKIQK-HLA A1101复合物结合的BIAcore动力学图谱。图谱显示,得到的可溶性TCR 分子都能够与AQIPEKIQK-HLA A0101复合物结合。
实施例5针对负载短肽的靶细胞,转染TCR的效应细胞的激活功能实验
IFN-γ是活化T淋巴细胞产生的一种强有力的免疫调节因子,因此本实施例通过本领域技术人员熟知的ELISPOT实验检测IFN-γ数,以验证转染本发明TCR的细胞的激活功能及抗原特异性。将实施例2获得的TCR2分子转染至从健康志愿者的血液中分离到的CD3+T细胞作为效应细胞,并以同一志愿者的转染靶向其他抗原的TCR(A6)的CD3+T细胞作为对照。所用的靶细胞为负载SSX2抗原短肽AQIPEKIQK的、负载其他肽的或空载的T2细胞。实验步骤:首先准备ELISPOT平板,ELISPOT平板乙醇活化包被,4℃过夜。实验第1天,去掉包被液,洗涤封闭,室温下孵育两个小时,去除封闭液,将试验的各个组分加入ELISPOT 平板:靶细胞为1×104个/孔,效应细胞为2×103个/孔(按转染的阳性率计算),短肽终浓度为1×10-6M/孔,并设置二个复孔。温育过夜(37℃,5%CO2)。
实验第2天,洗涤平板并进行二级检测和显色,干燥平板,再利用免疫斑点平板读数计 (ELISPOT READER system;AID20公司)计数膜上形成的斑点。
针对负载短肽的T2细胞,转染所述TCR2的效应细胞的激活功能实验结果如图5所示。针对负载了SSX2抗原短肽AQIPEKIQK的靶细胞,转染所述TCR2的效应细胞有明显的激活效应,而转染其他TCR的效应细胞基本无活性;同时,转染所述TCR2的效应细胞对于负载其他肽或空载的靶细胞基本无反应。
实施例6针对肿瘤细胞系,转染TCR的效应细胞的激活功能实验
为再次验证转染所述TCR的效应细胞的激活功能及特异性,本实施例利用肿瘤细胞系进行两轮ELISPOT实验。将TCR(TCR1、TCR2)转染至从健康志愿者的血液中分离到的CD3+T 细胞作为效应细胞,并以同一志愿者的转染其他TCR(A6)的CD3+T细胞作为阴性对照。
第一轮实验使用的SSX2阳性肿瘤细胞系为SK-MEL-28(SSX2过表达),阴性肿瘤细胞系为SK-MEL-28,所述的TCR为TCR1;
第二轮实验所用的SSX2阳性肿瘤细胞系为SK-MEL-28(SSX2过表达)、Huh-1-A11(HLA-A11过表达),阴性肿瘤细胞系为SNU423、HUCC-T1、SK-MEL-1、MOG-G-UVW及仅含有效应细胞,所述的TCR为TCR2。其中,SK-MEL-28、SNU423、HUCC-T1、SK-MEL-1、 MOG-G-UVW均来自广州赛库生物技术有限公司,Huh-1来自南京科佰生物科技有限公司。
实验步骤如实施例5所示,其中加入ELISPOT平板的各个组分为:靶细胞为2×104个/ 孔,效应细胞为2×103个/孔(按转染的阳性率计算)。
两轮实验结果如图6a和图6b所示,图6a为针对肿瘤细胞系,转染所述TCR1的效应细胞的激活功能实验结果;图6b为针对肿瘤细胞系,转染所述TCR2的效应细胞的激活功能实验结果。
针对SSX2阳性肿瘤细胞系,转染TCR的效应细胞起明显的激活效应,而转染其他TCR 的和/或空转导的效应细胞无活性;同时,转染本发明TCR的效应细胞对SSX2阴性肿瘤细胞系基本无活性。
实施例7针对肿瘤细胞系,转染本发明TCR的效应细胞的激活功能实验
为再次验证转染所述TCR的效应细胞的激活功能及特异性,本实施例利用肿瘤细胞系进行ELISA实验。将本发明TCR(TCR2)转染至从健康志愿者的血液中分离到的CD3+T细胞作为效应细胞,并以同一志愿者的转染其他TCR(A6)的CD3+T细胞作为阴性对照。实验所用的SSX2阳性肿瘤细胞系为HuH-1-A1101-B2M(HLA-A1101及B2M过表达),阴性肿瘤细胞系为HepG2-A1101-B2M、HepG2、HK-2-A1101、HK-2、Eca-109-A1101、Eca-109、SNU-423;其中,HuH-1购自南京科佰生物科技有限公司,SNU423和HK-2购自广州赛库生物技术有限公司,HepG2购自中国科学院细胞库,Eca-109购自广州威佳生物科技有限公司。
实验步骤:实验第一天接种细胞:将肿瘤细胞系与本发明TCR的细胞悬液接种于U形板:靶细胞为3×104个/孔,效应细胞为3×104个/孔(按转染的阳性率计算),并设置三个复孔,温育过夜(37℃,5%CO2)。IL-2用抗体包被于ELISA板后放至4℃冰箱,过夜。
实验第二天,去掉包被液,洗涤封闭,室温下孵育两个小时,去除封闭液。取肿瘤细胞系与所述TCR的共上清液加入ELISA板中,另取标准蛋白,按10倍比稀释后加入ELISA板,室温摇床两个小时。洗涤平板,加生物素标记二抗,室温摇床一个小时,洗涤并加入SA-HRP,室温摇床一个小时,洗涤,加入TMB显色5~10min,终止反应,进行检测,检测波长为450 nm。
针对肿瘤细胞系,转染所述TCR2的效应细胞的激活功能ELISA实验结果如图7所示,针对阳性肿瘤细胞系,转染所述TCR2的效应细胞起明显的激活效应,而转染其他TCR的及空传导的效应细胞无活性;同时,转染所述TCR2的效应细胞对SSX2阴性肿瘤细胞系基本无活性。
实施例8针对肿瘤细胞系,转染本发明TCR的效应细胞的杀伤功能LDH实验
乳酸脱氢酶(LDH)在胞浆内含量丰富,正常时不能通过细胞膜,当细胞受损伤或死亡时可释放到细胞外,此时细胞培养液中LDH活性与细胞死亡数目成正比。本实施例通过本领域技术人员熟知的非放射性细胞毒性实验,测定LDH的释放,从而验证转染本发明TCR(TCR2)的细胞的杀伤功能。
用从健康志愿者的血液中分离到的CD3+T细胞转染本发明TCR作为效应细胞,并以同一志愿者的转染其他TCR(A6)的CD3+T细胞作为阴性对照。所用的SSX2阳性肿瘤细胞系为SK-MEL-28-SXX2(SXX2过表达)、Huh-1-A11(HLA-A11过表达),阴性肿瘤细胞系为 SK-MEL-5、SNU23、SK-MEL-1、SKM-1。
