CN117430674A - 重组蛋白及其在hpv预防中的应用 - Google Patents
重组蛋白及其在hpv预防中的应用 Download PDFInfo
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- CN117430674A CN117430674A CN202210863270.XA CN202210863270A CN117430674A CN 117430674 A CN117430674 A CN 117430674A CN 202210863270 A CN202210863270 A CN 202210863270A CN 117430674 A CN117430674 A CN 117430674A
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Abstract
本发明公开了一种重组蛋白及其在HPV预防中的应用，属于生物医药领域。本发明的重组蛋白包含HPV五种血清型L2蛋白片段中的一种或多种，所述HPV五种血清型L2蛋白选自6(13‑75)、16(11‑75)、18(12‑75)、31(11‑75)、39(12‑75)。该重组蛋白以及和不同佐剂的组合物可以同时对HPV6、11、16、18、31、33、35、39、45、51、52、56、58、59、66、68、73这17种亚型产生良好的预防和/或治疗作用，实现高效预防和/或治疗HPV。
Description
技术领域
本发明属于生物医药领域，具体涉及一种重组蛋白及其在HPV预防中的应用。
背景技术
人类乳头瘤病毒(humanpapillomavirus，HPV)属于乳多空病毒科的乳头瘤空泡病毒，是球形DNA病毒，能引起人体皮肤黏膜的鳞状上皮增殖，是目前为已确认的致癌病毒。目前研究已经证实，几乎所有宫颈癌患者的宫颈组织内都可检测到高危型的HPV。国际上目前已经有预防性的二价、四价和九价疫苗分别可以预防2种、4种和9种型号的人乳头瘤病毒(HPV)感染。但是，人乳头瘤病毒有100多种型号，不同的型别引起不同的临床表现，不同国家和地区流行的人乳头瘤病毒也不同。采用简单地增加疫苗靶抗原种类来达到完全预防各地不同的人乳头瘤病毒感染的目的是不太现实的。另外，对于HPV感染后期的阳性患者，由于HPV病毒DNA整合到宿主细胞DNA，衣壳蛋白L1和L2表达缺失；造成以L1、L2为靶抗原的疫苗和治疗药物都失效。同时，致癌基因蛋白E6/E7过度表达，致癌作用强化，造成细胞无限增殖，宫颈组织由病变阶段恶性转化为癌症。
高危型HPV持续感染，其DNA与宿主基底膜细胞DNA整合，引起HPV的E2片段(E2蛋白是主要的病毒转录因子，参与转录调节)的缺失，其缺失加速宫颈病变的进展，增加恶性转化的可能性，由于E2片段缺失引起HPV的E6/E7蛋白的表达，可以使抑癌蛋白P53、RB和P21等失活，促进和维持HPV DNA与宫颈基底细胞DNA整合，使宫颈基底细胞异常增生，从而使正常宿主细胞向恶性方向转化，另外E6/E7蛋白可以使HPV逃逸宿主的免疫监视以及干扰机体免疫反应。
HPV至今已鉴定明确的大约有200多个亚型，高危型HPV包括HPV16、18、31、33、35、39、45、51、52、53、56、58等。其中HPV16和HPV18是最主要的流行株。患者经常是多种HPV同时感染，因此有必要开发针对多种HPV的治疗性药物。
因此，亟待研究一种针对更多型号的HPV感染都有预防和治疗作用的重组蛋白，使其能够高效简便地用于预防或治疗HPV。
发明内容
本发明的目的是提供一种重组蛋白及其在HPV预防和/或治疗中的应用，对更多型号的HPV感染都有预防和/或治疗作用，实现高效预防和/或治疗HPV。
为实现上述发明目的，本发明技术方案如下：
一方面，本发明提供一种重组蛋白，所述重组蛋白包含HPV五种血清型L2蛋白片段中的一种或多种，所述HPV五种血清型L2蛋白选自6(13-75)、16(11-75)、18(12-75)、31(11-75)、39(12-75)。
