CN114057875B - 抗cd133的单链抗体及其在制备治疗肿瘤的药物中的用途 - Google Patents
抗cd133的单链抗体及其在制备治疗肿瘤的药物中的用途 Download PDFInfo
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Classifications
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Abstract
本公开涉及一种抗CD133的单链抗体,该抗CD133的单链抗体的氨基酸序列包括SEQ ID NO.1所示的序列。表达该抗CD133的单链抗体的T淋巴细胞能够特异性杀伤CD133阳性的肿瘤细胞,且特异性较高、杀伤能力较强。
Description
技术领域
本公开涉及医药生物技术领域,具体地,涉及一种靶向CD133的嵌合抗原受体、其编码核酸、表达载体、细胞、药物组合物和它们的用途。
背景技术
嵌合抗原受体(Chimeric antigen receptor,CAR)是人工合成的T细胞受体,由抗原结合结构域、跨膜结构域和胞内信号传导结构域组成。抗原结合结构域位于T细胞膜外,包括单链抗体或配体,用于特异性地结合靶抗原。胞内信号传导结构域位于T细胞膜内,用于向T细胞内传导信号以刺激T细胞产生免疫反应。
CAR能够靶向识别肿瘤细胞表面的靶抗原,因此,表达CAR的T细胞能够用于靶向杀伤肿瘤细胞。然而,现有的表达嵌合抗原受体CAR的T细胞对肿瘤细胞的杀伤能力仍然较弱。
发明内容
本公开的目的是克服现有的表达嵌合抗原受体CAR的T细胞对肿瘤细胞的杀伤能力仍然较弱的问题,提供一种抗CD133的单链抗体。
为了实现上述目的,第一方面,本公开提供一种抗CD133的单链抗体,该抗CD133的单链抗体的氨基酸序列包括SEQ ID NO.1所示的序列。
第二方面,本公开提供一种核酸,该核酸编码第一方面所述的抗CD133的单链抗体;优选地,所述核酸具有SEQ ID NO.2所示的核苷酸序列。
第三方面,本公开提供一种融合蛋白,所述融合蛋白含有依次连接的抗原结合结构域、跨膜结构域和胞内信号传导结构域;所述抗原结合结构域的氨基酸序列包括第一方面所述的抗CD133的单链抗体的氨基酸序列;
优选地,所述抗原结合结构域包括抗CD133的单链抗体,所述胞内信号传导结构域包括抗TIM3的单链抗体和/或IL7Rα或者IL7Rα的截短体;
更优选地,所述融合蛋白具有SEQ ID NO.3、SEQ ID NO.4、SEQ ID NO.5或者SEQID NO.6中任一项所示的氨基酸序列。
第四方面,本公开提供一种融合核酸,所述融合核酸编码第三方面所述的融合蛋白;
优选地,所述融合核酸具有SEQ ID NO.7、SEQ ID NO.8、SEQ ID NO.9或者SEQ IDNO.10中任一项所示的核苷酸序列。
第五方面,本公开提供一种表达载体,所述表达载体插入有表达框,所述表达框包括编码抗原结合分子的第一核酸片段和编码胞内信号传导分子的第二核酸片段,所述抗原结合分子中含有第一方面所述的抗CD133的单链抗体,所述第一核酸片段与所述第二核酸片段之间插入有IRES元件或2A肽编码序列;
优选地,所述表达框为第四方面所述的融合核酸。
第六方面,本公开提供一种表达嵌合抗原受体的细胞,该表达嵌合抗原受体的细胞由宿主细胞转染第五方面所述的表达载体后得到,所述嵌合抗原受体中含有第一方面所述的抗CD133的单链抗体。
可选地,所述宿主细胞为T细胞。
第七方面,本公开提供第一方面所述的抗CD133的单链抗体、第二方面所述的核酸、第三方面所述的融合蛋白、第四方面所述的融合核酸、第五方面所述的表达载体、第六方面所述的表达嵌合抗原受体的细胞在制备治疗肿瘤的药物中的用途。
可选地,所述肿瘤为脑胶质瘤。
第八方面,本公开提供一种药物组合物,该药物组合物的有效成分包括第六方面所述的表达抗CD133嵌合抗原受体的细胞。
通过上述技术方案,本公开提供的抗CD133的单链抗体能够特异性识别并结合肿瘤细胞表面的CD133抗原,因此,表达抗CD133的单链抗体的T淋巴细胞能够特异性杀伤CD133阳性的肿瘤细胞,且特异性较高、杀伤能力较强。
本公开的其他特征和优点将在随后的具体实施方式部分予以详细说明。
附图说明
附图是用来提供对本公开的进一步理解,并且构成说明书的一部分,与下面的具体实施方式一起用于解释本公开,但并不构成对本公开的限制。在附图中:
图1是本公开实施例提供的CAR-T 1细胞的流式细胞仪检测结果图;
图2是本公开实施例提供的CAR-T 2细胞的流式细胞仪检测结果图;
图3是本公开实施例提供的CAR-T 3细胞的流式细胞仪检测结果图;
图4是本公开实施例提供的CAR-T 4细胞的流式细胞仪检测结果图;
图5是本公开实施例提供的CAR-T 5细胞的流式细胞仪检测结果图。
具体实施方式
以下结合附图对本公开的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本公开,并不用于限制本公开。
本公开的第一方面提供一种抗CD133的单链抗体,该抗CD133的单链抗体的氨基酸序列包括SEQ ID NO.1所示的序列。
其中,SEQ ID NO.1所示的序列如下所示:QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFEMHWVRQAPGQGLEWMGDIDPGTGDTAYNLKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCALGAFVYWGQGTLVTVSSGSTSGGGSGGGSGGGGSSDVVMTQSPLSLPVTPGEPASISCRSSQSLANSYGNTYLSWYLQKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKLEIK。
CD133是在多种肿瘤干细胞表面独立表达的特异标记分子,因此,可以将CD133作为肿瘤治疗的特异性靶点。针对CD133设计抗CD133的单链抗体,并利用设计的抗CD133的单链抗体构建嵌合抗原受体T细胞,能够特异性识别并杀伤CD133阳性的肿瘤细胞。
本公开的发明人发现,上述抗CD133的单链抗体能够特异性识别并结合肿瘤细胞表面的CD133抗原,因此,表达抗CD133的单链抗体的T淋巴细胞能够特异性杀伤CD133阳性的肿瘤细胞,且特异性较高、杀伤能力较强。
本公开的第二方面提供一种核酸,该核酸编码第一方面所述的抗CD133的单链抗体;优选地,所述核酸具有SEQ ID NO.2所示的核苷酸序列。
其中,SEQ ID NO.2所示的核苷酸序列如下所示:
caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggcttctggttacacctttaccgactttgaaatgcactgggtgcgacaggcccctggacaagggcttgagtggatgggagatattgatcctggaactggtgatactgcctacaatctgaagttcaagggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgaggtctgacgacacggccgtgtattactgtgcgttgggggcctttgtttactggggccagggaaccctggtcaccgtctcctcaggcagtactagcggtggtggctccgggggcggttccggtgggggcggcagcagcgatgttgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagtcagagtcttgcaaacagttatgggaacacctatttgtcttggtacctgcagaagccagggcagtctccacagctcctgatctatgggatttccaacagattttctggggtccctgacaggttcagtggcagtggatcaggcacagattttacactgaaaatcagcagagtggaggctgaggacgttggggtttattactgcttacaaggtacacatcagccgtacacgtttggccaggggaccaagctggagatcaaa。
本公开的第三方面提供一种融合蛋白,所述融合蛋白含有依次连接的抗原结合结构域、跨膜结构域和胞内信号传导结构域;所述抗原结合结构域的氨基酸序列包括第一方面所述的抗CD133的单链抗体的氨基酸序列;优选地,所述抗原结合结构域包括抗CD133的单链抗体,所述胞内信号传导结构域包括抗TIM3的单链抗体和/或IL7Rα或者IL7Rα的截短体;更优选地,所述融合蛋白具有SEQ ID NO.3、SEQ ID NO.4、SEQ ID NO.5或者SEQ IDNO.6中任一项所示的氨基酸序列。
其中,SEQ ID NO.3所示的融合蛋白由抗CD133的单链抗体、CD28和CD3组成。SEQID NO.3所示的氨基酸序列如下所示:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFEMHWVRQAPGQGLEWMGDIDPGTGDTAYNLKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCALGAFVYWGQGTLVTVSSGSTSGGGSGGGSGGGGSSDVVMTQSPLSLPVTPGEPASISCRSSQSLANSYGNTYLSWYLQKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR。
SEQ ID NO.4所示的融合蛋白由抗CD133的单链抗体、CD28、IL7Rα截短体和CD3组成。SEQ ID NO.4所示的氨基酸序列如下所示:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFEMHWVRQAPGQGLEWMGDIDPGTGDTAYNLKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCALGAFVYWGQGTLVTVSSGSTSGGGSGGGSGGGGSSDVVMTQSPLSLPVTPGEPASISCRSSQSLANSYGNTYLSWYLQKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR。
