CN114031688B - 一种人源化抗体及其应用 - Google Patents
一种人源化抗体及其应用 Download PDFInfo
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- CN114031688B CN114031688B CN202210009222.4A CN202210009222A CN114031688B CN 114031688 B CN114031688 B CN 114031688B CN 202210009222 A CN202210009222 A CN 202210009222A CN 114031688 B CN114031688 B CN 114031688B
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Abstract
本发明公开了一种人源化抗体及其应用，该人源化抗体包括重链可变区和轻链可变区，能够特异性靶向IgG的CH1结构域162位点唾液酸化表位，所述重链可变区的氨基酸序列如SEQ ID NO.1所示，轻链可变区的氨基酸序列如SEQ ID NO.2所示。该人源化抗体能够有效抑制肿瘤细胞生长、侵袭及悬浮生长能力，具有明显的抗肿瘤作用，还可以抑制肿瘤细胞c‑Met/Wnt信号通路及FAK的信号通路活化。
Description
技术领域
本发明涉及免疫及基因工程技术领域，具体涉及一种人源化抗体及其在抗肿瘤药物中的应用。
背景技术
前期的研究发现，不但是B细胞高表达IgG，多种不同谱系起源的非B细胞同样可表达IgG，而且，非B细胞来源的IgG在结构和功能上与传统认识上的B细胞来源的IgG有很大差别。特别是发现上皮性肿瘤细胞表达水平显著高于正常细胞，这类在肿瘤细胞高表达的IgG能够促进肿瘤细胞的黏附能力，在体外和体内都促进肿瘤细胞的迁移和侵袭力，并且肿瘤干细胞高表达的IgG能够增强肿瘤干细胞自我更新和肿瘤形成及转移能力。基于此，近期对上皮起源的肿瘤细胞表达的IgG进行研究发现，其在CH1结构域上具有独特的非典型N糖基化位点，且其N糖链末端发生高唾液酸化修饰，重要的是，肿瘤细胞表达的IgG恰恰依赖其独特的唾液酸修饰实现促肿瘤、特别是促肿瘤干细胞的自我更新和肿瘤形成及转移，其同样能够作为标志物来识别上皮性肿瘤细胞、特别是肿瘤干细胞。
RP215是加拿大一课题组基于卵巢癌细胞系获得的单克隆抗体，RP215 识别的分子称为 CA215（癌抗原 215），被认为是泛癌标志物，当时认为其结合至RP215的抗原表位包括Ig的糖链以及黏蛋白等多种蛋白，但并未研究出RP215识别的具体抗原及其表位。经过本发明人的前期研究，最终发现RP215可以识别肿瘤细胞表达的IgG，其抗原表位是IgG的CH1结构域唾液酸化修饰的162位点。该位点可以作为上皮性肿瘤的特异性识别位点（专利号ZL201510776518.9）。然而目前除了单抗RP215以外，还没有其它以该IgG为特异性靶点的诊断或者治疗药物。
发明内容
本发明的目的是提供一种人源化抗体及其应用，该人源化抗体能够特异性识别CH1结构域带有唾液酸化修饰的IgG，具有诊断和治疗意义。
本发明技术方案详述如下：
一种人源化抗体，包括重链可变区和轻链可变区，能够特异性靶向IgG的CH1结构域162位点唾液酸化表位，所述重链可变区的氨基酸序列如SEQ ID NO.1所示，轻链可变区的氨基酸序列如SEQ ID NO.2所示。
一种编码基因，用于编码上述人源化抗体的重链可变区和轻链可变区，编码重链可变区的核苷酸序列如SEQ ID NO.3所示，编码轻链可变区的核苷酸序列如SEQ ID NO.4所示。
一种表达载体，含有上述编码基因。
一种宿主细胞，含有上述表达载体。
上述人源化抗体在制备抗肿瘤药物中的应用。
一种抗肿瘤药物，含有上述人源化抗体。
优选的，上述抗肿瘤药物，所述肿瘤为上皮性肿瘤。
上述人源化抗体在制备c-Met信号通路抑制剂中的应用。
上述人源化抗体在制备Wnt信号通路抑制剂中的应用。
上述人源化抗体的制备FAK信号通路抑制剂中的应用。
与现有技术相比，本发明具有如下有益效果：
本发明通过免疫及基因工程技术，研制出能够特异性识别CH1结构域带有唾液酸化修饰的IgG的人源化抗体，该抗体能够有效抑制肿瘤细胞生长、侵袭及悬浮生长能力，可作为抗肿瘤药物，为肿瘤治疗提供新的途径。