优选地，所述重组蛋白包含上述HPV五种血清型L2蛋白片段中的任意两种、三种、四种或五种。
优选地，所述重组蛋白包含从氮端到碳端依次为(1)：6(13-75)和(2)：任意顺序连接的16(11-75)、18(12-75)、31(11-75)和39(12-75)。
优选地，所述重组蛋白包含从氮端到碳端依次为(1)：16(11-75)和(2)：任意顺序连接的6(13-75)、18(12-75)、31(11-75)、39(12-75)。
优选地，所述重组蛋白包含从氮端到碳端依次为(1)：18(12-75)和(2)：任意顺序连接的6(13-75)、16(11-75)、31(11-75)、39(12-75)。
优选地，所述重组蛋白包含从氮端到碳端依次为(1)：31(11-75)和(2)：任意顺序连接的6(13-75)、16(11-75)、18(12-75)、39(12-75)。
优选地，所述重组蛋白包含从氮端到碳端依次为(1)：39(12-75)和(2)：任意顺序连接的6(13-75)、16(11-75)、18(12-75)、31(11-75)。
优选地，所述L2蛋白片段之间直接连接。
优选地，所述L2蛋白片段之间通过氨基酸或多肽间接连接。
优选地，所述重组蛋白序列为SEQ ID NO.1。
SEQ ID NO.1：
ASATQLYQTCKLTGTCPPDVIPKVEHNTIADQILKWGSLGVFFGGLGIGTGSGTGGRTGYVPLKRASATQLYKTCKQAGTCPPDIIPKVEGKTIADQILQYGSMGVFFGGLGIGTGSGTGGRTGYIPLRASVTDLYKTCKQSGTCPPDVVPKVEGTTLADKILQWSSLGIFLGGLGIGTGSGTGGRTGYIPLKRASATQLYQTCKAAGTCPSDVIPKIEHTTIADQILRYGSMGVFFGGLGIGSGSGTGGRTGYVPLRASATDLYRTCKQSGTCPPDVVDKVEGTTLADKILQWTSLGIFLGGLGIGTGTGTGGRTGYIPL。
术语解释：本发明中，
“连接”若无特定指代，则包括直接连接或通过端点连接，同一条蛋白序列中的蛋白片段可以同时出现直接连接或端点连接，也可以全部直接连接或全部端点连接。
“6(13-75)”表示HPV 6型L2蛋白的第13-75位氨基酸；具体序列为ASATQLYQTCKLTGTCPPDVIPKVEHNTIADQILKWGSLGVFFGGLGIGTGSGTGGRTGYVPL。
“16(11-75)”表示HPV 16型L2蛋白的第11-75位氨基酸；具体序列为KRASATQLYKTCKQAGTCPPDIIPKVEGKTIADQILQYGSMGVFFGGLGIGTGSGTGGRTGYIPL。
“18(12-75)”表示HPV 18型L2蛋白的第12-75位氨基酸；具体序列为RASVTDLYKTCKQSGTCPPDVVPKVEGTTLADKILQWSSLGIFLGGLGIGTGSGTGGRTGYIPL。
“31(11-75)”表示HPV 31型L2蛋白的第11-75位氨基酸；具体序列为KRASATQLYQTCKAAGTCPSDVIPKIEHTTIADQILRYGSMGVFFGGLGIGSGSGTGGRTGYVPL。
“39(12-75)”表示HPV 39型L2蛋白的第12-75位氨基酸；具体序列为RASATDLYRTCKQSGTCPPDVVDKVEGTTLADKILQWTSLGIFLGGLGIGTGTGTGGRTGYIPL。