SEQ ID NO.5所示的融合蛋白由抗CD133的单链抗体、CD28、CD3、T2A和抗TIM3的单链抗体组成。SEQ ID NO.5所示的氨基酸序列如下所示:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFEMHWVRQAPGQGLEWMGDIDPGTGDTAYNLKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCALGAFVYWGQGTLVTVSSGSTSGGGSGGGSGGGGSSDVVMTQSPLSLPVTPGEPASISCRSSQSLANSYGNTYLSWYLQKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPREGRGSLLTCGDVEENPGPMTNKCLLQIALLLCFSTTALSQVQLQQSGPGLVKPSHTLSLTCTVSGGSISSGGYYWSWTRQHPGMGLEWIGYISYSGSIYYTPSLKSRLTISVDTSKNQFSLKLSSVTAADTAVYYCASLDSWGSNRDYWGQGTLVTVSSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK。
SEQ ID NO.6所示的融合蛋白由抗CD133的单链抗体、CD28、IL7Rα截短体、CD3、T2A和抗TIM3的单链抗体组成。SEQ ID NO.6所示的氨基酸序列如下所示:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFEMHWVRQAPGQGLEWMGDIDPGTGDTAYNLKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCALGAFVYWGQGTLVTVSSGSTSGGGSGGGSGGGGSSDVVMTQSPLSLPVTPGEPASISCRSSQSLANSYGNTYLSWYLQKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPREGRGSLLTCGDVEENPGPMTNKCLLQIALLLCFSTTALSQVQLQQSGPGLVKPSHTLSLTCTVSGGSISSGGYYWSWTRQHPGMGLEWIGYISYSGSIYYTPSLKSRLTISVDTSKNQFSLKLSSVTAADTAVYYCASLDSWGSNRDYWGQGTLVTVSSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK。
本公开的第四方面提供一种融合核酸,所述融合核酸编码第三方面所述的融合蛋白;优选地,所述融合核酸具有SEQ ID NO.7、SEQ ID NO.8、SEQ ID NO.9或者SEQ ID NO.10中任一项所示的核苷酸序列。
其中,SEQ ID NO.7所示的核苷酸序列用于编码SEQ ID NO.3所示的氨基酸序列。SEQ ID NO.7所示的核苷酸序列如下所示:
caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggcttctggttacacctttaccgactttgaaatgcactgggtgcgacaggcccctggacaagggcttgagtggatgggagatattgatcctggaactggtgatactgcctacaatctgaagttcaagggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgaggtctgacgacacggccgtgtattactgtgcgttgggggcctttgtttactggggccagggaaccctggtcaccgtctcctcaggcagtactagcggtggtggctccgggggcggttccggtgggggcggcagcagcgatgttgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagtcagagtcttgcaaacagttatgggaacacctatttgtcttggtacctgcagaagccagggcagtctccacagctcctgatctatgggatttccaacagattttctggggtccctgacaggttcagtggcagtggatcaggcacagattttacactgaaaatcagcagagtggaggctgaggacgttggggtttattactgcttacaaggtacacatcagccgtacacgtttggccaggggaccaagctggagatcaaaaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctatcgctcccgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcgg。
SEQ ID NO.8所示的核苷酸序列用于编码SEQ ID NO.4所示的氨基酸序列。SEQ IDNO.8所示的核苷酸序列如下所示:
caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggcttctggttacacctttaccgactttgaaatgcactgggtgcgacaggcccctggacaagggcttgagtggatgggagatattgatcctggaactggtgatactgcctacaatctgaagttcaagggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgaggtctgacgacacggccgtgtattactgtgcgttgggggcctttgtttactggggccagggaaccctggtcaccgtctcctcaggcagtactagcggtggtggctccgggggcggttccggtgggggcggcagcagcgatgttgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagtcagagtcttgcaaacagttatgggaacacctatttgtcttggtacctgcagaagccagggcagtctccacagctcctgatctatgggatttccaacagattttctggggtccctgacaggttcagtggcagtggatcaggcacagattttacactgaaaatcagcagagtggaggctgaggacgttggggtttattactgcttacaaggtacacatcagccgtacacgtttggccaggggaccaagctggagatcaaaaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctatcgctccaaaaaaaggattaagcctatcgtatggcccagtctccccgatcacaagaagactctggaacacctttgtaagaaaccaagaaaaaatttaaatgtgagtttcaatcctgaaagtttcctggactgccagattcatagggtggatgacattcaagctagagatgaagtggaaggttttctgcaagatacgtttcctcagcaactagaagaatctgagaagcagaggcttctgggatcaaatcaagaagaagcatatgtcaccatgtccagcttctaccaaaaccagcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcgg。
SEQ ID NO.9所示的核苷酸序列用于编码SEQ ID NO.5所示的氨基酸序列。SEQ IDNO.9所示的核苷酸序列如下所示:
caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggcttctggttacacctttaccgactttgaaatgcactgggtgcgacaggcccctggacaagggcttgagtggatgggagatattgatcctggaactggtgatactgcctacaatctgaagttcaagggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgaggtctgacgacacggccgtgtattactgtgcgttgggggcctttgtttactggggccagggaaccctggtcaccgtctcctcaggcagtactagcggtggtggctccgggggcggttccggtgggggcggcagcagcgatgttgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagtcagagtcttgcaaacagttatgggaacacctatttgtcttggtacctgcagaagccagggcagtctccacagctcctgatctatgggatttccaacagattttctggggtccctgacaggttcagtggcagtggatcaggcacagattttacactgaaaatcagcagagtggaggctgaggacgttggggtttattactgcttacaaggtacacatcagccgtacacgtttggccaggggaccaagctggagatcaaaaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctatcgctcccgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcgggagggaaggggttctctcctgacctgcggcgatgtggaggagaaccccggacccatgaccaacaagtgtctcctccaaattgctctcctgttgtgcttctccactacagctctttcccaggtgcagctacagcagtcgggcccaggactggtgaagccttcacacaccctgtccctcacctgcactgtctctggtggctccatcagcagtggtggttactactggagttggacccgtcagcacccagggatgggcctggagtggattggatacatctcttacagtgggagtatctattacactccgtccctcaagagtcgacttaccatatcagtggacacgtctaagaaccagttctccctgaagctgagctctgtgactgccgcggacacggccgtatattactgtgcgagtttggattcctggggatctaaccgtgactactggggccagggaaccctggtcaccgtctcgagtggaggtggtggatccgaaattgtgttgacgcagtctccagccaccctgtctttgtctccaggggaaagagccaccctctcctgcagggccagtcagagtgttagcagctacttagcctggtaccaacagaaacctggccaggctcccaggctcctcatctatgatgcatccaacagggccactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattactgtcagcagcgtagcaactggccgctcactttcggcggagggaccaaggtggagattaag。
