CN112625125B - 一株中和新型冠状病毒感染的单抗 - Google Patents
一株中和新型冠状病毒感染的单抗 Download PDFInfo
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Abstract
本发明公开了一株中和新型冠状病毒感染的单抗。本发明提供了一种抗体，其轻链可变区的氨基酸序列为序列表中序列2第1‑110位；其重链可变区的氨基酸序列为序列表中序列4第1‑120位。本发明鉴定出单抗N5对新型冠状病毒的S蛋白RBD(受体结合区)具有较强的结合特异性和亲和力，体外中和实验表明N5可有效中和新型冠状病毒SARS‑CoV‑2的感染活性。在此基础上，本发明对N5抗体的基因序列进行了测定，进而进行重组表达，表达出的重组抗体同样具有SARS‑CoV‑2的中和活性。
Description
技术领域
本发明属于生物技术领域，尤其涉及一株中和新型冠状病毒感染的单抗。
背景技术
新型冠状病毒属于冠状病毒科,目前已被命名为SARS-CoV-2,人群普遍易感,目前已在全球范围内造成了7000万余人的感染,死亡30万例。新冠病毒传播性强，严重危害人民健康，并极易造成社会恐慌。在年老体弱、免疫力低下的人群中，更易出现重症及高致死率。对于重症病例，目前仍没有特异性的治疗手段，新冠病人恢复期血清疗法是有效治疗的手段之一。研制特异性的治疗抗体对感染的病人的应急治疗中具有明确的、立竿见影的治疗效果，更具有临床应用价值。
发明内容
本发明的一个目的是提供一种抗体。
本发明提供的一种抗体，所述抗体的轻链可变区中LCDR1、LCDR2和LCDR3的氨基酸序列依次如序列2或序列6的第27-36位、第54-56位和第93-101位所示；
所述抗体的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如序列4或序列8的第25-48位、第50-57位和第96-109位所示。
上述抗体中，所述轻链可变区的氨基酸序列为序列表中序列2第1-110位(或序列6第1-110位)，或与序列2第1-110位(或序列6第1-110位)具有99％以上、95％以上、90％以上、85％以上、80％以上或者75％以上的一致性的序列；
所述重链可变区的氨基酸序列为序列表中序列4第1-120位(或序列8第1-120位)，或与序列4第1-120位(或序列8第1-120位)具有99％以上、95％以上、90％以上、85％以上、80％以上或者75％以上的一致性的序列。
上述抗体中，所述抗体的重链的类型为IgG1；所述抗体的轻链的类型为Kappa链。
上述抗体中，所述抗体的轻链恒定区和所述抗体的重链恒定区为人源或鼠源。
所述轻链恒定区的氨基酸序列为序列表中序列2第111-218位或与序列2第111-218位具有99％以上、95％以上、90％以上、85％以上、80％以上或者75％以上的一致性的序列；
或，所述轻链恒定区的氨基酸序列为序列表中序列6第111-218位或与序列6第111-218位具有99％以上、95％以上、90％以上、85％以上、80％以上或者75％以上的一致性的序列；
所述重链恒定区的氨基酸序列为序列表中序列4第121-444位或与序列4第121-444位具有99％以上、95％以上、90％以上、85％以上、80％以上或者75％以上的一致性的序列；
所述重链恒定区的氨基酸序列为序列表中序列8第121-450位或与序列8第121-450位具有99％以上、95％以上、90％以上、85％以上、80％以上或者75％以上的一致性的序列。
所述抗体为鼠源单克隆抗体或人源化人鼠嵌合抗体。
本发明所述抗体的重链可以是任何类别，如IgG、IgM、IgE、IgA或IgD。优选IgG1亚型。本发明所述抗体的轻链类型可以是κ链，也可以是λ链，优选为Kappa链。
在本发明的具体实施方式中，所述抗体具体为单克隆抗体N5和人源化人鼠嵌合抗体ch-N5。
编码所述抗体的核酸分子也是本发明保护的范围。
编码鼠源单克隆抗体N5轻链的核苷酸序列为序列表中序列1所示，其中，序列1第1-330位所示的核苷酸编码鼠源单克隆抗体N5轻链可变区，79-108为LCDR1基因，160-168为LCDR2基因，277-303为LCDR3基因，序列1第331-654位所示的核苷酸编码鼠源单克隆抗体N5轻链恒定区；
