CN110028578B - 广谱抗h7流感病毒的中和性人源单克隆抗体及其应用 - Google Patents
广谱抗h7流感病毒的中和性人源单克隆抗体及其应用 Download PDFInfo
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Abstract
本发明公开了一种广谱抗H7流感病毒的中和性人源单克隆抗体，该抗体能够特异性识别H7重组蛋白，对不同H7毒株具有血凝抑制(HI)活性和微量中和(MN)活性。其针对的表位为H7抗原保守的site A表位。此外，可将本发明的抗体制成预防和治疗H7禽流感病毒的抗体药物，从而在临床中用于预防和治疗H7病毒引起的急性呼吸道传染病。
Description
技术领域
本发明涉及生物技术领域，具体地指一种广谱抗H7流感病毒的中和性人源单克隆抗体及其应用。
背景技术
流感病毒属于正粘病毒科，是有包膜的，基因组分节段的单股负义RNA病毒。流感病毒可分为甲、乙、丙三型，其中甲型流感病毒宿主多，且容易引起流感大流行。根据膜表面蛋白血凝素(HA)和神经氨酸酶(NA)抗原性不同，甲型流感病毒可分为18个HA亚型和11个NA亚型。
目前季节性流感由H1N1，H3N2和乙型流感三类毒株引起，每年会感染约500万人，导致250,000-640,000例死亡。除了季节性流感，禽流感(H5、H7、H9亚型毒株)也能跨越宿主屏障感染人类。到目前为止感染人的H7亚型毒株有低致病性毒株(LP)H7N2、H7N3、H7N7、H7N9和高致病性毒株(HP)H7N3、H7N7、H7N9。鉴于2013年以来，H7N9毒株持续跨越宿主屏障感染人类。且在2016-2017第五波流行时出现了高致病感染人类的毒株，其引起流感大流行的风险较大。
目前已有针对H7毒株的疫苗进入临床I期研究，但是出现了疫苗只能诱导部分受试者产生高滴度的HI抗体，且抗体水平相比较于其他亚型的疫苗滴度偏低。因此疫苗研究有待进一步完善。
中和性抗体可以阻断病毒与靶细胞结合，诱导补体、免疫细胞杀死被病毒染的细胞，在流感病毒防控中具有极大优势。因此，研发针对H7流感病毒的广谱中和抗体对H7N9及其它H7Nx毒株的防控具有重要意义。
发明内容
本发明的目的在于应对H7流感病毒的防控，提供一种效果更好的广谱抗H7流感病毒的中和性人源单克隆抗体及其应用。
为实现上述目的，第一，本发明提供了一种H7流感病毒抗体的重链可变区，其特征在于：
所述重链可变区的互补决定区CDR如下：
SEQ ID NO.4所示的HCDR1；
SEQ ID NO.5所示的HCDR2；
SEQ ID NO.6所示的HCDR3。
优选地，所述重链可变区具有SEQ ID NO.2所示的氨基酸序列。
第二，本发明提供了一种H7流感病毒抗体的重链，所述重链具有如权利要求1所述的重链可变区，以及如SEQ ID NO.3所示的重链恒定区。
第三，本发明提供了一种H7流感病毒的中和性人源单克隆抗体，其特征在于：
所述抗体的重链可变区如权利要求1或2所述；
或所述抗体的重链如权利要求3所述。
优选地，所述H7流感病毒的中和性人源单克隆抗体的轻链可变区的互补决定区CDR如下：
SEQ ID NO.10所示的LCDR1；
SEQ ID NO.11所示的LCDR2；
SEQ ID NO.12所示的LCDR3。
更优选地，所述抗体的轻链可变区具有SEQ ID NO.8所示的氨基酸序列。
可选地，所述H7流感病毒的中和性人源单克隆抗体，所述抗体的具有如SEQ IDNO.9所示的轻链恒定区。
第四，本发明提供了一种H7流感病毒的中和性人源单克隆抗体的基因，其编码重链Fd片段和轻链VL+CL的核苷酸序列分别如SEQ ID NO.1和SEQ ID NO.7所示。
第五，本发明还提供了上述H7流感病毒抗体的重链可变区或重链在制备抗H7流感病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。
第六，本发明还提供了上述H7流感病毒抗体的中和性人源单克隆抗体在制备抗H7流感病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。
本发明提供的上述广谱抗H7流感病毒的中和性人源单克隆抗体，是通过以下方法得到：首先构建H7N9恢复期病人的Fab库，然后以Bac-to-Bac表达体系表达的H7流感病毒HA蛋白胞外域为抗原，经过4轮筛选，从第三和第四轮筛选中挑选克隆进行鉴定，得到了一种能中和H7流感病毒的抗体P52E03Fab，其通过重链识别抗原的保守位点来结合，通过轻链的突变成熟来提高其亲和力和中和活性。P52E03能广谱中和欧亚和北美的H7毒株，其筛选到的逃逸位点G151E通过在数据库GISAID(Global initiative on sharing all influenzadate)中分析，发现4395条HA(hemagglutinin)全长可获取的H7毒株中只有38株具有该突变，表明该抗体对大部分的H7毒株具有中和效果。
本发明的有益效果：所提供的抗体能够特异性识别H7重组蛋白，对不同H7毒株具有血凝抑制(HI)活性和微量中和(MN)活性。其针对的表位为H7抗原保守的site A表位。此外，可将本发明的抗体制成预防和治疗H7禽流感病毒的抗体药物，从而在临床中用于预防和治疗H7病毒引起的急性呼吸道传染病。
附图说明
图1为H7流感病毒HA蛋白表达纯化后的SDS验证凝胶电泳照片；
