CN114106176A - Cd22抗体及其应用 - Google Patents
Cd22抗体及其应用 Download PDFInfo
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- CN114106176A CN114106176A CN202110967318.7A CN202110967318A CN114106176A CN 114106176 A CN114106176 A CN 114106176A CN 202110967318 A CN202110967318 A CN 202110967318A CN 114106176 A CN114106176 A CN 114106176A
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Abstract
本发明提出了一种能够特异性识别CD22的抗体或其抗原结合片段。该抗体含有选自下列至少之一的CDR序列或与其具有至少95%同一性的氨基酸序列:重链可变区CDR序列:SEQ ID NO:1~9,轻链可变区CDR序列:SEQ IN NO:10~18。根据本发明实施例的抗体能够特异性识别CD22,与CD22的亲和力高,并且能够被靶标细胞内吞,可用于ADC药物的开发和应用。
Description
技术领域
本发明涉及生物技术领域,具体地,本发明涉及CD22抗体及其应用,更具体地,本发明涉及能够特异性识别CD22抗体或其抗原结合片段、核酸分子、表达载体、重组细胞、嵌合抗原受体、CART细胞、抗体偶联药物、药物组合物、制药用途以及检测CD22的试剂盒。
背景技术
血液肿瘤是中国十大高发恶性肿瘤之一,占肿瘤发病率的第六位。尤其是急性淋巴细胞白血病多发于青少年,是35岁以下人群发病率、病死率最高的恶性肿瘤,其中B-ALL(急性B淋巴细胞白血病)最为常见。
CD22为Ⅰ型跨膜糖蛋白,是唾液酸结合免疫球蛋白样凝集素家族成员。作为B细胞受体(BCR)的抑制性共受体,CD22对B细胞激活信号具有负性调节作用。CD22能够与包含α-2,6连接唾液酸的糖蛋白配体特异性结合,抗原激活BCR,也使CD22胞质区免疫受体酪氨酸抑制基序中的酪氨酸迅速磷酸化,并激活下游信号分子抑制钙离子内流而减弱BCR信号。CD22参与B细胞的归巢过程。
CD22分子量为140kDa,CD22的胞外域包含七个Ig域(residues 20–687AA),最远端的V-set Ig域在结合α2,6唾液酸(α2,6sia)配体中起主要作用,相连的C2-set Ig域的功能可能是允许V-set Ig域正确折叠。CD22的胞内域包括免疫受体酪氨酸抑制基序(ITIM)和免疫受体酪氨酸活化基序(ITAM)。Ig样结构域1和2包含配体结合区;当六个保守的酪氨酸残基中的一个或多个被磷酸化时,各种效应分子被募集到胞质域。CD22α(647aa)和CD22β(847aa)是CD22的两种亚型,其胞外域分别有5个和7个Ig域,这两种cDNA亚型来源于同一基因的不同拼接。
CD22相对特异地表达于B细胞表面,是调节B细胞免疫及治疗某些B细胞肿瘤的良好靶标。针对CD22开发新的抗体,以满足肿瘤治疗的需求,是科研工作者不断努力的方向。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。
为此,本申请的发明人在实验中意外而惊喜地筛选到一批对CD22具有高亲和力,并且容易被靶标细胞内吞的抗体,该CD22抗体可用于抗体偶联药物(ADC药物)的开发和应用。
在本发明的第一方面,本发明提出了一种能够特异性识别CD22的抗体或其抗原结合片段。根据本发明的实施例,所述抗体含有选自下列至少之一的CDR序列或与其具有至少95%同一性的氨基酸序列:重链可变区CDR序列:SEQ ID NO:1~9,轻链可变区CDR序列:SEQIN NO:10~18。根据本发明实施例的抗体能够特异性识别CD22,与CD22的亲和力高,并且能够被靶标细胞内吞,可用于ADC药物的开发和应用。
GFTFSNYW(SEQ ID NO:1)。
IRLKSNDYAT(SEQ ID NO:2)。
TR(SEQ ID NO:3)。
GFTFSYYW(SEQ ID NO:4)。
IRLKSHNYVT(SEQ ID NO:5)。
RT(SEQ ID NO:6)。
GYTFTDYE(SEQ ID NO:7)。
IDPETGAT(SEQ ID NO:8)。
TR(SEQ ID NO:9)。
SVSSIYL(SEQ ID NO:10)。
STS(SEQ ID NO:11)。
HQYHRSP(SEQ ID NO:12)。
QSVTND(SEQ ID NO:13)。
YAS(SEQ ID NO:14)。
QQDYRSP(SEQ ID NO:15)。
EDIYNR(SEQ ID NO:16)。
GAT(SEQ ID NO:17)。
QQYWSS(SEQ ID NO:18)。
根据本发明的实施例,上述抗体或其抗原结合片段还可以进一步包括如下附加技术特征至少之一:
根据本发明的实施例,所述抗体包括:分别如SEQ ID NO:1、2和3或者与SEQ IDNO:1、2和3具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:4、5和6或者与SEQ ID NO:4、5和6具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:7、8和9或者与SEQ ID NO:7、8和9具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列。
根据本发明的实施例,所述抗体包括:分别如SEQ ID NO:10、11和12或者与SEQ IDNO:10、11和12具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:13、14和15或者与SEQ ID NO:13、14和15具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:16、17和18或者与SEQ ID NO:16、17和18具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
根据本发明的实施例,所述抗体包括:分别如SEQ ID NO:1、2和3或者与SEQ IDNO:1、2和3具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列和分别如SEQ ID NO:10、11和12或者与SEQ ID NO:10、11和12具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:4、5和6或者与SEQ IDNO:4、5和6具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列和分别如SEQ ID NO:13、14和15或者与SEQ ID NO:13、14和15具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:7、8和9或者与SEQ IDNO:7、8和9具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列和分别如SEQ ID NO:16、17和18或者与SEQ ID NO:16、17和18具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
根据本发明的实施例,所述抗体或其抗原结合片段特异性识别CD22的胞外区。
根据本发明的实施例,所述抗体含有重链框架区序列和轻链框架区序列的至少之一,所述重链框架区序列根据本发明的实施例和轻链框架区序列的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体的至少之一。
根据本发明的实施例,所述抗体具有如SEQ ID NO:19~21任一项所示氨基酸序列的重链可变区。
EVKLEESGGGLVQPGGFMKLSCVASGFTFSNYWMNWVRQSPERGLEWVAEIRLKSNDYATHYAESVKGRFTISRDDSKSNVYLQMNNLRAEDTGIYYCTRVYYYGRDYAMDYWGQGTSVTVSS(SEQ ID NO:19)。
GVQSEVKIEESGGGLVQPGGSMKVSCVASGFTFSYYWMNWVRQSPEKGLEWVAEIRLKSHNYVTHYAESVNGSFTISRDDSRSSVYLQMNNLRTEDTGIYYCTRGAGYFDVWGAGTTVTVSS(SEQ ID NO:20)。
QVQLQQSGAELVRPGASVTLSCKASGYTFTDYEMHWVKQTLVHGLEWIGAIDPETGATAYNQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTRSNWDGWFAYWGQGTLVTVSA(SEQ ID NO:21)。
根据本发明的实施例,所述抗体具有如SEQ ID NO:22~24任一项所示氨基酸序列的轻链可变区。
QIVLTQSPAIMSASLGERVTMTCTASSSVSSIYLHWYQQKPGSSPKLWIYSTSNLASGVPGRFSGSGSGTSYSLTISSMEAEDAATYYCHQYHRSPRTFGGGTKLEIKR(SEQ ID NO:22)。
SIVMTQTPKFLLVSAGDRVAITCKASQSVTNDVTWYQQKPGQSPKLLIFYASNRYTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYRSPWTFGGGTKLEIRR(SEQ ID NO:23)。
DIQMTQSSSSFSVSLGDRVTITCKASEDIYNRLAWYQQKPGSAPRLLISGATSLETGVPSRFSGSGSGKDYTLNITSLQTEDVATYYCQQYWSSWTFGGGTKLEIKR(SEQ ID NO:24)。
根据本发明的实施例,所述抗体含有重链恒定区和轻链恒定区的至少之一,所述重链恒定区和轻链恒定区的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体的至少之一。
根据本发明的实施例,所述抗体的轻链恒定区和重链恒定区均来自于人源IgG抗体或其突变体。
根据本发明的实施例,所述抗体的轻链恒定区和重链恒定区均来自于人源IgG1,2。进而所述抗体的免疫原性可以得到有效降低。
根据本发明的实施例,所述抗体具有SEQ ID NO:25~27任一项所示氨基酸序列的重链和具有SEQ ID NO:28~30任一项所示氨基酸序列的轻链。
EVKLEESGGGLVQPGGFMKLSCVASGFTFSNYWMNWVRQSPERGLEWVAEIRLKSNDYATHYAESVKGRFTISRDDSKSNVYLQMNNLRAEDTGIYYCTRVYYYGRDYAMDYWGQGTSVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTKPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITNFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK(SEQ ID NO:25)
GVQSEVKIEESGGGLVQPGGSMKVSCVASGFTFSYYWMNWVRQSPEKGLEWVAEIRLKSHNYVTHYAESVNGSFTISRDDSRSSVYLQMNNLRTEDTGIYYCTRGAGYFDVWGAGTTVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTKPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITNFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK(SEQ ID NO:26)
QVQLQQSGAELVRPGASVTLSCKASGYTFTDYEMHWVKQTLVHGLEWIGAIDPETGATAYNQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTRSNWDGWFAYWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK(SEQ ID NO:27)
QIVLTQSPAIMSASLGERVTMTCTASSSVSSIYLHWYQQKPGSSPKLWIYSTSNLASGVPGRFSGSGSGTSYSLTISSMEAEDAATYYCHQYHRSPRTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC(SEQID NO:28)
SIVMTQTPKFLLVSAGDRVAITCKASQSVTNDVTWYQQKPGQSPKLLIFYASNRYTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYRSPWTFGGGTKLEIRRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC(SEQ IDNO:29)
DIQMTQSSSSFSVSLGDRVTITCKASEDIYNRLAWYQQKPGSAPRLLISGATSLETGVPSRFSGSGSGKDYTLNITSLQTEDVATYYCQQYWSSWTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC(SEQ IDNO:30)
其中,在本申请中,上述SEQ ID NO:25和28所组成的抗体被称为5CD22-111-1-C3,上述SEQ ID NO:26和29所组成的抗体被称为FC2-021,上述SEQ ID NO:27和30所组成的抗体被称为FC2-045。
