CN111171144B - 一种抗猪流行性腹泻病毒的抗体制备及应用 - Google Patents
一种抗猪流行性腹泻病毒的抗体制备及应用 Download PDFInfo
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Abstract
本发明公开了一种抗猪流行性腹泻病毒的抗体制备及应用。本发明提供的抗猪流行性腹泻病毒的抗体的基因是由重链和轻链组成；重链的氨基酸序列如序列表的序列2所示；轻链的氨基酸序列如序列表的序列4所示。本发明提供的抗猪流行性腹泻病毒的抗体可以抑制猪流行性腹泻病毒，在预防和/或治疗猪流行性腹泻中具有重要的应用价值。
Description
技术领域
本发明涉及一种抗猪流行性腹泻病毒的抗体制备及应用。尤其涉及该抗体制备制备及用于预防和/或治疗猪流行性腹泻病毒引起的疾病的药物中的应用，属于生物技术领域。
背景技术
猪流行性腹泻(Porcine Epidemic Diarrhea，PED)是由猪流行性腹泻病毒(Porcine Epidemic Diarrhea Virus，PEDV)引起的仔猪和育肥猪的一种急性肠道传染病，其与传染性胃肠炎很相似，在我国多发生在每年12月份至翌年1～2月，夏季也有发病的报道。PEDV属于冠状病毒科，冠状病毒属。目前还没有发现PEDV有不同的血清型。PEDV经口和鼻感染后，直接进入小肠。通过免疫荧光和电子显微镜检查，PEDV的复制在小肠和结肠绒毛上皮细胞浆中进行，其它脏器内未发现PEDV增殖。PEDV增殖首先造成细胞器的损伤，继而出现细胞功能障碍。肠绒毛萎缩，造成了吸收表面积的减少，小肠黏膜碱性磷酸酶含量显著减少进而引起营养物质吸收障碍，这是引起腹泻的主要原因，属于渗透性腹泻。严重腹泻引起脱水是导致病猪死亡的主要原因。
猪流行性腹泻只发生于猪，各种年龄的猪都能感染发病。哺乳猪、架子猪或肥育猪的发病率很高，尤以哺乳猪受害最为严重，母猪发病率变动很大，约为15％～90％。病猪是主要传染源。PEDV存在于肠绒毛上皮细胞和肠系膜淋巴结，随粪便排出后，因污染环境、饲料、饮水、交通工具及用具等而传染。主要感染途径是消化道，如果一个猪场陆续有不少窝仔猪出生或断奶，PEDV会不断感染失去母源抗体的断奶仔猪，使PED呈地方流行性，在这种繁殖场内，猪流行性腹泻可造成5～8周龄仔猪的断奶期顽固性腹泻。
疫苗是预防PED的主要途径，但是经常会出现免疫失败的问题，尤其是哺乳母猪发病，会引起PED在猪场流行。抗体法是清除PEDV的主要方法，也是治疗发病猪的最重要手段。具有完善翻译后修饰功能是哺乳动物细胞被选作大多数生物药蛋白表达宿主的主因。大肠杆菌BL21是用于外源抗体基因表达最为成功的宿主细菌，已有越来越多的抗体蛋白在其中获得了高效表达，该系统表达的人用重组抗体蛋白药物已上市。与其它表达系统相比表达产物高，成本低廉，适合动物经济实惠。
IgG类的免疫球蛋白是血液中最丰富的蛋白质，它们的半衰期可高达21天，而FC片段是IgG保持体内较长半衰期的主要原因，同时具有稳定蛋白的作用。
发明内容
本发明的目的是提供一种抗猪流行性腹泻病毒的抗体，在预防和/或治疗猪流行性腹泻制品中应用。
本发明的技术方案
1.本发明所述一种抗猪流行性腹泻病毒的抗体，其特征在于该抗体基因序列包括重链(序列2)和轻链(序列4)。
2.本发明所述一种抗猪流行性腹泻病毒的抗体，其特征在于该抗体基因序列编码的核酸分子由所述重链的编码基因和所述轻链的编码基因组成；
