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Ref Type Journal Article
PMID (31395690)
Authors Koganemaru S, Kuboki Y, Koga Y, Kojima T, Yamauchi M, Maeda N, Kagari T, Hirotani K, Yasunaga M, Matsumura Y, Doi T
Title U3-1402, a Novel HER3-Targeting Antibody-Drug Conjugate, for the Treatment of Colorectal Cancer.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 18 11 2019 11 2043-2050 Mol Cancer Ther
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Patritumab deruxtecan Patritumab deruxtecan 15 18
Drug Name Trade Name Synonyms Drug Classes Drug Description
Patritumab deruxtecan U3-1402|HER3-DXd|U3 1402|U31402 HER3 (ERBB3) Antibody 30 Patritumab deruxtecan (U3-1402) is an antibody-drug conjugate (ADC) comprising an ERBB3 (HER3) antibody and Exatecan, which once internalized may result in apoptotic cell death (PMID: 31395690, PMID: 31661465, PMID: 31471314).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB3 positive colorectal cancer predicted - sensitive Patritumab Preclinical - Cell line xenograft Actionable In a preclinical study, Patritumab treatment resulted in reduced Erbb3 (Her3) phosphorylation in Erbb3 (Her3)-positive colorectal cancer cell lines in culture and modest antitumor activity in cell line xenograft models (PMID: 31395690). 31395690
ERBB3 positive colorectal cancer sensitive Patritumab deruxtecan Preclinical - Cell line xenograft Actionable In a preclinical study, Patritumab Deruxtecan (U3-1402) decreased viability of Erbb3 (Her3)-positive colorectal cancer cell lines in culture and induced significant tumor growth inhibition in cell line xenograft models with intermediate to high Erbb3 (Her3) expression (PMID: 31395690). 31395690