CN112300277A - Csf1r抗体、基因、载体、宿主细胞和csf1r拮抗剂 - Google Patents
Csf1r抗体、基因、载体、宿主细胞和csf1r拮抗剂 Download PDFInfo
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- CN112300277A CN112300277A CN201910677008.4A CN201910677008A CN112300277A CN 112300277 A CN112300277 A CN 112300277A CN 201910677008 A CN201910677008 A CN 201910677008A CN 112300277 A CN112300277 A CN 112300277A
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Abstract
本发明涉及抗体技术领域，特别涉及CSF1R抗体、基因、载体、宿主细胞和CSF1R拮抗剂。该CSF1R抗体的重链包含SEQ ID NO：1所示序列的CDR1、SEQ ID NO：2所示序列的CDR2、SEQ ID NO：3所示序列的CDR3；CSF1R抗体的轻链包含SEQ ID NO：4所示序列的CDR4、SEQ ID NO：5所示序列的CDR5、SEQ ID NO：6所示序列的CDR6。本发明的CSF1R抗体可特异性的与细胞表面hCSF1R相结合，可作为CSF1R信号传导的拮抗剂，因此该抗体可用于治疗各种CSF1R相关性疾病，如癌症、炎症性病状和自体免疫性疾病。
Description
技术领域
本发明涉及抗体技术领域，特别涉及CSF1R抗体、基因、载体、宿主细胞和CSF1R拮抗剂。
背景技术
集落刺激因子1受体(CSF1R，CD115)是一种带有N端胞外结构域(ECD)和具有酪氨酸激酶活性的C端胞内结构域的I型膜蛋白。CSF1R已报道的配体有两个，分别为CSF1和IL34。配体与受体结合后导致受体二聚化、CSF1R蛋白酪氨酸激酶活性上调、CSF1R酪氨酸残基磷酸化和下游信号传导。CSF1和IL34两者都刺激单核细胞存活、增殖以及分化成巨噬细胞。已经发现许多肿瘤细胞分泌CSF1，CSF1通过CSF1R活化单核细胞/巨噬细胞。已经证明肿瘤内的CSF1水平与肿瘤内的肿瘤相关性巨噬细胞(TAM)水平有关。已经发现高水平的TAM与较差的患者预后有关。此外，已经发现，例如在小鼠的人乳癌异种移植物中CSF1促进肿瘤生长和发展成转移。成熟分化的骨髓系细胞如巨噬细胞、小神经胶质细胞和破骨细胞促进各种疾病(如类风湿性关节炎、多发性硬化症和骨质缺失疾病)的病理学。CSF1R刺激促进单核细胞从骨髓前体的发育，促进单核细胞增殖和存活以及促进周边血液单核细胞分化成分化的骨髓系细胞如巨噬细胞、小神经胶质细胞和破骨细胞。因此，CSF1R刺激促进分化的骨髓系细胞的增殖、存活、活化和成熟，且在病理学环境中，CSF1R刺激促进分化的骨髓系细胞介导疾病病理学的能力。CSF1R信号传导的其它拮抗剂因此将可用于治疗各种CSF1R相关性疾病，如癌症、炎症性病状和自体免疫性疾病。
发明内容
有鉴于此，本发明提供了CSF1R抗体、基因、载体、宿主细胞和CSF1R拮抗剂。该CSF1R抗体可特异性的与细胞表面hCSF1R相结合，可作为CSF1R信号传导的拮抗剂。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种CSF1R抗体，该CSF1R抗体的重链包含SEQ ID NO：1所示序列的CDR1、SEQ ID NO：2所示序列的CDR2、SEQ ID NO：3所示序列的CDR3；
CSF1R抗体的轻链包含SEQ ID NO：4所示序列的CDR4、SEQ ID NO：5所示序列的CDR5、SEQ ID NO：6所示序列的CDR6。
在本发明中，CSF1R抗体的重链与轻链之间由linker连接，linker的氨基酸序列如SEQ ID NO：7所示。
本发明还提供了一种CSF1R抗体，CSF1R抗体的氨基酸序列如SEQ ID NO：8所示。
作为优选，CSF1R抗体为人源化抗体。
本发明还提供了编码上述CSF1R抗体的基因，其碱基序列如SEQ ID NO：9所示。
本发明还提供了一种载体，包括编码CSF1R抗体的基因。
作为优选，载体所用质粒为pcDNA4/myc-HisA。
本发明还提供了一种宿主细胞，包括上述载体。
作为优选，宿主细胞为HEK293细胞。
本发明还提供了一种CSF1R抗体的制备方法，包括：将单链抗体scFv基因(SEQ IDNO：9所示)及IgG1-Fc基因融合后经HindIII与EcoRI双酶切克隆到载体pcDNA4/myc-HisA中，进行克隆和质粒小提，提取后的质粒在HEK293细胞中表达，通过protein A柱纯化。
本发明还提供了一种CSF1R拮抗剂，包括本发明提供的CSF1R抗体。
本发明提供了CSF1R抗体、基因、载体、宿主细胞和CSF1R拮抗剂。该CSF1R抗体的重链包含SEQ ID NO：1所示序列的CDR1、SEQ ID NO：2所示序列的CDR2、SEQ ID NO：3所示序列的CDR3；CSF1R抗体的轻链包含SEQ ID NO：4所示序列的CDR4、SEQ ID NO：5所示序列的CDR5、SEQ ID NO：6所示序列的CDR6。本发明具有的技术效果如下：
