CN111647067A - AP-2alpha抗体联合用药用于制备治疗宫颈癌的药物中的用途 - Google Patents
AP-2alpha抗体联合用药用于制备治疗宫颈癌的药物中的用途 Download PDFInfo
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- CN111647067A CN111647067A CN202010634618.9A CN202010634618A CN111647067A CN 111647067 A CN111647067 A CN 111647067A CN 202010634618 A CN202010634618 A CN 202010634618A CN 111647067 A CN111647067 A CN 111647067A
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Abstract
本发明涉及AP‑2alpha抗体与索拉非尼联合用药治疗宫颈癌的用途，其相比单独使用AP‑2alpha抗体或索拉非尼，具有更好的治疗效果，两种药物产生了协调效应，有很好的临床使用前景。
Description
技术领域
本发明涉及抗体领域，具体的涉及一种AP-2alpha的单克隆抗体及用于制备治疗宫颈癌的药物中的用途。
背景技术
宫颈癌是威胁广大妇女的重要疾病。据统计，世界范围每年约有_50万新发病例及24万患者死亡。而我国是世界上宫颈癌的高发区之一，每年新增的宫颈癌患者约13.15万左右，占世界宫颈癌新发病例总数的28.％。随着宫颈细胞学筛查的广泛开展，美国近50年来宫颈癌的死亡率显著降低。但经济原因导致发展中国家的宫颈癌筛查远远落后于发达国家，因而宫颈癌成为妇女常见的癌症类型。
宫颈癌的传统治疗方法只对早期患者有一定的疗效，且治疗创伤大，不能防止HPV再度感染。未感染HPV的患者，接种预防性疫苗是最佳选择，对于己感染HPV的患者，早干预及早治疗尤为重要。目前，HPV感染的治疗方面尚无特别有效的药物，在治疗过程中常常伴随着严重的副作用。
在过去的几十年中，靶向免疫激动或抑制性受体的免疫调节抗体能够提高宿主的抗肿瘤免疫力，产生了有效的治疗反应。关于这些疗法的一般前提是，携带癌症的宿主具有对存在于其体内的肿瘤抗原具有特异反应性T细胞，只是它们的功能受到肿瘤微环境的抑制。而这些免疫调节抗体有助于通过增加抗原呈递细胞和T细胞的表达和功能来抵消这种免疫抑制，最终使肿瘤消退。
除了目前较为成熟的靶向PD-1/PD-L1通路的治疗抗体，许多肿瘤坏死因子受体CTNFR)家族成员也成为潜在的免疫治疗抗体靶点，如CD40、OX40和4-1BB就是比较重要的共刺激受体分子。众所周知，幼稚T细胞的激活需要强大的T细胞受体一MHC抗原肽相互作用以及抗原呈递细胞表达的共刺激分子的参与。在没有这些共刺激信号的情况下，活化的幼稚T细胞则为无能状态或发生凋亡；因此，共刺激信号对于效应T细胞的应答必不可少。靶向CD40和4-1BB的激动性抗体，因其具有刺激活化T细胞和增强其克隆扩增和存活的潜力而得到了广泛关注。一些研究表明，治疗性疫苗与肿瘤坏死因子受体C TNFR家族共刺激分子的激动剂联合，可以诱导有效和持久的T细胞反应，极大地促进开发免疫应答的新联合方案。
刘志英等通过索拉非尼联合贝伐单抗对小鼠宫颈癌细胞株U14的作用,观察发现了抗体药物联合使用能够对细胞株U14的移植瘤细胞结构产生变化，具有抑制肿瘤生长的效果。杨亚培通过四甲基偶氮吐蓝(methyl thiazolyl tetrazolium,MTT)比色法及流式细胞术(flow cytometry,FCM)检测法发现S 1OOA4-单克隆抗体联合紫杉醇对Hela细胞体外生长具有相当的影响。
