申请/专利权人：宾夕法尼亚大学理事会;威斯塔解剖学和生物学研究所;艾诺奥医药品有限公司

申请日：2017-05-05

公开（公告）日：2024-03-19

公开（公告）号：CN110325546B

主分类号：C07K16/08

分类号：C07K16/08;C07K16/00;A61K48/00

优先权：["20160505 US 62/332,381","20160817 US 62/376,162"]

专利状态码：有效-授权

法律状态：2024.03.19#授权;2019.11.05#实质审查的生效;2019.10.11#公开

摘要：本文公开了包含编码抗流感‑血凝素合成抗体的重组核酸序列的组合物。本公开还提供了使用所述组合物以及生成方法预防和或治疗受试者的流感的方法。

主权项：1.一种编码一种或多种合成抗体的核酸分子，其中所述核酸分子包含选自以下的至少一种：a编码抗流感HA合成抗体的核苷酸序列；和b编码抗流感HA合成抗体的功能性片段的核苷酸序列；其中，所述抗流感HA合成抗体及其功能性片段包含SEQIDNO:1的氨基酸序列。

全文数据：靶向流感病毒的DNA单克隆抗体相关申请的引证本申请要求2016年5月5日提交的美国临时申请号62332,381和2016年8月17日提交的美国临时申请号62376,162的优先权，每个临时申请均特此通过引证整体并入。技术领域本发明涉及一种组合物，其包含用于在体内产生一种或多种合成抗体，包括抗流感血凝素抗体及其功能片段的重组核酸序列，并且涉及一种通过施用所述组合物预防和或治疗受试者的疾病的方法。背景技术尽管是有前景的创新，但流感疫苗和抗病毒药物不能对季节性感染提供全面保护，并且几乎不能立即防御新型和潜在的大流行性病毒株。已经开发了广泛的交叉保护性单克隆抗体，目的是提供针对高度相异的流感病毒的保护。因此，本领域需要改进的用于治疗流感的组合物和方法。发明内容本发明涉及一种编码一种或多种合成抗体的核酸分子，其中所述核酸分子包含选自以下的至少一种：a编码抗流感血凝素HA合成抗体的核苷酸序列；和b编码抗HA合成抗体的片段的核苷酸序列。在一个实施方案中，抗HA合成抗体选自结合流感HA的球状头部的抗体和结合流感HA的融合子结构域的抗体。在一个实施方案中，核酸分子包含至少一个选自以下的核苷酸序列：编码第一抗HA抗体的第一核苷酸序列；和编码第二抗HA抗体的第二核苷酸序列。在一个实施方案中，核酸分子包含编码裂解结构域的核苷酸序列。在一个实施方案中，所述核酸分子包含编码抗HA的可变重链区和可变轻链区的核苷酸序列。在一个实施方案中，所述核酸分子包含编码人IgG1κ的恒定重链区和恒定轻链区的核苷酸序列。在一个实施方案中，所述核酸分子包含编码下述多肽的核苷酸序列，所述多肽包含：抗HA的可变重链区；人IgG1κ的恒定重链区；裂解结构域；抗HA的可变轻链区；和IgG1κ的恒定轻链区。在一个实施方案中，所述核酸分子包含编码前导序列的核苷酸序列。在一个实施方案中，所述核酸分子包含表达载体。在一个实施方案中，本发明提供了包含核酸分子的组合物。在一个实施方案中，所述组合物还包含药学上可接受的赋形剂。在一个实施方案中，本发明提供了一种预防或治疗受试者的流感感染的方法，其包括向受试者施用本文所述的核酸或组合物。在一个实施方案中，流感感染是甲型流感感染。在一个实施方案中，流感感染是乙型流感感染。在一个实施方案中，本发明提供了用于在哺乳动物细胞或病毒载体中产生单克隆抗体的新型序列。附图说明图1显示抗流感抗体5J8结合的流感血凝素可变区。图2显示抗流感抗体FI6结合的流感血凝素可变区。图3，包括图3A和3B，描绘了证明DMAb质粒DNA构建体在293T细胞中表达的实验结果。图3A描绘了ELISA结果，其中通过定量ELISA测定上清液和裂解物人IgG1κ表达N＝3次转染重复，平均值±SEM。图3B描绘了代表性western印迹，证明上清液和裂解物重链和轻链肽裂解。图4，包括图4A和4B，描绘了证明肌内DNA电穿孔后，DMAb在小鼠血清中表达的实验结果。对小鼠注射5J8或FI6质粒DNA，然后进行肌内电穿孔。通过定量ELISA测定小鼠血清中的人IgG1κ抗体水平。图4A描绘了证明抗流感DMAb在BALBc小鼠中递送后7天表达，从53ngmL至1.1μgmL，高于第0天放血前基线水平的结果。定点递送和配制的优化策略增强了DMAb表达3倍。图4B描绘了裸鼠中DNA剂量递增的结果。在向免疫受损的裸鼠递送300μg质粒DNA后，FI6表达峰值达到2.6μgmL。DMAb的表达持续十周。N＝5，平均值±SEM。图5描绘了证明来自小鼠血清的DMAb保持了结合血凝素抗原的能力的实验结果。裸鼠经肌内电穿孔接受FI6300μg质粒DNA。四周后，通过ELISA测定血清DMAb与重组甲型流感H1血凝素抗原的结合。N＝5，平均值±SEM。图6描绘了甲型流感病毒株和乙型流感病毒株的系统发育树，证明了临床相关性流感病毒的多样性。图7描绘了证明分离的针对甲型和乙型流感的人单克隆抗体mAb具有广泛交叉反应性的实验结果。甲型流感特异性FluAmAb广泛地中和1类和2类的季节性和大流行性病毒。FluBmAb有效中和来自乙型流感病毒谱系的病毒。图8描绘了DMAb质粒构建和功能性mAb产生的示意图。图9描绘了流感致死攻击研究设计的示意图。图10描绘了证明FluA和FluBDMAb血清表达和功能的实验结果。在FluADMAb顶行和FluBDMAb底行电穿孔EP后5天收集血清并评价人IgG表达、对各种HA蛋白的结合活性和中和活性。图11描绘了证明FluADMAb保护小鼠免于致死性甲型流感感染，达到与0.3mgkg纯化FluAIgG相似的水平的实验结果。在感染时，DMAb的血清浓度与纯化IgG相关。