编码鼠源单克隆抗体N5重链的核苷酸序列为序列表中序列3所示，其中，序列3第1-360位所示的核苷酸编码鼠源单克隆抗体N5重链可变区，其中73-96为HCDR1区，148-171是HCDR2,286-327是HCDR3,序列3第361-1332位所示的核苷酸编码鼠源单克隆抗体N5重链恒定区。
编码人源化人鼠嵌合抗体ch-N5轻链的核苷酸序列为序列5，序列5第1-330位为鼠源单克隆抗体N5的轻链可变区编码基因，79-108为LCDR1基因，160-168为LCDR2基因，277-303为LCDR3基因，序列5第331-654位为人轻链恒定区编码基因(轻链类型为κ链)组成。
编码人源化人鼠嵌合抗体ch-N5重链的核苷酸序列为序列7，序列7第1-360位为鼠源单克隆抗体N5的重链可变区编码基因，73-96为HCDR1区，148-171是HCDR2，286-327是HCDR3,序列7第361-1350位为人重链恒定区编码基因(重链类型为IgG1)组成，且N5的重链可变区编码基因最后一位核苷酸紧邻人重链恒定区基因第一位核苷酸。
含有上述核酸分子的表达盒、重组载体或重组菌或重组病毒也是本发明保护的范围。
上述抗体、上述核酸分子或上述表达盒、重组载体或重组菌或重组病毒在具有如下1)-4)中至少一种功能或制备具有如下1)-4)至少一种功能的产品中的应用也是本发明保护的范围：
1)治疗或抑制冠状病毒；
2)中和冠状病毒；
3)结合冠状病毒的S蛋白；
4)阻断冠状病毒S蛋白与被侵染宿主细胞表面ACE2的结合。
本发明还有一个目的是提供一种具有如下1)-4)中至少一种功能产品。
本发明提供的产品，其包括上述抗体、上述核酸分子或上述表达盒、重组载体或重组菌或重组病毒；
1)治疗或抑制冠状病毒；
2)中和冠状病毒；
3)结合冠状病毒的S蛋白；
4)阻断冠状病毒S蛋白与被侵染宿主细胞表面ACE2的结合；具体是通过竞争结合S蛋白阻断S蛋白与宿主细胞表面ACE2的结合。
上述中，所述冠状病毒为新冠病毒。在本发明的实施例中S蛋白以新型冠状病毒S-RBD蛋白为例。
本发明制备出一种单克隆抗体N5，并将其人源化制备出人源化人鼠嵌合抗体ch-N5。经过鉴定单抗N5对新型冠状病毒的S蛋白RBD(受体结合区)具有较强的结合特异性和亲和力，体外中和实验表明单抗N5可有效中和新型冠状病毒SARS-CoV-2的感染活性。在此基础上，本发明对N5抗体的基因序列进行了测定，进而进行重组表达，表达出的重组抗体人源化人鼠嵌合抗体ch-N5同样具有SARS-CoV-2的中和活性。
附图说明
图1为N5抗体与新冠病毒S蛋白RBD区的结合活性分析。
图2为竞争ELISA检测N5抗体对新冠病毒S蛋白与ACE2受体结合的抑制活性。
图3为细胞病变法检测N5抗体对新型冠状病毒体外感染的中和活性。
图4为鼠源单抗N5的体外中和活性。
图5为人源化人鼠嵌合抗体N5与S蛋白RBD区结合亲和力分析。
图6为基因工程人源化人鼠嵌合抗体Ch-N5的中和活性。
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。
实施例1、单克隆抗体N5及人源化人鼠嵌合抗体ch-N5的制备
一、单克隆抗体N5的制备
1、单克隆抗体N5的发现
将SARS-CoV-2病毒的S蛋白(100ug/ml)，用等体积弗氏完全佐剂乳化后作为免疫原，采用背部皮下多点注射12周的雌性Balb/C健康小鼠(购自军事医学科学院实验动物中心)，注射剂量为每只小鼠注射0.4mL免疫原。免疫雌性Balb-c小鼠，共免疫3次，每次间隔2周。从第2次加强免疫开始，每次免疫后第3天，从小鼠眼眶采血，测定抗体效价，选择血清效价最佳的小鼠，解剖小鼠取脾脏制备脾细胞悬液，在37℃温箱中用DMEM完全培养液培养5天。将小鼠骨髓瘤细胞SP2/0与脾细胞融合培养制备可分泌抗SARS-CoV-2病毒的S蛋白的杂交瘤细胞。从中筛选出N5细胞株具有较高的结合活性，该细胞株表达单克隆抗体N5。
经过测定，该鼠源单克隆抗体N5中轻链的氨基酸序列如序列表中序列2所示，重链的氨基酸序列为序列表中序列4所示，鼠源单克隆抗体N5的重链类型为IgG1，轻链类型为κ链。
其中，序列2的第1-110位为轻链可变区，其中第27-36位为LCDR1,54-56为LCDR2,93-101位为LCDR3,序列2的第111-218位为轻链恒定区，