所述重链的3.本发明所述一种抗猪流行性腹泻病毒的抗体，其特征在于编码基因如序列1自5’末端起第1至1335位所示；所述轻链的编码基因如序列3所示。该抗体的制备是分别构建获得的表达序列2所示蛋白的重组质粒PED-L和表达序列4所示蛋白得到的重组质粒PED-H一起重组到重组PET32NdeI-XHOI框，得到同时表达重链和轻链的原核双表达载体，转入大肠杆菌BL21，经的高密度发酵获得抗猪流行性腹泻病毒的猪源化克隆抗体。
4.本发明所述一种抗猪流行性腹泻病毒的抗体，其特征在于所述抗体基因序列或/和所述核酸分子在制备用于抑制猪流行性腹泻病毒的药物中的应用。
5.本发明所述一种抗猪流行性腹泻病毒的抗体，其特征在于所述该抗体基因序列或/和所述核酸分子在抑制猪流行性腹泻病毒中的应用。
6本发明所述一种抗猪流行性腹泻病毒的抗体，其特征在于所述该抗体基因序列或/和所述核酸分子在制备用于预防和/或治疗猪流行性腹泻病毒引起的疾病的药物中的应用。
7.本发明所述一种抗猪流行性腹泻病毒的抗体，其特征在于所述该抗体基因序列或/和所述核酸分子在预防和/或治疗猪流行性腹泻病毒引起的疾病中的应用。
本领域普通技术人员可以很容易地采用已知的方法，例如定向进化和点突变的方法，对本发明的编码所述猪源化克隆抗体序列的核苷酸序列进行突变。那些经过人工修饰的，具有与本发明的所述猪源化克隆抗体序列的核苷酸序列75％或者更高同一性的核苷酸，只要编码所述猪源化克隆抗体序列且抗猪流行性腹泻病毒，均是衍生于本发明的核苷酸序列并且等同于本发明的序列。
这里使用的术语“同一性”指与天然核酸序列的序列相似性。“同一性”包括与本发明的编码序列表的序列2和/或序列4所示的氨基酸序列组成的蛋白质的核苷酸序列具有75％或更高，或80％或更高，或85％或更高，或90％或更高，或95％或更高同一性的核苷酸序列。同一性可以用肉眼或计算机软件进行评价。使用计算机软件，两个或多个序列之间的同一性可以用百分比(％)表示，其可以用来评价相关序列之间的同一性。
所述猪源化克隆抗体序列、或、编码所述猪源化克隆抗体序列的核酸分子在制备用于抑制猪流行性腹泻病毒的药物中的应用也属于本发明的保护范围。
所述猪源化克隆抗体序列、或、编码所述猪源化克隆抗体序列的核酸分子在抑制猪流行性腹泻病毒中的应用也属于本发明的保护范围。
所述猪源化克隆抗体序列、或、编码所述猪源化克隆抗体序列的核酸分子在制备用于预防和/或治疗猪流行性腹泻病毒引起的疾病的药物中的应用也属于本发明的保护范围。
所述猪源化克隆抗体序列、或、编码所述猪源化克隆抗体序列的核酸分子在预防和/或治疗猪流行性腹泻病毒引起的疾病中的应用也属于本发明的保护范围。
本发明还保护一种用于抑制猪流行性腹泻病毒的药物，其含有所述猪源化克隆抗体序列。
本发明还保护一种用于预防和/或治疗猪流行性腹泻病毒引起的疾病的药物，其含有所述猪源化克隆抗体序列。
上述任一所述猪流行性腹泻病毒引起的疾病具体可为猪流行性腹泻。
上述任一所述猪流行性腹泻病毒具体可为猪流行性腹泻病毒S蛋白。
实验证明，本发明提供的猪源化克隆抗体序列可以抑制猪流行性腹泻病毒，在预防和/或治疗猪流行性腹泻中具有重要的应用价值。
本发明新的技术效果
本发明涉及一种抗猪流行性腹泻病毒的抗体的制备及应用。本发明提供的抗体基因，由重链和轻链组成；重链的氨基酸序列如序列表的序列2所示；轻链的氨基酸序列如序列表的序列4所示。本发明提供的抗体可以抑制猪流行性腹泻病毒，在预防和/或治疗猪流行性腹泻中具有重要的应用价值。
附图说明
图1为猪重组大肠杆菌不同时间点表达抗体结果图中1为对照，2为诱导开始0小时,3、4、5、6、7、8、9为诱导后1-7小时表达的抗体。
图2为重组大肠杆菌株的表达目的蛋白的纯化实验结果图中1为对照，2-3显示的均为经纯化目的蛋白。
图3为动物保护实验的实验结果图中A为发病仔猪肠道水肿严重，B为发病仔猪肠道治疗后的肠道有明显改善。
