Both the epitope specificity and isotype are important in the antitumor effect of monoclonal antibodies against Her-2/neu antigen
Both the epitope specificity and isotype are important in the antitumor effect of monoclonal antibodies against Her-2/neu antigen
复制标题
DOI：
10.1002/ijc.10732
复制
发表时间：
2002-12-01
影响因子：
6.4
通讯作者：
Kang, CY
中科院分区：
文献类型：
--
作者：
Kim, KM;Shin, EY;Kang, CY
编码生长因子受体的Her-2/neu癌基因与人类腺癌的恶性程度有关。针对该分子的抗体先前已显示在体内具有抗肿瘤作用。为了了解抗肿瘤活性的机制，我们产生了2种单克隆抗体（mAb），HRO G1和HRT G1，其识别Her-2/neu上的不同表位。两种mAb均结合肿瘤表面上的HER 2/neu，导致HER 2/neu的磷酸化。我们还分别从这2种mAb产生了IgG 2a和IgG 2b mAb。体外研究结果表明，这些抗Her-2/neu单克隆抗体本身不能抑制表达Her-2/neu分子的肿瘤细胞的生长。然而，在使用小鼠脾细胞作为效应细胞的抗体依赖性细胞毒性研究中，HRT mAb的抗肿瘤活性上级于HRO mAb，表明表位特异性也可能参与抗体同种型的抗体依赖性细胞毒性。在补体依赖性细胞毒性研究中，无论表位特异性如何，IgG 2a和IgG 2b mAb均显示出比IgG 1同种型mAb更强的作用。体内实验结果也表明HRT单克隆抗体具有上级抗肿瘤活性。在HRT单抗中，HRT G2 b同种型的抗肿瘤活性最突出。HRT G 1也显示出中等的抗肿瘤作用，而HRT G 2 a仅显示出轻微的抑制作用。这些数据表明，单克隆抗体的表位特异性和Fc区的差异可能在抗肿瘤活性中发挥重要作用。(C)2002 Wiley-Liss，Inc.
The Her-2/neu oncogene, which encodes a growth factor receptor, was implicated in the malignancy of human adenocarcinomas. Antibodies directed to this molecule have been previously shown to have an antitumor effect in vivo. In an attempt to understand the mechanisms of the antitumor activity, we generated 2 monoclonal antibodies (mAbs), HRO G1 and HRT G1, that recognize different epitopes on Her-2/neu. Both of the mAbs bound HER2/neu on the tumor surface, resulting in phosphorylation of HER2/neu. We also generated IgG2a and IgG2b mAbs from these 2 mAbs, respectively. The results of in vitro studies showed that these anti-Her-2/neu mAbs could not inhibit the growth of the tumor cells that express Her-2/neu molecules by themselves. However, in an anti body-dependent cellular cytotoxicity study using mouse splenocytes as effector cells, HRT mAbs had antitumor activities superior to those of HRO mAbs, indicating that the epitope specificity may also partake in anti body-dependent cellular cytotoxicity with antibody isotype. In a complement-dependent cytotoxicity study, the IgG2a and IgG2b mAbs showed stronger effects than IgG1 isotype mAbs irrespective of the epitope specificities. The results of in vivo studies also showed that HRT mAbs had superior antitumor activity to those of HRO mAbs. The antitumor activity was most prominent in the HRT G2b isotype among HRT mAbs. HRT G I also showed a moderate antitumor effect, while HRT G2a showed only slight inhibition effect. These data indicate that both the epitope specificity and the differences in Fc region of mAbs could play important roles in the antitumor activities. (C) 2002 Wiley-Liss, Inc.