CN109929033B - 一种特异性结合四种血清型登革病毒的人源抗体 - Google Patents
一种特异性结合四种血清型登革病毒的人源抗体 Download PDFInfo
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Abstract
本发明公开了一种特异性结合四种血清型登革病毒的人源抗体。本发明所提供的人源抗体,其重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ ID No.1自N端起第26‑33位、第51‑58位、第97‑121位所示,轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.2自N端起第27‑32位、第50‑52位、第89‑97位所示。本发明所提供的抗体可有效预防四种血清型DENV的感染,治疗致死剂量DENV‑1和DENV‑2的感染。本发明对于开发预防及治疗登革病毒感染的药物具有重要意义。
Description
技术领域
本发明涉及生物技术领域,特别涉及一种特异性结合四种血清型登革病毒的人源抗体。
背景技术
登革病毒(Dengue virus,DENV)属于黄病毒科黄病毒属,是有包膜的单正链RNA病毒,根据其包膜的抗原性不同,分为四种血清型(DENV I-IV)。登革病毒主要以埃及伊蚊和白纹伊蚊为传播媒介,广泛流行于热带和亚热带地区。人类首次感染登革病毒会引起登革热(Classic Dengue Fever,DF),是一种自限性发热性疾病,同时登革病毒可以激发良好的细胞免疫和体液免疫,对感染的该亚型可提供终身的免疫力。但是当再次感染其他亚型的登革病毒时,首次感染产生的抗体会携带病毒攻击靶细胞,造成病毒大量的增殖,从而引发严重的登革出血热(Dengue Hemorrhagic Fever,DHF)和登革休克综合征(Dengue ShockSyndrome,DSS)甚至死亡,即抗体依赖增强(Antibody dependent enhancement,ADE)。世界上约有半数的人口生活在登革热疫区,每年有超过5000万的感染病例,其中有50万人发展为严重的DHF和DSS。但是,由于ADE现象的存在,临床上缺乏预防和治疗DENV感染的有效疫苗和药物,主要以对症支持治疗为主。
免疫球蛋白是治疗病毒感染类疾病的重要手段,不仅能中和病毒,还能通过补体依赖的细胞毒作用(complement dependent cytotoxicity,CDC)和抗体依赖细胞介导的细胞毒作用(antibody dependent cell-mediated cytotoxicity,ADCC)激活体内免疫***清除病毒。大量体内、外实验证明:中和抗体能有效阻止DENV的感染,不仅能发挥病毒感染前的预防作用,而且在病毒感染后的一段时期内,依然能发挥治疗病毒感染的作用。基于临床上针对DENV感染无有效防治手段的现状,以及近年来单克隆抗体技术在人源化、规模化培养制备等方面均取得的巨大进步,登革病毒的治疗性抗体研究也得到了长足的发展。
DENV的E蛋白是感染性病毒粒子表面暴露最充分的蛋白,也是中和抗体的主要靶点。目前全球报道的DENV中和抗体表位也多与E蛋白有关:(1)识别DENV EDⅡ:FL loop对应的交叉中和性抗体(E53)大都中和效率低且易产生ADE效应;针对BC loop的交叉中和抗体(1C19)不仅能高效中和DENV且还能与低效抗FL抗体竞争结合。(2)识别DENV EDⅢ:AB loop对应交叉中和抗体一般具弱中和性,EF loop附近形成的单抗(2B11A35/2D73A7)具高效交叉中和能力,A strand表位(单抗,DB32-6)具有高效中和活性;(3)识别E蛋白二聚体依赖性表位(E-dimer-dependent epitope,EDE):单抗(EDE1/EDE2)是一类新型高效广谱的人源中和抗体。此外,在抗体来源方面,大多数中和抗体为鼠源,少量人源化及人源抗体。人源化抗体与鼠源抗体相比具有以下特点:(1)免疫原性低于鼠源抗体;(2)亲和力弱于鼠源抗体,特异性优于鼠源抗体;(3)人源化抗体Fc段能够诱发机体的效应功能;(4)在体内半衰期长;(5)价格仍较昂贵。但人源化抗体仍含有10%~30%的鼠源蛋白,在临床应用时仍存在免疫排斥反应的潜在威胁,因而全人源中和抗体是DENV治疗性抗体的重要研发目标之一。
基于临床需求,探索和研发登革病毒中和抗体具有重要的生物学和医学意义。
发明内容
本发明的目的是提供一种特异性结合四种血清型登革病毒的人源抗体。
第一方面,本发明要求保护一种抗体。
