Key Laboratory of Thin Film and Microfabrication (Ministry of Education), Department of Micro/Nano Electronics, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
Genor Biopharma Co., Ltd. Building 3, 1690 Zhangheng Rd., Shanghai, 201203, People's Republic of China.
Sci Rep. 2020 Feb 19;10(1):2986. doi: 10.1038/s41598-020-59818-2.
HER2 overexpression is frequently associated with tumor metastasis and poor prognosis of breast cancer. More evidence indicates that HER3 is involved in HER2-resistant therapies. Combination treatments with two or more different monoclonal antibodies are a promising strategy to overcome resistance to HER2 therapies. We presented a novel fully human HER2-targeted monoclonal antibody, GB235, screened from a phage-display library against the HER2 antigen. GB235 in combination with Trastuzumab overcomes resistance in HER2-positive tumors and results in more sustained inhibition of tumor growth over time. The competition binding assay showed that the epitopes of GB235 do not overlap with those of Pertuzumab and Trastuzumab on HER2. Further HER2 mutagenesis results revealed that the binding epitopes of GB235 were located in the domain III of HER2. The mechanism of action of GB235 in blocking HER2-driven tumors is different from the mechanisms of Trastuzumab or Pertuzumab. GB235 does not affect the heterodimerization of HER2 and HER3, whereas the GB235 combined treatment with Trastuzumab significantly inhibited heregulin-induced HER3 phosphorylation and downstream signaling. Moreover, GB235 in combination with Trastuzumab reversed the resistance to heregulin-induced proliferation in HER2-overexpressing cancer cell lines. GB235 combined with Trastuzumab treatment in xenograft models resulted in improved antitumor activity. Complete tumor suppression was observed in the HER2-positive NCI-N87 xenograft model treated with the combination treatment with GB235 and Trastuzumab. In a Trastuzumab-resistant patient-derived tumor xenograft model GA0060, GB235 plus Trastuzumab reversed the resistance to Trastuzumab monotherapy. Because GB235 showed a different working mechanism with Pertuzumab and Trastuzumab, these agents can be considered complementary therapy against HER2 overexpression tumors.
HER2 过表达通常与乳腺癌的肿瘤转移和预后不良有关。更多证据表明，HER3 参与了 HER2 耐药治疗。使用两种或更多种不同的单克隆抗体联合治疗是克服 HER2 治疗耐药性的一种有前途的策略。我们提出了一种新型的全人源 HER2 靶向单克隆抗体 GB235，它是针对 HER2 抗原从噬菌体展示文库中筛选出来的。GB235 与曲妥珠单抗联合使用可克服 HER2 阳性肿瘤的耐药性，并随着时间的推移导致肿瘤生长的持续抑制。竞争结合测定表明，GB235 的表位与 Pertuzumab 和 Trastuzumab 在 HER2 上的表位不重叠。进一步的 HER2 突变结果表明，GB235 的结合表位位于 HER2 的 III 结构域内。GB235 阻断 HER2 驱动的肿瘤的作用机制与 Trastuzumab 或 Pertuzumab 不同。GB235 不影响 HER2 和 HER3 的异二聚化，而 GB235 与 Trastuzumab 的联合治疗显著抑制了 heregulin 诱导的 HER3 磷酸化和下游信号传导。此外，GB235 与 Trastuzumab 的联合治疗逆转了 HER2 过表达癌细胞系中 heregulin 诱导的增殖耐药性。GB235 与 Trastuzumab 联合治疗在异种移植模型中导致抗肿瘤活性提高。在接受 GB235 和 Trastuzumab 联合治疗的 HER2 阳性 NCI-N87 异种移植模型中观察到完全肿瘤抑制。在曲妥珠单抗耐药的患者来源肿瘤异种移植模型 GA0060 中，GB235 加曲妥珠单抗逆转了对曲妥珠单抗单药治疗的耐药性。由于 GB235 与 Pertuzumab 和 Trastuzumab 表现出不同的作用机制，因此这些药物可被视为针对 HER2 过表达肿瘤的互补治疗方法。