实验步骤:首先准备LDH平板,先按靶细胞3×104个细胞/孔、效应细胞3×104个细胞/ 孔(按转染的阳性率计算)加入对应孔中,并设置三个复孔。同时设置效应细胞自发释放孔,靶细胞自发释放孔,靶细胞最大孔,体积校正对照孔及培养基背景对照孔。温育过夜(37℃, 5%CO2)。实验第2天,检测显色,终止反应后用酶标仪(Bioteck)在490nm记录吸光值。
针对肿瘤细胞系,转染所述TCR2的效应细胞的杀伤功能LDH实验结果如图8所示,针对SSX2阳性肿瘤细胞系,转染所述TCR2的效应细胞同样表现出强杀伤效力,而转染其他TCR的T细胞基本不起反应;同时,转染所述TCR2的T细胞对阴性肿瘤细胞系基本无杀伤,进一步体现了转染所述TCR2的细胞的很好的特异性杀伤功能。
综上,本发明提供的TCR能够与SSX2抗原短肽复合物AQIPEKIQK-HLA A1101特异性结合,针对阳性靶细胞,转导所述TCR的效应细胞能够被特异性激活,同时,转导本发明 TCR的效应细胞还具有很强的杀伤功能。所述TCR可用于将细胞毒性剂或免疫刺激剂递送到靶细胞,或被转化入T细胞,使表达所述TCR的T细胞能够破坏肿瘤细胞,所述TCR在过继免疫治疗中具有重要的应用价值。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 香雪生命科学技术(广东)有限公司
<120> 一种结合SSX2抗原的TCR分子及其应用
<130> 2022
<160> 25
<170> PatentIn version 3.3
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gcagactgtg gcttcacctc cgagtcttac cagcaagggg tcctgtctgc caccatcctc 780
tatgagatct tgctagggaa ggccaccttg tatgccgtgc tggtcagtgc cctcgtgctg 840
atggccatgg tcaagagaaa ggattccaga ggc 873
<210> 11
<211> 309
<212> PRT
<213> 人工序列
<400> 11
Gly Thr Arg Leu Leu Cys Trp Val Val Leu Gly Phe Leu Gly Thr Asp
1 5 10 15
His Thr Gly Ala Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Ala Lys
20 25 30
Arg Gly Gln Asp Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His Val
35 40 45
Ser Leu Phe Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Glu Phe Leu
50 55 60
Thr Tyr Phe Gln Asn Glu Ala Gln Leu Asp Lys Ser Gly Leu Pro Ser
65 70 75 80
Asp Arg Phe Phe Ala Glu Arg Pro Glu Gly Ser Val Ser Thr Leu Lys
85 90 95
Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser
100 105 110
Ser Leu Val Gly Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
115 120 125
Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe
130 135 140
Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro
180 185 190
Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr
225 230 235 240
Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg
290 295 300
Lys Asp Ser Arg Gly
305
<210> 12
<211> 927
<212> DNA
<213> 人工序列
<400> 12
ggcaccaggc tcctctgctg ggtggtcctg ggtttcctag ggacagatca cacaggtgct 60
ggagtctccc agtcccctag gtacaaagtc gcaaagagag gacaggatgt agctctcagg 120
tgtgatccaa tttcgggtca tgtatccctt ttttggtacc aacaggccct ggggcagggg 180
ccagagtttc tgacttattt ccagaatgaa gctcaactag acaaatcggg gctgcccagt 240
gatcgcttct ttgcagaaag gcctgaggga tccgtctcca ctctgaagat ccagcgcaca 300
cagcaggagg actccgccgt gtatctctgt gccagcagct tagtcggcta cgagcagtac 360
ttcgggccgg gcaccaggct cacggtcaca gaggacctga aaaacgtgtt cccacccgag 420
gtcgctgtgt ttgagccatc agaagcagag atctcccaca cccaaaaggc cacactggtg 480
tgcctggcca caggcttcta ccccgaccac gtggagctga gctggtgggt gaatgggaag 540
