CN113563464A - 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 - Google Patents
人源化高中和活性抗新型冠状病毒单克隆抗体及应用 Download PDFInfo
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Abstract
本发明公开了一种人源化高中和活性抗新型冠状病毒单克隆抗体，本发明的中和抗体通过单个B细胞流式分选‑抗体基因扩增配对表达技术筛选获得，具有独特的CDR区域，能特异性与SARS‑COV‑2结合并且可以有效中和目前多株国际流行病毒(wuhan株，英国突变株B.1.1.7，南非突变株B.1.351，巴西突变株P.1，印度突变株B.1.617.1和B.1.617.2)，其IC50大部分在1μg/mL以下。本发明还涉及所述抗体制备新型冠状病毒病治疗或预防药物中的应用以及在制备新型冠状病毒检测试剂中的应用。所述抗体可以用于COVID‑19紧急预防和/或治疗，具有全人源化，高表达，稳定性好的特点，适合产业化。
Description
技术领域
本发明公开了一种多肽，更具体地，本发明公开一种抗体。
背景技术
SARS-Cov-2(也称为2019-nCov)属于正链RNA病毒的一种，属于冠状病毒家族的β属，其编码四种结构蛋白：spike(S),envelope(E),membrane(M),和nucleocapsid(N)、16种非结构蛋白，及5-8种辅助蛋白质。SARS Cov-2利用病毒表面的S蛋白与宿主细胞受体-血管紧张素转换酶II(ACE2)进入细胞。S蛋白根据蛋白结构功能又被分为两个功能单位，即S1和S2蛋白亚基。S1可分为NTD(N-terminal domain)和RBD(Receptor binding site)，RBD区域长约240个氨基酸，主要与宿主细胞受体结合，S2在病毒和细胞膜融合起作用。根据已有的报导，中和抗体主要作用于RBD区域，抗体结合于RBD，阻碍RBD与ACE2的结合，从而阻止病毒感染细胞。
目前国内外均有新冠中和抗体的分离研究报道，采用单细胞分选和抗体基因组深度测序方法，一批针对RBD的人源化单克隆抗体被分离出来，如1F11、2F6、CA1、CB6、BD-368-2等，这些抗体展现出了较强的体外中和活性(IC50<1μg/ml)，在表达ACE2的转基因小鼠动物体内也展现出了较好的治疗效果，可以显著降低小鼠肺部的病毒载量。但SARS-Cov-2处于不断变异中，一旦感染了中和表位发生变异的病毒，则已有的中和抗体将不再具有中和作用。事实上，已经有英国B.1.1.7突变株(N501Y、D614G)、巴西突变株P.1(N501Y、E484k、k417T、D614G)、南非突变株B.1.351(K417N、E484K、N501Y、D614G),印度突变株B.1.617(L452R、E484Q、D614G)相继出现，该三毒株对部分中和抗体或疫苗诱导出的抗体不敏感，且由于其较强的传播能力被世界卫生组织列为VOC(Variants of concern,受关注的变异病毒)。因此，有必要分离出更多的强效中和抗体作为备选，将这些针对不同表位的中和抗体进行各种配伍，探索鸡尾酒疗法，可以更有效地避免病毒发生免疫逃逸，目前科学界尚无已报道的类似广谱抗体以及抗体组合物。本发明的目的就是提供一组具有高中和活性抗新型冠状病毒单克隆抗体，在此基础上并提供所述高中和活性抗新型冠状病毒单克隆抗体在制备新冠病毒病治疗药物中的应用。
发明内容
基于上述发明目的，本发明首先提供了一种人源化广谱高中和活性抗新型冠状病毒单克隆抗体，所述抗体的重链可变区的CDR1、CDR2和CDR3以及轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如下所示：
(1)SEQ ID NO.1的第26-33、51-57和96-106位氨基酸以及SEQ ID NO.3的第27-32、50-52、89-97位氨基酸；或者
(2)SEQ ID NO.5的第26-33、51-57和96-106位氨基酸以及SEQ ID NO.7的第27-32、50-52和89-97位氨基酸；或者