其中，M泳道为分子量标准，SH02泳道为A/Shanghai/2/2013 H7N9的HA蛋白，17SF泳道为A/Guangdong/17SF003/2016 H7N9的HA蛋白。
图2为P52E03 IgG抗体纯化后的SDS验证凝胶电泳照片；
其中，M泳道为分子量标准，P52E03泳道为纯化后的P52E03 IgG。
图3为生物膜干涉(BLI)测定P52E03 IgG和H7流感病毒HA蛋白的结合情况比较图；
其中，和SH02抗原结合时，抗体有四个浓度1μM、333nM、111nM、37nM。和17SF抗原结合时，抗体有四个浓度200nM、50nM、12.5nM、3.125nM。
图4为P52E03 IgG对不同H7毒株的血凝抑制(HI)活性比较图；
其中，A/Shanghai/02/2013(H7N9)简写为shanghai13 H7N9，A/chicken/Netherlands/2586/2003(H7N7)简写为chickNL03 H7N7，A/chicken/BC/CN006/2004(H7N3)简写为chickBC04 H7N3，A/Rhea/North Carolina/39482/93(H7N1)简写为rheaNC93 H7N1，A/Puerto Rico/8/34(H1N1)简写为PR8 H1N1。以上毒株HA和NA片段来自其自身，其它6个片段来自于A/Puerto Rico/8/34(H1N1)。
图5为P52E03 IgG对不同H7毒株的微量中和(MN)活性比较图；
其中，A/Shanghai/02/2013(H7N9)简写为shanghai13 H7N9，A/chicken/Netherlands/2586/2003(H7N7)简写为chickNL03 H7N7，A/chicken/BC/CN006/2004(H7N3)简写为chickBC04 H7N3，A/Rhea/North Carolina/39482/93(H7N1)简写为rheaNC93 H7N1，A/Puerto Rico/8/34(H1N1)简写为PR8H1N1。以上毒株HA和NA片段来自其自身，其它6个片段来自于A/Puerto Rico/8/34(H1N1)。
图6为P52E03 IgG突变体对抗原的结合；6A为活性比较图，6B为各个P52E03 IgG突变体病毒的氨基酸序列比较图；
其中，P52E03 mHmL,抗体重链和轻链均为成熟形式；P52E03 mHgL，抗体重链为成熟形式轻链为胚系形式；P52E03 gHmL，抗体重连为胚系形式轻链为成熟形式；P52E03gHgL，抗体重链和轻链均为胚系形式。
图7为P52E03 IgG表位鉴定；P52E03 IgG对shanghai13毒株进行筛选，得到了单点突变的逃逸株。
具体实施方式
以下结合附图和具体实施例对本发明作进一步的详细描述。以下实施例是在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
实施例1：表达并纯化H7流感病毒HA蛋白
将A/Shanghai/2/2013 H7N9(SH02；GISAID database(http://www.gisaid.org)accession no.EPI138738)和A/Guangdong/17SF003/2016 H7N9(17SF；GISAID databaseaccession no.EPI266963)HA的胞外域11-505(根据H3 numbering)和N端gp67信号肽、C端T4三聚体结构域及twin-strep-His标签构建到pFastBac1载体(市售)，采用Bac-to-Bac表达体系表达。72h后收集上清，用Ni Sepharose excel(GE Healthcare)填料纯化，随后用截留分子量为30KD的超滤离心管超滤置换缓冲液，经SDS-PAGE验证其纯度，如图1。
实施例2：噬菌体展示库的构建及筛选
按照已有的文献(Zhu Z,Dimitrov DS,Methods Mol Biol,2009)做了一些改进，构建噬菌体Fab库，以Bac-to-Bac表达体系表达的H7流感病毒HA蛋白胞外域(SH02，17SF)为抗原进行了筛选。将纯化后的抗原在96孔板中4℃孵育过夜后，用噬菌体库进行淘选，特异性的噬菌体被抗原捕获，用PBS+0.05％Tween-20清洗，经过4轮筛选，得到了一株体外具有中和活性的克隆，命名为P52E03。
实施例3：P52E03 IgG的表达纯化
将P52E03 Fab的重链和轻链构建到IgG1表达载体pivotro2-neo-mcs(市售)，用PEI转染293F细胞进行表达，表达上清用protein A填料进行纯化，随后用截留分子量为15KD的超滤离心管超滤置换缓冲液，经SDS-PAGE验证其纯度，如图2。
实施例4：生物膜干涉(BLI)测定P52E03 IgG和H7流感病毒HA蛋白的结合
SHO2和17SF蛋白先生物素化，然后上到Sterptavidin(SA)探针上，用不同浓度的抗体来测定抗体和抗原的结合、解离情况，结果如图3。最后计算得出P52E03 IgG和SH02结合的KD＝1.57E-7M，P52E03 IgG和17SF结合的KD＝1.05E-8M。
实施例5：P52E03 IgG对不同H7毒株的血凝抑制(HI)活性