根据本发明的实施例,所述抗体为单链抗体、多聚体抗体、CDR移植抗体或小分子抗体。
根据本发明的实施例,所述抗体为单链抗体。
根据本发明的实施例,所述小分子抗体包括Fab抗体、Fv抗体、单域抗体以及最小识别单位的至少之一。
在本发明的第二方面,本发明提出了一种核酸。根据本发明的实施例,所述核酸分子编码前面所述的抗体或其抗原结合片段。根据本发明实施例的核酸分子所编码的抗体或抗原结合片段可特异性靶向结合CD22,亲和力高,并且能够被靶标细胞内吞,可用于ADC药物的开发和应用。
根据本发明的实施例,上述核酸还可以进一步包括如下附加技术特征至少之一:
根据本发明的实施例,所述核酸分子为DNA。
根据本发明的实施例,所述核酸分子具有如SEQ ID NO:31~33任一项所示核苷酸序列或具有SEQ ID NO:34~36任一项所示核苷酸序列。
GAAGTGAAGCTTGAGGAGTCTGGAGGAGGCTTGGTGCAACCTGGAGGATTCATGAAACTCTCCTGTGTTGCCTCTGGATTCACTTTCAGTAACTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAGGGGGCTTGAGTGGGTTGCTGAAATTAGATTGAAATCTAATGATTATGCAACACATTATGCGGAGTCTGTGAAAGGGAGGTTCACCATCTCAAGAGATGATTCCAAGAGTAATGTCTACCTGCAAATGAACAACTTAAGAGCTGAAGACACTGGCATTTATTACTGTACCAGAGTTTATTACTACGGTCGTGACTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAGACCACACCCCCTAGCGTGTACCCACTGGCTCCCGGAAGCGCCGCTCAGACTAATTCCATGGTGACCCTGGGCTGCCTCGTCAAGGGATATTTCCCTGAGCCAGTCACTGTGACCTGGAACTCCGGGTCTCTGAGCTCCGGTGTGCACACTTTTCCAGCCGTCCTCCAGTCCGACCTGTACACCCTCTCTAGTTCAGTCACAGTGCCCAGCTCCACTTGGCCTTCTCAGACAGTGACTTGTAATGTCGCTCATCCAGCATCTAGTACAAAGGTGGACAAGAAAATCGTCCCCAGGGATTGCGGTTGTAAACCATGCATTTGTACTGTCCCCGAGGTGTCAAGCGTCTTCATCTTTCCACCCAAGCCCAAAGACGTGCTGACCATTACACTCACTCCTAAGGTGACATGCGTGGTCGTGGATATCTCTAAAGACGATCCCGAGGTTCAGTTCAGTTGGTTTGTAGACGATGTCGAAGTGCACACTGCCCAGACCAAGCCTAGGGAGGAACAGTTCAACAGCACCTTCAGGAGCGTGAGCGAGCTGCCAATTATGCATCAGGACTGGCTCAATGGCAAGGAGTTCAAATGCCGGGTGAACTCTGCAGCCTTTCCCGCTCCTATCGAGAAGACAATTAGTAAGACTAAAGGACGCCCTAAAGCACCACAGGTGTACACAATCCCTCCACCCAAGGAACAGATGGCCAAGGATAAAGTGTCCCTGACCTGTATGATCACAAACTTCTTTCCCGAGGATATTACCGTGGAATGGCAGTGGAATGGGCAGCCTGCTGAGAACTATAAGAATACCCAGCCAATCATGGACACAGATGGTAGTTACTTCGTGTATTCAAAGCTGAACGTCCAGAAATCAAATTGGGAAGCAGGCAACACCTTTACATGTTCCGTGCTGCACGAGGGACTCCATAACCACCATACCGAAAAGAGCCTGTCCCACTCTCCTGGCAAA(SEQ ID NO:31)。
GGTGTCCAGAGTGAAGTGAAGATTGAGGAGTCTGGAGGAGGCTTGGTGCAACCTGGAGGATCCATGAAAGTCTCCTGTGTTGCCTCTGGATTCACTTTCAGTTATTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAGGGGCTTGAGTGGGTTGCTGAAATTAGATTGAAGTCTCATAATTATGTAACACATTATGCGGAGTCTGTGAATGGGAGTTTCACCATCTCAAGAGATGATTCCAGAAGTAGTGTCTACCTGCAAATGAACAACTTAAGAACTGAAGACACTGGCATTTATTACTGTACCAGGGGGGCTGGGTACTTCGATGTCTGGGGCGCAGGGACAACGGTCACCGTCTCCTCAGCCAAGACCACACCCCCTAGCGTGTACCCACTGGCTCCCGGAAGCGCCGCTCAGACTAATTCCATGGTGACCCTGGGCTGCCTCGTCAAGGGATATTTCCCTGAGCCAGTCACTGTGACCTGGAACTCCGGGTCTCTGAGCTCCGGTGTGCACACTTTTCCAGCCGTCCTCCAGTCCGACCTGTACACCCTCTCTAGTTCAGTCACAGTGCCCAGCTCCACTTGGCCTTCTCAGACAGTGACTTGTAATGTCGCTCATCCAGCATCTAGTACAAAGGTGGACAAGAAAATCGTCCCCAGGGATTGCGGTTGTAAACCATGCATTTGTACTGTCCCCGAGGTGTCAAGCGTCTTCATCTTTCCACCCAAGCCCAAAGACGTGCTGACCATTACACTCACTCCTAAGGTGACATGCGTGGTCGTGGATATCTCTAAAGACGATCCCGAGGTTCAGTTCAGTTGGTTTGTAGACGATGTCGAAGTGCACACTGCCCAGACCAAGCCTAGGGAGGAACAGTTCAACAGCACCTTCAGGAGCGTGAGCGAGCTGCCAATTATGCATCAGGACTGGCTCAATGGCAAGGAGTTCAAATGCCGGGTGAACTCTGCAGCCTTTCCCGCTCCTATCGAGAAGACAATTAGTAAGACTAAAGGACGCCCTAAAGCACCACAGGTGTACACAATCCCTCCACCCAAGGAACAGATGGCCAAGGATAAAGTGTCCCTGACCTGTATGATCACAAACTTCTTTCCCGAGGATATTACCGTGGAATGGCAGTGGAATGGGCAGCCTGCTGAGAACTATAAGAATACCCAGCCAATCATGGACACAGATGGTAGTTACTTCGTGTATTCAAAGCTGAACGTCCAGAAATCAAATTGGGAAGCAGGCAACACCTTTACATGTTCCGTGCTGCACGAGGGACTCCATAACCACCATACCGAAAAGAGCCTGTCCCACTCTCCTGGCAAA(SEQ ID NO:32)。
CAGGTGCAGCTGCAGCAGAGCGGCGCCGAGCTGGTGAGGCCCGGCGCCAGCGTGACCCTGAGCTGCAAGGCCAGCGGCTACACCTTCACCGACTACGAGATGCACTGGGTGAAGCAGACCCTGGTGCACGGCCTGGAGTGGATCGGCGCCATCGACCCCGAGACCGGCGCCACCGCCTACAACCAGAAGTTCAAGGGCAAGGCCACCCTGACCGCCGACAAGAGCAGCAGCACCGCCTACATGGAGCTGAGGAGCCTGACCAGCGAGGACAGCGCCGTGTACTACTGCACCAGGAGCAACTGGGACGGCTGGTTCGCCTACTGGGGCCAGGGCACCCTGGTGACCGTGAGCGCCGCCAAGACCACCGCCCCCAGCGTGTACCCCCTGGCCCCCGTGTGCGGCGACACCACCGGCAGCAGCGTGACCCTGGGCTGCCTGGTGAAGGGCTACTTCCCCGAGCCCGTGACCCTGACCTGGAACAGCGGCAGCCTGAGCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCGACCTGTACACCCTGAGCAGCAGCGTGACCGTGACCAGCAGCACCTGGCCCAGCCAGAGCATCACCTGCAACGTGGCCCACCCCGCCAGCAGCACCAAGGTGGACAAGAAGATCGAGCCCAGGGGCCCCACCATCAAGCCCTGCCCCCCCTGCAAGTGCCCCGCCCCCAACCTGCTGGGCGGCCCCAGCGTGTTCATCTTCCCCCCCAAGATCAAGGACGTGCTGATGATCAGCCTGAGCCCCATCGTGACCTGCGTGGTGGTGGACGTGAGCGAGGACGACCCCGACGTGCAGATCAGCTGGTTCGTGAACAACGTGGAGGTGCACACCGCCCAGACCCAGACCCACAGGGAGGACTACAACAGCACCCTGAGGGTGGTGAGCGCCCTGCCCATCCAGCACCAGGACTGGATGAGCGGCAAGGAGTTCAAGTGCAAGGTGAACAACAAGGACCTGCCCGCCCCCATCGAGAGGACCATCAGCAAGCCCAAGGGCAGCGTGAGGGCCCCCCAGGTGTACGTGCTGCCCCCCCCCGAGGAGGAGATGACCAAGAAGCAGGTGACCCTGACCTGCATGGTGACCGACTTCATGCCCGAGGACATCTACGTGGAGTGGACCAACAACGGCAAGACCGAGCTGAACTACAAGAACACCGAGCCCGTGCTGGACAGCGACGGCAGCTACTTCATGTACAGCAAGCTGAGGGTGGAGAAGAAGAACTGGGTGGAGAGGAACAGCTACAGCTGCAGCGTGGTGCACGAGGGCCTGCACAACCACCACACCACCAAGAGCTTCAGCAGGACCCCCGGCAAGGCAAAGACCACAGCCCCTTCTGTCTACCCCCTGGCCCCCGTGTGCGGAGACACTACCGGTAGCTCCGTCACCCTGGGCTGTCTCGTGAAGGGATATTTCCCCGAGCCTGTGACCCTGACATGGAACTCCGGGTCTCTCTCTAGTGGTGTCCACACCTTTCCAGCAGTGCTGCAGAGCGACCTGTACACACTCTCAAGCTCCGTCACTGTGACCTCTAGTACATGGCCCAGTCAGTCAATCACTTGCAACGTGGCCCATCCTGCTTCAAGCACAAAGGTGGATAAGAAAATCGAACCACGGGGCCCCACTATTAAGCCTTGTCCACCCTGCAAATGTCCAGCTCCCAATCTGCTCGGCGGACCAAGCGTGTTCATCTTTCCTCCAAAGATTAAAGACGTGCTGATGATCAGCCTCTCCCCAATTGTCACCTGCGTGGTCGTGGACGTGAGTGAGGACGATCCCGATGTCCAGATCTCCTGGTTCGTGAACAATGTCGAAGTGCACACCGCCCAGACACAGACTCATAGGGAGGATTACAACTCCACACTGAGAGTCGTGTCTGCTCTCCCCATTCAGCACCAGGACTGGATGTCCGGCAAGGAGTTCAAGTGCAAGGTGAACAACAAGGATCTGCCTGCTCCAATCGAGCGAACAATTTCAAAGCCTAAAGGAAGCGTGAGGGCACCACAGGTCTATGTGCTGCCCCCTCCAGAGGAAGAGATGACTAAGAAACAGGTCACCCTCACATGTATGGTGACCGACTTCATGCCCGAAGACATCTACGTGGAGTGGACTAACAATGGGAAGACCGAACTGAACTATAAAAATACTGAGCCTGTGCTCGACTCTGATGGTAGTTACTTTATGTATTCTAAGCTGCGGGTCGAAAAGAAAAACTGGGTGGAGCGCAATTCTTATAGTTGTTCAGTCGTGCACGAGGGCCTGCATAATCACCATACAACTAAGAGCTTCTCCAGAACACCTGGAAAA(SEQ ID NO:33)。
CAAATTGTTCTCACCCAGTCTCCAGCAATCATGTCTGCATCTCTAGGGGAACGGGTCACCATGACCTGCACTGCCAGCTCAAGTGTAAGTTCCATTTACTTGCACTGGTACCAGCAGAAGCCAGGATCCTCCCCCAAACTCTGGATTTATAGCACATCCAACCTGGCTTCTGGAGTCCCAGGTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGCATGGAGGCTGAAGATGCTGCCACTTATTACTGCCACCAGTATCATCGTTCCCCACGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAACGGGCAGACGCCGCTCCAACCGTGAGCATCTTCCCCCCTAGCTCCGAGCAGCTGACATCAGGCGGAGCCAGCGTGGTCTGCTTCCTCAACAACTTCTACCCCAAGGACATCAACGTGAAGTGGAAAATTGATGGGTCCGAACGGCAGAACGGCGTCCTGAACTCTTGGACAGACCAGGATTCCAAGGACTCTACTTATAGTATGTCTAGTACCCTGACACTCACTAAAGATGAGTACGAAAGGCACAATAGTTATACTTGCGAGGCTACCCATAAGACCTCAACAAGCCCCATTGTCAAATCTTTTAACAGAAATGAATGT(SEQ ID NO:34)。
