Abstract 5462: AMB303: A novel topo I payload ADC showing efficacy in NSCLC and TNBC, with potential for immune checkpoint combination therapy
Authors: Do-Hyun Nam, Yuna Park, Byeongkwi Min, Wonsik Jung, Yunsu Park, Hye-Mi Kim, Min-A Park, Nam-Gu Her
Journal: Cancer Research (2025)

Abstract Background: AMB303 is an ADC targeting ROR1 (Receptor Tyrosine Kinase-Like Orphan Receptor 1), a tumor-specific protein highly overexpressed in tumors. ROR1 is crucial for cancer cell differentiation, proliferation, migration, and metastasis, which drive recurrence and therapy resistance. These tumor-specific functions make ROR1 a highly attractive candidate for ADC development, offering the potential for more precise and effective cancer treatments. To optimize the therapeutic potential of AMB303, a novel topoisomerase I (Topo I) inhibitor payload has been incorporated, designed to overcome the limitations of existing Topo I inhibitors in clinical use. This novel payload aims to enhance the efficacy of AMB303, addressing drug resistance and minimizing the risk of tumor recurrence, offering a more effective approach to cancer treatment. Method: The novel antibody and drug-linker components of AMB303 were optimally characterized and integrated. The binding affinity and cellular internalization of the AMB303 were assessed in cells with high ROR1 expression. In vivo efficacy was evaluated using a non-small cell lung cancer (NSCLC) patient-derived xenograft (PDX) model, while triple negative breast cancer, colorectal, and ovarian cell-derived xenograft (CDX) models were used to investigate the correlation between in vivo efficacy and target expression levels. Additionally, the combination of AMB303 with mouse PD-1/PD-L1 inhibitors was tested to evaluate antitumor activity in syngeneic mouse models. Results: AMB303 has demonstrated excellent antitumor efficacy in in vitro and in vivo studies. By combining the new Topo I with an antibody showed target-specific binding affinity and rapid internalization, it also showed stronger cytotoxic effect compared to the clinically validated TopoI. Additionally, AMB303 demonstrated robust antitumor effect in NSCLC PDX and CDX models, including breast and colon cancer. In comparative studies with a benchmark ADC in clinical trials, AMB303 exhibited superior in vivo efficacy in a lung PDX model. In syngeneic mouse models, AMB303 demonstrated potential for enhanced efficacy when combined with PD-1/PD-L1 inhibitors. Conclusion: AMB303, an ADC conjugated with a novel Topo I inhibitor, is a potent therapeutic designed to target both primary tumor cells and recurrence or relapsed cancer tissues. When combined with immune checkpoint inhibitors, AMB303 demonstrated enhanced therapeutic efficacy, presenting a promising strategy to overcome immune resistance and improve treatment outcomes in cancer therapy. Citation Format: Do-Hyun Nam, Yuna Park, Byeongkwi Min, Wonsik Jung, Yunsu Park, Hye-Mi Kim, Min-A Park, Nam-Gu Her. AMB303: A novel topo I payload ADC showing efficacy in NSCLC and TNBC, with potential for immune checkpoint combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5462.