序列4的第1-120位为重链可变区，其中第25-48为HCDR1区，50-57是HCDR2,96-109是HCDR3，序列4的第121-444位为重链恒定区。
编码鼠源单克隆抗体N5轻链的核苷酸序列为序列表中序列1所示，其中，序列1第1-330位所示的核苷酸编码鼠源单克隆抗体N5轻链可变区，其中，第79-108为LCDR1编码核酸，160-168为LCDR2编码核酸，277-303为LCDR3编码核酸，序列1第331-654位所示的核苷酸编码鼠源单克隆抗体N5轻链恒定区；
编码鼠源单克隆抗体N5重链的核苷酸序列为序列表中序列3所示，其中，序列3第1-360位所示的核苷酸编码鼠源单克隆抗体N5重链可变区，其中，73-96为HCDR1区编码核酸，148-171是HCDR2编码核酸,286-327是HCDR3编码核酸,序列3第361-1332位所示的核苷酸编码鼠源单克隆抗体N5重链恒定区。
2、单克隆抗体N5的制备
将编码鼠源单克隆抗体N5的重链的核苷酸序列(序列3)插入pcDNA3.1表达载体(Invitrogen，V790-20)HindIII和NheI双酶切位点间，构建鼠源单克隆抗体N5重链的表达载体pcDNA3.1-N5H-鼠；
将编码鼠源单克隆抗体N5的轻链的核苷酸序列(序列1)插入pcDNA3.1表达载体(Invitrogen，V790-20)HindIII和NheI双酶切位点间，构建鼠源单克隆抗体N5轻链的表达载体pcDNA3.1-N5L-鼠；
将pcDNA3.1-N5H-鼠和pcDNA3.1-N5L-鼠等比例(等质量)混合后，转染HEK293(ATCC,A093)细胞，得到重组细胞。
然后将重组细胞放入37℃、5％CO2培养箱中培养。72h后培养上清。
利用Protein A亲和层析柱从培养上清中纯化抗体蛋白。具体操作是：先用PBS平衡Protein A柱(GE公司)，然后培养上清过柱，先采用A液(配方：溶剂为水，溶质及浓度为：20mM磷酸钠、500mM NaCl，pH5.0)预洗脱5个柱体积，再采用B液(配方：溶剂为水，溶质及浓度为：20mM醋酸钠、150mM NaCl，pH3.5)洗脱5个柱体积，收集洗脱峰，然后30KDa浓缩离心管浓缩获得所述抗体即获得鼠源单克隆抗体N5。
对鼠源单克隆抗体N5进行测序，结果显示，鼠源单克隆抗体N5为完整抗体，该抗体轻链的氨基酸序列如序列表中序列2所示，重链的氨基酸序列为序列表中序列4所示，鼠源单克隆抗体N5重链类型为IgG1，轻链类型为κ链。
抗体N5的轻链可变区中LCDR1、LCDR2和LCDR3的氨基酸序列依次如序列2第27-36位、第54-56位和第93-101位所示；抗体的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如序列4第25-48位、第50-57位和第96-109位所示。抗体N5的轻链恒定区的氨基酸序列为序列表中序列2第111-218位，抗体N5的重链恒定区的氨基酸序列为序列表中序列4第121-444位。
二、人源化人鼠嵌合抗体ch-N5的制备
1、人源化人鼠嵌合抗体ch-N5的制备
将编码鼠源单克隆抗体N5的可变区基因克隆至人抗体恒定区编码基因上游，构建人源化人鼠嵌合抗体表达载体并利用HEK293细胞实现瞬时表达纯化，制备人源化人鼠嵌合抗体ch-N5。具体如下：
将编码人源化人鼠嵌合抗体ch-N5轻链的核苷酸序列(序列5)插入pcDNA3.1表达载体(Invitrogen，V790-20)HindIII和NheI双酶切位点间，构建ch-N5抗体轻链表达载体pcDNA3.1-N5L；
序列5中，第1-330位为鼠源单克隆抗体N5的轻链可变区编码基因，序列5第331-654位为人轻链恒定区编码基因(轻链类型为κ链)组成。
将编码人源化人鼠嵌合抗体ch-N5重链的核苷酸序列(序列7)插入pcDNA3.1表达载体(Invitrogen，V790-20)HindIII和NheI双酶切位点间，构建ch-N5抗体重链表达载体pcDNA3.1-N5H；
序列7中，第1-360位为鼠源单克隆抗体N5的重链可变区编码基因，序列7第361-1350位为人重链恒定区编码基因(重链类型为IgG1)。
将ch-N5抗体轻链表达载体pcDNA3.1-N5L和ch-N5抗体重链表达载体pcDNA3.1-N5H等比例(等质量)混合后，转染HEK293(ATCC,A093)细胞，得到重组细胞。