具体实施方式
PED-IgG抗体的制备
1.PED-IgG抗体的编码基因的优化
本发明经过大量实验，按鼠类密码子偏好性优化了野生型PED-IgG抗体的编码基因。优化的PED-IgG抗体的重链(可变区到恒定区全片段)的氨基酸序列如序列表的序列2所示，其编码基因如序列表的序列1自5’末端起第1至1335位所示。优化的PED-IgG抗体的轻链(可变区到恒定区全片段)的氨基酸序列如序列表的序列4所示，其编码基因如序列表的序列3所示。
2.重组质粒的构建
一起重组到重组PET32NdeI-XHOI框，得到同时表达重链和轻链的原核双表达载体，转入大肠杆菌BL21，通过试管表达筛选到高表达的保存，建立重组大肠杆菌BL21种子库。
3.重组抗体的获得
(1)在发酵罐中进行重组大肠杆菌的高密度发酵
1)种子液制备或平板培养：重组大肠杆菌BL21种子LB培养基于30～37℃、250～280r/min培养10～12h。
2)二级种子制备：菌株于改良LB培养基,30～37℃、250～280r/min培养10～12h。
3)发酵生产：发酵培养基础。共分为三个阶段。
培养基为半合成培养基和补料培养基
菌体培养阶段、源饲喂阶段和诱导表达阶段的发酵培养结束后收获菌液。
4.目的蛋白质的纯化
(1)收获的发酵菌液在5000-8000r/min离心5～10min收集菌体-20保存按10％的量悬浮于缓冲裂解液体中经ATS高压均质下破菌，10000～15000r/min 20min分离细胞碎片，上清过0.45μm膜为粗样以备纯化。
(2)PED-IGG抗体亲和的制备
buffer A：含0.15M NaCl的pH7.2的20mM的PBS缓冲液。
buffer B的溶质及其浓度为：4.5mM柠檬酸钠和25mM柠檬酸，溶剂为水，pH值为3.0。
1)取步骤1得到的发酵菌体破菌澄清液，过滤。
2)取亲和层析柱，加入3个柱体积的buffer A，平衡(电导18ms/cm)。
3)完成步骤2)后，将步骤1)收集的滤液上样于亲和层析柱，加入5个柱体积的buffer A淋洗平衡。
4)完成步骤3)后，取所述亲和层析柱，加入5个柱体积的buffer B洗脱(电导1.27ms/cm)目的蛋白，收集过柱后溶液。
5)取步骤4)得到的过柱后溶液，将体系置换为pH7.4、0.2mM的PBS缓冲液，得到PED-IGG抗体溶液。
(3)PED-IgG抗体HIS亲和的制备：
取步骤1得到的发酵菌体破菌澄清液，过滤；
取亲和层析柱，加入3个柱体积的buffer A，平衡；
收集的滤液上样于亲和层析柱，加入5个柱体积的buffer A淋洗平衡；
取所述亲和层析柱，加入buffer B洗脱目的蛋白，收集过柱后溶液。
得到的过柱后溶液，将体系置换到pH7.4、0.2mM的PBS缓冲液以去除咪唑，得到PED-IgG抗体溶液。
本领域普通技术人员可以很容易地采用已知的方法，例如定向进化和点突变的方法，对本发明的编码所述猪源化克隆抗体序列的核苷酸序列进行突变。那些经过人工修饰的，具有与本发明的所述猪源化克隆抗体序列的核苷酸序列75％或者更高同一性的核苷酸，只要编码所述猪源化克隆抗体序列且抗猪流行性腹泻病毒，均是衍生于本发明的核苷酸序列并且等同于本发明的序列。
这里使用的术语“同一性”指与天然核酸序列的序列相似性。“同一性”包括与本发明的编码序列表的序列2和/或序列4所示的氨基酸序列组成的蛋白质的核苷酸序列具有75％或更高，或80％或更高，或85％或更高，或90％或更高，或95％或更高同一性的核苷酸序列。同一性可以用肉眼或计算机软件进行评价。使用计算机软件，两个或多个序列之间的同一性可以用百分比(％)表示，其可以用来评价相关序列之间的同一性。