AGTATTGTGATGACCCAGACTCCCAAATTCCTGCTTGTATCAGCAGGAGACAGGGTTGCCATAACCTGCAAGGCCAGTCAGAGTGTGACTAATGATGTTACTTGGTACCAACAGAAGCCAGGGCAGTCTCCTAAACTGCTGATATTCTATGCATCCAATCGCTACACTGGAGTCCCTGATCGCTTCACTGGCAGTGGATATGGGACGGATTTCACTTTCACCATCAGCACTGTGCAGGCTGAAGACCTGGCAGTTTATTTCTGTCAGCAGGATTATAGGTCTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAGACGGGCAGACGCCGCTCCAACCGTGAGCATCTTCCCCCCTAGCTCCGAGCAGCTGACATCAGGCGGAGCCAGCGTGGTCTGCTTCCTCAACAACTTCTACCCCAAGGACATCAACGTGAAGTGGAAAATTGATGGGTCCGAACGGCAGAACGGCGTCCTGAACTCTTGGACAGACCAGGATTCCAAGGACTCTACTTATAGTATGTCTAGTACCCTGACACTCACTAAAGATGAGTACGAAAGGCACAATAGTTATACTTGCGAGGCTACCCATAAGACCTCAACAAGCCCCATTGTCAAATCTTTTAACAGAAATGAATGT(SEQ ID NO:35)。
GACATCCAGATGACACAATCTTCATCCTCCTTTTCTGTATCTCTAGGAGACAGAGTCACCATTACTTGCAAGGCAAGTGAGGACATATATAATCGATTAGCCTGGTATCAGCAGAAACCAGGAAGTGCTCCTAGGCTCTTAATATCTGGTGCAACCAGTTTGGAAACTGGGGTTCCTTCAAGATTCAGTGGCAGTGGATCTGGAAAGGATTACACTCTCAACATTACCAGTCTTCAGACTGAAGATGTTGCTACTTATTACTGTCAACAGTATTGGAGTTCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAACGGGCAGACGCCGCTCCAACCGTGAGCATCTTCCCCCCTAGCTCCGAGCAGCTGACATCAGGCGGAGCCAGCGTGGTCTGCTTCCTCAACAACTTCTACCCCAAGGACATCAACGTGAAGTGGAAAATTGATGGGTCCGAACGGCAGAACGGCGTCCTGAACTCTTGGACAGACCAGGATTCCAAGGACTCTACTTATAGTATGTCTAGTACCCTGACACTCACTAAAGATGAGTACGAAAGGCACAATAGTTATACTTGCGAGGCTACCCATAAGACCTCAACAAGCCCCATTGTCAAATCTTTTAACAGAAATGAATGT(SEQ ID NO:36)。
其中,在本申请中,上述SEQ ID NO:31和34所示核苷酸序列分别编码5CD22-111-1-C3的重链和轻链,上述SEQ ID NO:32和35所示核苷酸序列分别编码FC2-021的重链和轻链,上述SEQ ID NO:33和36所示核苷酸序列分别编码FC2-045的重链和轻链。
在本发明的第三方面,本发明提出了一种表达载体。根据本发明的实施例,所述表达载体携带前面所述的核酸分子。根据本发明实施例的表达载体导入合适的受体细胞后,可在调控系统的介导下,有效实现前面所述的特异性识别CD22的抗体或其抗原结合片段表达,进而实现所述抗体或抗原结合片段的体外大量获得。
根据本发明的实施例,上述表达载体还可以进一步包括如下附加技术特征至少之一:
根据本发明的实施例,所述表达载体为真核表达载体。进而实现前面所述的特异性识别CD22的抗体或其抗原结合片段在真核细胞中的表达。
在本发明的第四方面,本发明提出了一种重组细胞。根据本发明的实施例,所述重组细胞携带前面所述的核酸分子和/或前面所述的表达载体,或者表达前面所述的抗体或其抗原结合片段。根据本发明实施例的重组细胞可用于前面所述的特异性识别CD22的抗体或其抗原结合片段体外表达和大量获得。
根据本发明的实施例,上述重组细胞还可以进一步包括如下附加技术特征至少之一:
根据本发明的实施例,所述重组细胞是通过将前面所述的表达载体引入至宿主细胞中而获得的。
根据本发明的实施例,所述重组细胞为真核细胞。
根据本发明的实施例,所述重组细胞为哺乳动物细胞。
在本发明的第五方面,本发明提出了一种嵌合抗原受体。根据本发明的实施例,所述嵌合抗原受体包括:胞外区,所述胞外区包括单链抗体的重链可变区和轻链可变区以及CD8铰链区,所述单链抗体特异性识别CD22;跨膜区,所述跨膜区包括免疫共刺激因子跨膜区;以及胞内区,所述胞内区包括免疫共刺激因子胞内段以及CD3ζ链;其中,所述单链抗体的重链可变区和轻链可变区如前面所描述的。发明人发现,表达根据本发明实施例的嵌合抗原受体CART细胞可特异性靶向CD22阳性肿瘤细胞,对CD22阳性肿瘤细胞的特异性杀伤效果优。
在本发明的第六方面,本发明提出了一种CART细胞。根据本发明的实施例,所述CART细胞表达前面所述的嵌合抗原受体。根据本发明实施例的CART细胞可特异性靶向CD22阳性肿瘤细胞,对CD22阳性肿瘤细胞的特异性杀伤效果优。
在本发明的第七方面,本发明提出了一种抗体偶联药物。根据本发明的实施例,所述抗体偶联药物包括抗体、连接子和小分子细胞毒药物,其中,所述抗体如前面所限定的。根据本发明实施例的抗体偶联药物可特异性靶向结合CD22阳性肿瘤细胞,并且CD22阳性肿瘤细胞可将前面所述的抗体内吞到细胞内,进而抗体偶联药物所携带的小分子细胞毒药物进入肿瘤细胞内,更好地发挥对肿瘤细胞的杀伤效果。
在本发明的第八方面,本发明提出了一种药物组合物。根据本发明的实施例,所述药物组合物含有前面所述的抗体、前面所述的核酸分子、前面所述的表达载体或前面所述的重组细胞、前面所述的嵌合抗原受体、前面所述的CART细胞或前面所述的抗体偶联药物中的至少之一。根据本发明实施例的药物组合物中所包含的抗体或表达的抗体能够特异性的靶向结合CD22,所包含的CART细胞对CD22阳性肿瘤细胞的特异性杀伤效果优,所包含的抗体偶联药物特异性靶向结合CD22阳性肿瘤细胞并且发生内吞,抗体偶联药物所携带的小分子细胞毒药物进入肿瘤细胞内,更好地发挥对肿瘤细胞的杀伤效果。
在本发明的第九方面,本发明提出了前面所述的抗体、前面所述的核酸分子、前面所述的表达载体或前面所述的重组细胞、前面所述的嵌合抗原受体、前面所述的CART细胞、前面所述的抗体偶联药物或前面所述的药物组合物在制备药物中的用途,所述药物用于治疗或者预防癌症。
根据本发明的实施例,所述癌症为B淋巴细胞白血病或B细胞淋巴瘤。
在本发明的第十方面,本发明提出了前面所述的抗体、前面所述的核酸分子、前面所述的表达载体或前面所述的重组细胞、前面所述的嵌合抗原受体、前面所述的CART细胞、前面所述的抗体偶联药物或前面所述的药物组合物在制备药物中的用途,所述药物用于杀伤CD22阳性的肿瘤细胞。根据本发明实施例的药物对于CD22阳性的肿瘤细胞有非常好的特异性杀伤功能。
在本发明的第十一方面,本发明提出了一种检测CD22的试剂盒。根据本发明的实施例,所述检测CD22的试剂盒包括前面所述的抗体。前面所述的CD22抗体能够特异性靶向结合CD22,根据本发明实施例的试剂盒可以实现CD22的特异性检测,如当抗体结合有荧光基团时,可以采用荧光检测装置实现对CD22的定位或实时检测。
在本发明的第十二方面,本发明提出了前面所述的抗体、前面所述的核酸分子、前面所述的表达载体或前面所述的重组细胞在制备试剂盒中的用途,所述试剂盒用于检测CD22或者诊断CD22相关的疾病。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解,其中:
图1是根据本发明实施例的抗体亲和力ELISA检测结果;
图2是根据本发明实施例的抗体亲和力Fortebio检测结果;
图3是根据本发明实施例的FACs检测抗体与肿瘤细胞系的结合的检测结果;
图4是根据本发明实施例的荧光显微镜成像法显示的CD22抗体内吞效果图;以及
图5是根据本发明实施例的流式检测法显示的CD22抗体内吞效果图。
具体实施方式
下面详细描述本发明的实施例,所述实施例的示例在附图中示出,其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的,旨在用于解释本发明,而不能理解为对本发明的限制。
此外,术语“第一”、“第二”仅用于描述目的,而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此,限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。在本发明的描述中,“多个”的含义是至少两个,例如两个,三个等,除非另有明确具体的限定。
抗体
本文中,术语“抗体”是能够与特异性抗原结合的免疫球蛋白分子。包括两条分子量较轻的轻链和两条分子量较重的重链,重链(H链)和轻链(L链)由二硫键连接形成一个四肽链分子。其中,肽链的氨基端(N端)氨基酸序列变化很大,称为可变区(V区),羧基端(C端)相对稳定,变化很小,称为恒定区(C区)。L链和H链的V区分别称为VL和VH。
在可变区中某些区域氨基酸组成和排列顺序具有更高的变化程度,称为高变区(Hypervariable region,HVR),高变区为抗原和抗体结合的位置,因此也称为决定簇互补区(complementarity-determining region,CDR)。重链可变区和轻链可变区上均有三个CDR区。
本发明利用CD22胞外段,通过免疫获得了高特异性的高亲和力的抗CD22的Fab(antigen-binding fragment)抗体片段。利用该抗体片段能够与CD22抗原特异性结合,从而可以靶向性治疗肿瘤等疾病。
在一些实施方案中,本发明提供了一种能够特异性识别CD22的抗体或者抗原结合片段,所述抗体含有选自下列至少之一的CDR序列或与其具有至少95%同一性的氨基酸序列:重链可变区CDR序列:SEQ ID NO:1~9,轻链可变区CDR序列:SEQ IN NO:10~18。在另一些实施方案中,本发明所提供的抗体或者抗原结合片段与上述重链和轻链相比,具有保守氨基酸取代。“抗原结合片段”是指保持特异性结合抗原能力的抗体片段。“保守氨基酸取代”指的是氨基酸被另一氨基酸发生生物学上、化学上或者结构上相似的残基所取代。生物学上相似的指的是该取代不破坏CD22抗体或者与CD22抗原的生物学活性。结构上相似指的是氨基酸具有相似长度的侧链,如丙氨酸、甘氨酸或丝氨酸,或具有相似大小的侧链。化学相似性指的是氨基酸具有相同的荷电或者都是亲水或者疏水的。例如疏水残基异亮氨酸、缬氨酸、亮氨酸或者甲硫氨酸相互取代。或者极性氨基酸相互取代,例如用精氨酸取代赖氨酸、谷氨酸取代天冬氨酸、谷氨酰胺取代天冬酰胺,丝氨酸取代苏氨酸等等。
在一些实施方案中,本发明提供了一种抗体或抗原结合片段,所述抗体或抗原结合片段具有SEQ ID NO:19~21任一项所示氨基酸序列的重链可变区和具有如SEQ ID NO:22~24任一项所示氨基酸序列的轻链可变区。发明人通过抗体序列比对数据库(NCBI、IMGT)可得到上述抗重链可变区序列的CDR区(如SEQ ID NO:1~9所示)和轻链可变区序列的CDR区(如SEQ ID NO:10~18所示)。在另一些实施方案中,所述抗体或抗原结合片段的重链可变区序列与SEQ ID NO:19~21所示氨基酸序列相比,具有保守氨基酸取代。在一些实施方案中,所述抗体或抗原结合片段的轻链可变区序列与SEQ ID NO:22~24任一项所示氨基酸序列相比,具有保守氨基酸取代。当然,这些保守氨基酸取代不会对抗体或者抗原结合片段的生物学功能带来改变。在一些具体方式中,这些保守氨基酸取代可以发生在重链可变区和轻链可变区中除了CDR区之外的氨基酸上。
在一些优选方案中,本发明提供了一种抗CD22抗体,该抗体具有SEQ ID NO:25~27任一项所示氨基酸序列的重链和具有SEQ ID NO:28~30任一项所示氨基酸序列的轻链。
在一些优选方案中,本发明提供了一种抗CD22单链抗体,该抗体通过连接肽将前面所述的重链可变区和轻链可变区连接,获得特异性靶向结合CD22的单链抗体,所述连接肽为常规制备单链抗体常用连接肽或经过改造后性能更优的连接肽。
核酸分子、表达载体、重组细胞
在制备或者获取这些抗体的过程中,可以利用表达这些抗体的核酸分子,与不同的载体连接,然后在不同细胞中表达,来获得相应抗体。
为此,本发明还提供了一种分离的核酸分子,所述核酸分子编码上述所述的抗体或抗原结合片段。
在一些实施方案中,所述分离核酸分子具有如SEQ ID NO:31~33任一项所示核苷酸序列或具有SEQ ID NO:34~36任一项所示核苷酸序列。
在一些实施方案中,所述分离的核酸分子与上述SEQ ID NO:31~33所示的核苷酸序列至少具有90%以上的同源性,优选具有95%以上的同源性,更优选具有98%、99%以上的同源性。在至少一些实施方案中,所述分离的多核苷酸与所述SEQ ID NO:34~36所示的核苷酸序列至少具有90%以上的同源性,优选具有95%以上的同源性,更优选具有98%、99%以上的同源性。这些与SEQ ID NO:31~33或者SEQ ID NO:34~36具有同源性的序列,能够表达与SEQ ID NO:25~27和SEQ ID NO:28~30相似的氨基酸序列,从而能够与CD22抗原特异性结合,实现抗体的靶向性功能。
在一些优选实施方式中,所述分离的核酸分子具有SEQ ID NO:31~33所示的重链核苷酸序列和SEQ ID NO:34~36所示的轻链核苷酸序列。这些核苷酸序列经过种属优化,更易在哺乳动物细胞中表达。