AP-2作为一个重要的转录因子家族，研究表明AP-2在宫颈癌中起着重要的调控作用。其中AP-2alpha在细胞生长和肿瘤发生中起着重要作用(Cancer Res，2004，64：631-638)。AP-2alpha的功能一部分是通过与AP-2alpha下游基因启动子区域结合，促进其表达来实现。癌基因ErbB2在宫颈癌中广泛过表达，一直以来是研究治疗的靶点。ErbB2在肿瘤细胞中功能丢失将导致细胞生长抑制，并引起凋亡。最新研究报道ErbB2基因的表达下调促进了宫颈癌细胞的凋亡，从而达到治疗宫颈癌的目的。有研究表明AP-2alpha与癌基因ErbB2基因启动子结合，促进ErbB2基因的转录和蛋白表达，从而显示了AP-2alpha在宫颈癌发生发展中的调控作用。
CN 101705227 A公开了利用生物数据库获得人AP-2alpha基因序列，设计一组能诱发人AP-2alpha的RNA干扰的siRNA，通过化学法合成一定量的siRNA，从而特异性降低人AP-2alpha基因的mRNA水平和蛋白表达水平，同时该siRNA极大地降低了转录因子AP-2alpha在宫颈癌细胞HeLa中对癌基因ErbB2的转录水平和蛋白水平的激活，从而抑制了肿瘤细胞的增殖。但是针对AP-2alpha的高亲和性特异性单克隆的抗体的研究还非常少，联合用药也涉及不多。
发明内容
本发明为了克服现有技术的缺陷，提供了一种AP-2alpha免疫原片段，其氨基酸序列如SEQ ID NO:1所示，其核苷酸序列如SEQ ID NO：2所示。
本发明还提供了一种表达载体，包括本发明提供的编码AP-2alpha免疫原片段的核苷酸。
本发明还提供了一种宿主细胞，转化本发明所述的表达载体。
本发明还提供了产生本发明所述抗AP-2alpha单克隆抗体的杂交瘤细胞株。
本发明还提供了产生本发明所述抗AP-2alpha单克隆抗体。
进一步的，所述抗体的重链可变区序列如SEQ ID NO:3所示，轻链可变区如SEQ IDNO:4所示.
本发明提供的抗AP-2alpha单克隆抗体的制备方法包括：
步骤1：以本发明提供的抗原免疫小鼠后，获得小鼠的脾细胞；
步骤2：融合所述脾细胞和骨髓瘤细胞，筛选能够与AP-2alpha结合的杂交瘤细胞株，经体外培养，制得抗AP-2alpha单克隆抗体。
本发明所述抗AP-2alpha单克隆抗体经化学标记或生物标记制得的结合物。
所述生物标记为生物素、亲和素或酶标记。
本发明所述抗AP-2alpha单克隆抗体、结合物和/或偶联物在制备检AP-2alpha表达的产品中的应用。
本发明还提供了一种试剂盒，包括所述抗AP-2alpha单克隆抗体、结合物和/或偶联物。
本发明所述抗AP-2alpha单克隆抗体在制备防治疾病的药物中的应用；所述疾病为宫颈癌。
本发明还提供了一种药物，包括本发明所述抗AP-2alpha单克隆抗体。
一种疾病的防治方法，给予本发明所述的药物；所述疾病为宫颈癌。
本发明进一步的，提供了一种药物组合物，其由索拉非尼和AP-2alpha单克隆抗体组成。
进一步的，所述药物组合物中个药物的用量为索拉非尼12mg/kg，5mg/kgAP-2alpha-3B6单抗。
有益效果
本发明通过制备杂交瘤细胞获得了特异性针对AP-2alpha肽段的高亲和力的单克隆AP-2alpha-3B6，其具有较好的抑制宫颈癌细胞增殖的效果。同时通过联合给药发现索拉非尼和AP-2alpha单克隆抗体能够具有更好的抑制癌细胞增殖的效果。
附图说明
图1 AP-2alpha蛋白纯化结果图，泳道1是Ni柱纯化结果，泳道2为空白载体对照纯化结果图。
图2单克隆抗体效价的检测结果图
图3 Western blot检测结果图
图4单抗抑制细胞增殖效果图
具体实施方式
本发明提供了抗AP-2alpha单克隆抗体及其应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
