CN101633695B - 基于erbB2蛋白胞外区C-端功能表位特征设计抗erbB2功能抗体 - Google Patents
基于erbB2蛋白胞外区C-端功能表位特征设计抗erbB2功能抗体 Download PDFInfo
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Abstract
本发明提供了一种基于erbB2蛋白胞外区C-端功能表位结构特征设计获得新型抗erbB2人源抗体。其特征在于重链可变区氨基酸序列选自SEQ_ID NO：1、SEQ_ID NO：2、SEQ_ID NO：3、SEQ_ID NO：4、SEQ_ID NO：5或SEQ_ID NO：6；其轻链可变区氨基酸序列选自SEQ_ID NO：7、SEQ_ID NO：8、SEQ_ID NO：9、SEQ_ID NO：10、SEQ_ID NO：11或SEQ_ID NO：12。本发明提供的抗体可以特异性识别靶抗原及靶细胞；可以体外抑制靶细胞的增殖并介导ADCC活性杀伤靶细胞。
Description
技术领域
本发明涉及基于erbB2蛋白胞外区C-端功能表位结构特征设计获得新型抗erbB2人源抗体。具体而言，即利用erbB2晶体结构模型以及其功能抗体Herceptin识别的表位(erbB2蛋白胞外区C-端)特征，通过计算机辅助分子设计方法获得一种抗erbB2人源抗体；经生物信息学相关手段进行反向翻译确定其合适的基因结构，应用分子生物学技术进行基因全合成，并通过细胞生物学实验对抗体的功能进行评价。
背景技术
作为表皮生长因子受体家族(ErbB家族)成员，erbB2(HER2，HER2/neu)是具有酪氨酸激酶活性的跨膜糖蛋白。erbB2的分子结构可分为胞外域、跨膜域和胞内域三部分，其中胞外域又可分为D1、D3两个极相似的由β片层围成的桶状结构域和D2、D4两个富含半胱氨酸的结构域，胞内部分具有酪氨酸激酶活性。
大量研究结果显示，erbB2在乳腺癌、卵巢癌、前列腺癌、胃癌、肺癌等多种上皮细胞来源的恶性肿瘤中过表达。免疫组化染色可见乳腺癌细胞的erbB2水平较正常乳腺细胞高10～100倍。因此erbB2是 肿瘤免疫治疗的理想靶分子。
1998年，美国食品药品监督管理局(FDA)批准由Genetech公司开发的靶向erbB2的人源化单克隆抗体Herceptin
(罗氏公司产品，注射用曲妥珠单抗，又称赫赛汀，英文名Trastuzumab)上市，应用于ErbB2过表达的乳腺癌患者的临床治疗。目前，Herceptin
已成为广泛应用于转移性乳腺癌的一线临床治疗药物。
然而，一系列临床试验表明，Herceptin
的疗效有限，单独应用其有效率仅为11.6～16％，与化疗药物联合治疗的有效率可达50％，不过，联合用药可导致明显的心脏毒性；与此同时，Herceptin
昂贵的治疗费用也令第三世界国家的普通患者难以承受。因此，研发新的靶向erbB2人源抗体具有重要的临床和研究意义。
伴随着计算机辅助分子设计方法的不断完善以及本单位提出的“基于抗原-抗体相互识别立体结构信息设计新功能分子”方案，在获得的erbB2晶体结构的基础上，本项发明通过erbB2胞外区C-端结构域的构象特征，从理论上获得了一系列抗erbB2抗体分子，并通过实验进行了评价。
发明内容
为了提供新的抗erbB2抗体分子，本发明公开了一组抗erbB2人源抗体，其特征在于重链可变区氨基酸序列选自SEQ_ID NO：1、SEQ_ID NO：2、SEQ_ID NO：3、SEQ_ID NO：4、SEQ_ID NO：5或SEQ_ID NO：6；其轻链可变区氨基酸序列选自SEQ_ID NO：7、 SEQ_ID NO：8、SEQ_ID NO：9、SEQ_ID NO：10、SEQ_ID NO：11或SEQ_ID NO：12。
本发明公开的抗erbB2抗体是基于erbB2蛋白胞外区C-端功能表位特征利用计算机辅助设计获得的抗体。
本发明公开的抗体的一个特征是能特异性识别靶抗原：设计获得的抗体能够与重组蛋白erbB2特异性结合。