所述猪源化克隆抗体序列、或、编码所述猪源化克隆抗体序列的核酸分子在制备用于抑制猪流行性腹泻病毒的药物中的应用也属于本发明的保护范围。
所述猪源化克隆抗体序列、或、编码所述猪源化克隆抗体序列的核酸分子在抑制猪流行性腹泻病毒中的应用也属于本发明的保护范围。
所述猪源化克隆抗体序列、或、编码所述猪源化克隆抗体序列的核酸分子在制备用于预防和/或治疗猪流行性腹泻病毒引起的疾病的药物中的应用也属于本发明的保护范围。
所述猪源化克隆抗体序列、或、编码所述猪源化克隆抗体序列的核酸分子在预防和/或治疗猪流行性腹泻病毒引起的疾病中的应用也属于本发明的保护范围。
本发明还保护一种用于抑制猪流行性腹泻病毒的药物，其含有所述猪源化克隆抗体序列。
本发明还保护一种用于预防和/或治疗猪流行性腹泻病毒引起的疾病的药物，其含有所述猪源化克隆抗体序列。
上述任一所述猪流行性腹泻病毒引起的疾病具体可为猪流行性腹泻。
上述任一所述猪流行性腹泻病毒具体可为猪流行性腹泻病毒S蛋白。
实验证明，本发明提供的猪源化克隆抗体序列可以抑制猪流行性腹泻病毒，在预防和/或治疗猪流行性腹泻中具有重要的应用价值。
实施例
以下的实施例便于更好地理解本发明，但并不限定本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的实验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。以下实施例中的定量实验，均设置三次重复实验，结果取平均值。
载体PET32和BL21细胞本公司的产品。限制性内切酶为TaKaRa公司的产品。猪流行性腹泻病毒JS-HZ2012，抗体基因经过JS-HZ2012免疫猪取B细胞流式分选单细胞测序结果
实施例1——PED-IGG抗体的制备
1.PED-IGG抗体的编码基因的优化
本发明的发明人经过大量实验，按鼠类密码子偏好性优化了野生型PED-IGG抗体的编码基因。优化的PED-IGG抗体的重链(可变区到恒定区全片段)的氨基酸序列如序列表的序列2所示，其编码基因如序列表的序列1自5’末端起第1至1335位所示。优化的PED-IGG抗体的轻链(可变区到恒定区全片段)的氨基酸序列如序列表的序列4所示，其编码基因如序列表的序列3所示。
2.重组质粒的构建
(1)将载体PET32的限制性内切酶NdeI和XhoI识别序列间的小片段替换为序列表中序列1所示的DNA分子，得到重组质粒PED-L。重组质粒PED-L表达序列表中序列2所示的蛋白质PED-L。(2)向载体PET32的限制性内切酶NdeI和XhoI酶切识别位点处插入序列表中序列3所示的DNA分子，得到重组质粒PED-H。重组质粒PED-H表达序列表中序列4所示的蛋白质PED-H。
将(1)步中正确载体XhoI酶切，将(2)步中表达框扩增出用重组酶重组酶重组到XhoI框，得到同时表达重链和轻链的原核双表达载体，转入大肠杆菌BL21试管筛选出高表达的大肠杆菌，建立重组种子库，并对大肠杆菌表达时间优化如图1。结果可以看出诱导1小时后蛋白即获得大量表达，随着诱导时间增加表达量提高，我们确定7小时诱导结束。
3.重组抗体的获得
(1)在发酵罐中大肠杆菌的高密度发酵
1)种子液制备或平板培养：菌株于LB(1％蛋白胨+0.5％NaCL+0.5％酵母粉或固体培养平板上含氨苄抗生素中50μg/ml),30～37℃、250～280r/min培养10～12h。
2)二级种子制备：菌株于改良LB培养基(0.5％甘油+1％蛋白胨+0.5％NaCL+0.5％酵母粉)含卡那抗生素中50μg/ml,30～37℃、250～280r/min培养10～12h。