本发明所要求保护的抗体为全人源单抗6B1,其重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ ID No.1自N端起第26-33位、第51-58位、第97-121位所示;所述抗体的轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.2自N端起第27-32位、第50-52位、第89-97位所示。
其中,HCDR1、HCDR2和HCDR3为重链可变区中的三个互补决定区,LCDR1、LCDR2和LHCDR3为轻链可变区中的三个互补决定区。互补决定区的序列根据Kabat定义。
进一步地,所述重链可变区的氨基酸序列可为SEQ ID No.1自N端起第1-121位,或者与SEQ ID No.1自N端起第1-121位具有至少90%的一致性(不一致处可在骨架区(FR))。所述轻链可变区的氨基酸序列可为SEQ ID No.2自N端起第1-109位,或者与SEQ ID No.2自N端起第1-109位具有至少90%的一致性(不一致处可在骨架区(FR))。
在本发明中,所述抗体为IgG。进一步地,所述IgG为IgG1。所述抗体的轻链类型为kappa(κ)型。
更进一步地,所述抗体的重链的氨基酸序列可为SEQ ID No.1,或者与SEQ IDNo.1具有至少90%的一致性(不一致处可在骨架区(FR))。所述抗体的轻链的氨基酸序列可为SEQ ID No.2或者与SEQ ID No.2具有至少90%的一致性(不一致处可在骨架区(FR))。
第二方面,本发明要求保护一种核酸分子。
本发明所要求保护的核酸分子为编码前文第一方面所述的抗体或所述抗体中的抗原结合部分的核酸分子。
进一步地,在所述核酸分子中,编码所述抗体的重链可变区中HCDR1、HCDR2和HCDR3的核苷酸序列可依次如SEQ ID No.3自5’端起第76-99位、第151-174位、第289-363位所示,编码所述抗体的轻链可变区中LCDR1、LCDR2和LHCDR3的核苷酸序列可依次如SEQ IDNo.4自5’端起第79-96位、第148-156位、第265-291位所示。
更进一步地,在所述核酸分子中,编码所述抗体的所述重链可变区的核苷酸序列可为SEQ ID No.3自5’端起第1-363位或者与SEQ ID No.3自5’端起第1-363位具有至少90%的一致性(不一致处在骨架区(FR)),编码所述抗体的所述轻链可变区的核苷酸序列可为SEQ ID No.4自5’端起第1-327位或者与SEQ ID No.4自5’端起第1-327位具有至少90%的一致性(不一致处在骨架区(FR))。
更加具体地,在所述核酸分子中,编码所述抗体的重链的核苷酸序列可为SEQ IDNo.3或者与SEQ ID No.3具有至少90%的一致性(不一致处可在骨架区(FR)),编码所述抗体的轻链的核苷酸序列可为SEQ ID No.4或者与SEQ ID No.4具有至少90%的一致性(不一致处可在骨架区(FR))。
第三方面,本发明要求保护含有前文第二方面所述核酸分子的表达盒、重组载体、重组细胞或重组菌。
在本发明的一个实施例中,将SEQ ID No.3自5’端起第1-363位所示DNA片段(抗体重链可变区的编码基因)克隆到pTSEG1n-S载体的酶切位点Sal I和Pml I之间后得到表达所述抗体的重链的重组表达载体;将SEQ ID No.4自5’端起第1-327位所示DNA片段(抗体轻链可变区的编码基因)克隆到pTSEK-S载体的酶切位点Sal I和Pml I之间后得到表达所述抗体的轻链的重组表达载体。所述重组细胞为将上述分别表达所述抗体重链和轻链的两个重组表达载体共转染FreeStyleTM 293F细胞后得到的重组细胞。
第四方面,本发明要求保护一种药物组合物。
本发明所要求保护的药物组合物包含前文第一方面中所述的抗体和药学可接受的赋形剂、稀释剂或载体。
第五方面,本发明要求保护如下任一所示应用:
(A1)前文所述核酸分子或表达盒、重组载体、重组细胞或重组菌在制备前文所述抗体或所述药物组合物中的应用;
(A2)前文所述抗体在制备前文所述药物组合物中的应用;
(A3)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于预防和/或治疗由登革病毒感染所致疾病的产品中的应用;
其中,所述由登革病毒感染所致疾病可为登革热(Classic Dengue Fever,DF)、登革出血热(Dengue Hemorrhagic Fever,DHF)或者登革休克综合征(Dengue ShockSyndrome,DSS)。
(A4)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于抑制登革病毒感染(中和登革病毒)的产品中的应用;
(A5)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于检测登革病毒的产品中的应用;
(A6)前文所述或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于结合登革病毒的产品中的应用;
(A7)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于检测登革病毒的E蛋白的产品中的应用;
(A8)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于结合登革病毒的E蛋白的产品中的应用。
进一步地,所述登革病毒可为I型登革病毒、II型登革病毒、III型登革病毒和/或IV型登革病毒。
本发明制备了一种能够特异性结合四种血清型登革病毒的人源抗体——全人源单抗6B1。实验证明,该抗体能够识别四种血清型登革病毒的E蛋白,对DENV-1和DENV-2的亲和力较高,但对DENV-3和DENV-4的亲和力较弱,对DENV-1和DENV-2的中和活性较强,但对DENV-3和DENV-4的中和活性较弱,可有效预防四种血清型DENV的感染,治疗致死剂量DENV-1和DENV-2的感染。本发明对于开发预防及治疗登革病毒感染的药物具有重要意义。
附图说明
图1为单抗6B1的抗体血清型特异性检测。注:非还原电泳;1:DENV-1;2:DENV-2;3:DENV-3;4:DENV-4。
图2为ELISA分析6B1与灭活登革病毒的结合。
图3为ELISA分析6B1与登革病毒重组E蛋白的结合。
图4为分析6B1与DENV-1重组E蛋白的亲和力。
图5为单抗6B1对四种血清型登革病毒的体外中和活性。
图6为乳鼠体内分析6B1对四种血清型登革病毒感染的预防作用。A:DENV-1;B:DENV-2;C:DENV-3;D:DENV-4。
图7为乳鼠体内分析6B1对DENV-1和DENV-2感染的治疗作用。A:DENV-1;B:DENV-2。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
四种血清型登革病毒,即I型登革病毒、II型登革病毒、III型登革病毒和/或IV型登革病毒:分离株,由军事医学研究院微生物流行病研究所提供。
重链表达载体为pTSEG1n-S:由北京百特美博生物有限公司提供。
轻链表达载体为pTSEK-S:由北京百特美博生物有限公司提供。
FreeStyleTM 293F细胞:Invitrogen公司,货号R79007。
C6/36细胞:ATCC。
BHK-21细胞:ATCC。
实施例1、全人源单抗6B1的制备
采集3例临床上确诊为登革热恢复期患者的外周血(患者知情同意),每人10mL,共30mL。分离单核淋巴细胞,利用流式细胞术两步分选单个B细胞,先分选出CD19highCD20low to negativeCD3negative,在从中分选出CD27highCD38high的B细胞,分至96孔板,每个孔一个细胞。利用反转录PCR和巢式PCR从单B细胞扩增抗体轻重链可变区基因,轻重链正确配对者进行PCR产物测序,获得了包括6B1在内的多对轻重链可变区基因序列。其中,抗体6B1的重链可变区基因如SEQ ID No.3自5’端起第1-363位所示;抗体6B1的轻链可变区基因如SEQ ID No.4自5’端起第1-327位所示。
全合成6B1的轻重链可变区基因,重链表达载体pTSEG1n-S和轻链表达载体pTSEK-S利用Sal I和Pml I双酶切,将6B1的轻重链可变区基因分别与酶切后的轻重链表达载体连接,构建能够表达抗体6B1的重链和轻链的两个真核表达质粒。其中,用于表达抗体6B1的重链的重组表达质粒中携带完整的SEQ ID No.3(SEQ ID No.3为抗体6B1的重链编码基因),用于表达抗体6B1的轻链的重组表达质粒中携带完整的SEQ ID No.4(SEQ ID No.4为抗体6B1的轻链编码基因)。
抗体6B1,其重链氨基酸序列如SEQ ID No.1所示,轻链氨基酸序列如SEQ ID No.2所示。
SEQ ID No.1,自N端第1-121位氨基酸残基组成重链可变区VH(其中,第26-33位氨基酸残基组成HCDR1,第51-58位氨基酸残基组成HCDR2,第97-121位氨基酸残基组成HCDR3),第122-222位氨基酸残基组成重链恒定区CH1,第223-237位氨基酸残基组成重链铰链区Hinge,第238-347位氨基酸残基组成重链恒定区CH2,第348-454位氨基酸残基组成重链恒定区CH3。