(3)SEQ ID NO.9的第26-33、51-58和97-109位氨基酸以及SEQ ID NO.11的第27-32、50-52和89-97位氨基酸。
在一个优选的实施方案中，所述抗体重链的可变区以及轻链的可变区的氨基酸序列分别如下所示：
(1)SEQ ID NO.1以及SEQ ID NO.3；在本发明中，具有该重链的可变区以及轻链的可变区氨基酸序列的一个具体技术方案的抗体被命名为“SW-C11”，或者
(2)SEQ ID NO.5以及SEQ ID NO.7；在本发明中，具有该重链的可变区以及轻链的可变区氨基酸序列的一个具体技术方案的抗体被命名为“WJQ-G10”，或者
(3)SEQ ID NO.9以及SEQ ID NO.11，在本发明中，具有该重链的可变区以及轻链的可变区氨基酸序列的一个具体技术方案的抗体被命名为“WJQ-C11”。
在一个更为优选的实施方案中，所述抗体重链恒定区的氨基酸序列如SEQ IDNO.13所示，所述轻链恒定区的氨基酸序列如SEQ ID NO.15所示。
其次，本发明提供了一种编码上述人源化广谱高中和活性抗新型冠状病毒单克隆抗体的多核苷酸，编码所述抗体重链的可变区的多核苷酸以及编码所述抗体轻链的可变区的多核苷酸组合的序列分别如下所示：
(1)SEQ ID NO.2以及SEQ ID NO.4；或者
(2)SEQ ID NO.6以及SEQ ID NO.8；或者
(3)SEQ ID NO.10以及SEQ ID NO.12。
在一个优选的实施方案中，编码抗体重链恒定区的多核苷酸的序列如SEQ IDNO.14所示，所述轻链恒定区的多核苷酸的序列如SEQ ID NO.16所示。
第三，本发明还提供了一种表达上述人源化高中和活性抗新型冠状病毒单克隆抗体的载体，所述载体含有上述编码所述抗体重链的可变区的多核苷酸以及编码所述抗体轻链的可变区的多核苷酸，所述载体可以是基因工程中常规使用的真核表达载体，在本发明的一个具体实施方案中，所述载体为IgH(重链表达载体)、Igκ(κ轻链表达载体)(具体参见Tiller et al.Efficient generation of monoclonal antibodies from single humanB cells by single cell RT-PCR and expression vector cloning,J ImmunolMethods.2008January 1；329(1-2):112–124.，本发明通过引用将该现有技术文件并入到本发明的说明书中)。
第四，本发明提供了一种表达上述人源化高中和活性抗新型冠状病毒单克隆抗体的宿主细胞，所述宿主细胞含有上述的载体。
所述宿主细胞可以为基因工程中常规使用的真核宿主细胞，在本发明的一个具体实施方案中，所述宿主细胞为293F细胞。
第五，本发明提供了上述人源化高中和活性抗新型冠状病毒单克隆抗体在制备新型冠状病毒病治疗和/或预防药物中的应用，所述抗体或者抗体组合物可以开发临床治疗药物，靶向药物、SARS-COV-2重组蛋白及亚单位疫苗。
在一个优选的实施方案中，所述应用可以为含有至少两种抗体的组合物应用。本发明提供的3种抗体不仅具有高中和活性，而且还具有广谱性，对目前世界范围内的多种新冠病毒变异株都具有较强的中和能力，因此应用含有本发明至少两种以上的抗体组合物能够更有效地提升对新冠病毒多个变异株广谱的中和能力，因此含有本发明的抗体组合物形式在开发临床治疗药物，靶向药物、SARS-COV-2重组蛋白及亚单位疫苗具有广阔的应用前景，具体的应用可以包括SW-C11与WJQ-G10的组合应用，SW-C11与WJQ-C11的组合应用，WJQ-G10与WJQ-C11的组合应用，以及SW-C11、WJQ-G10和WJQ-C11的3株抗体的组合应用。
最后，本发明提供了上述人源化高中和活性抗新型冠状病毒单克隆抗体在制备新型冠状病毒检测试剂中的应用。
本发明提供的人源化高中和活性抗新型冠状病毒单克隆抗体通过单个B细胞流式分选-抗体基因扩增配对表达技术筛选获得，具有独特的CDR区域，能与SARS-COV-2特异性结合并且可以有效中和目前多株国际流行病毒(wuhan株，英国突变株B.1.1.7，南非突变株B.1.351，巴西突变株P.1，印度突变株B.1.617.1和B.1.617.2)，对世界范围内多个不同的新型冠状病毒代表株具有显著的广谱中和能力。因此本发明提供的抗体以及含有两种抗体的组合物可以用于制备COVID-19紧急预防和/或治疗药物，具有全人源化，高表达，稳定性好的特点，适合产业化。此外，该抗体还可用于制备SARS-COV-2病毒检测试剂，用于检测病毒抗原以及用于发现有效中和抗原表位。