SEQ ID NO.10所示的核苷酸序列用于编码SEQ ID NO.6所示的氨基酸序列。SEQID NO.10所示的核苷酸序列如下所示:
caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggcttctggttacacctttaccgactttgaaatgcactgggtgcgacaggcccctggacaagggcttgagtggatgggagatattgatcctggaactggtgatactgcctacaatctgaagttcaagggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgaggtctgacgacacggccgtgtattactgtgcgttgggggcctttgtttactggggccagggaaccctggtcaccgtctcctcaggcagtactagcggtggtggctccgggggcggttccggtgggggcggcagcagcgatgttgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagtcagagtcttgcaaacagttatgggaacacctatttgtcttggtacctgcagaagccagggcagtctccacagctcctgatctatgggatttccaacagattttctggggtccctgacaggttcagtggcagtggatcaggcacagattttacactgaaaatcagcagagtggaggctgaggacgttggggtttattactgcttacaaggtacacatcagccgtacacgtttggccaggggaccaagctggagatcaaaaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctatcgctccaaaaaaaggattaagcctatcgtatggcccagtctccccgatcacaagaagactctggaacacctttgtaagaaaccaagaaaaaatttaaatgtgagtttcaatcctgaaagtttcctggactgccagattcatagggtggatgacattcaagctagagatgaagtggaaggttttctgcaagatacgtttcctcagcaactagaagaatctgagaagcagaggcttctgggatcaaatcaagaagaagcatatgtcaccatgtccagcttctaccaaaaccagcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcgggagggaaggggttctctcctgacctgcggcgatgtggaggagaaccccggacccatgaccaacaagtgtctcctccaaattgctctcctgttgtgcttctccactacagctctttcccaggtgcagctacagcagtcgggcccaggactggtgaagccttcacacaccctgtccctcacctgcactgtctctggtggctccatcagcagtggtggttactactggagttggacccgtcagcacccagggatgggcctggagtggattggatacatctcttacagtgggagtatctattacactccgtccctcaagagtcgacttaccatatcagtggacacgtctaagaaccagttctccctgaagctgagctctgtgactgccgcggacacggccgtatattactgtgcgagtttggattcctggggatctaaccgtgactactggggccagggaaccctggtcaccgtctcgagtggaggtggtggatccgaaattgtgttgacgcagtctccagccaccctgtctttgtctccaggggaaagagccaccctctcctgcagggccagtcagagtgttagcagctacttagcctggtaccaacagaaacctggccaggctcccaggctcctcatctatgatgcatccaacagggccactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattactgtcagcagcgtagcaactggccgctcactttcggcggagggaccaaggtggagattaagcgctcactttcggcggagggaccaaggtggagattaag。
本公开的第五方面提供一种表达载体,所述表达载体插入有表达框,所述表达框包括编码抗原结合分子的第一核酸片段和编码胞内信号传导分子的第二核酸片段,所述抗原结合分子中含有第一方面所述的抗CD133的单链抗体,所述第一核酸片段与所述第二核酸片段之间插入有IRES元件或2A肽编码序列;优选地,所述表达框为第四方面所述的融合核酸。
本公开的第六方面提供一种表达嵌合抗原受体的细胞,该表达嵌合抗原受体的细胞由宿主细胞转染第五方面所述的表达载体后得到,所述嵌合抗原受体中含有第一方面所述的抗CD133的单链抗体。可选地,所述宿主细胞为T细胞。
本公开的第七方面提供第一方面所述的抗CD133的单链抗体、第二方面所述的核酸、第三方面所述的融合蛋白、第四方面所述的融合核酸、第五方面所述的表达载体、第六方面所述的表达嵌合抗原受体的细胞在制备治疗肿瘤的药物中的用途。可选地,所述肿瘤为脑胶质瘤。
本公开的第八方面提供一种药物组合物,该药物组合物的有效成分包括第六方面所述的表达抗CD133嵌合抗原受体的细胞。
下面通过实施例来进一步说明本公开,但是本公开并不因此而受到任何限制。
实施例1
本实施例用于说明表达载体的构建。
(1)采用全序列合成方法,分别合成如SEQ ID NO.7~10所示的核苷酸序列。SEQID NO.7~10所示的核苷酸序列分别依次用于编码SEQ ID NO.3~6所示的融合蛋白。其中,SEQ ID NO.3~6所示的融合蛋白的组成如下:
G1:SEQ ID NO.3所示的融合蛋白由抗CD133的单链抗体、CD28和CD3组成;
G2:SEQ ID NO.4所示的融合蛋白由抗CD133的单链抗体、CD28、IL7Rα截短体和CD3组成;
G3:SEQ ID NO.5所示的融合蛋白由抗CD133的单链抗体、CD28、CD3、T2A和抗TIM3的单链抗体组成;
G4:SEQ ID NO.6所示的融合蛋白由抗CD133的单链抗体、CD28、IL7Rα截短体、CD3、T2A和抗TIM3的单链抗体组成。
(2)采用pLVX-IRES-ΔNGFR(购自Clontech公司,货号为631982)作为载体,采用常规方法分别插入步骤(1)中合成的4种核苷酸序列,得到本实施例的4种慢病毒表达载体。
实施例2
本实施例用于说明表达抗CD133的单链抗体的T细胞的制备及检测。
(1)将实施例1构建的4种慢病毒表达载体和pLVX-IRES-ΔNGFR空载体分别进行慢病毒包装,然后按照下述方法分别进行T细胞的体外培养、转染和扩增。
(2)按照下述方法分离血液中的T细胞:将1mL无菌PBS与1mL血液混匀,然后缓慢加入到淋巴细胞分离液Ficoll的上层,并于4℃、400g条件下离心30min,加减速分别设置为0。离心结束后,去掉上层血浆,吸取中间白膜层细胞,加入PBS重悬洗涤,并于100g条件下离心10min,加减速正常。离心结束后,去掉上层洗涤液,加入1mL的1640+10%FBS+1%双抗+1×Glutamine培养基重悬细胞,然后利用抗人CD3/CD28磁珠(购自Thermo Fisher公司)刺激扩增,其中,重悬后细胞浓度为1×106细胞/mL,磁珠加入量为100μL,再加入100IU/mL rhIL-2(Peprotech),刺激培养2天,得到T细胞。
(3)按照下述方法进行慢病毒转染:取5份上述分离得到的T细胞,分别加入步骤(1)包装好的慢病毒,然后加入终浓度为6μg/mL的polybrene,混匀,并于32℃、800g的条件下离心100min。离心结束后放入培养箱中继续培养24h。培养结束后将培养物于1500rpm的条件下离心15min,并将离心得到的细胞以1×106/mL的密度接种于培养板内,以rhIL2-100IU/mL刺激培养,以后每2-3天换液一次,直至2-4周,得到转染后的T淋巴细胞CAR-T 1、CAR-T 2、CAR-T 3、CAR-T 4、CAR-T 5。其中,CAR-T 1转染有SEQ ID NO.7所示的核苷酸序列,能够表达SEQ ID NO.3所示的融合蛋白;CAR-T 2转染有SEQ ID NO.8所示的核苷酸序列,能够表达SEQ ID NO.4所示的融合蛋白;CAR-T 3转染有SEQ ID NO.9所示的核苷酸序列,能够表达SEQ ID NO.5所示的融合蛋白;CAR-T 4转染有SEQ ID NO.10所示的核苷酸序列,能够表达SEQ ID NO.6所示的融合蛋白;CAR-T 5转染有空载体。
培养结束后,用PBS重悬细胞,并用流式细胞仪检测上述5种转染后的T淋巴细胞的比例及表面CAR蛋白的表达。检测方法为:分别离心收集转染后的待检测T细胞,PBS洗涤1次后弃上清,按抗体说明书加入相应检测量的单抗避光30min后,利用PBS洗涤、重悬,过膜后采用流式细胞仪进行检测,检测时使用的抗体为PE标记的山羊抗人VH+VL流式抗体。结果如图1~5所示。
图1是本公开实施例提供的CAR-T 1细胞的流式细胞仪检测结果图;