SEQ ID No.2中,自N端第1-109位氨基酸残基组成轻链可变区VL(其中,第27-32位氨基酸残基组成LCDR1,第50-52位氨基酸残基组成LCDR2,第89-97位氨基酸残基组成LCDR3),第110-214位氨基酸残基组成轻链恒定区CL。
SEQ ID No.3所示的DNA分子编码SEQ ID No.1所示的多肽(重链)。SEQ ID No.3中,自5’端第1-363位核苷酸编码VH(其中,第76-99位核苷酸编码HCDR1,第151-174位核苷酸编码HCDR2,第289-363位核苷酸编码HCDR3),第364-666位核苷酸编码CH1,第667-711位核苷酸编码Hinge,第712-1041位核苷酸编码CH2,第1042-1362位核苷酸编码CH3,第1363-1365位核苷酸为终止密码子。
SEQ ID No.4所示的DNA分子编码SEQ ID No.2所示的多肽(轻链)。SEQ ID No.4中,自5’端第1-327位核苷酸编码VL(其中,第79-96位核苷酸编码LCDR1,第148-156位核苷酸编码LCDR2,第265-291位核苷酸编码LCDR3),第328-642位核苷酸编码CL,第643-645位核苷酸为终止密码子。
其中,互补决定区的序列根据Kabat定义。
抗体6B1为全人源单抗,为IgG1,轻链类型为kappa(κ)型。
利用FectoPRO转染试剂(Polyplus-transfection公司产品,货号116-010),按说明书将上述构建好的抗体6B1的轻重链重组表达质粒共转染FreeStyleTM 293F细胞,在无血清悬浮培养条件下培养3天,离心收获培养上清。上清中的抗体用HitrapTM MabSelectXtra/SuRe(GE公司产品,货号28-4082-55)等ProteinA/G亲和层析柱按说明书进行纯化。然后利用HitrapTM Desalting(GE公司产品,货号29-0486-84)将抗体保存缓冲液置换为10mM柠檬酸盐缓冲液(pH6.0)或者其他合适的缓冲液。必要时,可以对抗体样品进行过滤除菌,然后分装分别置于4℃和-20℃保存。
实施例2、单抗6B1的血清型特异性
利用C6/36细胞分别接种培养四种血清型的登革病毒,收集培养上清收获病毒原液。取适量病毒原液,加入4×Loading buffer,水浴煮沸制备蛋白样品。取10μL蛋白样品行SDS-PAGE,然后将蛋白样品电转至PVDF膜(Amersham公司产品,货号10600023),用5%脱脂牛奶封闭。加入待检抗体6B1(1μg/mL)室温孵育2h或4℃冰箱孵育过夜。用TBS-T洗膜三次,每次10min,加入1:5000稀释的HRP-Goat anti human IgG(中杉金桥公司产品,货号ZB2304),室温孵育1h。用TBS-T洗膜三次,每次10min。膜上加显影液,用凝胶成像仪曝光显影。
图1显示6B1与四种血清型登革病毒都结合,但是与DENV-1和DENV-2结合较强,与DENV-3和DENV-4结合较弱,结合条带在70kD左右,与E蛋白的分子量一致,表明它识别的是四种血清型登革病毒的E蛋白。
实施例3、ELISA检测单抗6B1与抗原的结合
96孔酶联板分别包被四种血清型的登革病毒重组E蛋白(RayBiotech公司产品,货号分别为228-11688,228-11689,228-11690,228-11691),2μg/mL,100μL/孔,4℃包被过夜;或包被四种血清型的灭活登革病毒培养上清,100μL/孔,4℃包被过夜。弃包被液后PBST洗涤5min/次×3次,加入2%BSA-PBST,200μL/孔,置于37℃封闭2h。加入3倍倍比稀释的6B1抗体(浓度:30μg/mL-0.17ng/mL),50μL/孔,37℃孵育2h。弃一抗,PBST洗涤5min/次×3次,加入1:5000稀释的二抗HRP-Goat anti human IgG(中杉金桥公司产品,货号ZB2304),37℃孵育1h。弃二抗,PBST洗涤5min/次×3次,每孔加入100μL显色液,置于避光处,待显色完全每孔加入100μL终止液。酶标仪读取293nm/630nm波长吸光值。
图2、图3显示单抗6B1既可以结合灭活登革病毒,也可以结合重组E蛋白,说明6B1识别的可能是E蛋白上的线性表位。单抗6B1对DENV-1和DENV-2的亲和力较高,但对DENV-3和DENV-4的亲和力较弱,这也与图1显示的结果一致。
实施例4、单抗6B1的亲和力测定
