Immunotoxin IHP25-BT with low immunogenicity and off-target toxicity inhibits the growth and metastasis of trastuzumab-resistant tumor cells
Immunotoxin IHP25-BT with low immunogenicity and off-target toxicity inhibits the growth and metastasis of trastuzumab-resistant tumor cells
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免疫毒素IHP25-BT具有低免疫原性和脱靶毒性，可抑制曲妥珠单抗耐药肿瘤细胞的生长和转移。
DOI：
10.1016/j.ijpharm.2021.121081
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发表时间：
2021-09-16
影响因子：
5.8
通讯作者：
Lin, Juntang
中科院分区：
文献类型：
--
作者：
Guo, Rui;Zhang, Di;Lin, Juntang
人表皮生长因子受体2(HER2)在一些乳腺癌和胃癌患者中过度表达。曲妥珠单抗作为首个HER2靶向热抗体，可显著改善HER2阳性癌症患者的预后。然而，即使是有反应的患者，在治疗一段时间后，由于对曲妥珠单抗获得耐药性，病情也不可避免地恶化。许多针对HER2的抗体药物使用野生型肿瘤细胞进行相应的体内外临床前实验。然而，无法确定这些新开发的药物是否对曲妥珠单抗耐药的肿瘤细胞具有抗肿瘤效果。在这项研究中，产生了两个曲妥珠单抗耐药的HER2阳性肿瘤细胞群体NCI-N87-tR和BT474-tr。然后，我们检测了新构建的基于曲妥珠单抗耐药肿瘤细胞的低免疫原性和非靶向毒性的免疫毒素的体内外抗肿瘤效果。结果表明，免疫毒素IHP25-BT不仅能有效抑制小鼠移植瘤的生长，而且能抑制肿瘤细胞的肝转移。此外，还进行了肿瘤组织转录组测序，以阐明免疫毒素抑制肿瘤细胞远处转移的可能机制。总之，这项工作描述了一系列有吸引力的治疗性免疫毒素，低免疫原性和靶外毒性使它们有望用于曲妥珠单抗耐药的癌症治疗。
Human epidermal growth factor receptor 2 (HER2) is overexpressed in some breast and gastric cancer patients. As the first HER2-targeteed therpeutic antibody, trastuzumab could significantly improve the prognosis of HER2-positive cancer patients. However, even responding patients inevitably get worse due to acquired resistance to trastuzumab after a period of treatment. Many HER2-targeted antibody drugs used wild-type tumor cells to conduct their corresponding preclinical experiments in vitro and in vivo. However, it is impossible to determine whether these newly developed drugs have antitumor effective to trastuzumab-resistant tumor cells. In the study, two trastuzumab-resistant HER2-positive tumor cell populations NCI-N87-TR and BT474-TR were generated. Then, we examined the anti-tumor effects of newly constructed immunotoxins with low immunogenicity and off-target toxicity based on the trastuzumab-resistant tumor cells both in vitro and in vivo. Results demonstrated that the immunotoxin IHP25-BT could not only effectively inhibit tumor growth but also inhibit liver metastasis of tumor cells in a mouse xenograft model. Furthermore, tumor tissue transcriptome sequencing was performed to clarify the potential mechanisms of inhibiting tumor cell distant metastasis by immunotoxin. In conclusion, this work describes a series of attractive therapeutic immunotoxins, the low immunogenicity and off-target toxicity making them promising for trastuzumab-resistant cancer therapy.