然后将重组细胞放入37℃、5％CO2细胞培养箱中培养，72h后收集细胞培养上清。
利用Protein A亲和层析柱从培养上清中纯化抗体蛋白。具体操作是：先用PBS平衡Protein A柱(GE公司)，然后培养上清过柱，先采用A液(配方：溶剂为水，溶质及浓度为：20mM磷酸钠、500mM NaCl，pH5.0)预洗脱5个柱体积，再采用B液(配方：溶剂为水，溶质及浓度为：20mM醋酸钠、150mM NaCl，pH3.5)洗脱5个柱体积，收集洗脱峰，然后30KDa浓缩离心管浓缩获得所述抗体即获得人源化人鼠嵌合抗体ch-N5。
对人源化人鼠嵌合抗体ch-N5进行测序，结果显示，所得人源化人鼠嵌合抗体ch-N5为完整抗体。
该人源化人鼠嵌合抗体ch-N5由轻链和重链组成，轻链的氨基酸序列如序列表中序列6所示，重链的氨基酸序列为序列表中序列8所示，人源化人鼠嵌合抗体ch-N5的重链类型为IgG1，轻链类型为κ链。
其中，序列6的第1-110位为轻链可变区，序列6的第111-218位为轻链恒定区，
序列8的第1-120位为重链可变区，序列8的第121-450位为重链恒定区。
人源化人鼠嵌合抗体ch-N5轻链可变区中LCDR1、LCDR2和LCDR3的氨基酸序列依次如序列6第27-36位、第54-56位和第93-101位所示；抗体的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如序列8第25-48位、第50-57位和第96-109位所示。
编码人源化人鼠嵌合抗体ch-N5轻链的核苷酸序列为序列表中序列5所示，其中，序列5第1-330位所示的核苷酸编码人源化人鼠嵌合抗体ch-N5轻链可变区，79-108为LCDR1基因，160-168为LCDR2基因，277-303为LCDR3基因，序列5第331-654位所示的核苷酸编码人源化人鼠嵌合抗体ch-N5轻链恒定区；
编码人源化人鼠嵌合抗体ch-N5重链的核苷酸序列为序列表中序列7所示，其中，序列7第1-360位所示的核苷酸编码人源化人鼠嵌合抗体ch-N5重链可变区，73-96为HCDR1区，148-171是HCDR2,286-327是HCDR3,序列7第361-1350位所示的核苷酸编码人源化人鼠嵌合抗体ch-N5重链恒定区。
实施例2、单克隆抗体N5及人源化人鼠嵌合抗体ch-N5的应用
一、单抗N5抗体特异结合2019-n CoV新型冠状病毒的S蛋白RBD区
ELISA方法检测单抗N5抗体与新型冠状病毒S蛋白的结合活性，操作步骤如下：
1、包被：将重组表达的新型冠状病毒S-RBD蛋白(北京博奥龙免疫技术有限公司产品，BD-VP1488)稀释为5μg/ml，100μl/孔包被ELISA微孔板，其中，包被液的配方为：pH9.6的碳酸钠/碳酸氢钠缓冲液(0.1M)。4℃过夜。
2、封闭：用洗涤液(配方：含体积百分含量为0.5‰的Tween-20的磷酸盐缓冲液，简称PBST洗液)洗涤一遍，然后用封闭液(配方：含3％(3g/100ml)牛血清白蛋白的磷酸盐缓冲液)封闭，37℃封闭1h。
3、一抗：用含质量百分含量为0.1％BSA的PBS将实施例1制备的单克隆抗体N5进行系列稀释(20ug/ml，4ug/ml，0.8ug/ml，0.16ug/ml，0.032ug/ml，0.0064ug/ml)后，100μl/孔，加入检测孔中。37℃震荡孵育1h，使抗体与抗原充分结合后，PBST洗涤3次，同时设不加单克隆抗体N5的空白孔(blank)和加入阴性抗体A108(5种呼吸道病毒Array-ELISA检测方法的建立,生物技术通讯,2015,25,403)的阴性对照孔。
4、二抗：加入HRP标记的羊抗鼠IgG(效价1：2000，康为世纪公司产品)，100μl/孔，37℃震荡孵育30min，然后用PBST洗液洗涤3次，洗去未结合的抗体。
5、显色：加入TMB底物显色液(天根公司产品，其产品目录号为PA107-01)，100μl/孔，室温下避光放置5-20min，然后加入终止液(浓度为2M的H2SO4溶液)，利用酶联检测仪测450nm处的吸光值，根据OD450值进行结果判断。
以阴性对照孔的平均值加上3倍的标准差作为cutoff值，高于cutoff值的结果视为ELISA检测阳性，低于等于cutoff值的样本视为ELISA检测阴性。