本发明的CSF1R抗体可特异性的与细胞表面hCSF1R相结合，可作为CSF1R信号传导的拮抗剂，因此该抗体可用于治疗各种CSF1R相关性疾病，如癌症、炎症性病状和自体免疫性疾病。
附图说明
图1示抗CSF1R抗体特性鉴定结果，1-1为空白对照，1-2为阴性对照，1-3为anti-hCSF1R scFv抗体与细胞表面hCSF1R相结合的流式细胞图。
具体实施方式
本发明公开了CSF1R抗体、基因、载体、宿主细胞和CSF1R拮抗剂，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明提供的CSF1R抗体、基因、载体、宿主细胞和CSF1R拮抗剂中所用试剂、仪器或材料均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1：重组人CSF1R的表达和EGFP细胞制备
根据蛋白数据库Uniprot上人CSF1R的氨基酸序列(P07333)，得到人CSF1R胞外结构域的氨基酸序列(即Q07011中第1位残基至512位残基)；CSF1R氨基酸序列如下(其中下划线部分为胞外段)：
MGPGVLLLLLVATAWHGQGIPVIEPSVPELVVKPGATVTLRCVGNGSVEWDGPPSPHWTLYSDGSSSIL STNNATFQNTGTYRCTEPGDPLGGSAAIHLYVKDPARPWNVLAQEVVVFEDQDALLPCLLTDPVLEAGVSLVRVRGR PLMRHTNYSFSPWHGFTIHRAKFIQSQDYQCSALMGGRKVMSISIRLKVQKVIPGPPALTLVPAELVRIRGEAAQIV CSASSVDVNFDVFLQHNNTKLAIPQQSDFHNNRYQKVLTLNLDQVDFQHAGNYSCVASNVQGKHSTSMFFRVVESAY LNLSSEQNLIQEVTVGEGLNLKVMVEAYPGLQGFNWTYLGPFSDHQPEPKLANATTKDTYRHTFTLSLPRLKPSEAG RYSFLARNPGGWRALTFELTLRYPPEVSVIWTFINGSGTLLCAASGYPQPNVTWLQCSGHTDRCDEAQVLQVWDDPY PEVLSQEPFHKVTVQSLLTVETLEHNQTYECRAHNSVGSGSWAFIPISAGAHTHPPDEFLFTPVVVACMSIMALLLLLLLLLLYKYKQKPKYQVRWKIIESYEGNSYTFIDPTQLPYNEKWEFPRNNLQFGKTLGAGAFGKVVEATAFGLGKEDAVLKVAVKMLKSTAHADEKEALMSELKIMSHLGQHENIVNLLGACTHGGPVLVITEYCCYGDLLNFLRRKAEAMLGPSLSPGQDPEGGVDYKNIHLEKKYVRRDSGFSSQGVDTYVEMRPVSTSSNDSFSEQDLDKEDGRPLELRDLLHFSSQVAQGMAFLASKNCIHRDVAARNVLLTNGHVAKIGDFGLARDIMNDSNYIVKGNARLPVKWMAPESIFDCVYTVQSDVWSYGILLWEIFSLGLNPYPGILVNSKFYKLVKDGYQMAQPAFAPKNIYSIMQACWALEPTHRPTFQQICSFLQEQAQEDRRERDYTNLPSSSRSGGSGSSSSELEEESSSEHLTCCEQGDIAQPLLQPNNYQFC
其碱基序列如下：
atgggcccaggagttctgctgctcctgctggtggccacagcttggcatggtcagggaatcccagtgat agagcccagtgtccctgagctggtcgtgaagccaggagcaacggtgaccttgcgatgtgtgggcaatggcagcgtg gaatgggatggccccccatcacctcactggaccctgtactctgatggctccagcagcatcctcagcaccaacaacg ctaccttccaaaacacggggacctatcgctgcactgagcctggagaccccctgggaggcagcgccgccatccacct ctatgtcaaagaccctgcccggccctggaacgtgctagcacaggaggtggtcgtgttcgaggaccaggacgcacta ctgccctgtctgctcacagacccggtgctggaagcaggcgtctcgctggtgcgtgtgcgtggccggcccctcatgc gccacaccaactactccttctcgccctggcatggcttcaccatccacagggccaagttcattcagagccaggacta tcaatgcagtgccctgatgggtggcaggaaggtgatgtccatcagcatccggctgaaagtgcagaaagtcatccca gggcccccagccttgacactggtgcctgcagagctggtgcggattcgaggggaggctgcccagatcgtgtgctcag ccagcagcgttgatgttaactttgatgtcttcctccaacacaacaacaccaagctcgcaatccctcaacaatctga