gaggtgcaca gtggggtcag cacagacccg cagcccctca aggagcagcc cgccctcaat 600
gactccagat actgcctgag cagccgcctg agggtctcgg ccaccttctg gcagaacccc 660
cgcaaccact tccgctgtca agtccagttc tacgggctct cggagaatga cgagtggacc 720
caggataggg ccaaacctgt cacccagatc gtcagcgccg aggcctgggg tagagcagac 780
tgtggcttca cctccgagtc ttaccagcaa ggggtcctgt ctgccaccat cctctatgag 840
atcttgctag ggaaggccac cttgtatgcc gtgctggtca gtgccctcgt gctgatggcc 900
atggtcaaga gaaaggattc cagaggc 927
<210> 13
<211> 6
<212> PRT
<213> 人工序列
<400> 13
Ser Ser Tyr Ser Pro Ser
1 5
<210> 14
<211> 8
<212> PRT
<213> 人工序列
<400> 14
Tyr Thr Ser Ala Ala Thr Leu Val
1 5
<210> 15
<211> 10
<212> PRT
<213> 人工序列
<400> 15
Val Val Ser Ser Gly Asn Thr Pro Leu Val
1 5 10
<210> 16
<211> 5
<212> PRT
<213> 人工序列
<400> 16
Ser Gly His Val Ser
1 5
<210> 17
<211> 6
<212> PRT
<213> 人工序列
<400> 17
Phe Gln Asn Glu Ala Gln
1 5
<210> 18
<211> 10
<212> PRT
<213> 人工序列
<400> 18
Ala Ser Ser Leu Val Gly Tyr Glu Gln Tyr
1 5 10
<210> 19
<211> 206
<212> PRT
<213> 人工序列
<400> 19
Ala Gln Ser Val Thr Gln Leu Asp Ser His Val Ser Val Ser Glu Gly
1 5 10 15
Thr Pro Val Leu Leu Arg Cys Asn Tyr Ser Ser Ser Tyr Ser Pro Ser
20 25 30
Leu Phe Trp Tyr Val Gln His Pro Asn Lys Gly Leu Gln Leu Leu Leu
35 40 45
Lys Tyr Thr Ser Ala Ala Thr Leu Val Lys Gly Ile Asn Gly Phe Glu
50 55 60
Ala Glu Phe Lys Lys Ser Glu Thr Ser Phe His Leu Thr Lys Pro Ser
65 70 75 80
Ala His Met Ser Asp Ala Ala Glu Tyr Phe Cys Val Val Ser Ser Gly
85 90 95
Asn Thr Pro Leu Val Phe Gly Lys Gly Thr Arg Leu Ser Val Ile Ala
100 105 110
Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys
115 120 125
Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr
130 135 140
Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr
145 150 155 160
Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala
165 170 175
Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser
180 185 190
Ile Ile Pro Glu Asp Thr Phe Phe Cys Ser Pro Glu Ser Ser
195 200 205
<210> 20
<211> 242
<212> PRT
<213> 人工序列
<400> 20
Gly Ala Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Ala Lys Arg Gly
1 5 10 15
Gln Asp Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His Val Ser Leu
20 25 30
Phe Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Glu Phe Leu Thr Tyr
35 40 45
Phe Gln Asn Glu Ala Gln Leu Asp Lys Ser Gly Leu Pro Ser Asp Arg
50 55 60
Phe Phe Ala Glu Arg Pro Glu Gly Ser Val Ser Thr Leu Lys Ile Gln
65 70 75 80
Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu
85 90 95
Val Gly Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
115 120 125