附图说明
图1为肺鳞癌细胞-NCI-H520培养体系中分别加入mIgG、SIG-003F（人源化抗SIG1）、SIG-004F（人源化抗SIG 2）、RP215后细胞总蛋白中FAK信号通路和c-Met信号通路相关蛋白的Western blot检测结果。
图2为肺鳞癌细胞-NCI-H520培养体系中分别加入mIgG、SIG-002F、SIG-001、RP215后细胞总蛋白中FAK信号通路相关蛋白和c-Met信号通路相关蛋白的Western blot检测结果。
图3为肺鳞癌细胞-NCI-H520培养体系中分别加入mIgG、RP215、SIG-002F、SIG-001体培养7天后的细胞生长情况。
图4为图3实验统计数据柱形图。
图5为mIgG、RP215、SIG-001分别抑制肿瘤细胞增殖（上）及侵袭（下）的效果。
图6为mIgG、RP215、SIG-001分别抑制肿瘤干细胞体外形成微球生长（左）、抑制肿瘤细胞生长的能力（中）和抑制肿瘤细胞在体外克隆生长的能力（右）的效应对比结果。
图7为mIgG、RP215、SIG-001分别抑制肺鳞癌肿瘤生长（体现为体积及重量降低）的效应对比结果，左上为随时间增加体内肿瘤体积变化曲线图，右上为不同组取出的肿瘤大小对比，左下为不同组肿瘤体积数值分布，右下为不同组肿瘤重量数值分布。
图8为实施例2的2.3部分不同组实验小鼠肿瘤组织蛋白中c-Met信号通路相关蛋白以及Wnt信号通路中相关蛋白的Western blot检测结果。
图9为用RP215对肺鳞癌PDX肿瘤细胞进行免疫组化染色结果。
图10为mIgG、RP215、SIG-001分别抑制胰腺癌肿瘤生长（体现为体积及重量降低）的效应对比结果，左上为随着时间增加小鼠体重的变化曲线图，右上为随时间增加体内肿瘤体积变化曲线图，中图为不同组取出的肿瘤大小对比，左下为不同组肿瘤重量数值分布，右下为不同组肿瘤体积数值分布。
图11为mIgG、RP215、SIG-001分别抑制结肠癌肿瘤生长（体现为体积降低）的效应对比结果。
具体实施方式
下面结合较佳的具体实施例对本发明的技术方案进行详细解释和说明，以使本领域技术人员能够更好地理解本发明并予以实施。
实施例中，SIG表示来源于上皮性肿瘤细胞的CH1结构域162位点N糖链唾液酸修饰的分泌型IgG。
抗体的重链和轻链可变区（V区）由高变区 (hypervariable region，HVR)和骨架区(framework region，FR )组成，高变区又称互补决定区(complementarity-determiningregion, CDR)，是与抗原表位结构相互补的关键区域，骨架区用于稳定高变区的空间构型。抗体重链和轻链可变区中HVR通常由3个结构域组成：HVR1、HVR2、HVR3；FR通常由四个结构域组成：FR1、FR2、FR3、FR4。HVR序列和FR序列通常按照以下顺序出现在重链可变区和轻链可变区中：FR1- HVR1- FR2- HVR2- FR3- HVR3 –FR4。实施例中人源化抗体即是指包含来自非人HVR的氨基酸残基和来自人FR的氨基酸残基的嵌合抗体。
实施例1 人源化抗体制备及筛选
1、抗SIG单克隆抗体获得
构建带有氨基酸序列如SEQ ID NO.5所示的IgG抗原表位肽的编码基因的重组IgG质粒，转入宿主细胞进行培养，表达产物经检测验证氨基酸序列正确，CH1结构域162位点有N糖基唾液酸修饰，即确定为SIG，收集保存。
以SIG作为抗原，免疫BALB/c小鼠，多次免疫后取小鼠脾脏细胞，与骨髓瘤细胞融合，培养杂交瘤细胞，筛选出能产生抗SIG抗体的阳性杂交瘤细胞，并进行克隆扩增，再对其所分泌的抗SIG单抗进行免疫球蛋白类型、亚类、特异性、亲和力、识别抗原的表位及其分子量鉴定、测序，筛选符合预期要求的杂交瘤细胞株，保存备用。
2、人源化抗SIG抗体表达载体的构建
将步骤1中保存的杂交瘤细胞株活化培养，收集其分泌的抗SIG单抗。该抗SIG单抗为BALB/c小鼠来源。
将小鼠来源的抗SIG单抗的重链可变区及轻链可变区序列的FR核苷酸序列替换为人IgG可变区FR核苷酸序列。获得多条人源化抗体重链可变区核苷酸序列及轻链可变区核苷酸序列。
将不同的重链可变区核苷酸序列及轻链可变区核苷酸序列分别进行人工合并，再连接到人源化抗体表达载体上，插入位点为重链及轻链恒定区序列的5’端，完成多个人源化抗SIG抗体表达载体的构建。