“6(13-75)和任意顺序连接的16(11-75)、18(12-75)、31(11-75)、39(12-75)连接”是指6(13-75)为首位，后面连接任意顺序连接的16(11-75)、18(12-75)、31(11-75)、39(12-75)。举例但不限于：6(13-75)/16(11-75)/18(12-75)/31(11-75)/39(12-75)；6(13-75)/16(11-75)/31(11-75)/18(12-75)/39(12-75)；6(13-75)/18(12-75)/16(11-75)/39(12-75)/31(11-75)；6(13-75)/18(12-75)/39(12-75)/16(11-75)/31(11-75)等。其中，“/”表示“连接”，“连接”的具体含义如前所述。
“16(11-75)和任意顺序连接的6(13-75)、18(12-75)、31(11-75)、39(12-75)连接”、“18(12-75)和任意顺序连接的6(13-75)、16(11-75)、31(11-75)、39(12-75)连接”、“31(11-75)和任意顺序连接的6(13-75)、16(11-75)、18(12-75)、39(12-75)连接”、“39(12-75)和任意顺序连接的6(13-75)、16(11-75)、18(12-75)、31(11-75)连接”具有与前述相同的含义。
再一方面，本发明提供一种免疫组合物，包括上述重组蛋白和MF59佐剂。
优选地，所述重组蛋白和MF59佐剂的体积比为1:0.1-2，进一步优选为1:0.5-2，进一步优选为1:1。
再一方面，本发明提供一种免疫组合物，包括上述重组蛋白和铝佐剂。
优选地，所述铝佐剂选自氢氧化铝凝胶、磷酸铝、硫酸铝、铵明矾、钾明矾中的至少一种。
优选地，所述重组蛋白和铝佐剂的质量比为1:0.5-5，进一步优选为1:1-2.5，最优选为1:2。
再一方面，本发明提供上述重组蛋白或组合物在制备预防和/或治疗HPV感染药物、疫苗中的应用。
再一方面，本发明提供一种预防和/或治疗HPV感染的药物，包括上述重组蛋白或组合物。
所述的药物类型包括但不限于注射药剂或黏膜给药药剂。
所述药物的给药方式包括但不限于：吸入给药、经粘膜或经皮渗透给药、肠外(皮内、肌肉内、皮下、静脉或腹腔内)给药。
所述的药物可以单独给药，或者可以与一个或多个进一步复合物同时或顺序给药。
最后，本发明提供一种预防和/或治疗HPV感染的疫苗，包括上述重组蛋白或组合物。
所述的疫苗中包括前述的T细胞表位肽和/或串联多肽和/或嵌合或融合多肽和/或生物学载体和/或Ii-key杂交构建体。
所述的疫苗中还包括药学上可接受的载体、赋形剂、稀释剂、佐剂、冻干稳定剂、润湿或乳化剂、pH缓冲剂、凝胶或增粘添加剂以及防腐剂。
所述的药学上可接受的载体、赋形剂或稀释剂的例子包括但不限于脱矿水或蒸馏水、盐水溶液、植物油、硅油、挥发性有机硅、矿物油、低级聚烷二醇或低级烷基二醇、脂肪酸酯、聚乙烯吡咯烷酮、琼脂、卡拉胶、西黄胶、阿拉伯胶、凡士林。
进一步地，所述的植物油包括但不限于：花生油、花生油、红花油、橄榄油、棉籽油、玉米油、芝麻油或椰子油。
进一步地，所述的硅油包括但不限于：聚硅氧烷，如甲基聚硅氧烷、苯基聚硅氧烷和甲基苯基聚硅氧烷。
进一步地，所述的矿物油包括但不限于：对羟基硅氧烷。
所述的低级聚烷二醇或低级烷基二醇包括但不限于：聚乙二醇、聚丙二醇、乙二醇、丙二醇、1,3-丁二醇或甘油。
所述的脂肪酸酯包括但不限于：如棕榈酸异丙酯、肉豆蔻酸异丙酯或油酸乙酯。
在一些实施例中，所述的疫苗复合物可以是液体制剂，例如水溶液、油包水或水包油乳剂，或用于皮下、皮内、肌肉内或静脉给药的制剂，例如无菌悬浮液或乳剂。液体制剂也可以包括含有悬浮剂或乳化剂的悬浮液和乳状液。给药途径可以是经皮给药、粘膜给药或皮内、肌肉内、皮下、静脉或腹腔内给药。
在一些实施例中，所述的疫苗以疫苗接种试剂盒的形式存在，本发明还提供了疫苗接种试剂盒，该试剂盒包括任选的无菌容器，该容器包括免疫有效剂量的疫苗、用于注射疫苗的装置、以及任选的说明书，该说明书包括用于治疗和/或预防HPV感染相关疾病的复合物的免疫有效剂量的管理信息。
本发明的有益效果为：
本发明提供了一种重组蛋白及其在HPV预防和/或治疗中的应用，相对于现有九价疫苗，该重组蛋白以及和不同佐剂的组合物可以同时对HPV6、11、16、18、31、33、35、39、45、51、52、56、58、59、66、68、73这17种亚型产生良好的预防和/或治疗作用，实现高效预防和/或治疗HPV。