将纯化后的待检测抗体6B1用HBS-EP缓冲液(CM5芯片试剂盒中)稀释至1μg/mL,并偶联至预先包被有Protein G的CM5芯片(GE公司产品,货号BR100014)上,偶联条件为:温度25℃,流速5μL/min,偶联量为200RU。DENV重组E蛋白(RayBiotech公司产品,货号分别为228-11688,228-11689,228-11690,228-11691)作为流动相,用HBS-EP缓冲液做两倍浓度梯度稀释,其浓度范围为20nM-625pM,测试条件:温度25℃,流速30μL/min;结合时间为3min,解离时间为15min。完成一个反应后,对芯片进行再生,再生条件:3M MgCl2,30μL/min×30s,再生后继续偶联相同量的待测抗体,进行下一个反应。实验结束后,扣除空白对照的值,用BIAevaluation软件进行结果分析。检测结果显示单抗6B1对DENV-1重组E蛋白的亲和力KD=0.44nM(图4)。
实施例5、单抗6B1的体外中和活性
利用空斑减少中和实验(Plaque Reduction Neutralization Test,PRNT)检测抗体的体外中和活性。实验前24h取生长状态良好的BHK-21细胞,胰酶消化后调整细胞密度至2.5×105个/mL,接种6孔细胞培养板,每孔2mL。实验当天在96孔板中,3倍梯度稀释抗体6B1,由100μg/mL至5.65×10-4μg/mL,并设置无抗体阴性对照,100μL/孔。每孔加入等体积含约100PFU的登革病毒悬液,混匀后置于37℃5%CO2的培养箱中作用1h。弃去BHK-21细胞的培养基,每孔加入800μL DMEM细胞维持液。将孵育结束的登革病毒与抗体混合物加入到6孔板中,37℃5%CO2培养箱中继续孵育1h。弃上清,PBS缓冲液洗2遍,加入上层半固体培养基(1g低熔点琼脂糖(Amresco公司产品,货号0815)加入50mL水中,加热熔化后温度降至42℃左右,与50mL 2×DMEM培养基(含2mL胎牛血清)混合,使胎牛血清和低熔点琼脂糖的终浓度分别为2%和1%),继续培养4-5天。待细胞出现病变后,每孔加入1mL 4%多聚甲醛溶液,放置于4℃1h以固定细胞。去除上层琼脂糖,每孔加入1mL 1%结晶紫染液,室温染色30min。用去离子水冲洗后计数空斑,计算抗体对所有四种血清型登革病毒的抑制率。计算方法:抑制率=(阴性对照空斑数-实验组空斑数)/阴性对照空斑数×100%。
结果如图5所示,抗体的中和活性具有剂量依赖关系,在一定浓度范围内,随着抗体浓度的提高,对病毒感染的抑制作用显著增强。通过对抗体的中和活性效价进行非线性统计分析,计算得到PRNT50值。单抗6B1对四种血清型登革病毒的中和活性分别为:PRNT50=2.33μg/mL、2.89μg/mL、19.65μg/mL、12.64μg/mL。单抗6B1对DENV-1和DENV-2的中和活性较强,但对DENV-3和DENV-4的中和活性较弱,与亲和力结果一致。
实施例6、单抗6B1的体内抗病毒活性
一、病毒感染乳鼠的半数致死剂量(LD50)测定
将测定病毒滴度后的登革病毒原液10倍梯度稀释。出生24h内昆明种乳鼠颅内接种病毒原液,每个浓度接种1窝(约10只),每只1μL。继续观察21天,每天记录乳鼠的发病和死亡情况,根据每个浓度组小鼠存活数计算小鼠的存活率,并利用Graphpad软件,计算小鼠半数致死剂量(LD50)
二、乳鼠保护试验
1、预防效果评价
出生24h内昆明种乳鼠颅内注射5μL浓度为200μg/mL、20μg/mL、2μg/mL的抗体,24h后经颅途径接种10LD50的登革病毒5μL。观察21天,每天记录乳鼠发病和死亡情况,根据小鼠存活数计算小鼠的存活率,并用Graphpad软件作图分析,结果见图6。6B1针对DENV-1的感染,0.1μg/只的剂量可以保护70%的乳鼠,而1μg/只的剂量可以保护100%的乳鼠;6B1对DENV-2感染的保护效果更佳,0.01μg/只的剂量就可以保护90%的乳鼠,而1μg/只的剂量可以保护100%的乳鼠;6B1对DENV-3感染的保护效果稍弱一些,1μg/只的剂量只可以保护70%的乳鼠;6B1对DENV-4感染的保护效果最弱,5μg/只的剂量才可以保护70%的乳鼠。
2、治疗效果评级
出生24h内昆明种乳鼠颅内接种10LD50的登革病毒5μL,6h后经颅途径注射5μL浓度为200μg/mL的抗体,观察21天,每天记录乳鼠发病和死亡情况,根据小鼠存活数计算小鼠的存活率,并用Graphpad软件作图分析,结果见图7。6B1针对DENV-1和DENV-2的攻击,1μg/只的剂量可以保护50%的乳鼠。