3、人源化抗SIG抗体表达载体的表达
将步骤2获得的所有人源化抗SIG抗体表达载体分别转染到HEK293细胞中，在无血清培养基中培养6天，然后收集上清，再分别用Protein G亲和层析柱纯化获得不同的人源化抗SIG抗体。保留实验成功的，总计获得4种不同的人源化抗SIG抗体，即重组抗体，作为候选抗体，分别标记为SIG-003F、SIG-004F、SIG-002F、SIG-001。
4、人源化抗SIG抗体的生物学活性筛选
将步骤3获得的重组抗体进行生物学活性筛选。
4.1 对癌细胞增殖、迁移及侵袭能力的抑制作用
4.1.1 对FAK信号通路和c-Met信号通路的抑制作用
整合素（integrin）是位于细胞表面的一类糖蛋白，是由α和β亚基通过非共价键组成的异二聚体，通过整合素/ FAK/p130cas和paxillin信号通路，调节癌细胞的侵袭转移。
FAK（focal adhesion kinase，粘着斑激酶）是整合素介导的信号传导通路的中心分子，整合素β亚基胞内域是FAK激活所必需的结构，在受到整合素刺激后，FAK发生酪氨酸磷酸化而激活，其中主要的自主磷酸化部位是Tyr397。Src通过Src同源区域（src homologyregion2, SH2）与FAK作用，进而连接其他胞内蛋白激酶，引起激酶链式反应。FAK通过SH2与c-Src连接后，引起c-Src不断聚集，c-Src聚集后通过自身磷酸化而活化成为p-Src。其SH2结构又可与talin和柱蛋白（paxillin）等结合，使talin和paxillin磷酸化，通过下游信号通路，改变细胞骨架，引起细胞形态、黏附功能等改变。
因此，在癌细胞增殖、迁移及侵袭能力正常时，其蛋白中FAK信号通路相关蛋白p-FAK Tyr397（Tyr397位点磷酸化的FAK）、p-Src Tyr416（Tyr416位点磷酸化的Src）、p-paxillin Tyr118（Tyr118位点磷酸化的paxillin）呈高表达状态。
c-Met是一种酪氨酸激酶受体，一个由二硫键连接的异二聚体，包含α和β链。HGF（hepatocyte growth factor，肝细胞生长因子）是c-Met的天然配体。HGF和c-Met作用后，c-Met形成磷酸化的p-Met（phosphorylated Met）而被激活，介导多种下游效应蛋白，进而促进癌细胞的增殖、扩散、血管形成、细胞黏附、侵袭等。激活的HGF/c-Met轴进一步引起PI3K-Akt信号通路和RAS-MAPK信号通路的激活，促进Akt磷酸化为p-Akt，Erk1/2磷酸化为p-Erk1/2（Erk1/2信号转导通路是RAS-MAPK信号通路家族的其中一条，参与细胞内激酶级联反应），促进癌细胞存活。所以癌细胞增殖、扩散、侵袭等功能正常时，p-Met、p-Akt、p-Erk1/2等相关蛋白高表达。
本实验选用肺鳞癌细胞-NCI-H520作为实验对象，分为多组，每组中加入以下不同的抗体：mlgG（阴性对照）、SIG-003F、SIG-004F、SIG-002F、SIG-001、RP215（阳性对照），每组中分别设置两个抗体浓度：10µg/ml、20µg/ml (抗体占培养基浓度)，相同条件下培养24小时后分别提取各组细胞总蛋白，进行Western blot检测，观察加入抗体后癌细胞蛋白中的FAK信号通路相关蛋白FAK、Src、paxillin及其磷酸化状态的表达水平、以及c-Met信号通路相关蛋白Met、Akt、Erk1/2及其磷酸化状态的表达水平。同时以GAPDH作为内参对照。
Western blot检测结果请参考图1和图2。
图1显示每组加入抗体浓度为10µg/ml培养24小时的蛋白中各信号通路相关蛋白的变化。图中显示加入抗体SIG-004F的试验组p-FAK Tyr397（Tyr397位点磷酸化的FAK）和p-Src Tyr416（Tyr416部位磷酸化的Src蛋白）表达量略有降低，p Paxillin Tyr118（Tyr118部位磷酸化的paxillin蛋白）表达量显著降低，p AKT Ser473（Ser473部位磷酸化的AKT蛋白）和pErk1/2（磷酸化的Erk1/2蛋白）表达量略有降低，总体来说不及阳性对照RP215，对其余蛋白的表达几乎没影响，说明SIG-004F对FAK信号通路和c-Met信号通路有一定的抑制效应（抑制FAK信号通路相关蛋白FAK、Src、Paxillin磷酸化，抑制c-Met信号通路Akt、Erk1/2磷酸化）。而SIG-003F对两种信号通路都没有明显的抑制效应。加入抗体浓度为20µg/ml时的检测结果各组间差别与10µg/ml时的相当。