本发明获得的抗体的一个特征是能够特异性识别抗原表位：结合erbB2胞外区含有C-端功能表位的N-端缺失突变体erbB2-C，而与erbB2胞外区含有N-端功能表位的C-端缺失突变体erbB2-N不反应。
本发明公开的抗体的一个特征是设计获得的抗体能特异性地抑制erbB2阳性的SKOV3、MCF7以及SKBR3等肿瘤细胞增殖。
本发明公开的抗体的一个特征是设计获得的抗体能介导ADCC活性，特异性杀伤erbB2阳性的SKOV3、MCF7以及SKBR3等靶细胞。
本发明还公开了通过计算机辅助分子设计获得的抗erbB2人源抗体的设计流程(图16)。
具体实施过程如下：
1)抗原erbB2晶体结构及C-端功能表位结构特征分析；
2)利用计算机辅助分子设计获得的人源抗erbB2抗体可变区结构；
3)抗erbB2抗体与erbB2作用复合物结构模拟；
4)利用全合成PCR技术合成抗erB2抗体基因；
5)抗体的表达及鉴定
6)抗erbB2抗体生物学活性鉴定。
下面参照上述步骤详细描述抗erbB2人源抗体的设计及制备过程。设计及制备本发明抗体的方法仅仅是说明相关方法，并非是限制性的；也可以采用其他已知的方法，或者采用修改的方法。
1)抗原erbB2晶体结构及C-端功能表位结构特征分析
基于蛋白质结构数据库PDB提供的erbB2胞外区晶体结构(PDBcode：1n8y)，在CVFF、Amber力场下，依次选择最陡下降(收敛判据0.05kCal/mol，优化步长10000步)、共轭梯度(收敛判据0.02kCal/mol，优化步长20000步)，获得抗原erbB2胞外区理论空间构象。
利用erbB2与Herceptin
(罗氏公司产品，注射用曲妥珠单抗，又称赫赛汀，英文名Trastuzumab)相互作用的复合物晶体结构(PDBcode：1n8z)，在CVFF、Amber力场下，依次选择最陡下降(收敛判据0.05kCal/mol，优化步长20000步)、共轭梯度(收敛判据0.02kCal/mol，优化步长35000步)，获得erbB2与Herceptin
相互作用的理论空间构象。
通过计算机图形学、距离几何学以及分子间氢键理论，合理确定Herceptin
识别erbB2胞外区的功能表位。
2)利用计算机辅助分子设计获得的人源抗erbB2抗体可变区结构
在确定erbB2胞外区功能表位基础上，利用计算机虚拟筛选及计算机辅助分子设计方法设计拮抗erbB2功能的短肽(长度为10～15)，并将获得的一系列功能短肽作为抗体可变区的CDR区储备；借助源自TrEMBL、SwissProt、Kabat、IMGT等蛋白质数据库提供的抗体序列构建的人源抗体序列信息数据库；通过同源模建、力学优化技术将人源抗体序列信息数据库中人源抗体可变区框架与前面储备的CDR进行合理拼接构建合理的抗体可变区结构。
3)抗erbB2抗体与erbB2作用复合物结构模拟
借助分子对接、常温动力学模拟方法，合理评价构建的抗体可变区与erbB2相互作用模式，从理论上确定能够特异性识别erbB2的抗体可变区结构。
4)利用全合成PCR技术合成抗erB2抗体基因
根据获得的抗体序列，选择在哺乳动物细胞中常用的密码子进行反向翻译，获得相应的抗体基因。利用基因全合成PCR技术(见图1示意)，设计相应的引物，通过重叠PCR的方法获得全长基因；克隆入克隆载体，进行序列测定。
5)抗体的表达及鉴定
a)抗体的表达：将抗体基因构建至真核表达载体中，通过脂质体转染、电转等方法瞬时转染真核表达细胞，培养足够长时候后收获上清，其中含有表达的目的抗体。
b)双夹心酶联免疫吸附实验(ELISA)：以合适的抗体包被后作为捕获抗体，经过封闭后，加入待测样品以及标准样品进行捕获反应；随后利用合适的酶标二抗进行显色反应，测定样品中目的蛋白的含量。
c)SDS-PAGE：依据目的蛋白的大小配制合适浓度的聚丙烯酰胺凝胶，根据实验需要制备还原电泳样品或非还原电泳样品进行聚丙烯酰胺凝胶电泳，分离蛋白；经过考马斯亮蓝染色后，确定目的蛋白分子量。
6)抗erbB2抗体生物学活性鉴定