用致死性甲型流感感染攻击后的体重减轻和存活率，FluADMAb与对照DMAb相比有*显著存活益处，通过对数秩检验，p大卫·韦纳萨拉·埃利奥特阿米·帕特尔严健靶向流感病毒的DNA单克隆抗体206108-0061-00-WO.60633462332,3812016-05-0562376,1622016-08-1716PatentIn版本3.51735PRT人工序列pGX92111MetAspTrpThrTrpArgIleLeuPheLeuValAlaAlaAlaThrGly151015ThrHisAlaGlnValGlnLeuGlnGlnSerGlyProGlyLeuValLys202530ProSerGlnThrLeuSerLeuThrCysAlaIleSerGlyAspSerVal354045SerSerAsnAsnAlaValTrpAsnTrpIleArgGlnSerProSerArg505560GlyLeuGluTrpLeuGlyArgThrTyrTyrArgSerLysTrpTyrAsn65707580AspTyrAlaGluSerValLysSerArgIleThrIleAsnProAspThr859095SerLysAsnGlnPheSerLeuGlnLeuAsnSerValThrProGluAsp100105110ThrAlaValTyrTyrCysAlaArgSerGlyHisIleThrValPheGly115120125ValAsnValAspAlaPheAspMetTrpGlyGlnGlyThrThrValThr130135140ValSerSerAlaSerThrLysGlyProSerValPheProLeuAlaPro145150155160SerSerLysSerThrSerGlyGlyThrAlaAlaLeuGlyCysLeuVal165170175LysAspTyrPheProGluProValThrValSerTrpAsnSerGlyAla180185190LeuThrSerGlyValHisThrPheProAlaValLeuGlnSerSerGly195200205LeuTyrSerLeuSerSerValValThrValProSerSerSerLeuGly210215220ThrGlnThrTyrIleCysAsnValAsnHisLysProSerAsnThrLys225230235240ValAspLysLysValGluProLysSerCysAspLysThrHisThrCys245250255ProProCysProAlaProGluLeuLeuGlyGlyProSerValPheLeu260265270PheProProLysProLysAspThrLeuMetIleSerArgThrProGlu275280285ValThrCysValValValAspValSerHisGluAspProGluValLys290295300PheAsnTrpTyrValAspGlyValGluValHisAsnAlaLysThrLys305310315320ProArgGluGluGlnTyrAsnSerThrTyrArgValValSerValLeu325330335ThrValLeuHisGlnAspTrpLeuAsnGlyLysGluTyrLysCysLys340345350ValSerAsnLysAlaLeuProAlaProIleGluLysThrIleSerLys355360365AlaLysGlyGlnProArgGluProGlnValTyrThrLeuProProSer370375380ArgAspGluLeuThrLysAsnGlnValSerLeuThrCysLeuValLys385390395400GlyPheTyrProSerAspIleAlaValGluTrpGluSerAsnGlyGln405410415ProGluAsnAsnTyrLysThrThrProProValLeuAspSerAspGly420425430SerPhePheLeuTyrSerLysLeuThrValAspLysSerArgTrpGln435440445GlnGlyAsnValPheSerCysSerValMetHisGluAlaLeuHisAsn450455460HisTyrThrGlnLysSerLeuSerLeuSerProGlyLysArgGlyArg465470475480LysArgArgSerGlySerGlyAlaThrAsnPheSerLeuLeuLysGln485490495AlaGlyAspValGluGluAsnProGlyProMetValLeuGlnThrGln500505510ValPheIleSerLeuLeuLeuTrpIleSerGlyAlaTyrGlyAspIle515520525GlnMetThrGlnSerProSerSerLeuSerAlaSerValGlyAspArg530535540ValThrIleThrCysArgThrSerGlnSerLeuSerSerTyrLeuHis545550555560TrpTyrGlnGlnLysProGlyLysAlaProLysLeuLeuIleTyrAla565570575AlaSerSerLeuGlnSerGlyValProSerArgPheSerGlySerGly580585590SerGlyThrAspPheThrLeuThrIleSerSerLeuGlnProGluAsp595600605PheAlaThrTyrTyrCysGlnGlnSerArgThrPheGlyGlnGlyThr610615620LysValGluIleLysThrValAlaAlaProSerValPheIlePhePro625630635640ProSerAspGluGlnLeuLysSerGlyThrAlaSerValValCysLeu645650655LeuAsnAsnPheTyrProArgGluAlaLysValGlnTrpLysValAsp660665670AsnAlaLeuGlnSerGlyAsnSerGlnGluSerValThrGluGlnAsp675680685SerLysAspSerThrTyrSerLeuSerAsnThrLeuThrLeuSerLys690695700AlaAspTyrGluLysHisLysValTyrAlaCysGluValThrHisGln705710715720GlyLeuSerSerProValThrLysSerPheAsnArgGlyGluCys7257307352745PRT人工序列pGX92122MetAspTrpThrTrpArgIleLeuPheLeuValAlaAlaAlaThrGly151015ThrHisAlaGluValGlnLeuValGluSerGlyGlyGlyLeuValLys202530ProGlyGlySerLeuArgLeuSerCysAlaAlaSerGlyLeuThrPhe354045LeuAsnAlaTrpMetSerTrpValArgGlnAlaProGlyLysGlyLeu505560GluTrpVa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tgcagtcaggcaatagc2040caggagtccgtgacagaacaggactctaaagatagtacttattcactgagcaacaccctg2100acactgagcaaggcagactacgagaagcacaaagtgtatgcctgcgaagtgacccaccag2160gggctgagcagtccagtgaccaaatctttcaacaggggagaatgttgataa2211102241DNA人工序列pGX921210atggactggacttggaggattctgtttctggtggccgccgcaactggcactcatgccgag60gtgcagctggtggaatcagggggaggactggtgaagcctggcggatcactgcgactgagc120tgcgcagcttccggactgaccttcctgaacgcttggatgagctgggtgcgacaggcacca180gggaaaggcctggaatgggtcgggcgcatcaagagcaatacagacggcggaaccacagat240tacgcagcccccgtgaaaggcaggttcaccatttctcgggacgatagtaagaacacactg300tatctgcagatgagctccctgaaaaccgaggacacagccgtgtactattgcactaccgat360ggcccctacagcgacgatttccgctccggatatgctgcacggtaccgctattttgggatg420gacgtgtggggacaggggacaactgtcacagtgtctagtgcatctactaagggacctagc480gtgttcccactggccccctcaagcaaatcaactagcggagggaccgccgctctgggatgt540ctggtgaaggattacttccccgagcctgtcaccgtgagctggaactccggggccctgacc600tccggagtgcacacatttcctgctgtcctgcagtcctctgggctgtactctctgagttca660gtggtcacagtgccaagctcctctctgggcactcagacctatatctgcaacgtgaatcac720aaacctagcaatactaaggtcgacaagaaagtggaaccaaaaagctgtgataagacacat780acttgccctccctgtccagctccagagctgctgggcggaccatccgtgttcctgtttcca840cccaagcccaaagacaccctgatgatttcccggacaccagaagtgacttgcgtggtcgtg900gacgtgagccacgaggaccccgaagtgaagttcaactggtacgtggatggcgtcgaggtg960cataatgccaagacaaaacccagggaggaacagtacaactcaacttatagagtcgtgagc1020gtcctgaccgtgctgcaccaggactggctgaacggcaaggagtataagtgcaaagtgagc1080aacaaggccctgcctgctccaatcgagaagactattagcaaggctaaaggacagcctcgg1140gaaccacaggtgtacaccctgcctccatcccgcgacgagctgaccaaaaaccaggtgtct1200ctgacatgtctggtcaagggcttctatccctctgatatcgccgtggagtgggaaagtaat1260ggacagcctgaaaacaattacaagaccacaccccctgtgctggactctgatggcagtttc1320tttctgtatagtaaactgaccgtggacaagtcaagatggcagcagggaaacgtgttttcc1380tgctctgtcatgcatgaggccctgcacaatcattacacccagaagagtctgtcactgagc1440ccaggaaaacgagggaggaagaggagatccggctctggagccacaaacttctccctgctg1500aagcaggctggagacgtggaggaaaatcccgggcctatggtgctgcagacccaggtcttt1560atctccctgctgctgtggatttctggcgcttacggagatatccagatgacacagtctccc1620agttcagtcagtgcatcagtgggcgaccgcgtcaccatcacatgtcgagcatcacaggat1680attagcacctggctggcctggtaccagcagaagcccggaaaagctcctaagctgctgatc1740tatgcagccagctccctgcagtccggagtgccctctaggttcagcgggtccggctctgga1800acagactttactctgaccatttctagtctgcagcctgaggatttcgcaacttactattgc1860cagcaggccaacagcttcccacccacttttgggcagggcaccaaactggaaatcaagact1920gtggctgcacctagcgtcttcatttttcctccatccgacgagcagctgaagagtggcacc1980gcctcagtggtgtgcctgctgaacaacttctacccaagagaagcaaaagtgcagtggaag2040gtcgataacgccctgcagtcaggcaatagccaggagtccgtgacagaacaggactctaag2100gatagtacttatagtctgtcaaatacactgactctgagcaaagctgactacgagaagcat2160aaagtgtatgcatgcgaggtcactcaccagggactgtcttcacccgtcaccaaatctttc2220aatagaggagaatgctgataa2241112214DNA人工序列pGX222hc11atggactggacatggagaatcctgttcctggtcgccgccgctactgggactcacgcagaa60gtgcagctggtcgaatcagggcctgggctggtgaagccctcagacatcctgagcctgacc120tgcgccgtgtctggctacagtatcagctccaactactattggggatggattcggcagccc180cctggcaagggactggaatggatcgggtccatctaccactcaggcagcacctactataaa240ccttcactggagagccgcctgggaatttccgtggacacatctaagaatcagttcagcctg300aaactgtcctttgtctctgccgctgatactgcagtgtactattgcgcccgacatgtcagg360tccggctacccagacaccgcttactattttgataagtgggggcagggcaccctggtcaca420gtgtctagtgctagcaccaagggcccctccgtgttccctctggcaccatcaagcaaatcc480acatctggcggaactgcagccctgggatgtctggtgaaggattacttcccagagcccgtc540acagtgagttggaactcaggcgcactgacttctggagtccacacctttcccgccgtgctg600cagtcctctggcctgtacagcctgagttcagtggtcacagtgcctagctcctctctggga660actcagacctatatctgcaacgtgaatcacaagccctcaaatactaaagtcgacaagaaa720gtggaacctaagtcttgtgataaaacacatacttgcccaccatgtcctgcaccagagctg780ctgggaggaccaagcgtgttcctgtttcctccaaagcccaaagacaccctgatgatctcc840agaacccctgaagtgacatgtgtggtcgtggacgtctctcacgaggaccccgaagtcaag900tttaactggtacgtggatggcgtcgaggtgcataatgctaagacaaaaccccgcgaggaa960cagtacaactcaacctatcgagtcgtgagcgtcctgacagtgctgcaccaggactggctg1020aacggaaaggagtataagtgcaaagtgagcaataaggcactgcccgcccctatcgagaaa1080actatttccaaggctaaagggcagcccagggaacctcaggtgtacaccctgcccccttct1140agagacgagctgacaaagaaccaggtcagtctgacttgtctggtgaaaggattttatcca1200agtgatatcgcagtggagtgggaatcaaatgggcagcccgaaaacaattacaagaccaca1260ccacccgtgctggacagcgatggcagcttcttcctgtattccaagctgaccgtggacaaa1320tctcggtggcagcaggggaacgtcttcagttgctcagtgatgcacgaggccctgcacaat1380cattacacccagaagagcctgtccctgtctccaggcaagcggggacgcaaaaggagaagt1440ggatcaggggccacaaacttttccctgctgaaacaggctggagatgtggaggaaaatcca1500gggcccatggtcctgcagactcaggtgttcatcagcctgctgctgtggatttctggggcc1560tacggcagttatgtgctgacacagcctccaagcgtctccgtggctcctggcgaaactgca1620cgaatctcctgtggagggaacaatattgggactaaggtgctgcattggtaccagcagacc1680ccaggacaggctccagtgctggtcgtgtatgacgatagtgacagaccttcaggcatcccc1740gagcggttctctggaagtaactcagggaataccgccacactgactatttcccgcgtcgaa1800gtgggcgacgaagctgattactattgccaagtgtgggacatctctaccgatcaggccgtc1860ttcggcggagggactaagctgaccgtgctgggccagcccaaagctgcaccttccgtgaca1920ctgtttccccctagttcagaggaactgcaggctaacaaggcaaccctggtgtgtctgatt1980agcgacttctacccaggagcagtcacagtggcatggaaggctgatagctcccctgtcaaa2040gccggcgtggaaactaccacaccatctaagcagagtaacaacaagtacgccgcttctagt2100tatctgagcctgacacctgagcagtggaagtcccacaggagctattcctgccaagtgact2160catgagggcagtactgtcgaaaaaaccgtggccccaacagagtgtagctgataa2214122238DNA人工序列pGX222lc12atggact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gctgaactccgtgacccccgaggatacagccgtgtactattgcgccaga360tccggccacatcaccgtgttcggcgtgaatgtggacgcctttgatatgtggggccagggc420accacagtgaccgtgtctagcgcctctacaaagggcccaagcgtgtttccactggcaccc480tcctctaagagcacctccggcggcacagccgccctgggctgtctggtgaaggactacttc540ccagagcccgtgaccgtgtcttggaacagcggcgccctgaccagcggagtgcacacattt600cctgccgtgctgcagagctccggcctgtactccctgtctagcgtggtgaccgtgccatcc660tctagcctgggcacccagacatatatctgcaacgtgaatcacaagccaagcaatacaaag720gtggacaagaaggtggagcccaagtcctgtgataagacccacacatgccctccctgtcct780gcaccagagctgctgggcggcccaagcgtgttcctgtttccacccaagcctaaggacacc840ctgatgatctctcggacccccgaggtgacatgcgtggtggtggacgtgagccacgaggac900cccgaggtgaagttcaactggtacgtggatggcgtggaggtgcacaatgccaagacaaag960cctagggaggagcagtacaactccacctatagagtggtgtctgtgctgacagtgctgcac1020caggattggctgaacggcaaggagtataagtgcaaggtgtccaataaggccctgcccgcc1080cctatcgagaagaccatctctaaggcaaagggacagcctcgggagccacaggtgtacaca1140ctgcctccatcccgcgacgagctgaccaagaaccaggtgtctctgacatgtctggtgaag1200ggcttctatccttctgatatcgccgtggagtgggagagcaatggccagccagagaacaat1260tacaagaccacaccccctgtgctggactccgatggctctttctttctgtatagcaagctg1320accgtggacaagtcccgctggcagcagggcaacgtgttttcttgtagcgtgatgcacgaa1380gcactgcacaaccattacacccagaagtcactgtcactgtccccaggaaaatgataa143716693DNA人工序列pGX931116atggtgctgcagacccaggtgtttatttccctgctgctgtggattagcggcgcatacggc60gacattcagatgactcagagcccttcaagcctgtccgcctctgtgggcgacagggtgacc120atcacatgcagaaccagccagtccctgagctcctacctgcactggtatcagcagaagcca180ggcaaggcccccaagctgctgatctacgcagcctctagcctgcagagcggcgtgccttcc240cggttctctggcagcggctccggcaccgactttaccctgacaatctcctctctgcagcca300gaggatttcgccacatactattgccagcagtcccgcacctttggccagggcacaaaggtg360gagatcaagaccgtggccgccccctccgtgttcatctttcccccttctgacgagcagctg420aagtctggcacagccagcgtggtgtgcctgctgaacaatttctaccctagggaggccaag480gtgcagtggaaggtggataacgccctgcagtccggcaattctcaggagagcgtgaccgag540caggactccaaggattctacatattctctgagcaacaccctgacactgagcaaggccgat600tacgagaagcacaaggtgtatgcctgtgaggtcactcaccaggggctgtcatcacccgtc660accaaatcctttaataggggagaatgttgataa693

