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首页> 外文期刊>Asian Pacific Journal of Cancer Prevention >Epitope mapping of human HER2 specific mouse monoclonal antibodies using recombinant extracellular subdomains of HER2
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Epitope mapping of human HER2 specific mouse monoclonal antibodies using recombinant extracellular subdomains of HER2

机译：使用HER2的重组细胞外亚结构域对人HER2特异性小鼠单克隆抗体的表位作图

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Background: Human epidermal growth factor receptor 2 (HER2) is overexpresed in several human malignancies. Numerous studies show that HER2 plays an important role in the development and maintenance of the malignant phenotype. Targetting of HER2 molecule by monoclonal antibodies (mAbs) is a promising therapeutic approach. Anti-HER2 mAbs affect cancer cells differently, targeting distinct epitopes of HER2. Methods: Reactivity of a panel of 8 mouse anti-HER2 mAbs was investigated by ELISA and Western blotting using different subdomains of the extracellular domain (ECD) of HER2. All subdomains of HER2, including I, II, III, IV, I+II, III+IV and full HER2-ECD were constructed and expressed in CHO cells. Cross-reactivity of the mAbs with other members of the human HER family and Cynomolgus HER2 was also studied by ELISA. The mAbs were also tested by immunohistochemistry (IHC) using HER2 positive breast cancer tissues. Results: Our results demonstrated that 3 out of 8 mAbs detected conformational epitopes (1T0, 2A8 and 1B5), while 5 mAbs identified linear epitopes (1F2, 1H9, 4C7, 1H6 and 2A9). Three of the mAbs recognized subdomain I, one mAb reacted with subdomain I+II, 2 mAbs recognized either subdomain III or IV and 2 mAbs recognized subdomain III+IV. However, none of our mAbs recognized subdomain II of HER2 alone. The mAbs displayed either inhibitory or stimulatory effect on HER2-overexpressing tumor cells and did not react with other members of the human HER family. The pattern of IHC results implies better reactivity of the linear epitopes recognizing mAbs. Conclusion: Our findings suggest that paired subdomains of HER2 are essential for mapping of mAbs recognizing conformational epitopes. Moreover, it seems to be no association between subdomain specificity and antitumor activity of our anti-HER2 mAbs.
机译：背景：人类表皮生长因子受体2（HER2）在几种人类恶性肿瘤中过度表达。大量研究表明，HER2在恶性表型的发生和维持中起着重要作用。用单克隆抗体（mAb）靶向HER2分子是一种有前途的治疗方法。抗HER2 mAb对癌细胞的影响不同，靶向HER2的不同表位。方法：使用HER2胞外域（ECD）的不同亚域，通过ELISA和Western印迹研究了一组8种小鼠抗HER2单抗的反应性。在CHO细胞中构建并表达了HER2的所有子域，包括I，II，III，IV，I + II，III + IV和完整的HER2-ECD。还通过ELISA研究了mAb与人HER家族的其他成员和食蟹猴HER2的交叉反应性。还使用HER2阳性乳腺癌组织通过免疫组织化学（IHC）测试了mAb。结果：我们的结果表明，每8 mAb中有3个检测到构象表位（1T0、2A8和1B5），而5 mAb则鉴定了线性表位（1F2、1H9、4C7、1H6和2A9）。三个mAb识别亚结构域I，一个mAb与亚结构域I + II反应，2个mAb识别亚结构域III或IV，2 mAbs识别亚结构域III + IV。但是，我们的mAb都不能单独识别HER2的亚结构域II。单克隆抗体对过表达HER2的肿瘤细胞显示出抑制或刺激作用，并且不与人类HER家族的其他成员发生反应。 IHC结果的模式暗示了识别mAb的线性表位具有更好的反应性。结论：我们的发现表明，配对的HER2子域对于识别识别构象表位的mAb定位至关重要。此外，我们的抗HER2 mAb的亚域特异性与抗肿瘤活性之间似乎没有关联。

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