a)流式细胞分析：收集目的细胞；缓冲液(PBS+2％胎牛血清)洗涤后，加入一抗，4℃反应30mins；缓冲液洗涤2次，加入相应的二抗，4℃避光反应30mins，缓冲液洗涤2次后重悬在鞘液中直接进行流式细胞分析或者以1％的多聚甲醛固定，4℃避光保存。
b)间接免疫荧光检测：将目的细胞接种至平皿中，37℃5％CO2贴壁培养24h后，转染erbB2胞外区基因及其突变体基因(erbB2基因SwissProt注册号：P04626，胞外区为23位氨基酸到652位氨基酸，突变体构建参看图10A所示：N端缺失突变体erbB2-C为erbB2胞外区基因缺失含D1及D2结构域的23到302位氨基酸，C端缺失突变体erbB2-N为erbB2胞外区基因缺失含D3及D4结构域的306到652位氨基酸；目的基因通过酶切位点Xho I和Hind III构建到pEGFP-N1(Clonetech公司产品)载体上，获得的载体分别命名为pEGFP-N1-erbB2、pEGFP-N1-erbB2-N、pEGFP-N1-erbB2-C)。继续培养24h后，收集细胞。缓冲液(PBS+2％胎牛血清)洗涤后，加入一抗，4℃反应30mins；缓冲液洗涤2次，加入相应的二抗，4℃避光反应30mins，缓冲液洗涤2次后利用流式细胞分析，观察实验结果。
c)抑制生长实验：以erbB2阳性细胞作为靶细胞，加入不同浓度的抗体作用于靶细胞，设立阴性对照、阳性对照及实验组；作用24h后，以MTT法测定抗体对靶细胞生长抑制活性。
d)抗体依赖的细胞毒试验(ADCC)：标记erbB2阳性细胞作为靶细胞，用淋巴细胞分离液从外周血中分离出外周血单个核细胞作为效应细胞；根据相应比例混合后，加入不等量的抗体，于圆底96孔培养板上进行杀伤实验，设立实验孔、靶细胞自发释放孔、最大释放孔及背景孔；37℃孵育2h。利用多功能酶标仪进行检测，计算杀伤率。
附图说明
图1基因全合成PCR技术示意图。
图2基于erbB2胞外区晶体结构(PDB code：1n8y)，依次选择CVFF、Amber力场，利用力学优化方法通过分子模拟获得的erbB2胞外区理论空间构象飘带结构。
图3利用erbB2与Herceptin作用晶体结构，通过力学优化、常温动力学模拟获得的抗原(erbB2)与抗体(Herceptin)相互作用复合物理论空间结构。
图4合理确定的erbB2胞外区C-端功能表位分布结构。
图5利用计算机分子设计及虚拟筛选获得的抗体HF1与抗原erbB2相互作用的复合物结构。
图6重叠PCR技术全合成抗体基因。M：标准分子量对照；VH表示抗体的重链可变区基因，分子量约为350bp；VL表示抗体的轻链可变区基因，分子量大小约为320bp。
图7表达产物SDS-PAGE分析。A图显示非还原的SDS-PAGE分析结果，表达产物分子量为155KDa，提示表达产物与抗体分子量一致； B图结果显示，表达产物在还原条件下的SDS-PAGE分析呈现55KDa及25KDa两个条带，具有典型的抗体特征；提示获得的表达产物为抗体。
图8抗体亲和力分析。利用流式细胞分析技术测定抗体的亲和力，结果提示HF1高亲和力地结合靶细胞，并且抗体的亲和力优于Hercepin。
图9抗体识别特异性的鉴定。抗体HF1可特异性结合erbB2阳性肿瘤细胞SKOV3、MCF7、SKBR3，其结合的活性与上市抗体Herceptin类似(阴影图形表示对照，空白图形表示实验结果)。
图10抗体HF识别表位的鉴定。A：erbB2以及缺失突变体的构建，B：与Herceptin一致，HF1能特异性识别erbB2以及N端缺失突变体erbB2-C，而与erbB2胞外区C端缺失突变体erbB2-N不反应；提示设计筛选获得的抗体HF可以特异地结合erbB2胞外区C端表位(图中细线表示对照结果，粗线表示实验结果；)。
图11抗体HF1体外抑制erbB2阳性细胞增殖。A：抗体抑制SKOV3细胞增殖，B；抗体抑制MCF7细胞增殖，C：抗体抑制SKBR3细胞增殖。
图12抗体HF1体外通过介导ADCC效应杀伤erbB2阳性细胞，A：抗体介导ADCC效应杀伤SKOV3细胞，B；抗体介导ADCC效应杀伤MCF7细胞，C：抗体介导ADCC效应杀伤SKBR3细胞。