图2是本公开实施例提供的CAR-T 2细胞的流式细胞仪检测结果图;
图3是本公开实施例提供的CAR-T 3细胞的流式细胞仪检测结果图;
图4是本公开实施例提供的CAR-T 4细胞的流式细胞仪检测结果图;
图5是本公开实施例提供的CAR-T 5细胞的流式细胞仪检测结果图。
从图1~4可以看出,CAR-T 1细胞、CAR-T 2细胞、CAR-T 3细胞和CAR-T 4细胞中均检测出区别于正常T淋巴细胞的其它细胞;由图5可以看出,CAR-T 5细胞并未检测出区别于正常T淋巴细胞的其它细胞。由此说明本实施例中转染有融合基因的CAR-T细胞均已成功表达目标融合蛋白。
实施例3
本实施例用于验证表达抗CD133单链抗体的T细胞对CD133阳性肿瘤细胞的杀伤能力。
本实施例中进行LDH释放实验检测的试剂盒购自同仁化学公司。
分别取实施例2中转染并培养得到的5种CAR-T细胞,分别与CD44和CD133阳性的胶质瘤干细胞GSC20按照不同的效靶比(T细胞数量:胶质瘤干细胞数量)混合。将混合后的细胞置于96孔板中进行培养,其中,每孔中含有胶质瘤干细胞4×104个,每孔反应体系为200μL。培养条件包括:37℃,5%CO2,饱和湿度孵箱孵育4小时。
乳酸脱氢酶活性测定:离心结束后,每孔吸取上清液100μL置于96孔酶标板中,同时,每孔加入100μL LDH底物,室温避光反应30min。反应结束后,每孔加50μL终止液终止酶促反应。在酶标仪490nm测定光密度值(OD)。计算各组平均光密度值(OD),按下式计算每种T细胞对胶质瘤干细胞的裂解率。结果如表1所示。
裂解率%=(实验组OD-胶质瘤干细胞自发释放OD-效应细胞自然释放OD)/(胶质瘤干细胞最大释放OD-胶质瘤干细胞自发释放OD)
表1
由表1可以看出,本公开提供的表达抗CD133的单链抗体的T淋巴细胞能够特异性杀伤CD133阳性的肿瘤细胞,且特异性较高、杀伤能力较强。
对比例
采用靶向经典肿瘤靶点EGFR vIII的传统第二代CAR-T细胞(EGFR vIII-CD28-CD3)替换实施例3中的T细胞,然后按照实施例3的方法检测不同效靶比下该CAR-T对胶质瘤干细胞GSC20的杀伤率。检测结果见表2。
表2
由表2可以看出,靶向经典肿瘤干细胞靶点EGFR vIII的传统第二代CAR-T细胞对胶质瘤干细胞的杀伤力不如本公开提供的表达抗CD133的单链抗体的T细胞。
以上结合附图详细描述了本公开的优选实施方式,但是,本公开并不限于上述实施方式中的具体细节,在本公开的技术构思范围内,可以对本公开的技术方案进行多种简单变型,这些简单变型均属于本公开的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本公开对各种可能的组合方式不再另行说明。
此外,本公开的各种不同的实施方式之间也可以进行任意组合,只要其不违背本公开的思想,其同样应当视为本公开所公开的内容。
序列表
<110> 北京市神经外科研究所
<120> 抗CD133的单链抗体及其在制备治疗肿瘤的药物中的用途
<130> 17160BJNI-LGZ
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 244
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asp Pro Gly Thr Gly Asp Thr Ala Tyr Asn Leu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Gly Ala Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Ser Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro
130 135 140
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
145 150 155 160
Leu Ala Asn Ser Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys
165 170 175
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Leu Gln Gly Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
<210> 2
<211> 732
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc gactttgaaa tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggagat attgatcctg gaactggtga tactgcctac 180
aatctgaagt tcaagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag gtctgacgac acggccgtgt attactgtgc gttgggggcc 300
tttgtttact ggggccaggg aaccctggtc accgtctcct caggcagtac tagcggtggt 360
ggctccgggg gcggttccgg tgggggcggc agcagcgatg ttgtgatgac tcagtctcca 420
ctctccctgc ccgtcacccc tggagagccg gcctccatct cctgcaggtc tagtcagagt 480
cttgcaaaca gttatgggaa cacctatttg tcttggtacc tgcagaagcc agggcagtct 540
ccacagctcc tgatctatgg gatttccaac agattttctg gggtccctga caggttcagt 600
ggcagtggat caggcacaga ttttacactg aaaatcagca gagtggaggc tgaggacgtt 660
ggggtttatt actgcttaca aggtacacat cagccgtaca cgtttggcca ggggaccaag 720
ctggagatca aa 732
<210> 3
<211> 466
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asp Pro Gly Thr Gly Asp Thr Ala Tyr Asn Leu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Gly Ala Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Ser Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro
130 135 140
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
145 150 155 160
Leu Ala Asn Ser Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys
165 170 175
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Leu Gln Gly Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
245 250 255
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
260 265 270
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
275 280 285
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
290 295 300
Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu
305 310 315 320
Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
325 330 335
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
340 345 350
Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
355 360 365
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
370 375 380
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
385 390 395 400
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
405 410 415
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
420 425 430
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
435 440 445
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
450 455 460
Pro Arg
465
<210> 4
<211> 561
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asp Pro Gly Thr Gly Asp Thr Ala Tyr Asn Leu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Gly Ala Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Ser Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro
130 135 140
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
