An antibody-photosensitiser bioconjugate overcomes trastuzumab resistance in HER2-positive breast cancer

Abstract

HER2-positive breast cancer, characterized by the overexpression of HER2 receptors, often develops resistance to trastuzumab, limiting its therapeutic efficacy. In this study, we explore the use of photodynamic therapy (PDT) with a trastuzumab-IRDye700DX photoimmunoconjugate (Tz-IR700) as a strategy to overcome trastuzumab resistance. Tz-IR700 combines the antibody's selectivity for the tumoral cells with the cytotoxic effect of IR700, induced by red light. Our results demonstrate that Tz-IR700 selectively accumulates in trastuzumab-resistant HER2-positive tumours (HCC1954) thereby enabling precise tumour localization by fluorescence imaging. Upon irradiation with red light, Tz-IR700 induces significant HCC1954 cell viability reduction both in vitro and in vivo, notably overcoming trastuzumab resistance in this HER2-positive breast cancer cell line. Mechanistic studies unequivocally demonstrate that the primary cytotoxic species is singlet oxygen. These findings suggest that Tz-IR700 could serve as a valuable treatment option for trastuzumab-resistant HER2-positive breast cancer and may also be used as an adjuvant to fluorescence-guided surgery, improving surgical outcomes and reducing the likelihood of tumour recurrence and metastasis.

Keywords: Antibody-drug conjugates; Breast cancer; Photodynamic therapy; Singlet oxygen; Trastuzumab.