图13目的抗体的亲和力与Herceptin相近。
图14抗体体外抑制erbB2阳性细胞增殖。A：抗体抑制SKOV3细胞增殖，B；抗体抑制MCF7细胞增殖，C：抗体抑制SKBR3细胞增殖。
图15抗体体外通过介导ADCC效应杀伤erbB2阳性细胞，A：抗体介导ADCC效应杀伤SKOV3细胞，B：抗体介导ADCC效应杀伤SKBR3细胞，C：抗体介导ADCC效应杀伤MCF7细胞。
具体实施方式
图16计算机辅助分子设计获得的抗erbB2人源抗体的设计流程。
实施例一 抗erbB2抗体的合理设计
一、材料：
InsightII 2005程序包(MSI分子模拟，San Diego)，该程序包包括：
Homology同源模建；
Discover力学优化；
Discover_3常温动力学模拟；
Docking分子对接；
Delphi表观静电势能分析。
Ludi分子设计程序(1995)；
IBM图形工作站；
PDB 2008数据库(网络www.rcsb.org下载)；
SwissProt数据库(2008，网络下载)；
Kabat数据库(2001，网络下载)；
IMGT数据库(2008，网络下载)。
二、方法结果：
1、抗原erbB2胞外区空间构象模拟
利用已有的erbB2胞外区晶体结构(PDB code：1n8y)，在同源模建方法的基础上，合理加氢并附合适的力场参数，依次选择最陡下降、共轭梯度对erbB2胞外区结构进行优化，获得常温稳定、结构参数合理的理论空间构象(图2)。
借助主链碳原子均方根位移评判方法，将理论获得的erbB2胞外区结构与其晶体结构进行结构叠合，计算获得的RMSD(Root MeanSquare Distance，均方根位移)值为0.028nm，提示优化获得的结构是合理的。
2、erbB2胞外区C-端功能表位的合理确定
借助已有的erbB2胞外区与Herceptin
相互作用晶体结构(PDBcode：1n8z)，选择CVFF、Amber力场经最陡下降、共轭梯度对复合物结构进行力学优化，获得复合物稳定理论构象(图3)。
利用距离几何学、计算机图形学技术，通过分子间氢键形成理论、Van der Waals相互作用，对获得的复合物稳定构象进行理论分析，确定erbB2胞外区C-端功能表位(图4)。
3、新型抗erbB2抗体分子设计
利用确定的erbB2胞外区C-端功能表位的结构特征，通过Ludi程序经片段生长方法设计能够识别该特征表位的短肽序列；利用从头搭建与二级结构预测连用模拟拮抗短肽的空间构象。
借助源自网络数据库PDB、SwissProt、TrEMBL、Kabat、IMGT获得的抗体序列信息构成的人源抗体可变区框架结构数据库，与上述拮抗短肽合理组合拼接构成新型人源抗体可变区。利用设计的抗体可变区序列经同源模建技术搭建其空间构象。
利用分子对接方法构建抗体可变区与抗原erbB2相互作用的复合物结构。在考虑溶剂效应的前提下，通过常温动力学模拟获得抗体与抗原相互作用的复合物模型，通过相互作用能确定能够作用于抗原erbB2的抗体可变区结构。进一步优化获得的新型人源抗体可变区氨基酸序列，最终获得六条靶向erbB2的重链氨基酸序列(SEQ_ID NO：1、SEQ_ID NO：2、SEQ_ID NO：3、SEQ_ID NO：4、SEQ_ID NO：5和SEQ_ID NO：6)以及六条轻链可变区氨基酸序列(SEQ_ID NO：7、SEQ_ID NO：8、SEQ_ID NO：9、SEQ_ID NO：10、SEQ_ID NO：11和SEQ_ID NO：12)。
实施例二抗erbB2抗体HF1的制备及其功能验证
一、材料：