3)发酵生产：发酵培养基础。共分为三个阶段。
培养基为半合成培养基g/l：葡萄糖5、蛋白胨5、酵母粉10、KH2PO4 1、Na2HPO4.12H2O4、(NH4)2SO4 3.2、NH4Cl 0.6、MnSO4·5H2O 0.001、CoCl2.6H2O 0.004、Na2MoO4.2H2O 0.002、ZnCl2 0.002、CuSO4.5H2O 0.001、H3BO4 0.005、FeSO4·7H2O 0.02、CaCl.2·H2O 0.02 、MgSo4·7H2O 0.1、消泡剂 0.2。
补料培养基g/l：甘油(葡萄糖)60、蛋白胨60、酵母粉60、MgSo4.7H2O6及其它多种微量元素加蒸馏水配制1L,115℃灭菌15min使用。
①菌体培养阶段发酵培养基灭菌后，按每升培养基加入一定的抗生素(工作浓度20μg/ml氨苄),5％～10％接种种子液，30～37℃通气搅拌培养7h左右，在培养过程中随着菌株的生长，培养基中的糖逐渐消耗，当碳源消耗完后菌体不再生长，溶氧回升，培养过程中用氨水维持pH值7.0。
②源饲喂阶段确认上一步糖耗完后(以DO回升20％，同时在不加酸的情况下pH上升为标准)，开始此步骤。用补料控制用DO 10％～20％之间，维持0.15<u<0.2。用氨水维持在pH值7.0，此步可以维持2～6h。后开始诱导
③诱导表达阶段当补料达到期望菌体重量开始诱导。添加0.4mMIPTG诱导6h，用补料控制DO在10～30之间，整个诱导过程用氨水维持pH值在7.0。
4.目的蛋白质的纯化
(1)样品准备：发酵液菌体在5000-8000r/min离心5～10min收集菌体-20保存按10％的量悬浮于缓冲裂解液体中(缓冲裂解液：10mMTris-HCl，200mMNaCl，2mMEDTA，0.02％溶菌酶pH8.0)ATS高压均质下破菌，10000～15000r/min 20min分离细胞碎片，上清过0.45μm膜为粗样以备纯化。
(2)PED-IGG抗体亲和的制备
buffer A：含0.15M NaCl的pH7.2的20mM的PBS缓冲液。
buffer B的溶质及其浓度为：4.5mM柠檬酸钠和25mM柠檬酸，溶剂为水，pH值为3.0。
1)取步骤1得到的发酵菌体破菌澄清液，过滤。
2)取亲和层析柱，加入3个柱体积的buffer A，平衡(电导18ms/cm)。
3)完成步骤2)后，将步骤1)收集的滤液上样于亲和层析柱，加入5个柱体积的buffer A淋洗平衡。
4)完成步骤3)后，取所述亲和层析柱，加入5个柱体积的buffer B洗脱(电导1.27ms/cm)目的蛋白，收集过柱后溶液。
5)取步骤4)得到的过柱后溶液，将体系置换为pH7.4、0.2mM的PBS缓冲液，得到PED-IGG抗体溶液。
(3)PED-IGG抗体HIS亲和的制备：
buffer A：含0.15M NaCl，20mM咪唑的pH7.2的20mM的PBS缓冲液。
buffer B的溶质0.15M NaCl250mm咪唑的pH7.2的20mM的PBS缓冲液。
1)取步骤1得到的发酵菌体破菌澄清液，过滤。
2)取亲和层析柱，加入3个柱体积的buffer A，平衡。
3)完成步骤2)后，将步骤①1)收集的滤液上样于亲和层析柱，加入5个柱体积的buffer A淋洗平衡。
4)完成步骤3)后，取所述亲和层析柱，加入buffer B洗脱目的蛋白，收集过柱后溶液。
5)取步骤4)得到的过柱后溶液，将体系置换到pH7.4、0.2mM的PBS缓冲液以去除咪唑，得到PED-IGG抗体溶液，电泳纯化结果如图2，His标签能纯化出目的蛋白。
实施例2——安全性实验