ELISA检测结果如图1所示，可以看出，单克隆抗体抗体N5(N5抗体)与S蛋白RBD区特异结合，在0.16ug/ml以上即可表明出明显的结合活性。
上述结果表明，N5抗体可与新型冠状病毒S-RBD蛋白结合。
二、竞争ELISA结果表明N5可抑制S蛋白RBD区与ACE2的结合
在冠状病毒感染过程中，病毒主要通过S蛋白RBD区与宿主细胞表面ACE2受体结合而侵入细胞，从而达到感染宿主的目的。抑制病毒S蛋白与受体ACE2结合将会有效达到中和效果。因此，竞争ELISA也是早期初步筛选中和性抗体的方法之一。为了检测N5抗体是否可通过阻断S蛋白与ACE2受体的结合来发挥中和活性，采用竞争ELISA方法进行检测。
竞争ELISA实验步骤如下：
1、包被：将重组表达的新型冠状病毒S-RBD蛋白稀释为5μg/ml，100μl/孔包被ELISA微孔板，其中，包被液的配方为：PH9.6的碳酸钠/碳酸氢钠缓冲液(0.1M)。4℃过夜。
2、封闭：用洗涤液(配方：含体积百分含量为0.5‰的Tween-20的磷酸盐缓冲液，简称PBST洗液)洗涤一遍，然后用封闭液(配方：含3％(3g/100ml)牛血清白蛋白的磷酸盐缓冲液)封闭，37℃封闭1h。
3、一抗：用含0.1％BSA的PBS将实施例1制备的单克隆抗体N5稀释为1.5ug/ml和3ug/ml，得到稀释后N5抗体；用含0.1％BSA的PBS将ACE2-hFc融合蛋白(北京博奥龙免疫技术有限公司产品，BD-PD256437)稀释为1.5ug/ml，得到稀释后ACE2-hFc蛋白；将2个浓度稀释后N5抗体分别与稀释后的ACE2-hFc蛋白等体积混合后，按照100μl/孔加入检测孔中，37℃震荡孵育1h，使抗体与抗原充分结合后，PBST洗涤3次，同时设不加抗体N5的ACE2-hFc融合蛋白对照孔(NC对照)。
4、二抗：加入HRP标记的羊抗人抗体(效价1：2000，康为世纪公司产品)与ACE2-hFc蛋白结合，100μl/孔，37℃震荡孵育30min，然后用PBST洗液洗涤3次，洗去未结合的抗体。
5、显色：加入TMB底物显色液(天根公司产品，其产品目录号为PA107-01)，100μl/孔，室温下避光放置5-20min，然后加入终止液(2M H2SO4)，利用酶联检测仪测450nm处的吸光值，根据OD450值进行结果判断。
以ACE2-hFc阴性对照孔的平均值加上3倍的标准差作为cutoff值，低于cutoff值的20％以上结果视为竞争ELISA检测阳性，即N5抗体可竞争抑制S蛋白与ACE2受体的结合。
实验结果如图2所示，可以看出，以未加N5抗体只加入ACE2-hFc的孔作为对照组(NC对照)，加入N5和ACE2-hFc混合液的孔作为实验组(3ug/ml、1.5ug/ml)，比较实验组和对照组OD450的差异，结果显示实验组的OD450显著降低，达80％以上，表明与S蛋白与受体ACE2的结合受到N5抗体的抑制，N5可阻断S蛋白与ACE2的结合。
上述表明，N5抗体通过竞争结合S蛋白阻断S蛋白与宿主细胞表面ACE2的结合。
三、N5抗体中和2019-n CoV新型冠状病毒
采用病毒致细胞病变观察法测定N5抗体是否能够抑制新型冠状病毒感染宿主细胞，进而采用空斑减少中和实验的方法定量测定N5抗体对新型冠状病毒SARS-CoV-2的体外中和活性，确定其IC50的浓度。
1、病毒致细胞病变观察法
实验组：用细胞培养维持液(含2％胎牛血清的DMEM培养液)将SARS-CoV-2病毒株V34(Development of an automatic integrated gene detection system for novelSevere acute respiratory syndrome-related coronavirus(SARSCoV 2)，EmergingMicrobes&Infections，2020(9)，1489-1495)稀释为103pfu/ml，将实施例1制备的单克隆抗体N5系列稀释后(100ug/ml-0.16ug/ml，5倍系列稀释，共5个浓度)与等体积病毒混合并孵育1小时，得到抗体病毒混合液，然后将抗体病毒混合液加入已长满vero细胞(ATCC,CCL-81)的96孔细胞培养板中，每孔100微升，每个浓度4个复孔。
病毒对照组：50ul浓度为103pfu/ml SARS-CoV-2病毒株V34和50ul DMEM培养液的混合液，加入已长满vero细胞(ATCC,CCL-81)的96孔细胞培养板中，每孔100微升。