附图说明
图1.生物素化RBD蛋白的效价检测结果图，其中A.磁珠法检测RBD生物素化效率；B.ELISA法检测生物素化效率；
图2.流式分选RBD特异性B细胞示意图；
图3.抗体针对RBD结合能力的ELISA结果图；
图4.采用BLI技术检测SW-C11抗体的抗体-抗原亲和力结果图；
图5.采用BLI技术检测WJQ-G10抗体的抗体-抗原亲和力结果图；
图6.采用BLI技术检测WJQ-C11抗体的抗体-抗原亲和力结果图；
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的权利要求所限定的保护范围构成任何限制。
实施例1：新冠病毒RBD探针的合成、表达和生物素化及染色
1.1依据Genbank公布的数据(NC_045512)，合成携带6×His-Avi(His-His-His-His-His-His-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-Asp-Ile-Thr-Asn-Trp-Leu-Trp-Tyr-ILe-Lys-Lys-Lys)标签的RBD全长基因序列。
1.2经EcoRI和EcoRV双酶切后重新连接入真核表达载体pDRVI1.0(发明人构建并保存)，挑选克隆后经测序无误。
1.3将两探针质粒分别转染293F细胞进行表达，5-6天后离心培养液收取细胞上清，过镍柱纯化抗原蛋白。
1.4使用BirA 500生物素蛋白连接酶试剂盒(BirA500，Avidity)对探针蛋白进行生物素化。
将1mg分子探针蛋白溶解于0.7mL PBS缓冲液中，分别加入0.1mL10×缓冲液A、0.1mL 10×缓冲液B，再加入4μL BirA 500酶，混匀，30℃孵育30分钟；将混合物转移至10K浓缩管中，加10mL PBS，离心4000g15min至剩余体积0.5mL，重复这一操作5次；收集浓缩后的蛋白并测定浓度，存放至-80℃冰箱。
1.5检测分子探针生物素化活性
采用60微升链霉素标记的琼脂糖+10微克蛋白+500微升PBS置室温振荡器中摇30min，短暂离心，用1ml的PBS洗3次，最后一次尽量将液体吸弃干净，最后剩下大概30微升的琼脂糖，同时准备30微升的2×SDS凝胶加样缓冲液(100mM pH6.8 Tris-HCl、4％SDS、0.2％溴酚兰、20％甘油、200mMβ-巯基乙醇)上样缓冲液，将琼脂糖和混合缓冲液1:1混在一起，吸取20微升置于100℃,5-10min然后进行SDS-PAGE电泳；电泳结束后加适量考马斯亮蓝染色1小时后置于振荡器中脱色后观察电泳条带的深浅，判定生物素标记的效率，至少在50％以上可考虑进行荧光标记。
采用酶联免疫吸附试验(Enzyme-linked Immunosorbent Assay，ELISA)检测两探针的生物素化活性。用PBS将新冠抗原稀释至2μg/mL，加入96孔ELISA板中，每孔100μL，置于4℃过夜，次日用PBST(含0.05％吐温20的PBS)洗3次；每孔加入370μL封闭液(含2％牛奶和5％FBS的PBS)室温封闭1小时，用PBST(含0.05％吐温20的PBS)洗3次；向每孔加入100μL封闭液，第一行每孔再加入25μL稀释好的生物素标记的探针蛋白(生物素化的探针蛋白贮存浓度为50μg/mL，使用前5倍稀释于封闭液中)，混匀后从第一行每孔吸出25μL加入到第二行中，混匀后吸出25μL加入到第三行中，依次直至最后一行吸出25μL丢掉(每行之间形成五倍稀释梯度)，37℃孵育1小时，用PBST(含0.05％吐温20的PBS)洗5次；将辣根过氧化物酶标记的链霉亲和素(Sigma KPL HRP-SA)1000倍稀释于含有0.05％吐温20的封闭液中，每孔加100μL，37℃孵育1小时，用PBST洗5次板；每孔加入100μL底物，室温孵育20分钟后每孔加入50μL硫酸终止液立即终止反应，在酶标仪上读数保存。图1为生物素化RBD蛋白的效价检测结果，其中A为磁珠法检测RBD生物素化效率，泳道1-2为链霉亲和素磁珠从10μg生物素后的RBD蛋白中捕获生物素化成功的RBD，泳道3为10μg生物素化RBD，泳道4为分子量标志；由图1A可以看出，RBD生物素化效率超过50％；B为ELISA法检测生物素化效率，探针的终末浓度(end titer)为0.0032μg/mL。由结果可以看出，RBD的生物素化成功。