取25μl抗体P52E03 IgG，从1000μg/ml 2倍稀释，每孔再加入25μl 4个血凝价单位(HAU)的病毒，室温孵育1小时。然后每孔加入1％鸡血红细胞50μl，室温孵育30分钟，检测血凝情况。能引起血凝抑制的最低抗体浓度即为血凝抑制终点滴度(HI endpoint titer)，结果如图4。P52E03对欧亚毒株shanghai13 H7N9和chickNL03 H7N7，北美毒株chickBC04H7N3和rheaNC93 H7N1均具有血凝抑制活性，对阴性对照毒株PR8 H1N1没有血凝抑制活性。每组实验有两个重复。A/Shanghai/02/2013(H7N9)简写为shanghai13 H7N9，A/chicken/Netherlands/2586/2003(H7N7)简写为chickNL03 H7N7，A/chicken/BC/CN006/2004(H7N3)简写为chickBC04 H7N3，A/Rhea/North Carolina/39482/93(H7N1)简写为rheaNC93 H7N1，A/Puerto Rico/8/34(H1N1)简写为PR8 H1N1。以上毒株HA和NA片段来自其自身，其它6个片段来自于A/Puerto Rico/8/34(H1N1)，按照已有的文献(Hoffmann E et.al.,Proc NatlAcadSci USA,2000)通过反向遗传学8质粒共转体系拯救获得上述重组毒株。
实施例6：P52E03 IgG对不同H7毒株的微量中和(MN)活性
取50μl的抗体P52E03 IgG，从500μg/ml 2倍稀释，每孔再与50μl 100TCID50病毒室温孵育1小时，然后再把这100μl混合液加入到已用1×PBS预洗两遍且加有100μl维持液的MDCK细胞(TPCK终浓度1μg/ml)，37℃，5％CO2，培养72小时。然后每孔取50μl上清与50μl1％鸡血红细胞室温孵育30分钟，检测血凝情况，没有血凝现象的最低抗体浓度即为微量中和终点滴度(MN endpoint titer)，结果如图5。P52E03对欧亚毒株shanghai13 H7N9和chickNL03 H7N7，北美毒株chickBC04 H7N3和rheaNC93 H7N1均具有微量中和活性，对阴性对照毒株PR8 H1N1没有微量中和活性。每组实验有三个重复。
实施例7：P52E03 IgG突变体对H7流感病毒HA蛋白的结合
将P52E03 IgG的重链可变区和轻链可变区除CDR3以外突变为各自的胚系抗体IGHV3-9*01和IGKV3-20*01，如图6B。将这几种链进行组合，表达后验证与H7流感病毒HA蛋白的结合，发现所有组合均能和H7流感病毒HA蛋白结合，如图6A,嵌合抗体gHmL的亲和力与成熟抗体mHmL相当，这表明抗体重链的成熟不影响与抗原的结合。嵌合抗体mHgL的亲和力明显低于mHmL，这表明抗体轻链的成熟能提高其亲和力。抗体的胚系前体gHgL也能与抗原结合，这表明抗原可能通过重链识别抗原，通过轻链成熟提高其亲和力。
实施例8：P52E03 IgG表位鉴定
通过逃逸株筛选实验，把抗体P52E03 IgG和shanghai13 H7N9孵育，然后在细胞上传代，筛选到第8代，通过噬斑纯化得到了单克隆逃逸毒株，测序结果显示其具有G151E(从H7第一个甲硫氨酸起始)单点突变，如图7。通过血凝抑制(HI)和微量中和实验(MN)验证了该点突变。该突变位点位于H7的site A表位(RRSGSS)，该表位在H7中是保守的。
序列表
<110> 中国科学院武汉病毒研究所
<120> 广谱抗H7流感病毒的中和性人源单克隆抗体及其应用
<130> 2019
<160> 12
<170> SIPOSequenceListing 1.0
<210> 1
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<213> P52E03 Fd
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caggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaaggcctt 300
aatagcagtg gctggtacgt ctactttgac tactggggcc agggaaccct ggtcaccgtc 360
tcctcagcct ccaccaaggg cccatcggtc ttccccctgg caccctcctc caagagcacc 420
tctgggggca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 480
gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540
tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacc 600
cagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagaaagtt 660
gagcccaaat cttgtgacaa aactagt 687
<210> 2
<211> 122
<212> PRT
<213> P52E03 VH
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Leu Asn Ser Ser Gly Trp Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 107
<212> PRT
<213> P52E03 CH
<400> 3
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr Ser