细胞对照组：100ul DMEM培养液，加入已长满vero细胞(ATCC,CCL-81)的96孔细胞培养板的孔中。
上述三组置37℃、5％CO2培养箱中孵育1h；弃去上层培养液，加入细胞培养维持液，每孔100微升，置37℃、5％CO2培养箱中进行培养，每日在光学显微镜下观察细胞病变情况。
病毒和抗体共同作用组感染48小时后，显微镜下进行观察，结果如图3所示，与细胞对照组相比，病毒对照组可观察到明显的细胞病变情况；实验组(N5抗体的浓度20μg/mL)，可完全抑制病毒的致细胞病变效应，实验组中细胞生长状况良好，未出现明显的细胞病变，表明N5抗体可抑制新型冠状病毒感染宿主细胞。
2、空斑减少中和实验
实验组：用细胞培养维持液(含2％胎牛血清的DMEM培养液)将SARS-CoV-2病毒株V34稀释为103pfu/ml，将实施例1制备的单克隆抗体N5系列稀释为(0.0008mg/mL-0.2mg/mL，5倍系列稀释，共6个浓度)与等体积病毒混合并孵育1小时，然后将抗体病毒混合液加入已长满vero细胞的12孔细胞培养板中，每孔200微升，每个浓度2个复孔。
病毒对照组：100ul浓度为103pfu/ml的SARS-CoV-2病毒和100ul DMEM培养液的混合液，加入已长满vero细胞(ATCC,CCL-81)的96孔细胞培养板中，每孔200微升。
细胞对照组：200ul DMEM培养液，加入已长满vero细胞(ATCC,CCL-81)的12孔细胞培养板的孔中。
上述三组置37℃、5％CO2培养箱中孵育1h；然后将低熔点琼脂糖加热至融化，与含4％FBS(V/V)的2×DMEM等体积混合后置37℃水浴锅中备用；弃12孔板中的液体，向12孔板中加DMEM和琼脂糖混合液，每孔1mL，室温静置至其冷却凝固；将12孔板倒置，在37℃、5％CO2培养箱中培养，逐日观察细胞病变情况；培养48h后向12孔板中加入4％(V/V)多聚甲醛，每孔1mL，室温静置30min；弃多聚甲醛和琼脂盖，向12孔板中加入1％结晶紫溶液，每孔1mL，室温静置30min；弃结晶紫溶液，清水冲洗数次，观察噬斑并计数。通过公式计算抗体的中和浓度。
抗体抑制率计算公式：抑制率＝(病毒组空斑数-实验组空斑数)/病毒组空斑数×100％
空斑减少中和实验的结果表1和图4所示所示，图4中，V:病毒对照组；C:细胞对照组；其他标浓度的细胞孔是标示浓度的抗体和病毒共同作用的实验组；可以看出，将纯化抗体系列稀释后，用分离培养的新冠病毒株采用病毒感染空斑试验检测抗体的体外抗病毒活性，结果表明，N5抗体可显著抑制病毒的增殖，实验组中的抗体浓度在1.65ug/ml以上，即可抑制50％以上病毒活性，50ug/ml以上抗体浓度可抑制90％以上的病毒活性。经过统计分析，IC50为0.9ug/ml。
表1为空斑减少中和实验检测鼠源单抗N5的中和活性
| 实验组别 | 平均斑数 | 抑制率(％) |
| 病毒组 | 109 | |
| N5(0.0008mg/mL) | 78 | 44.6％ |
| N5(0.00165mg/mL) | 54 | 50.5％ |
| N5(0.0031mg/mL) | 41 | 62.4％ |
| N5(0.00625mg/mL) | 43 | 60.6％ |
| N5(0.0125mg/mL) | 41 | 62.4％ |
| N5(0.025mg/mL) | 28 | 74.3％ |
| N5(0.05mg/mL) | 7 | 93.6％ |
| N5(0.1mg/mL) | 0 | 100％ |
| N5(0.2mg/mL) | 0 | 100％ |
经过统计分析，鼠源单抗N5的IC50为0.9ug/ml。
四、人源化人鼠嵌合抗体的亲和力检测
1、Fortebio亲和力分析
将实施例1制备的人源化人鼠嵌合抗体ch-N5和单克隆抗体N5调整到统一的浓度60nM(浓度为0.01M pH值为7.2的PBS稀释)，将这2种抗体分别通过Loading上样步骤固定化到抗人Fc/抗鼠Fc的芯片(Gator公司产品，货号PL168-160003)上，用PBS将S-RBD抗原(益翘神州公司产品)稀释为100nM，然后用亲和力分析仪Fortebio进行亲和力分析。即抗原流过(Association)固定化抗人Fc/抗鼠Fc的芯片能够产生0.1-1RU可接受的检测信号，然后用PBS解离结合的抗原，分析抗原抗体结合的结合常数ka与解离常数kd值，计算出亲和力常数Kd作为比较不同抗体结合差异的基础。