本发明还提供了一种表达载体,所述表达载体包含上述分离的核酸分子。在将上述分离的多核苷酸连接到载体上时,可以将多核苷酸与载体上的控制元件直接或者间接相连,只要这些控制元件能够控制多核苷酸的翻译和表达等即可。当然这些控制元件可以直接来自于载体本身,也可以是外源性的,即并非来自于载体本身。当然,多核苷酸与控制元件进行可操作地连接即可。本文中“可操作地连接”是指将外源基因连接到载体上,使得载体内的控制元件,例如转录控制序列和翻译控制序列等等,能够发挥其预期的调节外源基因的转录和翻译的功能。当然用来编码抗体重链和轻链的多核苷酸,可以分别独立的插入到不同的载体上,常见的是插入到同一载体上。常用的载体例如可以为质粒、噬菌体等等。例如Plasmid-X质粒。
本发明还提供了一种重组细胞,该重组细胞中包含有该表达载体。可以将表达载体导入到哺乳动物细胞中,构建获得重组细胞,然后利用这些重组细胞表达本发明提供的抗体或者抗原结合片段。通过该重组细胞进行培养,即可以获得相应抗体。这些可用的哺乳动物细胞例如可以为CHO细胞等。
嵌合抗原受体、CAR
T细胞
本发明涉及嵌合抗原受体(CAR),CAR是结合基于抗体的针对期望的抗原(例如,肿瘤抗原)的特异性与T细胞受体-激活细胞内结构域以产生展示特异性抗肿瘤细胞免疫活性的嵌合蛋白的分子。
表达CAR的T细胞被称为CAR T细胞或CAR修饰的T细胞。
在一个实施方式中,本发明的CAR包括具有抗原识别结构域的胞外区、跨膜区和胞内区。
本发明的实施方案的CAR(包括其功能部分和功能变体)可通过本领域已知的方法获得。CAR可以通过制备多肽或蛋白质的任何合适的方法制备。从头合成多肽和蛋白质的合适的方法描述在参考文献,如Chan等,Fmoc Solid Phase Peptide Synthesis,OxfordUniversity Press,Oxford,United Kingdom,2000;Peptide and Protein DrugAnalysis,Reid,R.编辑,Marcel Dekker Inc.,2000;Epitope Mapping,Westwood等编辑,OxfordUniversity Press,Oxford,United Kingdom,2001;和美国专利5,449,752中。另外,多肽和蛋白质可利用标准的重组方法使用本文描述的核酸重组产生。参见,例如,Sambrook等,Molecular Cloning:A Laboratory Manual,第3版,Cold Spring HarborPress,ColdSpring Harbor,NY 2001;和Ausubel等,Current Protocols in MolecularBiology,Greene Publishing Associates以及John Wiley&Sons,NY,1994。此外,本发明的一些CAR(包括其功能部分和功能变体)可分离自和/或纯化自诸如植物,细菌,昆虫,哺乳动物如大鼠、人等的来源。分离和纯化方法为本领域熟知的。可选地,本文描述的CAR(包括其功能部分和功能变体)可通过诸如Synpep(Dublin,CA)、Peptide TechnologiesCorp.(Gaithersburg,MD)和Multiple Peptide Systems(San Diego,CA)的公司商业合成。在这方面,可合成、重组、分离和/或纯化本发明的CAR。
测试抗原结合至本发明CAR的任何功能部分的能力的方法为本领域已知的并且包括任何抗体-抗原结合测定,例如,放射性免疫测定(RIA)、ELISA、蛋白质印迹、免疫沉淀和竞争性抑制测定(参见,如Janeway等,下文和美国专利申请第2002/0197266A1号)。
本发明还包括在本发明范围内的是本文描述的本发明CAR的功能变体。本文使用的术语“功能变体”是指具有与亲本CAR大量的或显著的序列同一性或相似性的CAR、多肽或蛋白质,所述功能变体保留了CAR变体的生物活性。功能变体涵盖,例如,本文描述的CAR(亲本CAR)的那些变体,其保留了能够以与亲本CAR类似的程度、以与亲本CAR相同的程度或以比亲本CAR更高的程度识别靶细胞。关于亲本CAR,功能变体的氨基酸序列与亲本CAR的氨基酸序列可,例如,具有至少约30%、约50%、约75%、约80%、约90%、约98%、约99%或更高的同一性。
功能变体可,例如,包含具有至少一个保守性氨基酸置换的亲本CAR的氨基酸序列。替代地或另外地,功能变体可包含具有至少一个非保守性氨基酸置换的亲本CAR的氨基酸序列。在这种情况下,优选的是不会干扰或抑制功能变体的生物活性的非保守性氨基酸置换。非保守性氨基酸置换可以增强功能变体的生物活性,使得功能变体的生物活性与亲本CAR相比有所增加。
本发明CAR的氨基酸置换优选为保守性氨基酸置换。保守性氨基酸置换为本领域已知的,并且包括其中具有某些物理和/或化学性质的一个氨基酸被交换为具有相同或类似化学或物理性质的另一氨基酸的氨基酸置换。例如,保守性氨基酸置换可为将酸性/带负电荷的极性氨基酸置换为另一酸性/带负电荷的极性氨基酸(如,Asp或Glu)、具有非极性侧链的氨基酸置换为具有非极性侧链的另一氨基酸(如,Ala、Gly、Val、He、Leu、Met、Phe、Pro、Tip、Cys、Val等)、碱性/带正电荷的极性氨基酸置换为另一碱性/带正电荷的极性氨基酸(如Lys、His、Arg等)、具有极性侧链的不带电荷的氨基酸置换为具有极性侧链的另一不带电荷的氨基酸(如,Asn、Gln、Ser、Thr、Tyr等)、具有β分支侧链的氨基酸置换为具有β分支侧链的另一氨基酸(如,Ile、Thr和Val)、具有芳族侧链的氨基酸置换为具有芳族侧链的另一氨基酸(如,His、Phe、Trp和Tyr)等。
本发明的实施方案的CAR(包括本发明的功能部分和功能变体)可包含代替一个或多个天然存在的氨基酸的合成氨基酸。此类合成氨基酸为本领域已知的,并且包括例如,氨基环己烷羧酸、正亮氨酸、α-氨基正癸酸、高丝氨酸、S-乙酰氨甲基-半胱氨酸、反式-3-和反式-4-羟脯氨酸、4-氨基苯丙氨酸、4-硝基苯丙氨酸、4-氯苯丙氨酸、4-羧基苯丙氨酸、β-苯基丝氨酸、β-羟基苯丙氨酸、苯甘氨酸、α-萘基丙氨酸、环己基丙氨酸、环己基甘氨酸、吲哚啉-2-羧酸、1,2,3,4-四氢异喹啉-3-羧酸、氨基丙二酸、氨基丙二酸单酰胺、N'-苄基-N'-甲基-赖氨酸、Ν',Ν'-二苄基-赖氨酸、6-羟赖氨酸、鸟氨酸、α-氨基环戊烷羧酸、α-氨基环己烷羧酸、α-氨基环庚烷羧酸、α-(2-氨基-2-降莰烷)-羧酸、α,γ-二氨基丁酸、α,β-二氨基丙酸、高苯丙氨酸、以及α-叔丁基甘氨酸。
抗体偶联药物
本发明提供了一种抗体偶联药物。根据本发明的实施例,所述抗体偶联物包括抗体、连接子和小分子细胞毒药物,其中,所述抗体包括:分别如SEQ ID NO:1、2和3或者与SEQID NO:1、2和3具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:4、5和6或者与SEQ ID NO:4、5和6具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:7、8和9或者与SEQ IDNO:7、8和9具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;并且所述抗体包括:分别如SEQ ID NO:10、11和12或者与SEQ ID NO:10、11和12具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:13、14和15或者与SEQ ID NO:13、14和15具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:16、17和18或者与SEQ ID NO:16、17和18具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
根据本发明实施例的抗体偶联药物采用系统暴露的方式给药,首先进入血液系统,由于细胞毒药物相对分子质量仅为1ku,相对于抗体的分子量微不足道,ADC药物循环中抗体偶联药物的性质基本与“裸”抗体一致。抗体靶向结合CD22阳性肿瘤细胞,抗体与肿瘤细胞膜上的CD22受体的胞外段结合后,发生内吞,连接子在肿瘤细胞内溶酶体中裂解,释放出小分子细胞毒药物,小分子细胞毒药物发挥作用,杀伤肿瘤细胞。
根据本发明的实施例,所述连接子包括腙键、二硫键和肽键。腙键在酸性条件下即可发生水解。二硫键在细胞内高浓度的谷胱甘肽中可发生水解,因此不易在胞外脱落。肽键的结合最为紧密,仅在溶酶体蛋白水解酶的作用才发生断裂。
药物组合物、试剂盒及制药用途和在制备试剂盒中的用途
本发明还提供了一种药物组合物,所述药物组合物包括上述所述的抗体或者抗原结合片段、前面所述的CART细胞或前面所述的抗体偶联药物和药学可接受的载体。
本文提供的抗CD22抗体可以掺入适合受试者施用的药物组合物中。通常,这些药物组合物包括本文提供的抗CD22抗体以及药学上可接受的载体。“药学上可接受的载体”可以包括生理学上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和延迟吸收剂等等。具体实例可以是水、盐水、磷酸盐缓冲盐水、葡萄糖、甘油、乙醇等以及它们的组合物中的一种或多种。有许多情况下,药物组合物中包括等渗剂,例如糖类、多元醇(如甘露醇、山梨醇)或氯化钠等。当然药学上可接受的载体还可包括微量的辅助物质,例如润湿剂或乳化剂、防腐剂或缓冲剂,用来延长抗体的保存限期或效力。
例如,本发明的抗体可掺入适用于胃肠外施用(例如静脉内、皮下、腹膜内、肌肉内)的药物组合物中。这些药物组合物可以被制备成各种形式。例如液体、半固体和固体剂型等,包括但不限于液体溶液(例如,注射溶液和输注溶液)、分散剂或悬浮剂、片剂、丸剂、粉末、脂质体和栓剂。典型的药物组合物为注射溶液或输注溶液形式。所述抗体可通过静脉输注或注射或肌肉内或皮下注射来施用。
当然,本文中的抗CD22抗体还可以根据需要被制成试剂盒或者其他诊断性试剂的一部分。根据本发明的实施例,本发明还提供了一种试剂盒,所述试剂盒包括上述CD22抗体。应用本发明提供的试剂盒,例如可以用于免疫印迹、免疫沉淀等涉及到利用CD22抗原和抗体特异性结合性能,来检测的试剂盒等。这些试剂盒可包含下列中的任意一种或多种:拮抗剂、抗CD22抗体或者药物参照材料;蛋白纯化柱;免疫球蛋白亲和纯化缓冲剂;细胞的测定稀释剂;说明书或者文献等。抗CD22抗体可被用于不同类型的诊断测试,例如可以在体外或者体内检测各种各样的疾病或者药物、毒素或者其他蛋白等的存在。例如可以通过对受试者的血清或者血液进行检测,用来测试相关疾病。这种相关疾病可包括CD22相关疾病,例如癌症等等。当然本文提供的抗体也可以用于上述疾病的放射免疫检测和放射免疫治疗等等。
这些癌症或者肿瘤可以是任何不受调控的细胞生长。具体地,B淋巴细胞白血病或B细胞淋巴瘤。
在利用本发明所提供的抗CD22抗体、CART或抗体偶联药物治疗上述疾病时,可以将本发明提供的抗CD22抗体或CART细胞提供给受试者即可。为此,本发明提供了一种用于治疗上述疾病的方法,包括向有需要的受试者施用本发明所提供的抗体或其抗原结合片段CART细胞。
本发明的优势:
本发明通过免疫小鼠获得了全新的CD22抗体,该抗体亲和力高,特异性强,并且基于该序列的鼠单抗经实验验证具有细胞内吞特性,可用于ADC药物的开发和应用。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1靶向CD22抗体的获得
人CD22胞外段缀合His标签(以下简称hCD22-His,ACRO,CD2-H52H8)腹腔注射BALB/c小鼠(广东省医学实验动物中心)100μg/200μL/周/只/次,免疫3周后每周取小鼠尾血并检测血清中CD22抗体的表达;选择血清中CD22抗体表达量高的小鼠取脾细胞与瘤细胞(SP20,ATCC HB-12546)融合形成融合子,融合子培养10-14天后选择培养上清中表达CD22抗体融合子进行单克隆;选择表达CD22抗体的单克隆杂交瘤细胞株进行扩大培养,培养7-10天后收集细胞培养液纯化获得CD22抗体(FC2-010、FC2-027、FC2-014、5CD22-29-C2、5CD22-2-2-C4、FC2-021、2CD22-2-1-C5、FC2-009、FC2-013、5CD22-111-1-C3、FC2-045),对获得的CD22候选抗体进行测序。其中,下面实验中筛选出的能够被靶标细胞较好内吞的抗体的测序结果如下所示(黑体字加下划线示出了CDR序列):
轻链可变区氨基酸序列:VL1/VL2/VL3
5CD22-111-1-C3:
FC2-021:
FC2-045:
重链可变区氨基酸序列:VH1/VH2/VH3
5CD22-111-1-C3:
FC2-021:
FC2-045:
实施例2 CD22抗体5CD22-111-1-C3、FC2-021、FC2-045性质检测
1)抗体亚型检测:
不同抗体针对CD22亲和力的测定是通过ELISA方式检测的,具体做法如下:
将hCD22-His包被在96孔酶联包被板中,浓度为2μg/ml,100μL/孔,10μg/ml的抗体与重组蛋白结合,使用二抗anti Mouse IgG1-HR、anti Mouse IgG2a-HRP、anti MouseIgG2b-HRP、anti Mouse IgG3-HRP、anti Mouse IgG-HRP、anti Mouse IgM-HRP并显色,检测各抗体OD450值(具体操作步骤为一般ELISA操作步骤)。S-HCL-1为mIgG2b亚型CD22商业化抗体;RFB-4为mIgG1亚型CD22商业化抗体;M971为为mIgG1亚型CD22人源化抗体,具体序列和信息可以公开查找到,抗体由深圳市菲鹏治疗股份有限公司合成。表位鉴定结果如下表1所示,结果显示CD22抗体5CD22-111-1-C3为mIgG1亚型,FC2-021为mIgG1亚型,FC2-045为mIgG2b亚型。
表1:
2)亲和力检测:
不同抗体针对CD22亲和力的测定是通过ELISA、Fortebio检和FACs方式检测的,具体做法如下:
抗体亲和力ELISA检测:将h CD22-His包被在96孔酶联包被板中,浓度为2ug/ml,100uL/孔,3倍梯度稀释的抗体与抗原结合,检测各抗体EC50(具体操作步骤为一般ELISA操作步骤)。结果如下图1所示,CD22抗体5CD22-111-1-C3、FC2-021、FC2-045与阳性对照抗体S-HCL-1、RFB-4、M971 EC50处于同一水平。
抗体亲和力Fortebio检测:利用带ProA生物传感器(biosensor),先上样LoadingBuffer,再加入人类hCD22-His 5μg/mL,然后分别上样4个抗体(CD22抗体5CD22-111-1-C3、FC2-021、FC2-045与阳性对照抗体M971),分别检测4个抗体的KD,Kon和Kdis;具体操作步骤为一般用过Fortebio仪器的实验人员可以理解。检测结果如下图2所示。
FACs检测抗体与肿瘤细胞系的结合:
K562细胞为人慢性髓系白血病细胞,K562-CD22细胞为构建过表达CD22细胞细胞系,具体检测方法如下:收获细胞,PBS洗涤1次,PBS重悬,1E+6细胞/mL/200μl,抗体梯度稀释后与细胞4℃孵育30min,抗体起始浓度为10μg/mL,3倍稀释,共9个梯度,其后与PE标记的抗小鼠IgG第二抗体孵育,洗涤2次,Beckmanc cou LTER流式细胞仪检测,如下图3所示RFB-4、S-HCL-1、5CD22-111-1-C3、FC2-21、FC2-45与K562无结合活性,与K562-CD22细胞有浓度梯度依赖的结合,同时该结果说明抗体具有与CD22结合的特异性。
实施例3构建CD22内吞抗体筛选方法
1.荧光显微镜成像法
待筛选CD22鼠单抗0.1μg与1.0E+05个Daudi细胞在4℃孵育30min,体系100μL,孵育完后用4℃预冷的1mL PBS洗一遍,离心,300g,5min,离心完后弃上清,用100uL预冷的PBS重悬,加入0.1μgPE-gout anti mouse二抗,混匀,4℃孵育30min,孵育完后用4℃预冷的1mLPBS洗一遍,离心,300g,5min,离心完后弃上清,用90%1640+10%FBS完全培养基重悬Daudi细胞后放入24孔板中,放入37℃,5%二氧化碳的培养箱中孵育30min,然后进行荧光显微镜拍照,结果如图4所示,抗体5CD22-111-1-C3、FC2-021和FC2-045被内吞的效果更好。
2.流式检测法:
实验方法:Daudi细胞与抗体4℃孵育30min,Buffer洗去未结合的抗体,4℃/37℃放置(0/30/60/120/180/240min),4℃孵育荧光二抗30min,buffer洗去未结合二抗,Buffer重悬后上机检测。
内吞效率计算:
%of internalized=[total surface bound(4℃)–total surface bound(37℃)]/total surface bound(4℃)×100
图5结果显示:抗体FC2-009,FC2-021,5CD22-111-1-C3,FC2-045,5CD22-29-C2内吞效果更好。
综合荧光显微镜成像法和流式检测法结果,最终选择5CD22-111-1-C3、FC2-021和FC2-045三株抗体(抗体的序列如实施例1测序结果所示),这三株抗体的内吞效果更优、可信度更高。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
序列表
<110> 深圳市菲鹏生物治疗股份有限公司
<120> CD22抗体及其应用
<160> 36
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Gly Phe Thr Phe Ser Asn Tyr Trp
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<210> 2
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Ile Arg Leu Lys Ser Asn Asp Tyr Ala Thr
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<210> 3
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Thr Arg
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<210> 4
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Phe Thr Phe Ser Tyr Tyr Trp
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<210> 5
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
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Ile Arg Leu Lys Ser His Asn Tyr Val Thr
1 5 10
<210> 6
<211> 2
<212> PRT
<213> 人工序列(Artificial Sequence)
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Arg Thr
1
<210> 7
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Tyr Thr Phe Thr Asp Tyr Glu
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<210> 8
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
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Ile Asp Pro Glu Thr Gly Ala Thr
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<210> 9
<211> 2
<212> PRT
<213> 人工序列(Artificial Sequence)
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Thr Arg
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<210> 10
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
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Ser Val Ser Ser Ile Tyr Leu
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<210> 11
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
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Ser Thr Ser
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<210> 12
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
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His Gln Tyr His Arg Ser Pro
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<210> 13
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Gln Ser Val Thr Asn Asp
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<210> 14
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
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Tyr Ala Ser
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<210> 15
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Gln Asp Tyr Arg Ser Pro
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<210> 16
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Glu Asp Ile Tyr Asn Arg
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<210> 17
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Ala Thr
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<210> 18
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Gln Tyr Trp Ser Ser
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Phe Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Arg Gly Leu Glu Trp Val
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Ala Glu Ile Arg Leu Lys Ser Asn Asp Tyr Ala Thr His Tyr Ala Glu
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Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Asn
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Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
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Tyr Cys Thr Arg Val Tyr Tyr Tyr Gly Arg Asp Tyr Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Val Gln Ser Glu Val Lys Ile Glu Glu Ser Gly Gly Gly Leu Val
1 5 10 15
Gln Pro Gly Gly Ser Met Lys Val Ser Cys Val Ala Ser Gly Phe Thr
20 25 30
Phe Ser Tyr Tyr Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly
35 40 45
Leu Glu Trp Val Ala Glu Ile Arg Leu Lys Ser His Asn Tyr Val Thr
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His Tyr Ala Glu Ser Val Asn Gly Ser Phe Thr Ile Ser Arg Asp Asp
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Ser Arg Ser Ser Val Tyr Leu Gln Met Asn Asn Leu Arg Thr Glu Asp
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Thr Gly Ile Tyr Tyr Cys Thr Arg Gly Ala Gly Tyr Phe Asp Val Trp
100 105 110
Gly Ala Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 21
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Glu Met His Trp Val Lys Gln Thr Leu Val His Gly Leu Glu Trp Ile
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Gly Ala Ile Asp Pro Glu Thr Gly Ala Thr Ala Tyr Asn Gln Lys Phe
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Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
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Thr Arg Ser Asn Trp Asp Gly Trp Phe Ala Tyr Trp Gly Gln Gly Thr