ctttcataataaccgttaccaaaaagtcctgaccctcaacctcgatcaagtagatttccaacatgccggcaactac tcctgcgtggccagcaacgtgcagggcaagcactccacctccatgttcttccgggtggtagagagtgcctacttga acttgagctctgagcagaacctcatccaggaggtgaccgtgggggaggggctcaacctcaaagtcatggtggaggc ctacccaggcctgcaaggttttaactggacctacctgggacccttttctgaccaccagcctgagcccaagcttgct aatgctaccaccaaggacacatacaggcacaccttcaccctctctctgccccgcctgaagccctctgaggctggcc gctactccttcctggccagaaacccaggaggctggagagctctgacgtttgagctcacccttcgataccccccaga ggtaagcgtcatatggacattcatcaacggctctggcacccttttgtgtgctgcctctgggtacccccagcccaac gtgacatggctgcagtgcagtggccacactgataggtgtgatgaggcccaagtgctgcaggtctgggatgacccat accctgaggtcctgagccaggagcccttccacaaggtgacggtgcagagcctgctgactgttgagaccttagagca caaccaaacctacgagtgcagggcccacaacagcgtggggagtggctcctgggccttcatacccatctctgcagga gcccacacgcatcccccggatgagttcctcttcacaccagtggtggtcgcctgcatgtccatcatggccttgctgctgctgctgctcctgctgctattgtacaagtataagcagaagcccaagtaccaggtccgctggaagatcatcgagagctatgagggcaacagttatactttcatcgaccccacgcagctgccttacaacgagaagtgggagttcccccggaacaacctgcagtttggtaagaccctcggagctggagcctttgggaaggtggtggaggccacggcctttggtctgggcaaggaggatgctgtcctgaaggtggctgtgaagatgctgaagtccacggcccatgctgatgagaaggaggccctcatgtccgagctgaagatcatgagccacctgggccagcacgagaacatcgtcaaccttctgggagcctgtacccatggaggccctgtactggtcatcacggagtactgttgctatggcgacctgctcaactttctgcgaaggaaggctgaggccatgctgggacccagcctgagccccggccaggaccccgagggaggcgtcgactataagaacatccacctcgagaagaaatatgtccgcagggacagtggcttctccagccagggtgtggacacctatgtggagatgaggcctgtctccacttcttcaaatgactccttctctgagcaagacctggacaaggaggatggacggcccctggagctccgggacctgcttcacttctccagccaagtagcccagggcatggccttcctcgcttccaagaattgcatccaccgggacgtggcagcgcgtaacgtgctgttgaccaatggtcatgtggccaagattggggacttcgggctggctagggacatcatgaatgactccaactacattgtcaagggcaatgcccgcctgcctgtgaagtggatggccccagagagcatctttgactgtgtctacacggttcagagcgacgtctggtcctatggcatcctcctctgggagatcttctcacttgggctgaatccctaccctggcatcctggtgaacagcaagttctataaactggtgaaggatggataccaaatggcccagcctgcatttgccccaaagaatatatacagcatcatgcaggcctgctgggccttggagcccacccacagacccaccttccagcagatctgctccttccttcaggagcaggcccaagaggacaggagagagcgggactataccaatctgccgagcagcagcagaagcggtggcagcggcagcagcagcagtgagctggaggaggagagctctagtgagcacctgacctgctgcgagcaaggggatatcgcccagcccttgctgcagcccaacaactatcagttctgctga
根据蛋白数据库Uniprot上人免疫球蛋白gamma(γ)1(IgG1)的恒定区氨基酸序列(P01857)，得到人IgG1-Fc的结构域氨基酸序列(即P01857中第104位残基至330位残基)。IgG1-Fc的氨基酸序列如下：