图2显示每组加入抗体浓度为20µg/ml培养24小时的蛋白中各信号通路相关蛋白的变化，加入抗体SIG-001的试验组p-FAK Tyr397（Tyr397部位磷酸化的FAK蛋白）表达量显著降低，p-Met（磷酸化的Met蛋白）表达量略有降低，p-Src（磷酸化的Src蛋白）和p-Akt（磷酸化的Akt蛋白）表达量略有降低，总体来说与阳性对照RP215相当。说明SIG-001可以明显抑制FAK信号通路及c-Met信号通路（抑制该信号通路相关蛋白磷酸化）。而SIG-002F没有相应的效应。加入抗体浓度为10µg/ml时的检测结果各组间差别与20µg/ml时的相当。
因SIG-002F和SIG-001序列差别非常小，而SIG-001对FAK信号通路和c-Met信号通路影响较明显，所以决定使用SIG-002F和SIG-001进行后续筛选。
4.1.2 对癌细胞增殖速度的抑制
以肺鳞癌细胞-NCI-H520作为实验对象，分为四组，每个组设置了3个重复孔，每个培养孔均加1000个癌细胞，第一组加入mlgG，第二组加入SIG-002F，第三组加入SIG-001，第四组加入RP215，每组加入的抗体均为20µg/ml(占培养基浓度)。相同条件下培养7天。7天后检测各组细胞克隆数并对统计结果进行差异比较，结果如图3和图4所示。
结果显示，SIG-001可明显减少细胞克隆数（与阳性对照RP215相似），与阴性对照mlgG之间存在显著差异，表明SIG-001能够显著抑制癌细胞的增殖，而SIG-002F则没有相应的效应。
将SIG-001作为最终筛选到的人源化抗SIG抗体，抗体种属：人，重链亚型：IgG1，轻链亚型：κ。
重链氨基酸序列如SEQ ID NO.6所示，核苷酸序列如SEQ ID NO.7所示，其中的重链可变区部分氨基酸序列如SEQ ID NO.1所示；轻链（Kappa）氨基酸序列如SEQ ID NO.8所示，核苷酸序列如SEQ ID NO.9所示，其中的轻链可变区部分氨基酸序列如SEQ ID NO.2所示。
实施例2 人源化抗体的功能验证
2.1 抑制癌细胞增殖及侵袭
以肺鳞癌细胞-NCI-H520作为实验对象，分为三组，每组单孔加入10000个癌细胞，每组三个重复。第一组加入mlgG作为阴性对照，第二组加入SIG-001，第三组加入RP215作为阳性对照，各组加入量均为20μg/ml(占培养基浓度)，相同条件下培养7天，观察各组癌细胞的数量变化。另外通过Tran-swell侵袭实验检测三组抗体的侵袭能力。
结果如图5所示，上图可以看出加入抗体SIG-001的培养板孔内癌细胞数量与加入RP215的相当，显著少于加入mlgG的阴性对照组，说明SIG-001能够明显抑制癌细胞的增殖。下图Tran-swell侵袭实验结果显示相较于加入mlgG的阴性对照组来说，SIG-001能够明显抑制癌细胞的侵袭能力，效果与RP215相识。
2.2 抑制肿瘤细胞生长体外实验
以肺鳞癌细胞系NCI-H520作为实验对象，进行肿瘤干细胞微球培养实验：准备肿瘤干细胞单细胞悬液，计数后分三组，每组设两个浓度（10μg/ml、50μg/ml），每个浓度3个重复孔，每个孔10000个细胞，接种至无血清培养基，第一组加入mlgG作为阴性对照，第二组加入SIG-001，第三组加入RP215作为阳性对照，放入培养箱在相同条件下培养，每日摇晃数次，培养7天，观察微球形成情况。
实验结果参见图6，左图显示阳性对照RP215在10μg/ml、50μg/ml两个浓度时，其对肿瘤干细胞在体外形成微球生长的抑制能力差别不大。中图为同在10μg/ml的抗体浓度下SIG-001和RP215相较于阴性对照，每孔细胞计数的差别，显示SIG-001具有明显地抑制肿瘤细胞生长的能力，其效应与阳性对照RP215相似。右图为同在10μg/ml的抗体浓度下SIG-001和RP215相较于阴性对照，每孔细胞计数的差别，显示SIG-001具有明显地抑制肿瘤细胞在体外克隆生长的能力，其效应与阳性对照RP215相似。
2.3抑制肿瘤细胞生长体内实验
用来自肺鳞癌患者的肿瘤组织移植入重症联合免疫缺陷（SCID）-Beige小鼠体内，构建肺鳞癌PDX模型；