综上所述,6B1可有效预防四种血清型DENV的感染,治疗致死剂量DENV-1和DENV-2的感染。
<110> 中国人民解放军军事科学院军事医学研究院
<120> 一种特异性结合四种血清型登革病毒的人源抗体
<130> GNCLN190313
<160> 4
<170> PatentIn version 3.5
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gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcagtag cctgagtatg 60
agctgtgccg ccagcggctt caccttcgac gactactcca tgttctgggt gcgccaggcc 120
cctggcaaag gcctggaatg gatcagcggc atcagctgga acagcgccac catcggctac 180
gccgatagcg tgaagggccg gttcaccatc agccgggaca acgccaagaa gtccctggac 240
ctgcagatga acagcctgcg gcctgatgac accgccctgt actattgtgc caagggcgga 300
cctcgtggcc tgcagctgct gagtagctgg gtggagtatt tgggccaggg caccctcgtg 360
accgtgtcct cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420
agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 600
ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660
agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720
ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 780
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 840
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 900
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 960
ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 1020
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1080
tcccgggagg agatgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1140
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1200
acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 1260
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1320
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gatatccaga tgacccagag cccgagcagc ctgagcgcga gcgtgggtga tcgcgtgacc 60
attacctgcc gcgcgagcca ggatgtccgt agatacctga attggtatca gcagaaaccg 120
ggtaaagcgc cgaaactgtt aatttatact gccagcaccc gggagtctgg cgtgccgtcg 180
cgttttagcg gctcgggttc gggcaccgat tttaccctga ccatctcgag cttgcagccg 240
gaggacttcg ccacctacta ttgccagcaa gcggaccaga acccacagac cttcggtcag 300
ggcaccaaag tggagatcaa acgtacggtg gcggcgccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggtaccgct agcgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttga 645