将20头健康的3周龄的仔猪(雌雄各半)随机分为一组至四组，每组5头。将20头健康的5月龄的猪(雌雄各半)随机分为五组至八组，每组5头。
各组进行如下处理：
一组：实验第一天至第七天，每天进行如下处理：每头仔猪颈部肌肉注射实施例1步骤四2中(5)制备的PED-IGG抗体溶液2ml，注射剂量为每头2mgPED-IGG抗体；
二组：分别与实验第一天、第三天、第五天和第七天，每天进行如下处理：每头仔猪颈部肌肉注射5ml PED-IGG抗体溶液(见实施例1“4.目的蛋白质的纯化”步骤中制备的PED-IGG抗体溶液)；
三组、对照组每头仔猪颈部肌肉注射生理盐水2ml；
实验期间，每天观测各组猪的临床症状变化，包括精神、采食、活动、呼吸、饮水、注射炎症反应、排泄状况，每天体温检测，记录动物异常情况，如果有死亡猪需解剖，观测病例变化。
经过2周连续观测，对注射PED-IGG抗体前后的临床症状进行比较，发现一组、二组、三组猪均饮食正常，精神无不良变化，呼吸及排泄未见异常，注射部位无发炎现象，对三组和二组的猪的肝脏组织、肠道组织和肾组织进行免疫组化，发现组织质地均匀没有病例改变。上述结果表明，本发明制备的PED-IGG抗体溶液安全性高，动物应激反应小，即使高剂量注射也无明显副作用。
实施例3——动物保护实验
将25头健康的3周龄的仔猪(雌雄各半)随机分为五组，每组5头。各组进行如下处理：
一组：实验第0h，每头仔猪肌肉注射猪流行腹泻病毒强毒株(攻毒剂量为1×105TCID50/只)进行攻毒(以下同)；实验第12h，每头仔猪肌肉注射0.5mg/ml PED-IGG抗体2ml；
二组：实验第0h，每头仔猪肌肉注射猪流行腹泻株病毒株(攻毒剂量为1×105TCID50/只)进行攻毒；实验第12h，每头仔猪肌肉注射1mg/mlPED-IGG抗体2ml；
三组：实验第0h，每头仔猪肌肉注射猪流行腹泻株病毒株(攻毒剂量为1×105TCID50/只)进行攻毒；实验第12h，每头仔猪肌肉注射5mg/mlPED-IGG抗体2ml；
四组：实验第0h，每头仔猪肌肉注射猪流行腹泻株病毒株(攻毒剂量为1×105TCID50/只)进行攻毒；实验第12h，每头仔猪肌肉注射1mg/mlPED-IGG抗体和1mg/ml猪干扰素各1ml；
五组(对照组)：实验第0h，每头仔猪肌肉注射猪流行腹泻株病毒株(攻毒剂量为1×105TCID50/只)进行攻毒；实验第12h，每头仔猪肌肉注射生理盐水2ml。
整个实验过程中，每天观测仔猪临床症状变化，包括精神、采食、活动、呼吸、饮水、注射炎症反应、排泄状况，每天检测体温，记录异常情况，如果有死亡仔猪需解剖，观测病例变化。
实验结果如下：
1.实验第12h，各组仔猪的体温升高(在40～41.8℃之间)，开始拉黄绿色粪便如；实验第18h，一组的1头仔猪死亡，4头仔猪的症状开始明显缓解；实验第18h，二组的1头仔猪死亡，4头仔猪的症状开始明显缓解；实验第18h，三组的5头仔猪和四组的5头仔猪的症状均开始明显缓解；实验第24h，五组的仔猪在24～36h出现食欲下降，精神萎靡，运动功能障碍，严重腹泻，猪群扎堆现象，逐渐死亡。
2.将五组死亡的仔猪和其它组存活的仔猪进行剖检，观察肠道组织的病理变化。
部分实验结果见图3，其中A为发病仔猪肠道水肿严重，B为发病仔猪肠道治疗后的肠道有明显改善。结果表明，五组死亡的仔猪的肠道组织出现明显的肠道水肿。
3.实验过程中，收集各头仔猪的肠排泄物，依次进行如下处理：
(1)分别提取各头仔猪的肠排泄物的总RNA并以其为模板，反转录得到cDNA。