用来自胰腺癌患者的肿瘤组织移植入重症联合免疫缺陷（SCID）-Beige小鼠体内，构建胰腺癌PDX模型；
用结肠癌细胞系移植入重症联合免疫缺陷（SCID）-Beige小鼠体内，构建结肠癌CDX模型。
上述动物模型当肿瘤达到～100mm3后开始抗体治疗。每种模型小鼠分为三组，每组10只，以RP215作为阳性对照，以mIgG作为阴性对照，探讨SIG-001的抗肿瘤作用。将小鼠随机分配至各自的治疗组。通过尾静脉将mIgG或SIG-001或RP215（溶于PBS中）以5mg/kg的剂量每周两次注射、注射2周。治疗过程中在体测量各组小鼠肿瘤尺寸，监测肿瘤的生长情况。
肺鳞癌PDX模型体内BD44A-2抗体治疗效果参见图7，图7中左上为随治疗时间增加体内肿瘤体积变化曲线图，右上为治疗结束后各组小鼠体内取出的肿瘤大小，左下为不同组肿瘤体积数值分布，右下为不同组肿瘤重量数值分布。结果显示，随着治疗时间的增加，注射SIG-001的治疗组肺鳞癌PDX模型小鼠体内肿瘤的体积增长缓慢，取出肿瘤进行统计发现，其在抑制肿瘤组织的体积和重量方面和阳性对照RP215组无显著差异，而与阴性对照mIgG组有明显差异，说明SIG-001能够抑制体内肿瘤生长。
对实验过程中取出的肿瘤组织进行总蛋白提取，进行Western blot检测，观察总蛋白中c-Met信号通路相关蛋白Met、Akt、Erk1/2的磷酸化情况（p-Met、p-Akt、p-Erk1/2）以及Wnt信号通路中β-catenin的表达水平及GSK3β（糖原合成酶激酶3β）磷酸化情况（p-GSK3β），以GAPDH作为内参对照。
Wnt信号通路是一类在物种进化过程中高度保守的信号通路。Wnt信号通路包括三个分支，其中经典的Wnt信号通路即Wnt/β-cantenin信号通路。β-Catenin是检测Wnt是否激活的一个重要生物标志物。Wnt是一类分泌型糖蛋白，通过自分泌或旁分泌发挥作用。Wnt分泌后能与细胞表面特异性受体互相作用，通过一系列下游蛋白的磷酸化和去磷酸化过程，引起β-catenin积累。β-catenin是一种多功能的蛋白质，在细胞连接处与E-Cadherin（E型钙黏附蛋白）相互作用，参与形成黏合带，而游离的c-Catenin可进入细胞核，调节基因表达，其异常表达或激活能引起肿瘤。GSK3β（糖原合成酶激酶3beta）是一种丝氨酸/苏氨酸蛋白激酶，磷酸化的GSK3β（p-GSK3β）参与Wnt信号通路。
Western blot检测结果如图8所示，SIG-001治疗组肺鳞癌PDX模型小鼠肿瘤组织内p-Met、p-Akt、p-Erk1/2表达水平均显著低于阴性对照mIgG组，和阳性对照RP215组相当。SIG-001治疗组肺鳞癌PDX模型小鼠肿瘤组织内β-Catenin、p-GSK3β表达量显著低于阴性对照mIgG组，整体上效果和阳性对照RP215组相当。表明SIG-001能够明显地抑制PDX肿瘤c-Met/信号通路中Met、Akt及Erk1/2磷酸化，及Wnt通路中β-catenin及GSK3β磷酸化，其抑制效应与阳性抗体RP215相当。这可能是SIG-001能够抗肿瘤的作用机理之一。
图9显示了用RP215对肺鳞癌PDX肿瘤细胞进行免疫组化染色结果，表明肺鳞癌PDX肿瘤细胞膜呈现明显的阳性染色，即该细胞膜上含有大量CH1结构域162位点N糖基唾液酸修饰的分泌型IgG。
胰腺癌PDX模型体内BD44A-2抗体治疗效果参见图10。左上为随着时间增加小鼠体重的变化曲线图，右上为随时间增加体内肿瘤体积变化曲线图，中图为治疗结束后不同组小鼠体内取出的肿瘤大小，左下为不同组肿瘤重量数值分布，右下为不同组肿瘤体积数值分布。治疗结果显示，人源化抗体SIG-001能够明显地抑制肿瘤生长，体现为随着治疗时间增加，体内肿瘤的体积及重量增长与阴性对照组相比更为缓慢，其效应与阳性抗体RP215相似。值得说明的是，治疗过程中，SIG-001没有引起荷瘤小鼠体重的改变，小鼠体重变化趋势基本与阴性对照组mIgG一样（图10的左上图）。
结肠癌CDX模型体内BD44-2抗体治疗效果参见图11。上图为治疗后不同时间各组内小鼠体内肿瘤体积变化曲线，下图为阳性对照RP215治疗组、SIG-001治疗组以及阴性对照mIgG组内小鼠肿瘤体积测量数值分布的相互比较，显示RP215和SIG-001都与阴性对照有显著差异，SIG-001抑制体内肿瘤生长的效应与RP215无显著差异。