“抗体”是指由能特异结合抗原的一种或多种多肽构成的蛋白质。抗体的一种形式构成了抗体的基本结构单元。这种形式是四聚物，它由两对完全相同的抗体链构成，每一对都有一个轻链和一个重链。在每对抗体链中，轻链和重链的可变区联合在一起共同负责结合抗原，而恒定区则负责抗体的效应器功能。
“抗体”包括任何同型体的抗体或免疫球蛋白，或保持与抗原特异结合的抗体片段，包括但不限于Fab，Fv，scFv和Fd片段、嵌合抗体、人源化抗体、单链抗体以及包含抗体的抗原结合部分和非抗体蛋白质的融合蛋白质。抗体可以被标记和检测，例如，可以通过放射性同位素、能产生可检测物的酶、荧光蛋白质、生物素等等进行标记并被检测。抗体还可以结合于固相载体，包括但不限于聚苯乙烯平板或珠粒等等。
实施例1 AP-2alpha抗原肽片段的筛选及表达
根据NCBI上AP-2alpha的基因和氨基酸序列，通过抗原表位的优化筛选，发明人筛选并获得了具有较高免疫原性以及等电点的AP-2alpha抗原片段其氨基酸序列如SEQ IDNO：1所示，等电点pH 6.60适宜于原核表达，蛋白分子量为12.47KD左右。
SEQ ID NO：1：
1 QSQESGLLHT HRGLPHQLSG LDPRRDYRRH EDLLHGPHAL SSGLGDLSIH SLPHAIEEVPHVEDPGINIP DQTVIKKGPV
81 SLSKSNSNAV SAIPINKDNL FGGVVNPNEV FCSVPG
通过在密码子优化后，得到了相应的核苷酸序列，如SEQ ID NO：2所示。
SEQ ID NO：2：
将所述核苷酸序列通过全基因序列合成，克隆到原核表达载体pET-28a上获得pET-28a-AP-2alpha重组原核表达载体。pET-28a-AP-2alpha转化到BL21(DE3)菌株中，在37℃下培养至OD600nm值为0.8时，加入终浓度为1mM的IPTG诱导表达8h，然后收集菌体并进行超声破碎，10000r/min离心后留上清，用Ni柱对目的蛋白进行纯化。结果如图1所示，目的蛋白大小为13Kd左右，并且是上清表达，而且表达量较高，通过Ni柱纯化后，纯度达到95％以上。将纯化后的蛋白配制成为10mg/mL的浓度，备用。
实施例2单克隆杂交瘤的制备
1、小鼠的免疫：
以抗原与佐剂的体积为1:1的比例对免疫原人AP-2alpha(实施例1制得)进行乳化，首次免疫使用弗氏完全佐剂乳化抗原，2周后，开始第二次免疫，使用弗氏不完全佐剂乳化抗原，皮下2点注射，每只小鼠注射的抗原的量为10μg，每个注射点注射的体积为20μL，共10只。
在第二次免疫后3天，对小鼠进行眼眶采血，取少量血液样本进行血清效价检测，经间接ELISA方法检测血清效价滴度达到1:150000的小鼠AP1、AP3和AP6进行加强免疫。
2、饲养细胞和骨髓瘤细胞的准备
饲养细胞的准备，剪开正常BALB/C小鼠(拉颈处死)的腹部皮肤。暴露腹膜。用注射器吸取DMEM培养基后，注入小鼠腹腔中，洗涤吸取出腹腔巨噬细胞，收集于离心管中1500rmp/min离心3min，取下层褐色沉淀重悬后备用。
骨髓瘤细胞准备，提前一周复苏P3X63Ag8.653，并用含1X 8-氮鸟嘌呤的完全培养基培养，融合前两天换用15％胎牛血清的DMEM培养，维持P3X63Ag8.653的密度为80％至融合当天。
3、细胞融合及HAT筛选：
脾细胞的获取和制备：取加强免疫后的小鼠AP1、AP3和AP6，采集免疫血清后处死并浸泡于75％酒精中。剪开免疫小鼠的腹部侧面的皮肤和腹膜，暴露脾脏。用剪尖剔除周围组织获取脾脏，用研磨棒研磨后，经细胞筛网过滤后制备成单细胞悬液。
细胞融合前处理：收集培养瓶内的P3X63Ag8.653，1000rpm/5min离心后弃上清，重悬后进行活细胞计数。2000rpm/5min离心脾细胞悬液，弃上清后重悬并进行活细胞计数。记录P3X63Ag8.653活细胞数，脾细胞活细胞数。