引物设计软件为biosun软件，引物由上海英骏生物技术有限公司合成；Pyrobest DNA polymerase为TAKARA公司产品；dNTP为TAKARA公司产品；pGEM-T Easy vector system为Invitrogen公司产品；T4DNA连接酶为NEB公司产品；基因测序由北京诺赛基因组研究中心有限公司完成；抗体真核表达载体pTGS-FRT-DHFR由本公 司构建并申请国家专利(专利授权号：ZL200510064335.0)；脂质体、MTT为Invitrogen公司产品，羊抗人IgG、及辣根酶标记的羊抗人IgG及人IgG为本公司制备；pEGFP-N1载体为Clonetech公司产品；内切酶为NEB公司产品；SKVO3、MCF7、SKBR3购自ATCC；DELFIAEuTDA细胞毒作用试剂盒为PE公司产品；其他试剂为市购产品。
二、方法结果
1、抗体与抗原相互作用的复合物模型搭建
随机选择SEQ_ID NO：1及SEQ_ID NO：7分别作为抗体HF1的重链和轻链可变区氨基酸序列，经同源模建技术搭建其空间构象。利用分子对接方法构建抗体可变区与抗原erbB2相互作用的复合物结构。在考虑溶剂效应的前提下，通过常温动力学模拟获得抗体与抗原相互作用的复合物模型，通过相互作用能确定能够作用于抗原erbB2的抗体可变区结构。图5给出了抗体HF1与抗原erbB2相互作用的复合物结构。
2、抗体基因全合成
2.1抗体氨基酸序列通过反向翻译获得核苷酸序列
选择在哺乳动物细胞中使用频率较高的密码子，将计算机设计筛选获得的抗体轻重链可变区氨基酸序列反向翻译，获得抗体的可变区核苷酸序列。根据构建抗体真核表达载体需要，在抗体轻链可变区基因5’端及3’端分别引入EcoR V和Xho I酶切位点；在抗体重链链 可变区基因5’端及3’端分别引入Pvu II和BstE II酶切位点。
2.2引物设计
根据基因全合成的原理，利用计算机辅助设计软件，设计引物，考虑引物的二级结构、GC含量等相关参数。每条基因设计10条引物，分别编号为P1、P2、P3、P4、P5、P6、P7、P8、P9及P10，用于基因全合成。
2.3全基因合成
1)引物合成后以无菌水稀释，方法如下：
a)取引物管12000RPM离心2mins，引物按100μM的浓度稀释，-20℃保存；
b)取少量引物P2～P9混合成终浓度为10μM作为使用液；
c)取少量引物P1和P10混合稀释成终浓度为10μM作为使用液P1/P10；
2)基因全合成，采用Pyrobest DNA polymerase，方法如下：
a)取1μL P2～P9混合引物作为模板，配制如下重叠PCR体系：
P2～P9混合引物 1μL
dNTP 3μL
10×Buffer 5μL
Pyrobest DNA polymerase 0.3μL
P1/P10引物 4μL(引物先不加)
无菌水补足总体积为50μL
b)将以上PCR体系进行如下反应：
95℃ 5mins
72℃ 7mins
反应结束后，降到室温。
加入引物P1/P10，进行如下PCR反应：
95℃ 5mins
72℃ 7mins
反应结束后，降到室温。
c)1～2％琼脂糖凝胶电泳分离PCR产物，抗体重链基因回收350bp大小片段，轻链基因回收320bp大小片段。
d)回收加尾(Pyrobest DNApolymerase不能在PCR产物3’端加尾A，所以不能直接连接T载体)，作如下10μL体系：
回收片段 8.2μL
10×Buffer 1μL
dNTP 0.5μL
普通Taq酶 0.3μL
反应条件如下：72℃20mins，反应结束后，降到室温。
e)取加尾产物，连接pGEM-T Easy载体：
加尾产物 4.2μL
2×连接Buf 5μL
T载体 0.5μL
T4连接酶 0.3μL
室温连接2h或者4℃连接过夜，连接产物转化JM109大肠杆菌，涂布在含有100μg/mL氨卞青霉素(终浓度)的LB琼脂培养基上。获得的克隆在含有100μg/mL氨卞青霉素(终浓度)的LB液体培养基中培养，用质粒提取试剂盒(博大泰克公司)提取质粒，获得的质粒进行核酸测序鉴定。
重叠PCR扩增后经过琼脂糖凝胶电泳分析，获得特异大小的目的条带(图6)；产物经过回收、加尾、克隆等分子生物学技术，成功克隆入pGEM-T Easy载体；经过测序鉴定，合成的基因与目的序列一致，获得的载体分别命名为pGEM-T-HF1VL和pGEM-T-HF1VH。
3、抗体的表达
3.1抗体真核表达载体的构建