附图说明
图1为层析1纯化图谱。
具体实施方式
以下非限制性实施例可以使本领域的普通技术人员更全面的理解本发明，但不以任何方式限制本发明。下述内容仅仅是对本申请要求保护的范围的示例性说明，本领域技术人员可以根据所公开的内容对本申请的发明做出多种改变和修饰，而其也应当属于本申请要求保护的范围之中。
下面以具体实施例的方式对本发明作进一步的说明。本发明实施例中所使用的各种化学试剂如无特殊说明均通过常规商业途径获得。若无特殊说明，下文中所述含量均为质量含量。若无特殊说明，理解为在室温下进行。
下述实施例中，所用磷酸铝购自CRODA，货号为21645-51-2；所用MF59购自Invitrogen，货号为Vac-adx-10。
实施例1重组蛋白的制备
(1)重组HPV目的抗原的制备
pET-L2重组质粒的制备：基因合成SEQ ID NO.1基因序列，并构建到Pet表达载体上，转化到大肠杆菌克隆载体，待培养后，采用质粒提取试剂盒提取重组质粒。
将pET L2重组质粒转化至大肠杆菌表达菌株，挑取重组子测序，将验证正确的重组子单菌落接种LB液体培养基中，37℃、220r/min恒温振荡培养过夜，取200μL培养基转接含抗生素的培养基中，相同条件培养，至培养液吸光度A值为0.6时，加入IPTG诱导融合蛋白的表达后收集菌体，置-80℃保存备用。
(2)重组HPV目的抗原的纯化
菌体重悬后以高压匀质仪破菌，离心去除上清；用洗涤缓冲液洗涤包涵体沉淀，沉淀溶于盐酸胍溶液中；再用疏水平衡缓冲液化，用不同浓度的缓冲溶液进行洗脱。将收集的层析流穿液、P1和P2收集液用10％SDS-PAGE检测，分析目的蛋白的纯化效果。第一步疏水层析，使用的填料包括但不限于Capto Phenyl，Capto Phenyl Impress，Phenyl-Sepharose6Fast Flow,Fractogel EMD Phenyl等苯基相关的疏水填料；第二步阳离子层析，使用的填料包括但不限于：Capto S，Capto SP Impress,FractogelEMD SO3-(M),Fractogel/>EMDSE Hicap(M),Fractogel/>EMD COO-(M)等；第三步分子筛层析，S200,Superdex200pg，Superdex75pg等。层析1图谱见图1。
所制备的重组蛋白序列如SEQ ID NO.1所示。
SEQ ID NO.1：
ASATQLYQTCKLTGTCPPDVIPKVEHNTIADQILKWGSLGVFFGGLGIGTGSGTGGRTGYVPLKRASATQLYKTCKQAGTCPPDIIPKVEGKTIADQILQYGSMGVFFGGLGIGTGSGTGGRTGYIPLRASVTDLYKTCKQSGTCPPDVVPKVEGTTLADKILQWSSLGIFLGGLGIGTGSGTGGRTGYIPLKRASATQLYQTCKAAGTCPSDVIPKIEHTTIADQILRYGSMGVFFGGLGIGSGSGTGGRTGYVPLRASATDLYRTCKQSGTCPPDVVDKVEGTTLADKILQWTSLGIFLGGLGIGTGTGTGGRTGYIPL。
对制备完成的重组蛋白进行相关检测，包括含量，纯度，无菌，内毒素、宿主DNA残留、宿主蛋白质残留，检测结果如下表。
实施例2免疫组合物的制备
无佐剂组：实施例1所得重组蛋白，用生理盐水稀释至0.2mg/ml。
MF59佐剂组：实施例1所得重组蛋白溶液，与MF59佐剂按照体积比1:2混合。
AL佐剂组：实施例1所得重组蛋白，与AL佐剂按照质量比1:2混合。
实施例3免疫过程
将制备好的免疫组合物与HPV 9价(Gardasil 9组)开展免疫原性比较(家兔)。