1.6生物素化的探针蛋白进行荧光标记
RBD-Avi探针蛋白用PE(藻红蛋白)进行荧光标记，以备单细胞流式分选时使用。
实施例2:抗SARS-COV-2人源化单克隆抗体的筛选和鉴定
2.1配制细胞裂解液：每孔20μl细胞裂解液，包含0.5μl去RNA酶，5μl 5×FirstStrand缓冲液，1.25μL 0.1M DTT，0.0625μl Igepal，13.25μl水，盖好封板膜，4℃冰箱放置待用。
2.2样本准备：
(1)新冠感染后康复者PBMCs细胞复苏：将冻存细胞管从液氮拿出后，迅速置于37℃水浴中，待融化至有冰芯时拿出，在生物安全柜中打开，缓慢滴入R10+Benzonase培养基(1支细胞使用5mL R10+Benzonase培养基)。1500rpm离心10分钟，弃去上清，用残液悬起细胞，加入10mL R10，混匀，取50μl进行细胞计数，1500rpm离心10分钟；调整细胞浓度：弃去上清，用残液悬起细胞，使用R10培养基调整浓度，向96孔U型板中2.5×106个/孔；
(2)配制2mM的EDTA/PBS溶液，下文用E-PBS表示；
(3)将96孔细胞板置于离心机内，4℃，2000rpm离心3分钟，弃去上清(生物安全柜内操作，纸巾高压放台内)；
(4)每孔加入50μl Vivid工作液(配制Vivid(UV)工作液：1:1000用PBS稀释，混匀)，混匀，避光冰上孵育20分钟；
(5)每孔加入150μl E-PBS，4℃，2000rpm离心3分钟；
(6)弃去上清，加入50μl胞外抗体混合液(2μl Anti-CD3-Alexflour700，1.5μlAnti-CD8-Pacific Blue，1.5μl Anti-CD14-Pacific Blue，1μl Anti-CD19-PECy7，2.5μlAnti-CD20-ECD，2μl Anti-CD27-APCCy7，1μl Anti-IgG-FITC，1μl Anti-IgM-PECy5，5μlAnti-RBD-PE，不足用E-PBS补齐)，混匀，避光冰上孵育60分钟；
(7)每孔加入150μL E-PBS，4℃，2000rpm离心3分钟，弃去上清；
(8)每孔加入200μL E-PBS，4℃，2000rpm离心3分钟，弃去上清；
(9)每孔加入200μL E-PBS，混匀，同一样本细胞悬液过滤到同一支流式管内，4℃避光保存供分选。
(10)单染管对照：设置1个未染色管对照(加入1滴补偿微球，200μl E-PBS)和10个单独染色管(每管加入补偿微球1滴，分别加入2μl Anti-CD3-Alexflour 700，1.5μl Anti-CD8-Pacific Blue，1.5μl Anti-CD14-Pacific Blue，1μl Anti-CD19-PECy7，2.5μl Anti-CD20-ECD，2μl Anti-CD27-APCCy7，1μl Anti-IgG-FITC，1μl Anti-IgM-PECy5，5μl Anti-RBD-PE，50μl UV工作液)，混匀，避光冰上孵育20分钟后每孔加入150μl E-PBS，4℃，2000rpm离心3分钟，弃上清，200μl E-PBS重悬。
2.3单个B细胞流式分选：选择CD3-CD8-CD14-CD19+CD20+CD27+IgG+IgM-RBD+的细胞进行分选，合计分选到56个细胞。首选圈定出单淋巴细胞群，再圈定出CD3-CD8-CD14-的活细胞以排除T细胞和巨噬细胞，再圈出CD19+CD20+的B细胞，再圈定出CD27+的记忆B细胞，再圈出IgG+IgM-的B细胞，最后圈出与探针RBD结合的记忆性B细胞。将这些B细胞每孔1个分选入含有以下裂解液体系的96孔板中(表1)。分选结束后，立刻用封口膜封好96孔板，在干冰上凝固，再转移入-80℃冰箱，过夜，第二天进行PCR操作。结果：流式分选的结果如图2所示。