细胞融合：按脾细胞：P3X63Ag8.653＝6:1的比例混合细胞，2000rpm/5min离心后倒净上清，震散细胞沉淀，在37℃水浴中缓慢滴加1mL预热的55％PEG4000溶液，并使管底在37℃水中轻轻摇动，上述操作时间控制在1min，静置反应30s，于管内由慢到快地加入37℃预热的DMEM培养基，终止反应。将终止反应后的细胞悬液800rpm离心3min后弃去上清，轻轻震散细胞沉淀。
HAT培养基筛选：配制含1×HAT、1×青-链霉素、15％胎牛血清和85％DMEM培养基的HAT筛选培养基。用上述的HAT筛选培养基重悬鼠杂交瘤细胞和饲养细胞，并混合两者。按300μl/孔将细胞悬液加到20块96孔细胞培养板中，置于37℃细胞培养箱中培养。培养1周后，用HT培养基进行第一次换液，并置于37℃细胞培养箱中培养；培养3天后，用HT培养基进行第二次换液。
4、阳性细胞株的筛选
融合后2周，取细胞上清进行ELISA实验，检测细胞上清与人AP-2alpha蛋白的结合情况，筛选出ELISA结果为阳性的细胞后，进行第二次Elisa实验的复测将阳性细胞株从96孔中转入24孔中培养，待长满后转入25cm2培养瓶中培养。
5、有限稀释法亚克隆
吹打混匀阳性细胞株，并吸取少量进行活细胞计数。吸取约100个细胞加入40mL完全培养基中混匀，铺板2块；另吸取约100个细胞加入20mL完全培养基中混匀，铺板1块；另吸取约1000个细胞加入20mL完全培养基中混匀，铺板1块；共以3个不同的细胞密度铺板4块，分别为0.5细胞/孔,1细胞/孔,10细胞/孔。将96孔板置37℃5％CO2培养箱中培养。
6、克隆检测和扩大培养
取单克隆细胞孔上清进行ELISA实验，检测细胞克隆抗体与AP-2alpha蛋白的结合情况。其中ELISA检测为强阳性的细胞株1株命名为AP-2alpha-3B6从96孔中转入24孔中培养，待长满后转入25cm2培养瓶中培养，取部分细胞冷藏备用。
7.单克隆抗体的大量制备
选取6周龄BALB/c小鼠，腹腔注射弗氏不完全佐剂0.5mL/只；3天后腹腔注射AP-2alpha-3B6杂交瘤细胞，每只小鼠105-106个细胞，杂交瘤细胞用1640基础培养基重悬；注射第8天起可观察到小鼠腹腔微隆，继续饲养，鼠腹腔涨圆，行动不便时，可收取腹水。方法如下:小鼠腹部皮毛经酒精棉球消毒后，在超净工作台中，用20mL注射器的针头穿刺至小鼠腹腔，流出的淡黄色液体收集至离心管中。1000g,离心10min，取上清即为腹水。
实施例3单克隆抗体效价的检测
采用间接ELIS A法检测所获得的腹水的效价，具体操作方法为:用28a-AP-2alpha纯化蛋白和pET-28a空载体蛋白包被酶标板，将腹水1:200倍开
始进行倍比稀释作为一抗，以HRP标记的羊抗鼠IgG为二抗。当OD630值大于1时，杂交瘤细胞腹水的最大稀释倍数为ELISA效价。
间接ELISA检测结果如图所示(图2)，AP-2alpha-3B6抗体腹水效价为1:409600。
实施例4单克隆抗体的亚型鉴定
用SouthernBiotech公司的抗体亚型鉴定试剂盒进行检测，方法如下:TMB底物和检测孔提前平衡至室温，用TBS将腹水按1:75000进行稀释(即先取1uL腹水加入到5mL TBS中，再从中取67ul的稀释液加入到933uL TBS中)；将稀释好的单克隆抗体样品加入到检测孔中，再加入SOIL HRP羊抗小鼠IgG+IgA+IgM,轻轻混匀，室温孵育1h；弃去酶标板中的液体，加入200uL 1XWash Buffer洗涤5min，重复3次；加入75uL TMB底物显色15min；最后加入75uL终止液，用酶标仪测定OD450值，大于0.2的判定为阳性。结果如下表1所示：