结果如图5及表2所示，可以看出，人源化人鼠嵌合抗体ch-N5与新冠病毒S-RBD蛋白的亲和力与鼠源抗体N5相似，亲和力常数分别为2.19×10-10M和4.44E-10×10-10M,表明人源化人鼠嵌合抗体ch-N5具有鼠源抗体N5的功能，能结合新冠病毒S蛋白。
表2为N5抗体和ch-N5重组表达抗体与新冠病毒S蛋白的亲和力分析结果
2、人源化人鼠嵌合抗体Ch-N5中和活性分析
采用空斑减少中和实验，对基因工程人源化人鼠嵌合抗体ch-N5的抗病毒活性进行评估，方法与上述三的2类似，不同仅为是实验组中将单克隆抗体N5替换为人源化人鼠嵌合抗体ch-N5。
实验组：用细胞培养维持液(含2％胎牛血清的DMEM培养液)将SARS-CoV-2病毒株V34稀释为103pfu/ml，用PBS将实施例1制备的人源化人鼠嵌合抗体ch-N5系列稀释后(0.00165mg/mL-0.1mg/mL，5倍系列稀释，共6个浓度)与等体积病毒混合并孵育1小时，然后将抗体病毒混合液加入已长满vero细胞的12孔细胞培养板中，每孔200微升，每个浓度2个复孔。
病毒对照组：100ul浓度为103pfu/ml的SARS-CoV-2病毒和100ul DMEM培养液的混合液，加入已长满vero细胞(ATCC,CCL-81)的96孔细胞培养板中，每孔200微升。
细胞对照组：200ul DMEM培养液，加入已长满vero细胞(ATCC,CCL-81)的12孔细胞培养板的孔中。
结果如图6和表3所示，图6中，V:病毒对照组；C:细胞对照组；其他标浓度的细胞孔是标示浓度的抗体和病毒共同作用的实验组；确认其抗病毒活性与原鼠抗体相比无明显变化，结果表明人源化改造后的抗体保持与原抗体相似的中和活性，用Graphpad软件进行统计分析人源化人鼠嵌合抗体ChN5的IC50为2.1ug/ml。
表3为人源化人鼠嵌合抗体Ch-N5空斑减少中和实验
| 样本 | 平均斑数 | 抑制率(％) |
| 细胞组 | 0 | |
| 病毒组 | 112 | |
| ChN5(0.00165mg/mL) | 78 | 44.7％ |
| ChN5(0.0031mg/mL) | 50 | 55.3％ |
| ChN5(0.00625mg/mL) | 39 | 65.2％ |
| ChN5(0.0125mg/mL) | 42 | 62.5％ |
| ChN5(0.025mg/mL) | 26 | 76.8％ |
| ChN5(0.05mg/mL) | 21 | 81.3％ |
| ChN5(0.1mg/mL) | 5.5 | 95.1％ |
上述结果表明，人源化人鼠嵌合抗体ChN5可以抑制新冠病毒SARS-CoV-2，可以中和新冠病毒SARS-CoV-2，具体是人源化人鼠嵌合抗体ChN5通过竞争结合新冠病毒的S蛋白阻断新冠病毒S蛋白与被侵染宿主细胞表面ACE2的结合实现。
SEQUENCE LISTING
<110>中国人民解放军军事科学院军事医学研究院
<120>一株中和新型冠状病毒感染的单抗
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cagcagaaac caggacagcc acccaaactc ctcatctata ttgcatccaa cctagaatct 180
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atcttcccgc catctgatga gcagttgaaa tctggtaccg ctagcgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
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gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 660
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcctccatc tcgggatgag 1080
