Abstract
HER3 is overexpressed in several cancers, including colorectal cancer. Although therapies with anti-HER3 antibodies have been investigated, significant clinical benefits have not been reported. U3-1402 is a novel HER3-antibody-drug conjugate (ADC) composed of the HER3 antibody patritumab and a novel topoisomerase I inhibitor, DX-8951 derivative (DXd). The sensitivity of DXd was evaluated by a growth inhibition assay. The antitumor activity of U3-1402 was evaluated in a murine xenograft model in which its effects on cells, with a range of HER3 expression levels, were compared with those of patritumab alone, irinotecan, control-ADC, and saline. In the growth inhibition assay, all colorectal cancer cell lines were sensitive to DXd. In the tumor xenograft model, significant tumor regression with U3-1402 was observed both in the DiFi cell line (high HER3 expression; KRAS wild type) and in SW620 (high HER3 expression; KRAS mutation), but no treatment effect was observed in Colo320DM (low HER3 expression). Notably, SW620 tumor growth was significantly suppressed with U3-1402 compared with the saline-treated group (P < 0.001) and showed greater activity compared with the irinotecan group. By contrast, patritumab alone, control-ADC, and saline did not significantly differ in tumor growth inhibition. The antitumor activity of U3-1402 was dependent on HER3 expression level, but not on KRAS mutation status. These results support further investigation of development strategies for U3-1402 in patients with HER3-expressing colorectal cancer.
Highlights
Colorectal cancer is a major cause of cancer death worldwide [1]
Anti-EGFR antibodies such as cetuximab and panitumumab are already used as a standard treatment in patients with RAS wild-type metastatic colorectal cancer; and dual-targeted therapy with anti-HER2 antibody and lapatinib has shown activity in patients with KRAS codon 12/13 wild-type/HER2 positive mCRC in clinical trials [12,13,14]
HER3 expression of each cell line The number of HER3 molecules expressed on the surface of individual cells in each cell line was calculated by a QIFIKIT
Summary
Multimodality therapies that include surgery, chemotherapy, and radiotherapy are required to treat operable colorectal cancer [2,3,4], whereas chemotherapy is the main treatment for inoperable cancers. Despite recent advances in cytotoxic chemotherapy, targeted therapies, and immune therapy [5,6,7,8,9], the longterm prognosis remains poor, especially for patients with recurrent or inoperable colorectal cancer [10]. Some anti-EGFR or anti-HER2 antibodies are widely used to treat several cancer types. Anti-EGFR antibodies such as cetuximab and panitumumab are already used as a standard treatment in patients with RAS wild-type metastatic colorectal cancer (mCRC); and dual-targeted therapy with anti-HER2 antibody (trastuzumab) and lapatinib has shown activity in patients with KRAS codon 12/13 wild-type/HER2 positive mCRC in clinical trials [12,13,14]
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