选择本公司获得的含有人IgG1抗体恒定区基因的表达载体pTGS-FRT-DHFR(专利授权号：ZL200510064335.0)作为本发明抗体的表达载体。将实施例一所述获得的抗体轻重链可变区基因克隆载体用相应的内切酶消化(重链可变区基因用Pvu II和BstE II消化， 轻链可变区基因用EcoR V和Xho I消化)后，与经相同内切酶消化的载体连接。经过转化等分子生物学常用技术，构建获得真核表达载体。具体实施如下：
a)取pGEM-T-HF1VL用EcoRV和Xho I消化；
b)取1μg pTGS-FRT-DHFR载体，用EcoR V和Xho I消化。用DNA连接酶T4连接所得的经EcoR V及Xho I消化的pTGS-FRT-DHFR载体和用EcoR V及Xho I消化的抗体轻链可变区基因。连接产物转化JM109大肠杆菌，涂布在含有100μg/mL氨卞青霉素(终浓度)的LB琼脂培养基上。获得的克隆在含有100μg/mL氨卞青霉素(终浓度)的LB液体培养基中培养，用质粒提取试剂盒(博大泰克公司)提取质粒。所提取的质粒经EcoRV和Xho I消化后，用1％琼脂糖凝胶电泳分析，选择一个携带有抗体轻链可变区基因的克隆。作为上述程序的结果，获得的携带抗erbB2人源抗体轻链可变区基因的质粒pTGS-HF1VL。
d)取pGEM-T-HF1VH用Pvu II和BstE II消化；
e)取1μg pTGS-HF1VL载体，用Pvu II和BstE II消化。用DNA连接酶T4连接所得的经Pvu II和BstE II消化的pTGS-HF1VL载体和用Pvu II和BstE II消化的抗体重链可变区基因。连接产物转化JM109大肠杆菌，涂布在含有100μg/mL氨卞青霉素(终浓度)的LB琼脂培养基上。获得的克隆在含有100μg/mL氨卞青霉素(终浓度)的LB液体培养基中培养，用质粒提取试剂盒(博大泰克公司)提取质粒。所提取的质粒经Pvu II和BstE II消化后，用1％琼脂糖凝胶 电泳分析，选择一个携带有抗体重链可变区基因的克隆。
作为上述程序的结果，在pTGS-HF1VL基础上获得的携带抗erbB2人源抗体重链可变区基因的质粒pTGS-HF1。
3.2抗体表达
将获得的真核表达载体，通过脂质体介导的方法瞬时转染至CHO细胞，48h后收获上清，通过双夹心ELISA法以及SDS-PAGE等实验分析目的抗体的表达情况。
利用羊抗人IgG以及辣根酶标记的羊抗人IgG进行双夹心ELISA法检测上清中抗体的含量，以未转染上清作为阴性对照，人IgG纯品作为标准品。实验结果显示，表达获得的目的蛋白可以被羊抗人IgG抗体识别，含有人IgG抗体的恒定区，具有人IgG抗体特征。以非还原的形式进行SDS-PAGE实验，结果显示表达的目的蛋白约为155KDa，符合抗体的分子量(图7A)。还原形式进行的SDS-PAGE实验结果显示，目的蛋白在还原条件下呈两条特异性条带，分别为55KDa和25KDa(图7B)，具有典型的抗体特征。提示获得的抗体序列经过反向翻译得到的基因在真核细胞中可成功表达，表达获得的蛋白为抗体分子，具有典型的IgG抗体特征。
4、抗体的功能鉴定
4.1HF1单克隆抗体的识别鉴定
SKVO3细胞为乳腺癌细胞系，细胞表面表达大量的erbB2抗原，利用该细胞对获得的抗体HF1进行功能鉴定。流式细胞分析结果(图 8)显示，经过计算机辅助设计获得的靶向erbB2抗原的HF1可以特异性识别SKVO3细胞，并且抗体的亲和力优于Hercepin。
进一步鉴定HF1的识别活性，流式细胞分析结果(图9)显示，该抗体可以特异性地识别SKVO3、MCF7、SKBR3等肿瘤细胞系。
将erbB2胞外区及跨膜区基因构建在pEGFP-N1载体上，与EGFP融合表达；同时构建erbB2胞外区N端缺失突变体erbB2-C以及erbB2胞外区C端缺失突变体erbB2-N。将这些载体分别转染293T细胞后，通过间接免疫荧光观察抗体HF1对其识别功能。结果显示(图10)，HF 1能特异性识别erbB2以及N端缺失突变体erbB2-C，而与erbB2胞外区C端缺失突变体erbB2-N不反应；提示设计筛选获得的抗体HF可以特异地结合erbB2胞外区C端表位。