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
其碱基序列如下：
gacaaaactcacacatgcccaccgtgcccagctccggaactcctgggcggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgttggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa
利用DNAworks在线工具(http://helixweb.nih.gov/dnaworks/)设计对应的编码DNA序列得到hCSF1R-Fc融合蛋白的基因。
根据蛋白数据库Uniprot上信息得到增强型绿色荧光蛋白EGFP氨基酸序列(C5MKY7)、人CSF1R的氨基酸序列(P07333)，EGFP氨基酸序列如下：MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLTYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGITLGMDELYK
其碱基序列如下：
atggtgagcaagggcgaggagctgttcaccggggtggtgcccatcctggtcgagctggacggcgacgtaaacggccacaagttcagcgtgtccggcgagggcgagggcgatgccacctacggcaagctgaccctgaagttcatctgcaccaccggcaagctgcccgtgccctggcccaccctcgtgaccaccctgacctacggcgtgcagtgcttcagccgctaccccgaccacatgaagcagcacgacttcttcaagtccgccatgcccgaaggctacgtccaggagcgcaccatcttcttcaaggacgacggcaactacaagacccgcgccgaggtgaagttcgagggcgacaccctggtgaaccgcatcgagctgaagggcatcgacttcaaggaggacggcaacatcctggggcacaagctggagtacaactacaacagccacaacgtctatatcatggccgacaagcagaagaacggcatcaaggtgaacttcaagatccgccacaacatcgaggacggcagcgtgcagctcgccgaccactaccagcagaacacccccatcggcgacggccccgtgctgctgcccgacaaccactacctgagcacccagtccgccctgagcaaagaccccaacgagaagcgcgatcacatggtcctgctggagttcgtgaccgccgccgggatcactctcggcatggacgagctgtacaag
利用DNAworks在线工具(http://helixweb.nih.gov/dnaworks/)设计对应的编码DNA序列得到hCSF1R与EGFP融合蛋白的基因，hCSF1R-EGFP的基因。通过人工合成的方式得到其DNA片段。合成好的基因序列分别经Fermentas公司的HindIII与EcoRI双酶切亚克隆到商业化载体pcDNA4/myc-HisA(Invitrogen,V863-20)中，测序验证构建质粒的准确性，获得重组质粒DNA即：pcDNA4-hCSF1R-Fc和pcDNA4-hCSF1R-EGFP。
将相关的EGFP重组质粒转染到HEK293(ATCC,CRL-1573TM)细胞中，转染48h后通过荧光激活信号分选(FACS)确认hCSF1R的表达。
将pcDNA4-hCSF1R-Fc瞬时转染至HEK293细胞用于蛋白生产。将重组表达质粒用Freestyle293培养基稀释并加入转化所需PEI(Polyethylenimine)溶液，将每组质粒/PEI混合物分别加入细胞悬液中，放置在37℃，10％CO2，90rpm中培养；培养5～6天后，收集瞬时表达培养上清液，通过ProteinA亲和层析法，初步纯化得到hCSF1R-Fc蛋白样品，用于以下各实施例。得到的蛋白样品利用SDS-PAGE进行初步的检测，可以清晰的看到目的条带。
实施例2：从酵母展示文库中筛选抗CSF1R抗体、克隆表达
采用酵母展示技术筛选针对人CSF1R的全人抗体。通过克隆来自50个健康人的PBMC的IgM和IgG cDNA中的VH和VL基因，构建scFV酵母展示文库(VH和VL中间的连接序列是GILGSGGGGSGGGGSGGGGS连接肽，库容为5×108。将10倍库容的酵母库复苏，诱导酵母表面表达抗体，用100nM生物素化的hCSF1R-Fc抗原利用磁珠分选的方式富集二次，然后用生物素化的hCSF1R-Fc做流式分选再富集两次。得到的酵母涂板，挑取单克隆。单克隆酵母经扩增和诱导表达后用生物素化的hCSF1R-Fc染色分析，确定阳性酵母。将经过FACS确认的酵母克隆进行酵母菌落PCR和测序，PCR引物为：
sequence-F：CGTAGAATCGAGACCGAGGAGA；
sequence-R：CTGGTGGTGGTGGTTCTGCTAGC；
测序的引物为sequence-R。得到测序结果后用BioEdit软件对序列进行比对分析。