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Leu Val Thr Val Ser Ala
115
<210> 22
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
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Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ile
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Gly Arg Phe Ser
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Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
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Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Tyr His Arg Ser Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 23
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Ala Ile Thr Cys Lys Ala Ser Gln Ser Val Thr Asn Asp
20 25 30
Val Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Phe Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Arg Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg
100 105
<210> 24
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Ser Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Asn Ile Thr Ser Leu Gln Thr
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Ser Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 25
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Phe Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Arg Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Leu Lys Ser Asn Asp Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Asn
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Thr Arg Val Tyr Tyr Tyr Gly Arg Asp Tyr Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro
115 120 125
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
130 135 140
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
180 185 190
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
195 200 205
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
210 215 220
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
245 250 255
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
260 265 270
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
290 295 300
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
305 310 315 320
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
340 345 350
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
355 360 365
Ile Thr Asn Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
370 375 380
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
385 390 395 400
Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
405 410 415
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
420 425 430
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 26
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Gly Val Gln Ser Glu Val Lys Ile Glu Glu Ser Gly Gly Gly Leu Val
1 5 10 15
Gln Pro Gly Gly Ser Met Lys Val Ser Cys Val Ala Ser Gly Phe Thr
20 25 30
Phe Ser Tyr Tyr Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly
35 40 45
Leu Glu Trp Val Ala Glu Ile Arg Leu Lys Ser His Asn Tyr Val Thr
50 55 60
His Tyr Ala Glu Ser Val Asn Gly Ser Phe Thr Ile Ser Arg Asp Asp
65 70 75 80
Ser Arg Ser Ser Val Tyr Leu Gln Met Asn Asn Leu Arg Thr Glu Asp
85 90 95
Thr Gly Ile Tyr Tyr Cys Thr Arg Gly Ala Gly Tyr Phe Asp Val Trp
100 105 110
Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro
115 120 125
Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met
130 135 140
Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val
180 185 190
Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His
195 200 205
Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys
210 215 220
Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe
225 230 235 240
Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro
245 250 255
Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val
260 265 270
Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu
290 295 300
Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys
305 310 315 320
Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro
340 345 350
Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile
355 360 365
Thr Asn Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly
370 375 380
Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp
385 390 395 400
Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp
405 410 415
Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His
420 425 430
Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 27
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Glu Met His Trp Val Lys Gln Thr Leu Val His Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Asp Pro Glu Thr Gly Ala Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Asn Trp Asp Gly Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro
115 120 125
Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn
145 150 155 160
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr
180 185 190
Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser
195 200 205
Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro
210 215 220
Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu
245 250 255
Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro
260 265 270
Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala
275 280 285
Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val
290 295 300
Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe
305 310 315 320
Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr
325 330 335
Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu
340 345 350
Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys
355 360 365
Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn
370 375 380
Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys
405 410 415
Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly
420 425 430
Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
435 440 445
<210> 28
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ile
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Gly Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Tyr His Arg Ser Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala
100 105 110
Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser
115 120 125
Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp
130 135 140
Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val
145 150 155 160
Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met
165 170 175
Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser
180 185 190
Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys
195 200 205
Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 29
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Ala Ile Thr Cys Lys Ala Ser Gln Ser Val Thr Asn Asp
20 25 30
Val Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Phe Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Arg Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 30
<211> 213
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Ser Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Asn Ile Thr Ser Leu Gln Thr
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Ser Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 31
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
gaagtgaagc ttgaggagtc tggaggaggc ttggtgcaac ctggaggatt catgaaactc 60
tcctgtgttg cctctggatt cactttcagt aactactgga tgaactgggt ccgccagtct 120
ccagagaggg ggcttgagtg ggttgctgaa attagattga aatctaatga ttatgcaaca 180
cattatgcgg agtctgtgaa agggaggttc accatctcaa gagatgattc caagagtaat 240
gtctacctgc aaatgaacaa cttaagagct gaagacactg gcatttatta ctgtaccaga 300
gtttattact acggtcgtga ctatgctatg gactactggg gtcaaggaac ctcagtcacc 360
gtctcctcag ccaagaccac accccctagc gtgtacccac tggctcccgg aagcgccgct 420
cagactaatt ccatggtgac cctgggctgc ctcgtcaagg gatatttccc tgagccagtc 480
actgtgacct ggaactccgg gtctctgagc tccggtgtgc acacttttcc agccgtcctc 540
cagtccgacc tgtacaccct ctctagttca gtcacagtgc ccagctccac ttggccttct 600
cagacagtga cttgtaatgt cgctcatcca gcatctagta caaaggtgga caagaaaatc 660
gtccccaggg attgcggttg taaaccatgc atttgtactg tccccgaggt gtcaagcgtc 720
ttcatctttc cacccaagcc caaagacgtg ctgaccatta cactcactcc taaggtgaca 780
tgcgtggtcg tggatatctc taaagacgat cccgaggttc agttcagttg gtttgtagac 840
gatgtcgaag tgcacactgc ccagaccaag cctagggagg aacagttcaa cagcaccttc 900
aggagcgtga gcgagctgcc aattatgcat caggactggc tcaatggcaa ggagttcaaa 960
tgccgggtga actctgcagc ctttcccgct cctatcgaga agacaattag taagactaaa 1020
ggacgcccta aagcaccaca ggtgtacaca atccctccac ccaaggaaca gatggccaag 1080
gataaagtgt ccctgacctg tatgatcaca aacttctttc ccgaggatat taccgtggaa 1140
tggcagtgga atgggcagcc tgctgagaac tataagaata cccagccaat catggacaca 1200
gatggtagtt acttcgtgta ttcaaagctg aacgtccaga aatcaaattg ggaagcaggc 1260
aacaccttta catgttccgt gctgcacgag ggactccata accaccatac cgaaaagagc 1320
ctgtcccact ctcctggcaa a 1341
<210> 32
<211> 1338
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
ggtgtccaga gtgaagtgaa gattgaggag tctggaggag gcttggtgca acctggagga 60
tccatgaaag tctcctgtgt tgcctctgga ttcactttca gttattactg gatgaactgg 120
gtccgccagt ctccagagaa ggggcttgag tgggttgctg aaattagatt gaagtctcat 180
aattatgtaa cacattatgc ggagtctgtg aatgggagtt tcaccatctc aagagatgat 240
tccagaagta gtgtctacct gcaaatgaac aacttaagaa ctgaagacac tggcatttat 300
tactgtacca ggggggctgg gtacttcgat gtctggggcg cagggacaac ggtcaccgtc 360
tcctcagcca agaccacacc ccctagcgtg tacccactgg ctcccggaag cgccgctcag 420
actaattcca tggtgaccct gggctgcctc gtcaagggat atttccctga gccagtcact 480
gtgacctgga actccgggtc tctgagctcc ggtgtgcaca cttttccagc cgtcctccag 540
tccgacctgt acaccctctc tagttcagtc acagtgccca gctccacttg gccttctcag 600
acagtgactt gtaatgtcgc tcatccagca tctagtacaa aggtggacaa gaaaatcgtc 660
cccagggatt gcggttgtaa accatgcatt tgtactgtcc ccgaggtgtc aagcgtcttc 720
atctttccac ccaagcccaa agacgtgctg accattacac tcactcctaa ggtgacatgc 780
gtggtcgtgg atatctctaa agacgatccc gaggttcagt tcagttggtt tgtagacgat 840
gtcgaagtgc acactgccca gaccaagcct agggaggaac agttcaacag caccttcagg 900
agcgtgagcg agctgccaat tatgcatcag gactggctca atggcaagga gttcaaatgc 960
cgggtgaact ctgcagcctt tcccgctcct atcgagaaga caattagtaa gactaaagga 1020
cgccctaaag caccacaggt gtacacaatc cctccaccca aggaacagat ggccaaggat 1080
aaagtgtccc tgacctgtat gatcacaaac ttctttcccg aggatattac cgtggaatgg 1140
cagtggaatg ggcagcctgc tgagaactat aagaataccc agccaatcat ggacacagat 1200
ggtagttact tcgtgtattc aaagctgaac gtccagaaat caaattggga agcaggcaac 1260
acctttacat gttccgtgct gcacgaggga ctccataacc accataccga aaagagcctg 1320
tcccactctc ctggcaaa 1338
<210> 33
<211> 2334
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 33
caggtgcagc tgcagcagag cggcgccgag ctggtgaggc ccggcgccag cgtgaccctg 60
agctgcaagg ccagcggcta caccttcacc gactacgaga tgcactgggt gaagcagacc 120
ctggtgcacg gcctggagtg gatcggcgcc atcgaccccg agaccggcgc caccgcctac 180
aaccagaagt tcaagggcaa ggccaccctg accgccgaca agagcagcag caccgcctac 240
atggagctga ggagcctgac cagcgaggac agcgccgtgt actactgcac caggagcaac 300
tgggacggct ggttcgccta ctggggccag ggcaccctgg tgaccgtgag cgccgccaag 360
accaccgccc ccagcgtgta ccccctggcc cccgtgtgcg gcgacaccac cggcagcagc 420
gtgaccctgg gctgcctggt gaagggctac ttccccgagc ccgtgaccct gacctggaac 480
agcggcagcc tgagcagcgg cgtgcacacc ttccccgccg tgctgcagag cgacctgtac 540
accctgagca gcagcgtgac cgtgaccagc agcacctggc ccagccagag catcacctgc 600
aacgtggccc accccgccag cagcaccaag gtggacaaga agatcgagcc caggggcccc 660
accatcaagc cctgcccccc ctgcaagtgc cccgccccca acctgctggg cggccccagc 720
gtgttcatct tcccccccaa gatcaaggac gtgctgatga tcagcctgag ccccatcgtg 780
acctgcgtgg tggtggacgt gagcgaggac gaccccgacg tgcagatcag ctggttcgtg 840
aacaacgtgg aggtgcacac cgcccagacc cagacccaca gggaggacta caacagcacc 900
ctgagggtgg tgagcgccct gcccatccag caccaggact ggatgagcgg caaggagttc 960
aagtgcaagg tgaacaacaa ggacctgccc gcccccatcg agaggaccat cagcaagccc 1020
aagggcagcg tgagggcccc ccaggtgtac gtgctgcccc cccccgagga ggagatgacc 1080
aagaagcagg tgaccctgac ctgcatggtg accgacttca tgcccgagga catctacgtg 1140
gagtggacca acaacggcaa gaccgagctg aactacaaga acaccgagcc cgtgctggac 1200
agcgacggca gctacttcat gtacagcaag ctgagggtgg agaagaagaa ctgggtggag 1260
aggaacagct acagctgcag cgtggtgcac gagggcctgc acaaccacca caccaccaag 1320
agcttcagca ggacccccgg caaggcaaag accacagccc cttctgtcta ccccctggcc 1380
cccgtgtgcg gagacactac cggtagctcc gtcaccctgg gctgtctcgt gaagggatat 1440
ttccccgagc ctgtgaccct gacatggaac tccgggtctc tctctagtgg tgtccacacc 1500
tttccagcag tgctgcagag cgacctgtac acactctcaa gctccgtcac tgtgacctct 1560