以上实施例验证了本发明获得的人源化抗体SIG-001在体外和体内均具有抑制肿瘤细胞增殖、生长的作用，并抑制肿瘤细胞FAK、c-Met/wnt信号通路的活化。
本文中应用了具体个例对发明构思进行了详细阐述，以上实施例的说明只是用于帮助理解本发明的核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离该发明构思的前提下，所做的任何显而易见的修改、等同替换或其他改进，均应包含在本发明的保护范围之内。
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<110> 北京大学
北京艾赛吉生物医药科技有限公司
<120> 一种人源化抗体及其应用
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cagaagttca agggcaaggt gaccctgaca gtggacacca gcaccagcac agcctttatg 300
caactttcct ccctgacctc tgaggacaca gcagtctact actgtgccag gagcatctat 360
gactggggac aaggcaccct ggtgacagtg tcctctgcta gcaccaaggg cccatcggtc 420
ttccccctgg caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg 480
gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc cctgaccagc 540
ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac tctactccct cagcagcgtg 600
gtgaccgtgc cctccagcag cttgggcacc cagacctaca tctgcaacgt gaatcacaag 660
cccagcaaca ccaaggtgga caagaaagtt gagcccaaat cttgtgacaa aactcacaca 720
tgcccaccgt gcccagcacc tgaactcctg gggggaccgt cagtcttcct cttcccccca 780
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 840
gtgagccacg aagaccccga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 900
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 960
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1020
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1080
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1140
acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1200
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1260
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1320
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1380
ggtaaatga 1389
<210> 8
<211> 239
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Val
20 25 30
Ser Val Gly Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu
35 40 45
Leu Asn Ser Ser Asn Gln Lys Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