(2)分别以cDNA为模板，以PED-F：5’-gacgtttctt ttatgactct g-3’21(序列5)和PED-R：5’-aatactcata ctaaagttg-3’19(序列6)为引物进行RT-PCR，得到PCR扩增产物，然后进行如下判断：如果PCR扩增产物中含有459bp的DNA片段，则其对应的仔猪依旧感染猪流行腹泻株病毒；如果PCR扩增产物中不含有459bp的DNA片段，则其对应的仔猪不再感染猪流行腹泻株病毒。PCR扩增产物中459bp的DNA片段的条带越亮，则猪流行腹泻株病毒复制越活跃。
结果表明，五组的仔猪的肠排泄物的PCR扩增产物中均含有459bp的DNA片段，且条带越来越亮。其它四组存活的仔猪中，实验前12h收集的肠排泄物的PCR扩增产物中均含有459bp的DNA片段，注射PED-IGG抗体后，条带越来越暗甚至消失。
上述结果表明，向4～6周龄仔猪每头注射0.5mg/mlPED-IGG抗体2ml，即可治疗猪流行腹泻，达到治疗目的。
序列表
<110> 北京中海生物科技有限公司
<120> 一种抗猪流行性腹泻病毒的抗体制备及应用
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gttggtacca aaaccaaacc gccgtgcccg atctgcccgg gttgcgaagt tgctggtccg 780
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ttcaaatgca aagttaacaa cgttgacctg ccggctccga tcacccgtac catctctaaa 1080
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tctcgttcta aagttaccgt tacctgcctg gttatcggtt tctacccgcc ggacatccac 1200
gttgaatgga aatctaacgg tcagccggaa ccggaaggta actaccgtac caccccgccg 1260
cagcaggacg ttgacggtac cttcttcctg tactctaaac tggctgttga caaagctcgt 1320
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Claims (4)
1.一种抗猪流行性腹泻病毒的抗体，其特征在于该抗体的核酸分子由重链的编码基因和轻链的编码基因组成；
所述重链的编码基因如序列1自5’末端起第1至1335位所示；所述轻链的编码基因如序列3所示。
2.如权利要求1所述一种抗猪流行性腹泻病毒的抗体，其特征在于该抗体的制备方法是分别构建获得表达序列2所示蛋白的重组质粒PED-L和表达序列4所示蛋白得到的重组质粒PED-H，并将其一起重组到重组PET32NdeI-XHOI框，得到同时表达重链和轻链的原核双表达载体，转入大肠杆菌BL21，经高密度发酵获得抗猪流行性腹泻病毒的抗体。
3.如权利要求1所述一种抗猪流行性腹泻病毒的抗体，其特征在于所述抗体在预防和/或治疗猪流行性腹泻病毒引起的疾病中的应用。
4.如权利要求1所述一种抗猪流行性腹泻病毒的抗体在制备预防和/或治疗猪流行性腹泻病毒引起的疾病的药物中的应用。
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| CN108586609A (zh) * | 2018-05-24 | 2018-09-28 | 青岛博隆基因工程有限公司 | 一种抗猪流行性腹泻病毒的单克隆抗体及应用 |
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