4.2抑制及杀伤肿瘤细胞功能
利用SKVO3、MCF7、SKBR3等肿瘤细胞系对获得的抗体抑制肿瘤细胞生长及杀伤肿瘤细胞的功能进行验证。
利用SKVO3、MCF7、SKBR3进行生长抑制实验(图11)，与人IgG对照组相比较，目的抗体具有明显的抑制SKVO3、MCF7及SKBR3细胞生长的活性，并且抑制活性与阳性对照Hercetpin类似；同时，与erbB2在SKVO3、MCF7及SKBR3细胞上表达的丰度呈正相关性，抗体HF对细胞增殖的抑制率：SKVO3＞SKBR3＞MCF7。
ADCC实验中以标记的SKVO3、MCF7、SKBR3细胞为靶细胞，以人外周血单个核细胞为效应细胞，当效靶比为50∶1时，抗体都能有效杀伤靶细胞；抗体浓度为20μg/mL时，杀伤率可达50％左右(图 12)，对于erbB2低表达的MCF7细胞，抗体介导的杀伤率(约30％)明显低于SKBR3及SKVO3细胞；结果与阳性对照Hercetpin类似。
实施例三抗erbB2抗体HF2、HF3、HF4、HF5、HF6的制备及其功能验证
根据实施例二所述的方法，随机选择SEQ_ID NO：2及SEQ_IDNO：8分别作为抗体HF2的重链和轻链可变区氨基酸序列；SEQ_IDNO：3及SEQ_ID NO：9分别作为抗体HF3的重链和轻链可变区氨基酸序列；SEQ_ID NO：4及SEQ_ID NO：10分别作为抗体HF4的重链和轻链可变区氨基酸序列；SEQ_ID NO：5及SEQ_ID NO：11分别作为抗体HF5的重链和轻链可变区氨基酸序列；SEQ_ID NO：6及SEQ_ID NO：12分别作为抗体HF6的重链和轻链可变区氨基酸序列；利用计算机辅助分析，考察这些抗体与靶抗原erbB2的复合物作用模式的合理性。利用实施例二所述的方法，对抗体的氨基酸序列进行反向翻译、全基因合成，进而对抗体进行表达以及功能鉴定。
获得的靶向erbB2抗原的抗体均可以特异性识别SKVO3细胞，并且抗体的亲和力与Hercepin相近(图13)。
利用SKVO3、MCF7、SKBR3等肿瘤细胞系对获得的抗体抑制肿瘤细胞生长及杀伤肿瘤细胞的功能进行验证。结果显示，与人IgG对照组相比较，目的抗体均具有明显的抑制SKVO3、MCF7及SKBR3细胞生长的活性，并且抑制活性与阳性对照Hercetpin类似(图14)。 ADCC实验中，以标记的SKVO3、MCF7、SKBR3细胞为靶细胞，以人外周血单个核细胞为效应细胞，当效靶比为50∶1时，抗体都能有效杀伤靶细胞；抗体浓度为20μg/mL时，杀伤率可达50％左右(图15)；对于erbB2低表达的MCF7细胞，抗体介导的杀伤率略低于SKBR3及SKVO3细胞，约为40％；结果与阳性对照Hercetpin类似。
序列表
<110>北京天广实生物技术有限公司
中国人民解放军军事医学科学院基础医学研究所
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Gln Ile Val Met Thr Gln Thr Pro Ser Ser Leu Ser Val Ser Leu
1 5 10 15
Gly Glu Lys Ala Thr Met Ser Cys Arg Ala Thr Asn Ser Val Ser
20 25 30
Ser Ala Thr Ala Trp Tyr Leu Gln Lys Ser Gly Thr Ser Pro Arg
35 40 45
Leu Leu Val Tyr Ser Gly Thr Tyr Ile Phe Ser Gly Ile Pro Glu
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Phe Thr Phe Thr Val
65 70 75
Ser Ser Leu Gln Pro Asp Asp Phe Gly Val Tyr Tyr Cys Phe Asn
80 85 90