表1单克隆抗体的亚型鉴定
| AP-2alpha-3B6 | |
| Ig亚型 | IgG<sub>2b</sub> |
| 轻链 | Kappa |
根据OD450值进行判断从表1可以看出，本发明的单克隆抗体亚型，重链是IgG2b，轻链为Kappa。
实施例5单克隆抗体基因测序
1.单克隆抗体基因测序
将AP-2alpha-3B6单克隆抗体细胞株进行总RNA提取，并反转录成cDNA，然后以cDNA为模板PCR扩增抗体的重链可变区和轻链可变区。总RNA采用Invitrogen公司的RNA提取试剂盒按照其说明书进行提取。接着采用Takara公司的5’RACE FULL试剂盒，以总RNA为模板，试剂盒中的随机引物进行反转录为第一链cDNA，然后重链以恒定区设计引物CTCAGGGAARTARCCYTTGAC和试剂盒中的接头引物进行PCR扩增，轻链以恒定区设计引物TCACTGCCATCAATCTTCCAC和试剂盒中的接头引物进行PCR扩增。琼脂糖凝胶回收试剂盒回收PCR片段进行TA克隆后调单克隆进行PCR鉴定，鉴定引物为M13-F和M13-R，鉴定正确的菌株送至Invitrogen测序。最终确定重链可变区。
重链可变区蛋白序列为SEQ ID N0：3
QVQLVQSQAEVKKPGATVKVSCKASPVSFTGGGMHWVRQAPGQGLEWMGWYNSNSQQANYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCSRECVRVPSTYAAYMSYWGKGTTVTVSS
轻链可变区蛋白序列为SEQ ID N0：4
DVVMTQSPDGLPVTPGESATISYRSSVSAQYSNGYYMLDWYLLKPGQSPQLLIYMSYNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGLYYCRSRLESSYAFGQGTRLEIK
实施例6单克隆抗体AP-2alpha-3B6与人AP-2alpha蛋白的亲和力测定
使用Biacore T200仪器检测人AP-2alpha抗体的亲和力常数，通过氨基共价结合将抗小鼠Fc抗体偶联在CM5生物传感芯片上，芯片上的抗小鼠Fc抗体捕获候选单克隆抗体，不同浓度的实施例的人AP-2alpha重组蛋白以30μL/min流速流过过芯片上的候选抗体，人AP-2alpha重组蛋白与候选抗体进行结合，结合时间为120s，解离时间为300s。用BIAevalution软件进行动力学拟合，获得亲和力常数结果如下表2：
表2单克隆抗体AP-2alpha-3B6与人AP-2alpha的亲和力测定结果
| 抗体名称 | Ka(1/Ms) | Kd(1/s) | KD(nM) |
| AP-2alpha-3B6 | 3.23E5 | 0.006472 | 19.9 |
实施例7抗体的Western blot检测
将实施例1制备的蛋白经过SDS-PAGE后蛋白转移到PVDF膜上，以14V的电压电转50min。将膜放入预先用PBST缓冲液洗涤后的平皿，用1％的脱脂乳4℃过夜封闭，用PBST缓冲液洗涤PVDF膜3次，每次15min。加入1∶500比例稀释的来自实施例2腹水并纯化的单克隆抗体，37℃孵育4h，用PBST缓冲液洗涤PVDF膜3次，每次15min，然后加入1:5000比例稀释的辣根过氧化氢酶标记的兔抗羊IgG,37℃孵育2h,PBST缓冲液洗涤PVDF膜3次，每次15min。后用显色剂显色后拍照。从图3可以看出，使用Western blot检测发现重组蛋白可以有效的结合单克隆抗体，并且具有加好的特异性。
实施例8 AP-2alpha单克隆抗体对宫颈癌HeLa细胞的作用