表1.B细胞裂解液体系
2.4利用RT-PCR技术扩增全人源抗体可变区基因
配置如表2所示RT-PCR反应体系，每孔加入6μl，进行RT-PCR反应
表2.RT-PCR反应体系
RT-PCR反应程序设定：42℃反应10min，25℃反应10min，50℃反应50min，94℃反应5min，4度保存。
(1)进行两轮PCR反应，反应体系如下
第一轮PCR反应体系(表3)补充引物序列(表4)
表3.第一轮PCR反应体系
表4.第一轮PCR扩增用引物序列如下
第一轮PCR扩增用引物的扩增目的片段如表5所示。
表5.第一轮PCR扩增用引物的扩增目的片段
第一轮PCR反应程序如表6所示。
表6.第一轮PCR程序
第一轮PCR反应结束后进行第二轮PCR反应，第二轮PCR反应体系如表7所示。
表7.第二轮PCR反应体系
第二轮PCR引物序列如表8所示。
表8.第二轮PCR引物序列
第二轮PCR扩增用引物的扩增目的片段如表9所示。
表9.第二轮PCR扩增用引物的扩增目的片段
第二轮PCR反应程序如表10所示。
表10.第二轮PCR程序
(2)电泳、测序、家系分析
电泳检测二轮PCR产物，将重链和轻链产物直接测序；使用抗体家系基因数据库(http://www.imgt.org/IMGT_vquest/vquest)对测序结果进行分析，设计并合成带有酶切位点的抗体可变区序列(重链：5‘-Age I，3’-Sal I；Kappa链：5‘-Age I，3‘-BsiW I；Lambda链：5‘-Age I，3’-Xho I)，共计获得97对重链和轻链配对克隆。
2.5单克隆抗体表达载体构建和质粒转化
将合成的基因用相应的酶进行酶切后再次凝胶电泳回收，使用T4DNA连接酶将可变区基因与相应载体IgH(重链表达载体)、Igκ(κ轻链表达载体)、Igλ(λ轻链表达载体)(具体参见Tiller et al.Efficient generation of monoclonal antibodies from singlehuman B cells by single cell RT-PCR and expression vector cloning,J ImmunolMethods.2008January 1；329(1-2):112–124.，本发明通过引用将该现有技术文件并入到本发明的说明书中)在16℃连接仪上连接过夜16℃水浴过夜，转化。将10μL连接产物加入50μL DH5α感受态细胞中，振动摇匀，冰浴30分钟，42℃水浴热激45秒。离心管放入冰浴2分钟后，加入1mL无抗性的LB培养基，37℃，200rpm振荡培养1小时，4000rpm离心4分钟，将残留菌液涂布在抗性的LB平板上。37℃倒置培养14-16小时。挑取单克隆菌落接种到抗性的LB液体培养基中，37℃，200rpm振荡培养14-16小时后进行质粒提取(Omega公司的Plasmid MidiKit)。
2.6抗体表达和纯化
将293F细胞浓度调整为1.2×106个/ml，培养2小时。配置A液：25ml的opti-MEM加入500μg抗体重链DNA和500μg抗体轻链DNA，B液：25ml的opti-MEM中加入5ml的PEI转染试剂，静置5分钟。将A和B液混合，静置20分钟，逐滴加入1L的293F细胞中，边滴边摇匀，置于8％CO2，37℃下，摇动培养5天。
利用Protein A亲和柱(GE health公司产品)纯化得到抗体。利用NanoDrop2000超微量分光光度计(Thermo公司产品)测定抗体浓度，4℃放置待检测。本步骤从97个抗体轻/重链配对中表达出61个抗体(抗体量>10μg,抗体浓度>10μg/mL)。
实施例3抗体对SARS-COV-2假病毒的中和活性测定
3.1假病毒的包装：人工合成SARS-CoV-2(GenBank:MN908947)的S蛋白基因全长插入pcDNA3.1表达质粒，构建pcDNA-SARS-CoV2-S。带有突变的假病毒突变位点如表11所示，在S基因上引入。
表11.假病毒突变位点