采用肌肉注射给药(兔大腿外侧肌肉，包括但不限于臀大肌和股四头肌，本次实验为臀大肌)，每次给药体积0.5ml/只(含重组蛋白0.1mg)，分别于第0天、第21天和第42天肌肉注射三次，每次给药1剂，每剂0.5ml。分别于第2天、第40天和第61天耳缘静脉采血，保证采血量不少于1ml。血清保存于-80℃供后续实验检测。采用ELISA检测兔血清抗L2抗体滴度。采用假病毒中和试验检测血清中和效价。对各组数据进行方差分析，P<0.05为差异具有统计学意义。
检测过程参考专利CN112439059B，免疫原性的评价方法为本领域的行规技术手段，本申请中，假病毒中和实验法更具体的操作方式如下：
将2×106cells/mlMCF 10A细胞接种在96孔细胞板培养，置于37℃，5％CO2培养箱中培养24h，再经过细胞裂解液理解处理，完成细胞基质膜的制备。
将制备的HPV假病毒接种于细胞基质膜中，再置于37℃，5％CO2培养箱中培养72h，加入表达了弗林酶的CHO-furin细胞上期，加入滴度稀释后的血清，37℃孵育12h，再接种pgsA-745细胞于基质膜中，于37℃，5％CO2中培养72h，取出细胞培养板，根据将荧光素酶检测试剂盒操作，取出反应液，在96孔化学发光检测板中，读取发光强度值。
中和抑制率：
抑制率＝[1－(供试品组的发光强度均值－细胞对照CC均值)/(病毒对照VC的发光强度均值－细胞对照CC均值)]×100％。
根据中和抑制率结果，利用Reed-Muench法计算IC50。
公式1：距离比例＝(抑制率高于50％的百分数-50％)/(抑制率高于50％的百分数-抑制率低于50％的百分数)；
公式2：lg(中和抗体效价)＝抑制率高于50％稀释度的对数+距离比例×稀释系数的对数。
计算中和抗体滴度，完成针对HPV6/11/16/18/31/33/45/39/45/51/52/56/58/59/66/68/73共17个型别的比较。结果如下：
从结果可以看出，本发明的重组蛋白可以同时对HPV6、11、16、18、31、33、35、39、45、51、52、56、58、59、66、68、73这17种亚型产生良好的预防和/或治疗作用，同时跟佐剂联合使用后可以使得效果进一步提高，同时，本发明的重组蛋白相对于Gardasil 9组(HPV 9价)而言，通过对额外8种高危HPV亚型的检测，证明可更高效地预防和/或治疗HPV。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (11)
1.一种重组蛋白，其特征在于，所述重组蛋白包含HPV五种血清型L2蛋白片段中的一种或多种，所述HPV五种血清型L2蛋白选自6(13-75)、16(11-75)、18(12-75)、31(11-75)、39(12-75)。
2.根据权利要求1所述的重组蛋白，其特征在于，所述的L2蛋白之间直接连接，或者通过氨基酸或多肽间接连接。
3.根据权利要求1所述的重组蛋白，其特征在于，所述重组蛋白序列为SEQ ID NO.1。
4.一种免疫组合物，其特征在于，包括权利要求1-3任一项所述重组蛋白和MF59佐剂。
5.根据权利要求4所述的免疫组合物，其特征在于，所述重组蛋白和MF59佐剂的体积比1:0.1-2。
6.一种免疫组合物，其特征在于，包括权利要求1-3任一项所述重组蛋白和铝佐剂。
7.根据权利要求6所述的免疫组合物，其特征在于，所述铝佐剂选自氢氧化铝凝胶、磷酸铝、硫酸铝、铵明矾、钾明矾中的至少一种。
8.根据权利要求6所述的免疫组合物，其特征在于，所述重组蛋白和铝佐剂的质量比为1:0.5-5。
9.权利要求1-3任一项所述重组蛋白或权利要求4-8任一项所述组合物在制备预防和/或治疗HPV感染药物、疫苗中的应用。
10.一种预防和/或治疗HPV感染的药物，其特征在于，包括权利要求1-3任一项所述重组蛋白或权利要求4-8任一项所述组合物。
11.一种预防和/或治疗HPV感染的疫苗，其特征在于，包括权利要求1-3任一项所述重组蛋白或权利要求4-8任一项所述组合物。
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