145 150 155 160
Leu Ala Asn Ser Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys
165 170 175
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Leu Gln Gly Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
245 250 255
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
260 265 270
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
275 280 285
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
290 295 300
Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu
305 310 315 320
Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
325 330 335
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
340 345 350
Arg Ser Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp
355 360 365
His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu
370 375 380
Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg
385 390 395 400
Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp
405 410 415
Thr Phe Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln Arg Leu Leu Gly
420 425 430
Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn
435 440 445
Gln Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln
450 455 460
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
465 470 475 480
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
485 490 495
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
500 505 510
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
515 520 525
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
530 535 540
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
545 550 555 560
Arg
<210> 5
<211> 737
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asp Pro Gly Thr Gly Asp Thr Ala Tyr Asn Leu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Gly Ala Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Ser Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro
130 135 140
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
145 150 155 160
Leu Ala Asn Ser Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys
165 170 175
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Leu Gln Gly Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
245 250 255
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
260 265 270
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
275 280 285
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
290 295 300
Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu
305 310 315 320
Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
325 330 335
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
340 345 350
Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
355 360 365
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
370 375 380
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
385 390 395 400
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
405 410 415
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
420 425 430
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
435 440 445
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
450 455 460
Pro Arg Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu
465 470 475 480
Asn Pro Gly Pro Met Thr Asn Lys Cys Leu Leu Gln Ile Ala Leu Leu
485 490 495
Leu Cys Phe Ser Thr Thr Ala Leu Ser Gln Val Gln Leu Gln Gln Ser
500 505 510
Gly Pro Gly Leu Val Lys Pro Ser His Thr Leu Ser Leu Thr Cys Thr
515 520 525
Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Thr
530 535 540
Arg Gln His Pro Gly Met Gly Leu Glu Trp Ile Gly Tyr Ile Ser Tyr
545 550 555 560
Ser Gly Ser Ile Tyr Tyr Thr Pro Ser Leu Lys Ser Arg Leu Thr Ile
565 570 575
Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val
580 585 590
Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Ser Leu Asp Ser Trp
595 600 605
Gly Ser Asn Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
610 615 620
Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr
625 630 635 640
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser
645 650 655
Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
660 665 670
Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile
675 680 685
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
690 695 700
Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
705 710 715 720
Arg Ser Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
725 730 735
Lys
<210> 6
<211> 832
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asp Pro Gly Thr Gly Asp Thr Ala Tyr Asn Leu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Gly Ala Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Ser Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro
130 135 140
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
145 150 155 160
Leu Ala Asn Ser Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys
165 170 175
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Leu Gln Gly Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
245 250 255
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
260 265 270
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
275 280 285
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
290 295 300
Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu
305 310 315 320
Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
325 330 335
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
340 345 350
Arg Ser Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp
355 360 365
His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu
370 375 380
Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg
385 390 395 400
Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp
405 410 415
Thr Phe Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln Arg Leu Leu Gly
420 425 430
Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn
435 440 445
Gln Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln
450 455 460
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
465 470 475 480
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
485 490 495
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
500 505 510
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
515 520 525
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
530 535 540
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
545 550 555 560
Arg Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn
565 570 575
Pro Gly Pro Met Thr Asn Lys Cys Leu Leu Gln Ile Ala Leu Leu Leu
580 585 590
Cys Phe Ser Thr Thr Ala Leu Ser Gln Val Gln Leu Gln Gln Ser Gly
595 600 605
Pro Gly Leu Val Lys Pro Ser His Thr Leu Ser Leu Thr Cys Thr Val
610 615 620
Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Thr Arg
625 630 635 640
Gln His Pro Gly Met Gly Leu Glu Trp Ile Gly Tyr Ile Ser Tyr Ser
645 650 655
Gly Ser Ile Tyr Tyr Thr Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser
660 665 670
Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr
675 680 685
Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Ser Leu Asp Ser Trp Gly
690 695 700
Ser Asn Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
705 710 715 720
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
725 730 735
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
740 745 750
Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
755 760 765
Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro
770 775 780
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
785 790 795 800
Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg
805 810 815
Ser Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
820 825 830
<210> 7
<211> 1398
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc gactttgaaa tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggagat attgatcctg gaactggtga tactgcctac 180
aatctgaagt tcaagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag gtctgacgac acggccgtgt attactgtgc gttgggggcc 300
tttgtttact ggggccaggg aaccctggtc accgtctcct caggcagtac tagcggtggt 360
ggctccgggg gcggttccgg tgggggcggc agcagcgatg ttgtgatgac tcagtctcca 420
ctctccctgc ccgtcacccc tggagagccg gcctccatct cctgcaggtc tagtcagagt 480
cttgcaaaca gttatgggaa cacctatttg tcttggtacc tgcagaagcc agggcagtct 540
ccacagctcc tgatctatgg gatttccaac agattttctg gggtccctga caggttcagt 600
ggcagtggat caggcacaga ttttacactg aaaatcagca gagtggaggc tgaggacgtt 660
ggggtttatt actgcttaca aggtacacat cagccgtaca cgtttggcca ggggaccaag 720
ctggagatca aaaccactac cccagcaccg aggccaccca ccccggctcc taccatcgcc 780
tcccagcctc tgtccctgcg tccggaggca tgtagacccg cagctggtgg ggccgtgcat 840
acccggggtc ttgacttcgc ctgcgatatc tacatttggg cccctctggc tggtacttgc 900
ggggtcctgc tgctttcact cgtgatcact ctttactgta ggagtaagag gagcaggctc 960
ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020
cagccctatg ccccaccacg cgacttcgca gcctatcgct cccgcgtgaa attcagccgc 1080
agcgcagatg ctccagccta caagcagggg cagaaccagc tctacaacga actcaatctt 1140
ggtcggagag aggagtacga cgtgctggac aagcggagag gacgggaccc agaaatgggc 1200
gggaagccgc gcagaaagaa tccccaagag ggcctgtaca acgagctcca aaaggataag 1260
atggcagaag cctatagcga gattggtatg aaaggggaac gcagaagagg caaaggccac 1320
gacggactgt accagggact cagcaccgcc accaaggaca cctatgacgc tcttcacatg 1380
caggccctgc cgcctcgg 1398
<210> 8
<211> 1683