将3×106(300万)个293T/17细胞接种于T75细胞培养瓶，5％CO2 37℃培养20-24小时。使用Fugene 6Transfection Reagent(Promega,Cat#E2691)进行转染：将30ug质粒pcDNA-SARS-CoV2-S转染T75培养瓶中的293T细胞，同时加入1.05×106TCID50的G*ΔG-VSV病毒感染293T，8小时后更换培养基。转染24小时后，收集培养上清并过滤获得SARS-CoV2 S蛋白的假病毒，-80℃冷冻保存。
3.2中和实验：
在一块96孔板中每孔加入100μL梯度稀释的抗体稀释液随后，用DMEM完全培养基将假病毒稀释至1.3×104TCID50/mL，于第3-11列每孔加50μL，使假病毒的加入量为650TCID50/孔。将上述96孔板置于细胞培养箱中(37℃、5％CO2)孵育1小时。当孵育时间至半小时，取出准备好的Vero细胞，吸弃培养基，加入PBS缓冲液清洗细胞，弃去PBS，加入胰酶-EDTA消化离心后，加入完全培养基重悬细胞，细胞计数。将细胞悬液稀释至2×105个/mL。孵育至1小时，向96孔板中每孔加100μL细胞，使每孔细胞为2×104个。将96孔板前后左右轻轻晃动，使细胞在孔中分散均匀，将96孔板放入细胞培养箱中，37℃、5％CO2培养28小时。从细胞培养箱中取出96孔板，用多道移液器从每个上样孔中吸弃150μL上清，然后加入100μL荧光素酶检测试剂，室温避光反应2分钟。反应结束后，于平板振荡器震荡混匀，放入多功能读板机中读取发光值。
计算中和抑制率：根据中和抑制率结果，计算抗体的IC50。
从61个测试抗体中，我们筛选出3株针对新冠南非突变株、新冠巴西变异株、新冠英国变异株、新冠印度变异株、新冠武汉株假病毒均具备较强中和活性的广谱中和抗体，所述3株抗体的编号分别为SW-C11、WJQ-G10和WJQ-C11。3株抗体针对不同变异株假病毒的中和能力结果见表12。
表12.抗体针对不同变异株假病毒的中和能力(IC50，μg/mL)
通过对编码上述抗体株的克隆进行测序，所述3株抗体的氨基酸及核苷酸序列如下：
抗体SW-C11的重链可变区核苷酸序列如SEQ ID NO.2所示，重链可变区的氨基酸序列如SEQ ID NO.1所示，其中，重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQID NO.1的第26-33、51-57和96-106位氨基酸所示；轻链可变区核苷酸序列如SEQ ID NO.4所示，轻链可变区的氨基酸序列如SEQ ID NO.3所示，其中，轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.3的第27-32、50-52、89-97位氨基酸所示。
抗体WJQ-G10的重链可变区核苷酸序列如SEQ ID NO.6所示，重链可变区的氨基酸序列如SEQ ID NO.5所示，其中，重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQID NO.5的第26-33、51-57和96-106位氨基酸所示；轻链可变区核苷酸序列如SEQ ID NO.8所示，轻链可变区的氨基酸序列如SEQ ID NO.7所示，其中，轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.7的第27-32、50-52、89-97位氨基酸所示。
抗体WJQ-C11的重链可变区核苷酸序列如SEQ ID NO.10所示，重链可变区的氨基酸序列如SEQ ID NO.9所示，其中，重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQID NO.9的第26-33、51-58和97-109位氨基酸所示；轻链可变区核苷酸序列如SEQ ID NO.12所示，轻链可变区的氨基酸序列如SEQ ID NO.11所示，其中，轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.11的第27-32、50-52、89-97位氨基酸所示。
上述3株抗体享有相同的重链恒定区和轻链恒定区。所述重链恒定区的核苷酸序列如SEQ ID NO.14所示，所述重链恒定区的氨基酸序列如SEQ ID NO.13所示，所述轻链为Kappa型，其恒定区的核苷酸序列如SEQ ID NO.16所示，所述重链恒定区的氨基酸序列如SEQ ID NO.15所示.
