Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
Invest New Drugs. 2021 Jun;39(3):697-704. doi: 10.1007/s10637-020-01048-4. Epub 2021 Jan 3.
Immunotherapy of HER2-overexpressing cancers by FDA approved monoclonal antibodies (mAbs) such as trastuzumab and pertuzumab has shown promising results. We have recently produced a novel humanized anti-HER2 mAb, hersintuzumab, which did not sterically inhibit binding of trastuzumab and pertuzumab to HER2, thus recognizing a distinct epitope on subdomain I + II of HER2. In this study, we assessed the in vitro and in vivo anti-tumor activity of this mAb individually and in combination with trastuzumab. Different HER2-overexpressing human cancer cell lines, including SKOV3, NCI-N87 HCC1954 and BT-474 were cultured and binding reactivity of Hersintuzumab to these cell lines was analyzed by flow cytometry. In addition, the inhibitory effect of different concentrations of hersintuzumab, trastuzumab and their combination on tumor cells growth was assessed by XTT assay. For Assessment of tumor growth inhibition in xenograft model, Balb/c athymic nude mice were subcutaneously injected with NCI-N87 and SKOV3 tumor cells and then treated intravenously with these mAbs. Our results showed that hersintuzumab could bind to all HER2-overexpressing cell lines similar to trastuzumab. In vitro experiments showed that both hersintuzumab and trastuzumab individually and in combination inhibited growth of all cell lines with the exception of HCC-1954.Inhibitory effect of the combination of mAbs was significantly higher than that of each mAb alone. Similar results were obtained in the gastric (NCI-N87) and ovarian (SKOV-3) tumor xenograft models. Hersintuzumab in combination with trastuzumab induces synergic anti-tumor effects on HER2-overexpressing cells in vitro and in vivo and is potentially a therapeutic tool for treatment of HER2-overexpressing cancers.
经美国食品药品监督管理局批准的单克隆抗体（mAbs），如曲妥珠单抗和帕妥珠单抗，对 HER2 过表达癌症的免疫治疗显示出了有前景的结果。我们最近生产了一种新型的人源化抗 HER2 mAb，hersintuzumab，它不会在空间上抑制曲妥珠单抗和帕妥珠单抗与 HER2 的结合，因此可以识别 HER2 的 I 区+II 区上的一个独特表位。在这项研究中，我们评估了该 mAb 单独使用和与曲妥珠单抗联合使用的体外和体内抗肿瘤活性。培养了不同的 HER2 过表达人癌细胞系，包括 SKOV3、NCI-N87 HCC1954 和 BT-474，并通过流式细胞术分析 Hersintuzumab 与这些细胞系的结合反应性。此外，通过 XTT 测定评估了不同浓度的 hersintuzumab、曲妥珠单抗及其组合对肿瘤细胞生长的抑制作用。为了评估在异种移植模型中肿瘤生长抑制作用，将 Balb/c 无胸腺裸鼠皮下注射 NCI-N87 和 SKOV3 肿瘤细胞，然后静脉内给予这些 mAbs 治疗。我们的结果表明，hersintuzumab 可以与所有 HER2 过表达细胞系结合，类似于曲妥珠单抗。体外实验表明，hersintuzumab 和曲妥珠单抗单独或联合使用均可抑制所有细胞系的生长，除了 HCC-1954 之外。mAbs 联合使用的抑制作用明显高于单独使用每种 mAb 的作用。在胃癌（NCI-N87）和卵巢癌（SKOV-3）肿瘤异种移植模型中也获得了类似的结果。hersintuzumab 与曲妥珠单抗联合使用在体外和体内对 HER2 过表达细胞具有协同抗肿瘤作用，可能是治疗 HER2 过表达癌症的一种治疗工具。