His Phe Thr Ser Pro Pro Ser Phe Gly Gly Gly Thr Lys Leu Glu
95 100 105
Ile Arg
107
Claims (2)
1.一种抗erbB2人源抗体，其特征在于重链可变区氨基酸序列为SEQ_ID NO：4；轻链可变区氨基酸序列为SEQ_ID NO：10。
2.权利要求1所述抗体在制备诊断或治疗erbB2高表达恶性肿瘤的药物中的应用。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9714294B2 (en) | 2010-05-27 | 2017-07-25 | Genmab A/S | Monoclonal antibodies against HER2 epitope |
| US9862769B2 (en) | 2010-05-27 | 2018-01-09 | Genmab A/S | Monoclonal antibodies against HER2 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140170149A1 (en) | 2011-04-20 | 2014-06-19 | Genmab A/S | Bispecific antibodies against her2 and cd3 |
| CN118206662A (zh) * | 2024-05-14 | 2024-06-18 | 中国人民解放军军事科学院军事医学研究院 | 一种靶向Her2的新型单克隆抗体及其应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008019290A2 (en) * | 2006-08-04 | 2008-02-14 | Astrazeneca Ab | Human antibodies to erbb 2 |
| CN101165068A (zh) * | 2006-10-18 | 2008-04-23 | 上海复旦张江生物医药股份有限公司 | 抗HER2/ErbB2抗原的单克隆抗体及其制备方法和药物组合物 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008019290A2 (en) * | 2006-08-04 | 2008-02-14 | Astrazeneca Ab | Human antibodies to erbb 2 |
| CN101165068A (zh) * | 2006-10-18 | 2008-04-23 | 上海复旦张江生物医药股份有限公司 | 抗HER2/ErbB2抗原的单克隆抗体及其制备方法和药物组合物 |
Non-Patent Citations (1)
| Title |
|---|
| 宋淑霞 等.抗人c2erbB2单克隆抗体的制备及其特异性鉴定.《细胞与分子免疫学杂志》.2005,第21卷(第3期),319-321. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9714294B2 (en) | 2010-05-27 | 2017-07-25 | Genmab A/S | Monoclonal antibodies against HER2 epitope |
| US9862769B2 (en) | 2010-05-27 | 2018-01-09 | Genmab A/S | Monoclonal antibodies against HER2 |
Also Published As
| Publication number | Publication date |
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| CN101633695A (zh) | 2010-01-27 |
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