实施例4：抗体对活病毒的中和实验
提前1天将Vero-E6细胞按照25000/孔的细胞数接种于48孔板，用含10％FBS和双抗的MEM培养基培养。
抗体配置：用含5％FBS和双抗的MEM培养基稀释抗体。按照48孔板最终体积500μL/孔、每个浓度3个复孔计算，每个浓度的抗体配置750μL(250μL/孔)，按照实际作用浓度的2倍配置抗体。从最高浓度开始，按照一定倍数(如3倍)进行倍比稀释。同时，设置相应的阳性和阴性对照。将配置好的抗体加入48孔板，带入P3实验室。
将新冠病毒储存液按照MOI＝100比例用含5％FBS的MEM培养基稀释，按照1：1的体积比将病毒液(250μL/孔)加入配置好的抗体，37℃孵育3小时。将对数生长期的Vero-E6细胞板上清吸净，加入孵育好的抗体病毒混合液(500μL/孔)，37℃培养7天。后续检测：观察细胞病变，推算中和百分比为50％的中和抗体的浓度，计为IC50。结果见表13。三种单抗均能有效中和武汉株活病毒和印度变异株活病毒，SW-C11和WJQ-G10对武汉、巴西、南非、印度变异株均有良好的中和作用；SW-C11中和武汉和印度毒株能力最强，IC50可分别达到0.0173μg/mL和0.0056μg/mL。
表13.抗体针对活病毒的中和能力(IC50,μg/mL)
实施例5抗体结合能力测定
通过ELISA方法测定所述3种抗体的抗原结合能力。将RBD蛋白(NC_045512)用PBS稀释至2μg/ml，每孔100μl包被96孔ELISA板(Corning Costar公司)，4℃过夜。用PBS-T溶液(0.05％吐温-20)洗板5次；每孔加入250μl封闭液(PBS，2％BSA+5％脱脂奶粉)室温封闭1小时。PBS-T洗板3次。将抗体以10μg/ml为起始浓度，用封闭液进行5倍系列稀释，分别取100μl样本加入到ELISA板中，37℃孵育1小时。PBS-T洗板5次。每孔加入100μl用封闭液1：5000稀释后的辣根酶标记的山羊抗人IgG(H+L)(北京中杉金桥生物技术有限公司)，37℃孵育1小时。PBS-T洗板5次。加入TMB显色溶液(北京金豪制药股份有限公司)100μl，室温避光显色20分钟。每孔加入50μl终止液(北京金豪制药股份有限公司)终止反应，酶标仪读取450nm波长的吸光度值(OD)结果如图3所示，图3中VRC01为抗HIV中和抗体，作为阴性对照。并计算End-titer值如下表14所示。
表14.中和抗体的End-titer值
实施例6抗原-抗体亲和力动力学测定
利用Octet Red 96系统(Fortebio,USA)和链霉亲和素传感器，采用BLI技术对SW-C11、WJQ-G10、WJQ-C11与RBD蛋白(NC_045512)的亲和力进行检测，用PBST(含有0.02％吐温20和0.1％牛血清白蛋白的PBS)将SARS-Cov-2的生物素化RBD稀释至5μg/mL的浓度，然后固定到链霉亲和素生物传感器(Sartorius AG，Germany)上60秒。在用PBST进行60秒洗涤步骤后，将生物传感器探针浸入含有连续稀释抗体(500nM、250nM、125nM、62.5nM、31.25nM、15.625nM和7.8125nM)的孔中并结合120秒，然后进行300秒解离步骤。KD值采用数据分析软件9.0中的1:1结合模型计算。得出WJQ-G10的亲和力常数为(1.37×10-9±3.53×10-11)M，WJQ-C11的亲和力常数为(5.29×10-9±6.16×10-11)M,SW-C11与RBD的亲和力常数KD<10-12M(10-12M为BLI技术测定的亲和力下限)，结果如图4-图6所示。显示这3个抗体针对RBD具有极强的亲和力。
序列表
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<120> 人源化高中和活性抗新型冠状病毒单克隆抗体及应用
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<212> PRT
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<212> DNA
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aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 660
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 720
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 780
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<212> PRT
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Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
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<212> DNA
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aacagaggag aatgc 315
Claims (11)
1.一种人源化高中和活性抗新型冠状病毒单克隆抗体及应用，其特征在于，所述抗体的重链可变区的CDR1、CDR2和CDR3以及轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如下所示：
(1)SEQ ID NO.1的第26-33、51-57和96-106位氨基酸以及SEQ ID NO.3的第27-32、50-52、89-97位氨基酸；或者
(2)SEQ ID NO.5的第26-33、51-57和96-106位氨基酸以及SEQ ID NO.7的第27-32、50-52和89-97位氨基酸；或者
(3)SEQ ID NO.9的第26-33、51-58和97-109位氨基酸以及SEQ ID NO.11的第27-32、50-52和89-97位氨基酸。
2.根据权利要求1所述的单克隆抗体，其特征在于，所述抗体重链的可变区以及轻链的可变区的氨基酸序列分别如下所示：
(1)SEQ ID NO.1以及SEQ ID NO.3；或者
(2)SEQ ID NO.5以及SEQ ID NO.7；或者