将上述得到的单链抗体scFv基因及前述的人IgG1-Fc基因融合后经Fermentas公司的HindIII与EcoRI双酶切克隆到商业化载体pcDNA4/myc-HisA中，按照分子克隆的标准操作进行克隆和质粒小提。提取后的质粒在HEK 293细胞中瞬时表达，并通过protein A柱纯化。anti-hCSF1RscFv抗体的氨基酸序列如SEQ ID NO：8所示(VH-Linker-VL，波浪线部分是CDR，下划线是linker)：
其碱基序列如SEQ ID NO：9所示：
caggtccagctggtgcagtctggggctgaggtgaagaaacctggggcctcagtgaaggtctcttgcaaggtttccggagacaccctcactgatttatccattcactgggtgcgacaggctcctgggaaagggcttgagtggatgggaggttttgaccctgaagatggtgaaacaatctactcacagaacttccagggcagagtcaccatgaccgaggacacatcaacagacacagcctacatggagttgagcagcctgagatccgaagacacggccgtcttttattgtgcaacagggagaaattattttccggattattggggccagggaaccctggtcaccgtctcctcaggaattctaggatccggtggcggtggcagcggcggtggtggttccggaggcggcggttctaattttatgctgactcagccccactctgtggcggagtctccgggaaagacggtaaccatctcctgcacccgcagcagtggcagcattgccagcagctatgtgcagtggtatcagcagcgcccgggcagatcccccaccactgtgatctttgaggataaccaaagaccctctggggtccctgatcgtttctctggctccatcgacagctcttccaactctgcctccctcaccatctctggactgaagactgaggacgaggctgactactactgtcagtcttatgatacctacaatcataattgggtgttcggcggagggaccaagctgaccgtccta
实施例3：抗CSF1R抗体特性鉴定(与CSF1R结合鉴定-FACS法)
取hCSF1R-EGFP细胞，重悬于0.5％PBS-BSA Buffer中，加入上述纯化后2μg的anti-hCSF1R scFv抗体，同时设置相关对照，阴性对照为2μg的hIgG1蛋白。二抗为eBioscience的anti-hIg-PE。染色完毕后流式细胞仪进行检测。以此方法鉴定能结合细胞表面hCSF1R抗原的抗体。如图1所示，anti-CSF1R1#可以与细胞表面hCSF1R相结合，而阴性对照不能够与细胞表面hCSF1R相结合。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 苏州丁孚靶点生物技术有限公司
<120> CSF1R抗体、基因、载体、宿主细胞和CSF1R拮抗剂
<130> MP1917790
<160> 9
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Asp Leu Ser Ile His
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ser Gln Asn Phe Gln
1 5 10 15
Gly
<210> 3
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Gly Arg Asn Tyr Phe Pro Asp Tyr
1 5
<210> 4
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Thr Arg Ser Ser Gly Ser Ile Ala Ser Ser Tyr Val Gln
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Glu Asp Asn Gln Arg Pro Ser
1 5
<210> 6
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Ser Tyr Asp Thr Tyr Asn His Asn Trp Val
1 5 10
<210> 7
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gly Ile Leu Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 8
<211> 249
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
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 Val Ser Gly Asp Thr Leu Thr Asp Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ser Gln Asn Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Phe Tyr Cys
