Immunotoxin IHP25-BT with low immunogenicity and off-target toxicity inhibits the growth and metastasis of trastuzumab-resistant tumor cells

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.

Automated summary

The study generated two trastuzumab-resistant HER2-positive tumor cell populations and examined the anti-tumor effects of newly constructed immunotoxins with low immunogenicity and off-target toxicity based on these resistant tumor cells both in vitro and in vivo. Results showed that the immunotoxin not only effectively inhibited tumor growth, but also suppressed liver metastasis of tumor cells in a mouse xenograft model. Transciptome sequencing of tumor tissue was performed to elucidate the potential mechanisms of inhibiting tumor cell distant metastasis by immunotoxin, highlighting their promise for trastuzumab-resistant cancer therapy.