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc gactttgaaa tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggagat attgatcctg gaactggtga tactgcctac 180
aatctgaagt tcaagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag gtctgacgac acggccgtgt attactgtgc gttgggggcc 300
tttgtttact ggggccaggg aaccctggtc accgtctcct caggcagtac tagcggtggt 360
ggctccgggg gcggttccgg tgggggcggc agcagcgatg ttgtgatgac tcagtctcca 420
ctctccctgc ccgtcacccc tggagagccg gcctccatct cctgcaggtc tagtcagagt 480
cttgcaaaca gttatgggaa cacctatttg tcttggtacc tgcagaagcc agggcagtct 540
ccacagctcc tgatctatgg gatttccaac agattttctg gggtccctga caggttcagt 600
ggcagtggat caggcacaga ttttacactg aaaatcagca gagtggaggc tgaggacgtt 660
ggggtttatt actgcttaca aggtacacat cagccgtaca cgtttggcca ggggaccaag 720
ctggagatca aaaccactac cccagcaccg aggccaccca ccccggctcc taccatcgcc 780
tcccagcctc tgtccctgcg tccggaggca tgtagacccg cagctggtgg ggccgtgcat 840
acccggggtc ttgacttcgc ctgcgatatc tacatttggg cccctctggc tggtacttgc 900
ggggtcctgc tgctttcact cgtgatcact ctttactgta ggagtaagag gagcaggctc 960
ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020
cagccctatg ccccaccacg cgacttcgca gcctatcgct ccaaaaaaag gattaagcct 1080
atcgtatggc ccagtctccc cgatcacaag aagactctgg aacacctttg taagaaacca 1140
agaaaaaatt taaatgtgag tttcaatcct gaaagtttcc tggactgcca gattcatagg 1200
gtggatgaca ttcaagctag agatgaagtg gaaggttttc tgcaagatac gtttcctcag 1260
caactagaag aatctgagaa gcagaggctt ctgggatcaa atcaagaaga agcatatgtc 1320
accatgtcca gcttctacca aaaccagcgc gtgaaattca gccgcagcgc agatgctcca 1380
gcctacaagc aggggcagaa ccagctctac aacgaactca atcttggtcg gagagaggag 1440
tacgacgtgc tggacaagcg gagaggacgg gacccagaaa tgggcgggaa gccgcgcaga 1500
aagaatcccc aagagggcct gtacaacgag ctccaaaagg ataagatggc agaagcctat 1560
agcgagattg gtatgaaagg ggaacgcaga agaggcaaag gccacgacgg actgtaccag 1620
ggactcagca ccgccaccaa ggacacctat gacgctcttc acatgcaggc cctgccgcct 1680
cgg 1683
<210> 9
<211> 2211
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc gactttgaaa tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggagat attgatcctg gaactggtga tactgcctac 180
aatctgaagt tcaagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag gtctgacgac acggccgtgt attactgtgc gttgggggcc 300
tttgtttact ggggccaggg aaccctggtc accgtctcct caggcagtac tagcggtggt 360
ggctccgggg gcggttccgg tgggggcggc agcagcgatg ttgtgatgac tcagtctcca 420
ctctccctgc ccgtcacccc tggagagccg gcctccatct cctgcaggtc tagtcagagt 480
cttgcaaaca gttatgggaa cacctatttg tcttggtacc tgcagaagcc agggcagtct 540
ccacagctcc tgatctatgg gatttccaac agattttctg gggtccctga caggttcagt 600
ggcagtggat caggcacaga ttttacactg aaaatcagca gagtggaggc tgaggacgtt 660
ggggtttatt actgcttaca aggtacacat cagccgtaca cgtttggcca ggggaccaag 720
ctggagatca aaaccactac cccagcaccg aggccaccca ccccggctcc taccatcgcc 780
tcccagcctc tgtccctgcg tccggaggca tgtagacccg cagctggtgg ggccgtgcat 840
acccggggtc ttgacttcgc ctgcgatatc tacatttggg cccctctggc tggtacttgc 900
ggggtcctgc tgctttcact cgtgatcact ctttactgta ggagtaagag gagcaggctc 960
ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020
cagccctatg ccccaccacg cgacttcgca gcctatcgct cccgcgtgaa attcagccgc 1080
agcgcagatg ctccagccta caagcagggg cagaaccagc tctacaacga actcaatctt 1140
ggtcggagag aggagtacga cgtgctggac aagcggagag gacgggaccc agaaatgggc 1200
gggaagccgc gcagaaagaa tccccaagag ggcctgtaca acgagctcca aaaggataag 1260
atggcagaag cctatagcga gattggtatg aaaggggaac gcagaagagg caaaggccac 1320
gacggactgt accagggact cagcaccgcc accaaggaca cctatgacgc tcttcacatg 1380
caggccctgc cgcctcggga gggaaggggt tctctcctga cctgcggcga tgtggaggag 1440
aaccccggac ccatgaccaa caagtgtctc ctccaaattg ctctcctgtt gtgcttctcc 1500
actacagctc tttcccaggt gcagctacag cagtcgggcc caggactggt gaagccttca 1560
cacaccctgt ccctcacctg cactgtctct ggtggctcca tcagcagtgg tggttactac 1620
tggagttgga cccgtcagca cccagggatg ggcctggagt ggattggata catctcttac 1680
agtgggagta tctattacac tccgtccctc aagagtcgac ttaccatatc agtggacacg 1740
tctaagaacc agttctccct gaagctgagc tctgtgactg ccgcggacac ggccgtatat 1800
tactgtgcga gtttggattc ctggggatct aaccgtgact actggggcca gggaaccctg 1860
gtcaccgtct cgagtggagg tggtggatcc gaaattgtgt tgacgcagtc tccagccacc 1920
ctgtctttgt ctccagggga aagagccacc ctctcctgca gggccagtca gagtgttagc 1980
agctacttag cctggtacca acagaaacct ggccaggctc ccaggctcct catctatgat 2040
gcatccaaca gggccactgg catcccagcc aggttcagtg gcagtgggtc tgggacagac 2100
ttcactctca ccatcagcag cctagagcct gaagattttg cagtttatta ctgtcagcag 2160
cgtagcaact ggccgctcac tttcggcgga gggaccaagg tggagattaa g 2211
<210> 10
<211> 2534