agtacatggc ccagtcagtc aatcacttgc aacgtggccc atcctgcttc aagcacaaag 1620
gtggataaga aaatcgaacc acggggcccc actattaagc cttgtccacc ctgcaaatgt 1680
ccagctccca atctgctcgg cggaccaagc gtgttcatct ttcctccaaa gattaaagac 1740
gtgctgatga tcagcctctc cccaattgtc acctgcgtgg tcgtggacgt gagtgaggac 1800
gatcccgatg tccagatctc ctggttcgtg aacaatgtcg aagtgcacac cgcccagaca 1860
cagactcata gggaggatta caactccaca ctgagagtcg tgtctgctct ccccattcag 1920
caccaggact ggatgtccgg caaggagttc aagtgcaagg tgaacaacaa ggatctgcct 1980
gctccaatcg agcgaacaat ttcaaagcct aaaggaagcg tgagggcacc acaggtctat 2040
gtgctgcccc ctccagagga agagatgact aagaaacagg tcaccctcac atgtatggtg 2100
accgacttca tgcccgaaga catctacgtg gagtggacta acaatgggaa gaccgaactg 2160
aactataaaa atactgagcc tgtgctcgac tctgatggta gttactttat gtattctaag 2220
ctgcgggtcg aaaagaaaaa ctgggtggag cgcaattctt atagttgttc agtcgtgcac 2280
gagggcctgc ataatcacca tacaactaag agcttctcca gaacacctgg aaaa 2334
<210> 34
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 34
caaattgttc tcacccagtc tccagcaatc atgtctgcat ctctagggga acgggtcacc 60
atgacctgca ctgccagctc aagtgtaagt tccatttact tgcactggta ccagcagaag 120
ccaggatcct cccccaaact ctggatttat agcacatcca acctggcttc tggagtccca 180
ggtcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagcatggag 240
gctgaagatg ctgccactta ttactgccac cagtatcatc gttccccacg gacgttcggt 300
ggaggcacca agctggaaat caaacgggca gacgccgctc caaccgtgag catcttcccc 360
cctagctccg agcagctgac atcaggcgga gccagcgtgg tctgcttcct caacaacttc 420
taccccaagg acatcaacgt gaagtggaaa attgatgggt ccgaacggca gaacggcgtc 480
ctgaactctt ggacagacca ggattccaag gactctactt atagtatgtc tagtaccctg 540
acactcacta aagatgagta cgaaaggcac aatagttata cttgcgaggc tacccataag 600
acctcaacaa gccccattgt caaatctttt aacagaaatg aatgt 645
<210> 35
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 35
agtattgtga tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggttgcc 60
ataacctgca aggccagtca gagtgtgact aatgatgtta cttggtacca acagaagcca 120
gggcagtctc ctaaactgct gatattctat gcatccaatc gctacactgg agtccctgat 180
cgcttcactg gcagtggata tgggacggat ttcactttca ccatcagcac tgtgcaggct 240
gaagacctgg cagtttattt ctgtcagcag gattataggt ctccgtggac gttcggtgga 300
ggcaccaagc tggaaatcag acgggcagac gccgctccaa ccgtgagcat cttcccccct 360
agctccgagc agctgacatc aggcggagcc agcgtggtct gcttcctcaa caacttctac 420
cccaaggaca tcaacgtgaa gtggaaaatt gatgggtccg aacggcagaa cggcgtcctg 480
aactcttgga cagaccagga ttccaaggac tctacttata gtatgtctag taccctgaca 540
ctcactaaag atgagtacga aaggcacaat agttatactt gcgaggctac ccataagacc 600
tcaacaagcc ccattgtcaa atcttttaac agaaatgaat gt 642
<210> 36
<211> 639
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 36
gacatccaga tgacacaatc ttcatcctcc ttttctgtat ctctaggaga cagagtcacc 60
attacttgca aggcaagtga ggacatatat aatcgattag cctggtatca gcagaaacca 120
ggaagtgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180
agattcagtg gcagtggatc tggaaaggat tacactctca acattaccag tcttcagact 240
gaagatgttg ctacttatta ctgtcaacag tattggagtt cgtggacgtt cggtggaggc 300
accaagctgg aaatcaaacg ggcagacgcc gctccaaccg tgagcatctt cccccctagc 360
tccgagcagc tgacatcagg cggagccagc gtggtctgct tcctcaacaa cttctacccc 420
aaggacatca acgtgaagtg gaaaattgat gggtccgaac ggcagaacgg cgtcctgaac 480
tcttggacag accaggattc caaggactct acttatagta tgtctagtac cctgacactc 540
actaaagatg agtacgaaag gcacaatagt tatacttgcg aggctaccca taagacctca 600
acaagcccca ttgtcaaatc ttttaacaga aatgaatgt 639
Claims (15)
1.一种能够特异性识别CD22的抗体或其抗原结合片段,其特征在于,所述抗体含有选自下列至少之一的CDR序列或与其具有至少95%同一性的氨基酸序列:
重链可变区CDR序列:SEQ ID NO:1~9,
轻链可变区CDR序列:SEQ IN NO:10~18。
2.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体包括:
分别如SEQ ID NO:1、2和3或者与SEQ ID NO:1、2和3具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;或者
分别如SEQ ID NO:4、5和6或者与SEQ ID NO:4、5和6具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;或者
分别如SEQ ID NO:7、8和9或者与SEQ ID NO:7、8和9具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列。
3.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体包括:
分别如SEQ ID NO:10、11和12或者与SEQ ID NO:10、11和12具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者
分别如SEQ ID NO:13、14和15或者与SEQ ID NO:13、14和15具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者
分别如SEQ ID NO:16、17和18或者与SEQ ID NO:16、17和18具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
4.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体包括:
分别如SEQ ID NO:1、2和3或者与SEQ ID NO:1、2和3具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列和分别如SEQ ID NO:10、11和12或者与SEQ IDNO:10、11和12具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者
分别如SEQ ID NO:4、5和6或者与SEQ ID NO:4、5和6具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列和分别如SEQ ID NO:13、14和15或者与SEQ IDNO:13、14和15具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者
分别如SEQ ID NO:7、8和9或者与SEQ ID NO:7、8和9具有至少95%同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列和分别如SEQ ID NO:16、17和18或者与SEQ IDNO:16、17和18具有至少95%同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
5.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体具有如SEQ IDNO:19~21任一项所示氨基酸序列的重链可变区;
任选地,所述抗体具有如SEQ ID NO:22~24任一项所示氨基酸序列的轻链可变区;
任选地,所述抗体含有重链恒定区和轻链恒定区的至少之一,所述重链恒定区和轻链恒定区的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体的至少之一;
任选地,所述抗体的轻链恒定区和重链恒定区均来自于人源IgG抗体或其突变体。
6.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体具有SEQ IDNO:25~27任一项所示氨基酸序列的重链和具有SEQ ID NO:28~30任一项所示氨基酸序列的轻链。
7.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体为单链抗体、多聚体抗体、CDR移植抗体或小分子抗体;
任选地,所述小分子抗体包括Fab抗体、Fv抗体、单域抗体以及最小识别单位的至少之一。
8.一种核酸分子,其特征在于,所述核酸分子编码权利要求1~7任一项所述的抗体或其抗原结合片段。
9.根据权利要求8所述的核酸分子,其特征在于,所述核酸分子为DNA;
任选地,所述核酸分子具有如SEQ ID NO:31~33任一项所示核苷酸序列或具有SEQ IDNO:34~36任一项所示核苷酸序列。
10.一种嵌合抗原受体,其特征在于,所述嵌合抗原受体包括:
胞外区,所述胞外区包括单链抗体的重链可变区和轻链可变区以及CD8铰链区,所述单链抗体特异性识别CD22;
跨膜区,所述跨膜区包括免疫共刺激因子跨膜区;以及
胞内区,所述胞内区包括免疫共刺激因子胞内段以及CD3ζ链;
其中,所述单链抗体的重链可变区和轻链可变区如权利要求1~5任一项所限定的。
11.一种CART细胞,其特征在于,表达权利要求10所述的嵌合抗原受体。
12.一种抗体偶联药物,其特征在于,包括抗体、连接子和小分子细胞毒药物,其中,所述抗体如权利要求1~7任一项所限定的。
13.一种药物组合物,其特征在于,含有权利要求1~7任一项所述的抗体、权利要求8或9所述的核酸分子、权利要求10所述的嵌合抗原受体、权利要求11所述的CART细胞或权利要求12所述的抗体偶联药物中的至少之一。
14.权利要求1~7任一项所述的抗体、权利要求8或9所述的核酸分子、权利要求10所述的嵌合抗原受体、权利要求11所述的CART细胞、权利要求12所述的抗体偶联药物或权利要求13所述的药物组合物在制备药物中的用途,所述药物用于治疗或者预防癌症。
15.一种检测CD22的试剂盒,其特征在于,包括权利要求利要求1~7任一项所述的抗体。
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