100 105
<210> 4
<211> 8
<212> PRT
<213> P52E03 HCDR1
<400> 4
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 5
<211> 8
<212> PRT
<213> P52E03 HCDR2
<400> 5
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 6
<211> 15
<212> PRT
<213> P52E03 HCDR3
<400> 6
Ala Lys Gly Leu Asn Ser Ser Gly Trp Tyr Val Tyr Phe Asp Tyr
1 5 10 15
<210> 7
<211> 648
<212> DNA
<213> P52E03 VL+CL
<400> 7
gaaattgtgc tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gactgttgcc aggaactact tagcctggta tcagcagaaa 120
cctggccagg ctcccaggct cctcatgtat gatccatcca gcaggcccgc tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ctgcagtata tttttgtcag caatatggta gtccaccgct cactttcggc 300
ggagggacga aaatagagat caaacgaact gtggctgcac catccgtctt catcttcccg 360
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540
acgctgagca aagcagacta cgagaaacac aaactctacg cctgcgaagt cacccatcag 600
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgttaa 648
<210> 8
<211> 108
<212> PRT
<213> P52E03 VL
<400> 8
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ala Arg Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Met Tyr Asp Pro Ser Ser Arg Pro Ala Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ser Ala Val Tyr Phe Cys Gln Gln Tyr Gly Ser Pro Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Ile Glu Ile Lys
100 105
<210> 9
<211> 107
<212> PRT
<213> P52E03 CL
<400> 9
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 10
<211> 7
<212> PRT
<213> P52E03 LCDR1
<400> 10
Gln Thr Val Ala Arg Asn Tyr
1 5
<210> 11
<211> 3
<212> PRT
<213> P52E03 LCDR2
<400> 11
Asp Pro Ser
1
<210> 12
<211> 7
<212> PRT
<213> P52E03 LCDR3
<400> 12
Gln Gln Tyr Gly Ser Pro Pro
1 5
Claims (7)
1.一种H7流感病毒的中和性人源单克隆抗体，其特征在于：
重链可变区的互补决定区CDR如下：
SEQ ID NO.4所示的HCDR1；
SEQ ID NO.5所示的HCDR2；
SEQ ID NO.6所示的HCDR3；
所述抗体的轻链可变区的互补决定区CDR如下：
SEQ ID NO.10所示的LCDR1；
SEQ ID NO.11所示的LCDR2；
SEQ ID NO.12所示的LCDR3。
2.根据权利要求1所述H7流感病毒的中和性人源单克隆抗体，其特征在于：所述重链可变区具有SEQ ID NO.2所示的氨基酸序列。
3.根据权利要求2所述H7流感病毒的中和性人源单克隆抗体，其特征在于：其重链具有如SEQ ID NO.3所示的重链恒定区。
4.根据权利要求1所述H7流感病毒的中和性人源单克隆抗体，其特征在于：所述抗体的轻链可变区具有SEQ ID NO.8所示的氨基酸序列。
5.根据权利要求4所述H7流感病毒的中和性人源单克隆抗体，其特征在于：所述抗体的具有如SEQ ID NO.9所示的轻链恒定区。
6.一种编码H7流感病毒的中和性人源单克隆抗体的基因，其编码重链Fd片段和轻链VL+CL的核苷酸序列分别如SEQ ID NO.1和SEQ ID NO.7所示。
7.权利要求1所述H7流感病毒抗体的中和性人源单克隆抗体在制备抗H7流感病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。
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