权利要求：1.一种编码一种或多种合成抗体的核酸分子，其中所述核酸分子包含选自以下的至少一种：a编码抗流感血凝素HA合成抗体的核苷酸序列；和b编码抗流感HA合成抗体的片段的核苷酸序列。2.根据权利要求1所述的核酸分子，其中所述抗流感HA合成抗体选自结合流感HA的球状头部的抗体和结合流感HA的融合子结构域的抗体。3.根据权利要求1所述的核酸分子，其中核酸分子编码抗流感HA合成抗体，所述抗流感HA合成抗体包含选自与SEQIDNO:1-8至少90％同源的序列及其片段的氨基酸序列。4.根据权利要求3所述的核酸分子，其中所述核酸分子包含选自与SEQIDNO:9-16至少90％同源的序列及其片段的核苷酸序列。5.根据权利要求1所述的核酸分子，包含至少一个选自以下的核苷酸序列：编码第一抗流感HA抗体的第一核苷酸序列；和编码第二抗流感HA抗体的第二核苷酸序列。6.根据权利要求1所述的核酸分子，还包含编码裂解结构域的核苷酸序列。7.根据权利要求1所述的核酸分子，包含编码抗流感HA抗体的可变重链区和可变轻链区的核苷酸序列。8.根据权利要求1所述的核酸分子，包含编码人IgG1κ的恒定重链区和恒定轻链区的核苷酸序列。9.根据权利要求1所述的核酸分子，包含编码下述多肽的核苷酸序列，所述多肽包含：抗流感HA的可变重链区、人IgG1κ的恒定重链区、裂解结构域、抗流感HA的可变轻链区、和IgG1κ的恒定轻链区。10.根据权利要求1所述的核酸分子，其中所述核苷酸序列编码前导序列。11.根据权利要求1-10中任一项所述的核酸分子，其中所述核酸分子包含表达载体。12.一种组合物，包含根据权利要求1-11中任一项所述的核酸分子。13.根据权利要求12所述的组合物，还包含药学上可接受的赋形剂。14.一种治疗受试者的流感感染的方法，所述方法包括向所述受试者施用根据权利要求1-11中任一项所述的核酸分子或根据权利要求12-13中任一项所述的组合物。15.根据权利要求14所述的方法，其中所述流感感染选自甲型流感感染和乙型流感感染。

百度查询： 宾夕法尼亚大学理事会;威斯塔解剖学和生物学研究所;艾诺奥医药品有限公司 靶向流感病毒的DNA单克隆抗体

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