85 90 95
Ala Thr Gly Arg Asn Tyr Phe Pro Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Ile Leu Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn Phe Met Leu Thr Gln Pro
130 135 140
His Ser Val Ala Glu Ser Pro Gly Lys Thr Val Thr Ile Ser Cys Thr
145 150 155 160
Arg Ser Ser Gly Ser Ile Ala Ser Ser Tyr Val Gln Trp Tyr Gln Gln
165 170 175
Arg Pro Gly Arg Ser Pro Thr Thr Val Ile Phe Glu Asp Asn Gln Arg
180 185 190
Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Ile Asp Ser Ser Ser
195 200 205
Asn Ser Ala Ser Leu Thr Ile Ser Gly Leu Lys Thr Glu Asp Glu Ala
210 215 220
Asp Tyr Tyr Cys Gln Ser Tyr Asp Thr Tyr Asn His Asn Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 9
<211> 747
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
caggtccagc tggtgcagtc tggggctgag gtgaagaaac ctggggcctc agtgaaggtc 60
tcttgcaagg tttccggaga caccctcact gatttatcca ttcactgggt gcgacaggct 120
cctgggaaag ggcttgagtg gatgggaggt tttgaccctg aagatggtga aacaatctac 180
tcacagaact tccagggcag agtcaccatg accgaggaca catcaacaga cacagcctac 240
atggagttga gcagcctgag atccgaagac acggccgtct tttattgtgc aacagggaga 300
aattattttc cggattattg gggccaggga accctggtca ccgtctcctc aggaattcta 360
ggatccggtg gcggtggcag cggcggtggt ggttccggag gcggcggttc taattttatg 420
ctgactcagc cccactctgt ggcggagtct ccgggaaaga cggtaaccat ctcctgcacc 480
cgcagcagtg gcagcattgc cagcagctat gtgcagtggt atcagcagcg cccgggcaga 540
tcccccacca ctgtgatctt tgaggataac caaagaccct ctggggtccc tgatcgtttc 600
tctggctcca tcgacagctc ttccaactct gcctccctca ccatctctgg actgaagact 660
gaggacgagg ctgactacta ctgtcagtct tatgatacct acaatcataa ttgggtgttc 720
ggcggaggga ccaagctgac cgtccta 747
Claims (10)
1.一种CSF1R抗体，其特征在于，所述CSF1R抗体的重链包含SEQ ID NO：1所示序列的CDR1、SEQ ID NO：2所示序列的CDR2、SEQ ID NO：3所示序列的CDR3；
所述CSF1R抗体的轻链包含SEQ ID NO：4所示序列的CDR4、SEQ ID NO：5所示序列的CDR5、SEQ ID NO：6所示序列的CDR6。
2.根据权利要求1所述的CSF1R抗体，其特征在于，所述CSF1R抗体的重链与轻链之间由linker连接，所述linker的氨基酸序列如SEQ ID NO：7所示。
3.一种CSF1R抗体，其特征在于，所述CSF1R抗体的氨基酸序列如SEQ ID NO：8所示。
4.根据权利要求3所述的CSF1R抗体，其特征在于，所述CSF1R抗体为人源化抗体。
5.编码权利要求3或4所述CSF1R抗体的基因，其特征在于，其碱基序列如SEQ ID NO：9所示。
6.一种载体，其特征在于，包括权利要求5所述的基因。
7.根据权利要求6所述的载体，其特征在于，所述载体所用质粒为pcDNA4/myc-HisA。
8.一种宿主细胞，其特征在于，包括权利要求6所述的载体。
9.根据权利要求8所述的宿主细胞，其特征在于，所述宿主细胞为HEK293细胞。
10.一种CSF1R拮抗剂，其特征在于，包括权利要求1至4中任一项所述CSF1R抗体。
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