Ser Glu Cys Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
130 135 140
Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
145 150 155 160
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
165 170 175
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser Ser Arg Leu
180 185 190
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
195 200 205
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
210 215 220
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
225 230 235 240
Ala Asp
<210> 21
<211> 112
<212> PRT
<213> 人工序列
<400> 21
Ala Gln Ser Val Thr Gln Leu Asp Ser His Val Ser Val Ser Glu Gly
1 5 10 15
Thr Pro Val Leu Leu Arg Cys Asn Tyr Ser Ser Ser Tyr Ser Pro Tyr
20 25 30
Leu Phe Trp Tyr Val Gln His Pro Asn Lys Gly Leu Gln Leu Leu Leu
35 40 45
Lys Tyr Thr Ser Ala Ala Thr Leu Val Lys Gly Ile Asn Gly Phe Glu
50 55 60
Ala Glu Phe Lys Lys Ser Glu Thr Ser Phe His Leu Thr Lys Pro Ser
65 70 75 80
Ala His Met Ser Asp Ala Ala Glu Tyr Phe Cys Val Ile Ser Leu Gly
85 90 95
Asn Thr Pro Leu Val Phe Gly Lys Gly Thr Arg Leu Ser Val Ile Ala
100 105 110
<210> 22
<211> 206
<212> PRT
<213> 人工序列
<400> 22
Ala Gln Ser Val Thr Gln Leu Asp Ser His Val Ser Val Ser Glu Gly
1 5 10 15
Thr Pro Val Leu Leu Arg Cys Asn Tyr Ser Ser Ser Tyr Ser Pro Ser
20 25 30
Leu Phe Trp Tyr Val Gln His Pro Asn Lys Gly Leu Gln Leu Leu Leu
35 40 45
Lys Tyr Thr Ser Ala Ala Thr Leu Val Lys Gly Ile Asn Gly Phe Glu
50 55 60
Ala Glu Phe Lys Lys Ser Glu Thr Ser Phe His Leu Thr Lys Pro Ser
65 70 75 80
Ala His Met Ser Asp Ala Ala Glu Tyr Phe Cys Val Val Ser Ser Gly
85 90 95
Asn Thr Pro Leu Val Phe Gly Lys Gly Thr Arg Leu Ser Val Ile Ala
100 105 110
Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys
115 120 125
Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr
130 135 140
Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr
145 150 155 160
Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala
165 170 175
Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser
180 185 190
Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser
195 200 205
<210> 23
<211> 242
<212> PRT
<213> 人工序列
<400> 23
Gly Ala Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Ala Lys Arg Gly
1 5 10 15
Gln Asp Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His Val Ser Leu
20 25 30
Phe Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Glu Phe Leu Thr Tyr
35 40 45
Phe Gln Asn Glu Ala Gln Leu Asp Lys Ser Gly Leu Pro Ser Asp Arg
50 55 60
Phe Phe Ala Glu Arg Pro Glu Gly Ser Val Ser Thr Leu Lys Ile Gln
65 70 75 80
Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu