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc gactttgaaa tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggagat attgatcctg gaactggtga tactgcctac 180
aatctgaagt tcaagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag gtctgacgac acggccgtgt attactgtgc gttgggggcc 300
tttgtttact ggggccaggg aaccctggtc accgtctcct caggcagtac tagcggtggt 360
ggctccgggg gcggttccgg tgggggcggc agcagcgatg ttgtgatgac tcagtctcca 420
ctctccctgc ccgtcacccc tggagagccg gcctccatct cctgcaggtc tagtcagagt 480
cttgcaaaca gttatgggaa cacctatttg tcttggtacc tgcagaagcc agggcagtct 540
ccacagctcc tgatctatgg gatttccaac agattttctg gggtccctga caggttcagt 600
ggcagtggat caggcacaga ttttacactg aaaatcagca gagtggaggc tgaggacgtt 660
ggggtttatt actgcttaca aggtacacat cagccgtaca cgtttggcca ggggaccaag 720
ctggagatca aaaccactac cccagcaccg aggccaccca ccccggctcc taccatcgcc 780
tcccagcctc tgtccctgcg tccggaggca tgtagacccg cagctggtgg ggccgtgcat 840
acccggggtc ttgacttcgc ctgcgatatc tacatttggg cccctctggc tggtacttgc 900
ggggtcctgc tgctttcact cgtgatcact ctttactgta ggagtaagag gagcaggctc 960
ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020
cagccctatg ccccaccacg cgacttcgca gcctatcgct ccaaaaaaag gattaagcct 1080
atcgtatggc ccagtctccc cgatcacaag aagactctgg aacacctttg taagaaacca 1140
agaaaaaatt taaatgtgag tttcaatcct gaaagtttcc tggactgcca gattcatagg 1200
gtggatgaca ttcaagctag agatgaagtg gaaggttttc tgcaagatac gtttcctcag 1260
caactagaag aatctgagaa gcagaggctt ctgggatcaa atcaagaaga agcatatgtc 1320
accatgtcca gcttctacca aaaccagcgc gtgaaattca gccgcagcgc agatgctcca 1380
gcctacaagc aggggcagaa ccagctctac aacgaactca atcttggtcg gagagaggag 1440
tacgacgtgc tggacaagcg gagaggacgg gacccagaaa tgggcgggaa gccgcgcaga 1500
aagaatcccc aagagggcct gtacaacgag ctccaaaagg ataagatggc agaagcctat 1560
agcgagattg gtatgaaagg ggaacgcaga agaggcaaag gccacgacgg actgtaccag 1620
ggactcagca ccgccaccaa ggacacctat gacgctcttc acatgcaggc cctgccgcct 1680
cgggagggaa ggggttctct cctgacctgc ggcgatgtgg aggagaaccc cggacccatg 1740
accaacaagt gtctcctcca aattgctctc ctgttgtgct tctccactac agctctttcc 1800
caggtgcagc tacagcagtc gggcccagga ctggtgaagc cttcacacac cctgtccctc 1860
acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ttggacccgt 1920
cagcacccag ggatgggcct ggagtggatt ggatacatct cttacagtgg gagtatctat 1980
tacactccgt ccctcaagag tcgacttacc atatcagtgg acacgtctaa gaaccagttc 2040
tccctgaagc tgagctctgt gactgccgcg gacacggccg tatattactg tgcgagtttg 2100
gattcctggg gatctaaccg tgactactgg ggccagggaa ccctggtcac cgtctcgagt 2160
ggaggtggtg gatccgaaat tgtgttgacg cagtctccag ccaccctgtc tttgtctcca 2220
ggggaaagag ccaccctctc ctgcagggcc agtcagagtg ttagcagcta cttagcctgg 2280
taccaacaga aacctggcca ggctcccagg ctcctcatct atgatgcatc caacagggcc 2340
actggcatcc cagccaggtt cagtggcagt gggtctggga cagacttcac tctcaccatc 2400
agcagcctag agcctgaaga ttttgcagtt tattactgtc agcagcgtag caactggccg 2460
ctcactttcg gcggagggac caaggtggag attaagcgct cactttcggc ggagggacca 2520
aggtggagat taag 2534
Claims (14)
1.一种抗CD133的单链抗体,其特征在于,该抗CD133的单链抗体的氨基酸序列为SEQID NO. 1所示的序列。
2.一种核酸,其特征在于,该核酸编码权利要求1所述的抗CD133的单链抗体。
3.根据权利要求2所述的核酸,其中,所述核酸具有SEQ ID NO. 2所示的核苷酸序列。
4.一种融合蛋白,其特征在于,所述融合蛋白含有依次连接的抗原结合结构域、跨膜结构域和胞内信号传导结构域;所述抗原结合结构域的氨基酸序列包括权利要求1所述的抗CD133的单链抗体的氨基酸序列。
5.根据权利要求4所述的融合蛋白,其中,所述抗原结合结构域包括抗CD133的单链抗体,所述胞内信号传导结构域包括抗TIM3的单链抗体和/或IL7Rα或者IL7Rα的截短体。
6.根据权利要求4所述的融合蛋白,其中,所述融合蛋白具有SEQ ID NO.3、SEQ ID NO.4、SEQ ID NO. 5或者SEQ ID NO. 6中任一项所示的氨基酸序列。
7.一种融合核酸,其特征在于,所述融合核酸编码权利要求4所述的融合蛋白。
8.根据权利要求7所述的融合核酸,其中,所述融合核酸具有SEQ ID NO. 7、SEQ IDNO. 8、SEQ ID NO. 9或者SEQ ID NO. 10中任一项所示的核苷酸序列。
9.一种表达载体,其特征在于,所述表达载体插入有表达框,所述表达框包括编码抗原结合分子的第一核酸片段和编码胞内信号传导分子的第二核酸片段,所述抗原结合分子中含有权利要求1所述的抗CD133的单链抗体,所述第一核酸片段与所述第二核酸片段之间插入有IRES元件或2A肽编码序列。
10.根据权利要求9所述的表达载体,其中,所述表达框为权利要求7所述的融合核酸。
11.一种表达嵌合抗原受体的细胞,其特征在于,该表达嵌合抗原受体的细胞由宿主细胞转染权利要求9所述的表达载体后得到,所述嵌合抗原受体中含有权利要求1所述的抗CD133的单链抗体。
12.根据权利要求11所述的细胞,其特征在于,所述宿主细胞为T细胞。
13.权利要求1所述的抗CD133的单链抗体、权利要求2所述的核酸、权利要求4所述的融合蛋白、权利要求7所述的融合核酸、权利要求9所述的表达载体、权利要求11所述的表达嵌合抗原受体的细胞在制备治疗脑胶质瘤的药物中的用途。
14.一种药物组合物,其特征在于,该药物组合物的有效成分包括权利要求11所述的表达抗CD133嵌合抗原受体的细胞。
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EP21849059.7A EP4174090A1 (en) | 2020-07-31 | 2021-07-30 | Anti-cd133 single-chain antibody and use thereof in preparation of drug for treating tumor |
PCT/CN2021/109863 WO2022022718A1 (zh) | 2020-07-31 | 2021-07-30 | 抗cd133的单链抗体及其在制备治疗肿瘤的药物中的用途 |
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CN110526970A (zh) * | 2018-05-25 | 2019-12-03 | 深圳宾德生物技术有限公司 | 靶向cd133的单链抗体、嵌合抗原受体t细胞及其制备方法和应用 |
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CN110526970A (zh) * | 2018-05-25 | 2019-12-03 | 深圳宾德生物技术有限公司 | 靶向cd133的单链抗体、嵌合抗原受体t细胞及其制备方法和应用 |
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