HER3-Targeted U3-1402a: A Promising Anti-Cancer Agent with DNA Topoisomerase I Inhibitory Action

HER3 is a receptor frequently overexpressed in various cancer types, including breast, lung, melanoma, gastric, and pancreatic cancers. U3-1402a is an antibody-drug conjugate (ADC) that targets HER3 with a human anti-HER3 IgG1 antibody linked to a topoisomerase I inhibitor, exatecan derivative (DXd). This innovative ADC is designed to deliver the payload effectively post internalization, inducing apoptosis in cancer cells with a high drug-to-antibody ratio.

In the preclinical evaluation, both in vitro and in vivo studies were conducted to assess the efficacy of U3-1402a. The in vitro assays focused on the sensitivity of a HER3-positive breast cancer cell line (HCC1569) and a HER3-negative cervical carcinoma cell line (C33A) to U3-1402a and its payload, MAAA-1181. The in vivo studies examined the dose-dependent response in a HER3-positive breast cancer xenograft model, MDA-MB-453, and evaluated the sensitivity across different xenograft models with varying HER3 expression levels.

The in vitro results demonstrated that U3-1402a was effective against the HER3-positive breast cancer cells, while the HER3-negative cell line was not affected. In the in vivo experiments, U3-1402a showed a dose-dependent antitumor effect and induced tumor regression specifically in models with HER3 expression levels of 2+ and 3+.

The conclusion from these studies is that U3-1402a has shown promising antitumor activity in breast cancer models both in vitro and in vivo, with efficacy linked to HER3 expression. This suggests that U3-1402a may be a potential treatment for a range of cancers that overexpress HER3.