85 90 95
Val Gly Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
115 120 125
Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
130 135 140
Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
145 150 155 160
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
165 170 175
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
180 185 190
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
195 200 205
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
210 215 220
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
225 230 235 240
Ala Asp
<210> 24
<211> 6
<212> PRT
<213> 人工序列
<400> 24
Ser Ser Tyr Ser Pro Tyr
1 5
<210> 25
<211> 10
<212> PRT
<213> 人工序列
<400> 25
Val Ile Ser Leu Gly Asn Thr Pro Leu Val
1 5 10
Claims (10)
1.一种TCR分子,其特征在于,所述TCR分子包含TCRα链可变域和TCRβ链可变域,所述TCR分子具有结合AQIPEKIQK-HLA A1101复合物的活性,并且所述TCRα链可变域的氨基酸序列与SEQ ID NO:1所示的氨基酸序列有至少90%的序列同源性,和所述TCRβ链可变域的3个CDR区的氨基酸序列为:
βCDR1-SGHVS (SEQ ID NO:16)
βCDR2-FQNEAQ (SEQ ID NO:17)
βCDR3-ASSLVGYEQY (SEQ ID NO:18)。
2.一种多价TCR复合物,其特征在于,所述多价TCR复合物包含至少两个TCR分子,并且其中的至少一个TCR分子为权利要求1所述的TCR分子。
3.一种核酸分子,其特征在于,所述核酸分子包含编码权利要求1所述的TCR分子的核苷酸序列,或编码权利要求1所述的TCR分子的核苷酸序列的互补序列。
4.一种载体,其特征在于,所述载体含有权利要求3所述的核酸分子。
5.一种宿主细胞,其特征在于,所述宿主细胞中含有权利要求4所述的载体,或所述宿主细胞的染色体中整合有外源的权利要求3所述的核酸分子。
6.一种分离的细胞,其特征在于,所述分离的细胞表达权利要求1所述的TCR分子;
优选地,所述分离的细胞还表达外源的CD8受体。
7.一种药物组合物,其特征在于,所述药物组合物包含权利要求1所述的TCR分子、权利要求2所述的多价TCR复合物或权利要求6所述的分离的细胞中任意一种或至少两种的组合;
优选地,所述药物组合物还含有药学上可接受的载体。
8.一种治疗疾病的方法,其特征在于,所述治疗疾病的方法包括给需要治疗的对象施用权利要求1所述的TCR分子、权利要求2所述的多价TCR复合物、权利要求6所述的分离的细胞或权利要求7所述的药物组合物中任意一种或至少两种的组合;
优选地,所述疾病包括SSX2阳性肿瘤。
9.权利要求1所述的TCR分子、权利要2所述的多价TCR复合物或权利要求6所述的分离的细胞中任意一种或至少两种的组合在制备治疗肿瘤的药物中的用途;
优选地,所述肿瘤包括SSX2阳性肿瘤。
10.一种权利要求1所述的TCR分子的制备方法,其特征在于,所述制备方法包括如下步骤:
(i)培养权利要求5所述的宿主细胞,从而表达权利要求1所述的TCR分子;
(ii)分离或纯化出所述TCR分子。
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CN202210691744.7A CN117304301A (zh) | 2022-06-17 | 2022-06-17 | 一种结合ssx2抗原的tcr分子及其应用 |
PCT/CN2023/098275 WO2023241391A1 (zh) | 2022-06-17 | 2023-06-05 | 一种结合ssx2抗原的tcr分子及其应用 |
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EP3015477B1 (en) * | 2013-06-26 | 2021-08-18 | XLifeSc, Ltd. | High-stability t-cell receptor and preparation method and application thereof |
CN106188274A (zh) * | 2015-05-06 | 2016-12-07 | 广州市香雪制药股份有限公司 | 识别rhamm抗原短肽的t细胞受体 |
WO2021016887A1 (zh) * | 2019-07-30 | 2021-02-04 | 广东香雪精准医疗技术有限公司 | 识别ssx2抗原短肽的t细胞受体 |
CN112442119B (zh) * | 2019-09-05 | 2023-02-24 | 香雪生命科学技术(广东)有限公司 | 一种识别ssx2的高亲和力t细胞受体 |
CN114524870A (zh) * | 2020-11-23 | 2022-05-24 | 香雪生命科学技术(广东)有限公司 | 源自于ssx2抗原的短肽 |
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