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 1260
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320
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<210> 8
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20 25 30
Ile Glu Trp Ile Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile Gly
35 40 45
Gln Ile Phe Pro Gly Ser Gly Ser Ser Asn Tyr Asn Glu Lys Phe Lys
50 55 60
Gly Lys Ala Thr Phe Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Met
65 70 75 80
Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr His Cys Ala
85 90 95
Arg Trp Asp Gly Asn Leu Phe Tyr Tyr Ala Met Asp Tyr Trp Gly Leu
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
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Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
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275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
Claims (9)
1.一种与新型冠状病毒SARS-CoV-2结合的抗体，其特征在于：
所述抗体的轻链可变区中LCDR1、LCDR2和LCDR3的氨基酸序列依次为序列2第27-36位、第54-56位和第93-101位所示；
所述抗体的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次为序列4第25-48位、第50-57位和第96-109位所示。
2.根据权利要求1所述的抗体，其特征在于：
所述轻链可变区的氨基酸序列为序列表中序列2第1-110位；
所述重链可变区的氨基酸序列为序列表中序列4第1-120位。
3.根据权利要求1或2所述的抗体，其特征在于：
所述抗体的重链的类型为IgG1；
所述抗体的轻链的类型为Kappa链。
4.根据权利要求1或2所述的抗体，其特征在于：
所述抗体的轻链恒定区和所述抗体的重链恒定区为人源或鼠源。
5.根据权利要求4所述的抗体，其特征在于：
所述轻链恒定区的氨基酸序列为序列表中序列2第111-218位；
或，所述轻链恒定区的氨基酸序列为序列表中序列6第111-218位；
所述重链恒定区的氨基酸序列为序列表中序列4第121-444位；
或，所述重链恒定区的氨基酸序列为序列表中序列8第121-450位。
6.编码权利要求1-5任一所述抗体的核酸分子。
7.含有权利要求6所述核酸分子的表达盒、重组载体或重组菌或重组病毒。
8.权利要求1-5任一所述抗体、权利要求6所述核酸分子或权利要求7所述表达盒、重组载体或重组菌或重组病毒在制备具有如下1）-4）至少一种功能的产品中的应用：
1）治疗或抑制新型冠状病毒；
2）中和新型冠状病毒；
3）结合新型冠状病毒的S蛋白；
4）阻断新型冠状病毒S蛋白与被侵染宿主细胞表面ACE2的结合。
9.一种具有如下1）-4）中至少一种功能的产品，其包括权利要求1-5任一所述抗体、权利要求6所述核酸分子或权利要求7所述表达盒、重组载体或重组菌或重组病毒；
1）治疗或抑制新型冠状病毒；
2）中和新型冠状病毒；
3）结合新型冠状病毒的S蛋白；
4）阻断新型冠状病毒S蛋白与被侵染宿主细胞表面ACE2的结合。
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