Claims (14)
1.抗体,其特征在于:所述抗体的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ ID No.1自N端起第26-33位、第51-58位、第97-121位所示;所述抗体的轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.2自N端起第27-32位、第50-52位、第89-97位所示。
2.根据权利要求1所述的抗体,其特征在于:所述重链可变区的氨基酸序列为SEQ IDNo.1自N端起第1-121位;
所述轻链可变区的氨基酸序列为SEQ ID No.2自N端起第1-109位。
3.根据权利要求1或2所述的抗体,其特征在于:所述抗体为IgG。
4.根据权利要求3所述的抗体,其特征在于:所述IgG为IgG1。
5.根据权利要求1或2所述的抗体,其特征在于:所述抗体的轻链类型为kappa型。
6.根据权利要求1或2所述的抗体,其特征在于:所述抗体的重链的氨基酸序列为SEQID No.1;
所述抗体的轻链的氨基酸序列为SEQ ID No.2。
7.核酸分子,其特征在于:所述核酸分子编码权利要求1-6中任一所述的抗体或所述抗体中的抗原结合部分。
8.根据权利要求7所述的核酸分子,其特征在于:在所述核酸分子中,编码所述抗体的重链可变区中HCDR1、HCDR2和HCDR3的核苷酸序列依次如SEQ ID No.3自5’端起第76-99位、第151-174位、第289-363所示,编码所述抗体的轻链可变区中LCDR1、LCDR2和LHCDR3的核苷酸序列依次如SEQ ID No.4自5’端起第79-96位、第148-156位、第265-291位所示。
9.根据权利要求8所述的核酸分子,其特征在于:在所述核酸分子中,编码所述抗体的所述重链可变区的核苷酸序列为SEQ ID No.3自5’端起第1-363位,编码所述抗体的所述轻链可变区的核苷酸序列为SEQ ID No.4自5’端起第1-327位。
10.根据权利要求9所述的核酸分子,其特征在于:在所述核酸分子中,编码所述抗体的重链的核苷酸序列为SEQ ID No.3,编码所述抗体的轻链的核苷酸序列为SEQ ID No.4。
11.含有权利要求7-10中任一所述核酸分子的表达盒、重组载体、重组细胞或重组菌。
12.药物组合物,其特征在于:所述药物组合物包含权利要求1-6中任一所述的抗体和药学可接受的赋形剂、稀释剂或载体。
13.应用,为如下任一所示:
(A1)权利要求7-10中任一所述的核酸分子或权利要求11所述的表达盒、重组载体、重组细胞或重组菌在制备权利要求1-6中任一所述抗体或权利要求12所述药物组合物中的应用;
(A2)权利要求1-6中任一所述抗体在制备权利要求12所述药物组合物中的应用;
(A3)权利要求1-6中任一所述抗体或权利要求7-10中任一所述核酸分子或权利要求11所述的表达盒、重组载体、重组细胞或重组菌或权利要求12所述的药物组合物在制备用于预防和/或治疗由登革病毒感染所致疾病的产品中的应用;
(A4)权利要求1-6中任一所述抗体或权利要求7-10中任一所述核酸分子或权利要求11所述的表达盒、重组载体、重组细胞或重组菌或权利要求12所述的药物组合物在制备用于抑制登革病毒感染的产品中的应用;
(A5)权利要求1-6中任一所述抗体或权利要求7-10中任一所述核酸分子或权利要求11所述的表达盒、重组载体、重组细胞或重组菌或权利要求12所述的药物组合物在制备用于检测登革病毒的产品中的应用;
(A6)权利要求1-6中任一所述抗体或权利要求7-10中任一所述核酸分子或权利要求11所述的表达盒、重组载体、重组细胞或重组菌或权利要求12所述的药物组合物在制备用于结合登革病毒的产品中的应用;
(A7)权利要求1-6中任一所述抗体或权利要求7-10中任一所述核酸分子或权利要求11所述的表达盒、重组载体、重组细胞或重组菌或权利要求12所述的药物组合物在制备用于检测登革病毒的E蛋白的产品中的应用;
(A8)权利要求1-6中任一所述抗体或权利要求7-10中任一所述核酸分子或权利要求11所述的表达盒、重组载体、重组细胞或重组菌或权利要求12所述的药物组合物在制备用于结合登革病毒的E蛋白的产品中的应用。
14.根据权利要求13所述的应用,其特征在于:所述登革病毒为I型登革病毒、II型登革病毒、III型登革病毒和/或IV型登革病毒。
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