50 55 60
Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Phe Ala Ser Thr Arg Glu
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Val Ala Asp Tyr Phe
100 105 110
Cys Gln Gln His Tyr Ser Thr Pro Ser Thr Phe Gly Gly Gly Thr Lys
115 120 125
Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
130 135 140
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
165 170 175
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 9
<211> 720
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
atgggctggt cctgtatcat cctgttcctg gtggctacag ccacaggagt gcatagtgac 60
attgtgatga cccagagccc atcctccctg tctgtgtctg tgggacaaaa ggtgacaatg 120
agttgtaagt ccagccagtc cctgctgaac tccagcaacc agaagtccta cctggcttgg 180
tatcaacaga agcctggaca aagcccaaaa ctgctgattt actttgccag caccagggag 240
tctggagtgc ctgacaggtt ctctggctct ggctctggca cagacttcac cctgaccatc 300
tcctctgtcc aggctgagga tgtggctgac tacttctgtc aacaacacta cagcacacca 360
agcacctttg gaggaggcac caaattggag attaagcgta cggtggctgc accatctgtc 420
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 480
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 540
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 600
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 660
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 720
Claims (10)
1.一种人源化抗体，包括重链可变区和轻链可变区，其特征在于，特异性靶向IgG的CH1结构域162位点唾液酸化表位，所述重链可变区的氨基酸序列如SEQ ID NO.1所示，轻链可变区的氨基酸序列如SEQ ID NO.2所示。
2.一种编码基因，其特征在于，用于编码权利要求1所述人源化抗体的重链可变区和轻链可变区，编码重链可变区的核苷酸序列如SEQ ID NO.3所示，编码轻链可变区的核苷酸序列如SEQ ID NO.4所示。
3.一种表达载体，其特征在于，含有权利要求2所述的编码基因。
4.一种宿主细胞，其特征在于，含有权利要求3所述的表达载体。
5.权利要求1所述人源化抗体在制备抗肿瘤药物中的应用，所述肿瘤为上皮性肿瘤。
6.一种抗肿瘤药物，其特征在于，含有权利要求1所述的人源化抗体，所述肿瘤为上皮性肿瘤。
7.根据权利要求6所述的抗肿瘤药物，其特征在于，所述肿瘤为肺鳞癌、胰腺癌和结肠癌中的一种或几种。
8.权利要求1所述人源化抗体在制备c-Met信号通路抑制剂中的应用。
9.权利要求1所述人源化抗体在制备Wnt信号通路抑制剂中的应用。
10.权利要求1所述人源化抗体在制备FAK信号通路抑制剂中的应用。
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