靶向HER2/EGFR双特异抗体在曲妥珠耐药胃癌中的抗肿瘤研究

Trastuzumab, a humanized monoclonal antibody directed against HER2, is anti-HER2 agent approved for clinical use for patients with HER2-overexpressing metastatic gastric carcinoma in 2010. Despite the effectiveness of transtuzumab, the majority of trastuzumab-responsive patients develop resistance within one year of treatment initiation. Thus, there is an urgent need to overcome trastuzumab resistance..Trastuzumab resistance primarily due to the acquisition of alternative RTKs signaling activation that compensate for HER2 inhibition. Cross-talk between different HER family receptors is believed to be associated with resistance to trastuzumab therapy. Here we developed an anti-HER2/EGFR bispecific antibody using trastuzumab and panitumumab. The bispecific antibody retained the antigen-binging activity of both parental mAbs. The bispecific antibody was effective in inhibiting EGF-stimulated HER2/EGFR heterodimer formation and downstream signaling pathways. We will investigate the mechanism of the specific anti-HER2/EGFR bispecific tetravalent antibody against trastuzumab-resistant gastric carcinoma in vitro and in vivo. It may be a promising therapeutic agent for the treatment of HER2 low-expressing gastric carcinoma.

人表皮生长因子受体2（HER2）人源化单抗曲妥珠已于2010年获批用于HER2高表达转移性胃癌的治疗。临床数据显示曲妥珠对HER2高表达转移性胃癌的有效率仅有30%，而患者也常于治疗一年左右产生耐药。研究发现，持续的曲妥珠治疗肿瘤细胞表面HER2表达呈现低密度状态，但可诱导肿瘤细胞上调其他酪氨酸激酶受体，可能与HER2形成异源二聚体激活下游信号通路。因此，打破HER2异源二聚体形成和下调其他表皮生长因子家族受体酪氨酸激酶活化可能是治疗曲妥珠耐药的有效方法。我们的研究表明，胃癌细胞表面EGFR异常表达可能与曲妥珠耐药相关。本项目中，我们拟通过构建靶向EGFR和HER2双特异抗体，可最大程度阻断HER2/EGFR异源二聚体形成，抑制受体及下游信号通路的激活而抑制肿瘤细胞生长。我们将通过体内外实验探讨双特异抗体的抗肿瘤作用并阐明其机理，为HER2低表达胃癌的治疗提供有效的靶向抗体制剂。

ErbB2靶向抗体曲妥珠单抗已被批准用于ErbB2阳性胃癌。尽管曲妥珠单抗在ErbB2阳性胃癌治疗上有效，但ErbB2靶向抗体Trstuzumab抵抗仍然是常见的。前期，我们用曲妥珠单抗和帕尼单抗成功地设计了一种抗EGFR/ErbB2双特异性抗体（TP-BsAb），并在曲妥珠单抗抵抗的转移性乳腺癌中显示出显著的疗效。在本研究中，TP-BsAb在抑制曲妥珠单抗敏感和耐药胃癌模型的生长方面依然显示出出众的疗效。我们进一步的数据表明，TP-BsAb的抗肿瘤活性增强可能与其阻断EGFR/Erbb2异二聚体化和信号传导的能力以及诱导EGFR和ErbB2受体内化有关。这些表明TP-BsAb可能在曲妥珠单抗抵抗胃癌治疗应用中具有潜力。