(3)SEQ ID NO.9以及SEQ ID NO.11。
3.根据权利要求2所述的单克隆抗体，其特征在于，所述抗体重链恒定区的氨基酸序列如SEQ ID NO.13所示，所述轻链恒定区的氨基酸序列如SEQ ID NO.15所示。
4.一种编码权利要求2或3所述人源化广谱高中和活性抗新型冠状病毒单克隆抗体的多核苷酸，其特征在于，编码所述抗体重链的可变区的多核苷酸以及编码所述抗体轻链的可变区的多核苷酸组合的序列分别如下所示：
(1)SEQ ID NO.2以及SEQ ID NO.4；或者
(2)SEQ ID NO.6以及SEQ ID NO.8；或者
(3)SEQ ID NO.10以及SEQ ID NO.12。
5.根据权利要求4所述的编码单克隆抗体的多核苷酸，其特征在于，编码抗体重链恒定区的多核苷酸的序列如SEQ ID NO.14所示，所述轻链恒定区的多核苷酸的序列如SEQ IDNO.16所示。
6.一种表达权利要求2或3所述人源化高中和活性抗新型冠状病毒单克隆抗体的载体，其特征在于，所述载体含有权利要求4所述编码所述抗体重链的可变区的多核苷酸以及编码所述抗体轻链的可变区的多核苷酸。
7.一种表达权利要求2或3所述人源化高中和活性抗新型冠状病毒单克隆抗体的宿主细胞，其特征在于，所述宿主细胞含有权利要求6所述的载体。
8.根据权利要求7所述的宿主细胞，其特征在于，所述宿主细胞为293F细胞。
9.权利要求1-3任一所述的人源化高中和活性抗新型冠状病毒单克隆抗体在制备新型冠状病毒病治疗和/或预防药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述应用为含有至少两种抗体的组合物应用。
11.权利要求1-3任一所述的人源化高中和活性抗新型冠状病毒单克隆抗体在制备新型冠状病毒检测试剂中的应用。
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| CN114044821A (zh) * | 2022-01-10 | 2022-02-15 | 中国人民解放军军事科学院军事医学研究院 | 一种抗新冠病毒全人源广谱中和抗体zwc12及应用 |
| CN114106166A (zh) * | 2022-01-29 | 2022-03-01 | 中国疾病预防控制中心病毒病预防控制所 | 人源抗新冠病毒中和性抗体d2及其应用 |
| CN114316040A (zh) * | 2022-03-02 | 2022-04-12 | 南昌大学 | 一种抗新型冠状病毒的全人源单克隆抗体及其用途 |
| CN114426577A (zh) * | 2022-02-07 | 2022-05-03 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化广谱抗新型冠状病毒单克隆抗体及应用 |
| CN114790240A (zh) * | 2022-06-10 | 2022-07-26 | 郑州大学 | SARS-CoV-2中和性单克隆抗体及应用 |
| CN114805562A (zh) * | 2022-05-07 | 2022-07-29 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化纳米抗体及其应用 |
| CN114805557A (zh) * | 2021-12-31 | 2022-07-29 | 中国科学院微生物研究所 | 人源化抗SARS-CoV-2单克隆抗体及其应用 |
| CN114989292A (zh) * | 2021-11-25 | 2022-09-02 | 浙江安维珞诊断技术有限公司 | 一种抗SARS-CoV-2全人源化单克隆抗体及应用 |
| WO2023011147A1 (zh) * | 2021-08-01 | 2023-02-09 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
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| WO2023011147A1 (zh) * | 2021-08-01 | 2023-02-09 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
| CN114989292A (zh) * | 2021-11-25 | 2022-09-02 | 浙江安维珞诊断技术有限公司 | 一种抗SARS-CoV-2全人源化单克隆抗体及应用 |
| CN114989292B (zh) * | 2021-11-25 | 2023-01-06 | 浙江安维珞诊断技术有限公司 | 一种抗SARS-CoV-2全人源化单克隆抗体及应用 |
| WO2023102692A1 (zh) * | 2021-12-06 | 2023-06-15 | 广州医科大学附属市八医院 | 协同中和新型冠状病毒的人源抗体和抗体组合及其应用 |
| CN114805557A (zh) * | 2021-12-31 | 2022-07-29 | 中国科学院微生物研究所 | 人源化抗SARS-CoV-2单克隆抗体及其应用 |
| CN114805557B (zh) * | 2021-12-31 | 2023-07-21 | 中国科学院微生物研究所 | 人源化抗SARS-CoV-2单克隆抗体及其应用 |
| CN114044821A (zh) * | 2022-01-10 | 2022-02-15 | 中国人民解放军军事科学院军事医学研究院 | 一种抗新冠病毒全人源广谱中和抗体zwc12及应用 |
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| CN114805562A (zh) * | 2022-05-07 | 2022-07-29 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化纳米抗体及其应用 |
| CN114790240A (zh) * | 2022-06-10 | 2022-07-26 | 郑州大学 | SARS-CoV-2中和性单克隆抗体及应用 |
| CN114790240B (zh) * | 2022-06-10 | 2023-06-06 | 郑州大学 | SARS-CoV-2中和性单克隆抗体及应用 |
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