将单克隆抗体浓度依次配置成为1μg/mL、10μg/mL、20μg/mL、50μg/mL。实验设1个空白组、4个不同浓度的实验组。空白组是仅含有RPMI1640培养液，对照组是含有Hela细胞和RPMI1640培养液，每孔设5个平行对照。每组分别培养24小时、48小时、72小时后，采用MTT法测单抗对细胞的抑制率。结果如图4所示(空白对照对细胞增殖基本没有影响，在此没有在图中显示)，同一浓度的单克隆抗体在不同作用时间对宫颈癌Hela细胞增殖有抑制作用，随着药物作用延长，细胞抑制率缓慢增加。该单抗药物对宫颈癌Hela细胞的抑制作用于抗体作用时间有关联，在50μg/mL的浓度下，作用72h后，细胞的抑制率最高达到了65％，具有较好的效果。
实施例9联合给药对宫颈癌细胞的抑制效果实验
人宫颈癌SiHa细胞购自上海冠导生物工程有限公司(C4431)。常规方法从液氮罐中取出SiHa细胞冻存液，迅速经37℃水浴后加入RPMI-1640培养液吹打混匀，1000r/min离心5min，弃上清液，加入适量含10％牛血清的RPMI-1640培养液，吹打成细胞悬液，置于37℃、5％CO2。培养箱内培养。观察细胞生长情况，细胞长至80％融合时，用胰酶消化传代后备用。
BALB/c裸小鼠适应性生长1周后，取对数生长期的SiHa细胞，用胰酶消化后，用PBS分别配制成1×107/mL浓度的单细胞悬液，在无菌条件下皮下注射接种于裸小鼠背侧近右腋窝处，每只0.2mL。在皮下接种SiHa的第6天,挑取肿瘤直径≥5mm的荷瘤鼠48只,按照完全随机化分组的方法将小鼠分为6组,分别为空白对照组(A组)、AP-2alpha-3B6单抗组(B组)、AP-2alpha-3B6单抗+贝伐单抗(C组)、索拉非尼+AP-2alpha-3B6单抗(D组)、贝伐单抗(E组)、索拉非尼(F组)，用药均采用腹腔注射,用药24d后,处死小鼠，计算抑瘤率，具体用药量以及结果如下表3所示。
表3联合用药的抑瘤率结果
结果显示在药物腹腔注射开始至最后，小鼠体重开始缓慢持续增加,各组小鼠趋势基本一致。D组小鼠抑瘤率为81.70％,抑瘤率最高,效果相对最好。这说明本发明的单抗可以和化药索拉非尼进行联合用药，具有较好的抑制效果，比与贝伐单抗联用的药效要好，具有有效促进肿瘤细胞凋亡的效果,为临床治疗提供了依据。
尽管本发明的内容已经通过上述优选实施例作了详细介绍，但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后，对于本发明的多种修改和替代都将是显而易见的。因此，本发明的保护范围应由所附的权利要求来限定。
序列表
<110> 北京广未生物科技有限公司
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Claims (5)
1.一种组合，其特征在于：由索拉非尼和AP-2alpha单克隆抗体组成，其中AP-2alpha单克隆抗体具有氨基酸序列为SEQ ID NO:3的重链可变区，和氨基酸序列为SEQ ID NO:4的轻链可变区。
2.如权利要求1所述的组合，其特征在于所述药物组合物中个药物的用量为索拉非尼12mg/kg，AP-2alpha单克隆抗体5mg/kg。
3.索拉非尼和AP-2alpha单克隆抗体的组合在制备用于制备治疗宫颈癌的药物中的用途；其中AP-2alpha单克隆抗体具有氨基酸序列为SEQ ID NO:3的重链可变区和氨基酸序列为SEQ ID NO:4的轻链可变区。
4.如权利要求3所述的用途，其特征在于所述药物组合物中各药物的用量为索拉非尼12mg/kg，AP-2alpha单克隆抗体5mg/kg。
5.如权利要求4所述的用途，其特征在于所述的抗AP-2alpha单克隆抗体其重链类型为IgG2b；其轻链类型为Kappa。
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