Abstract 220: U3-1402, a novel HER3-targeting ADC, inhibits the tumor growth of colorectal cancer xenografts

Background: HER3 (human epidermal growth factor receptor 3) is a member of the HER family and overexpressed in a broad range of cancer types including colorectal cancer. HER3 targeted therapies such as anti-HER3 antibodies have been investigated in clinical trials; however, no HER3-targeting therapy has been approved to date. U3-1402 is a novel antibody drug conjugate (ADC) composed of a fully human anti-HER3 antibody (patritumab) and a novel topoisomerase I inhibitor (DXd) which is conjugated via an enzymatically cleavable peptide-linker with high drug antibody ratio (DAR: 7-8 to 1). Purpose: To investigate the antitumor efficacy of U3-1402 in HER3-expressing colorectal cancer xenograft models. Material and methods: The following cell lines were used in this study; WiDr, Colo320DM, and DiFi with KRAS wild type, DLD-1, HCT15, HCT116, LoVo, SW480, and SW620 harboring KRAS mutation. The sensitivities of 9 colorectal cancer cell lines to DXd were evaluated by in vitro cell killing assay. Cells were treated with DXd at different concentrations (0.5pM to 500nM) over 144 hours, and the 50% inhibitory concentration (IC50) values were determined. Cell surface HER3 antigen was quantified by flow cytometry. In vivo screening assay and tumor growth inhibition assay were performed in tumor xenograft models exhibiting a range of HER3 expression levels. In addition, the efficacy of U3-1402 was compared to that of parental antibody patritumab, CPT-11, control-ADC, and saline in SW620 tumor xenograft model harboring KARS mutation. All results were expressed as mean ± standard deviation (SD) and statistical significance was analyzed using ANOVA with Dunnet multiple comparison. Results: In in vitro study, the range of IC50 value of DXd for each cell line was 2.16 ± 0.11 nM to 16.04 ± 0.10 nM. Most of the cell lines were sensitive to DXd. In in vivo screening assay, the maximum regression from U3-1402 was observed in the tumor xenograft model of both DiFi (high HER3 expression; KRAS wild type) and SW620 (high HER3 expression; KRAS mutation). In in vivo tumor growth inhibition assay, the antitumor efficacy was dependent on the HER3 expression level. Notably, SW620 tumor growth was significantly suppressed with U3-1402 compared with that of saline group (p < 0.001) and had improved potency compared with CPT-11. Of note, no significant difference in tumor growth inhibition was observed amongst the treatments with the same dose of patritumab or control-ADC and saline. Tumor regression was only observed in U3-1402 treated group, and some of which achieved complete regression. Conclusions: The antitumor efficacy of U3-1402 in xenograft models was dependent on HER3 expression and did not show a clear relationship to KRAS mutation status. These results support further investigation of development strategies for U3-1402 in patients with HER3-expressing colorectal cancer. Citation Format: Shigehiro Koganemaru, Yasutoshi Kuboki, Yoshikatsu Koga, Takashi Kojima, Mayumi Yamauchi, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Masahiro Yasunaga, Yasuhiro Matsumura, Toshihiko Doi. U3-1402, a novel HER3-targeting ADC, inhibits the tumor growth of colorectal cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 220.