Abstract 5463: AMB304: A next generation ADC with topo I inhibitor, demonstrating robust preclinical efficacy against target overexpression tumors and high tolerability in non-human primate (NHP)

Abstract Background: AMB304 is an antibody-drug conjugate (ADC) combining a human IgG1 monoclonal antibody and a high efficacious topoisomerase I inhibitor (Topo I) payload with site-specific conjugation. The target of AMB304 is a cell surface expressed glycoprotein, elevated in a range of tumors, and is associated with cancer survival, growth, metastasis, drug resistance and poor prognosis. This target is highly expressed in various epithelial cancers, including triple negative breast cancer and non-small cell lung cancer. Additionally, advanced malignancies with limited treatment options also demonstrate high target expression, suggesting that AMB304 may provide potential clinical benefits. Furthermore, elevated expression of the target is associated with resistance to anti-tumor drugs, such as EGFR TKIs (e.g., Gefitinib) and trastuzumab, via signaling. In this study, we investigated the cancer-specific therapeutic potential of AMB304, focusing on its preclinical characterization, including anti-cancer efficacy and safety profile. Methods: Various types of tumor cell lines were treated with AMB304 using tumor spheroid model. For in vivo efficacy study, cancer cell lines or patients derived cells were inoculated subcutaneously in mice xenograft models. Target expression intensity in each tumor model was identified through immunohistochemistry (IHC). The toxicity profiles of AMB304 were analyzed, and its pharmacokinetics were evaluated in cynomolgus monkeys. Results: AMB304 exhibited robust potency against target-expressing cancer cell lines, as evidenced by cell viability assay and compelling efficacy in various xenograft models, with IHC confirming its tumor regression depends on target expression. It exhibited target-specific binding, efficient internalization, and a strong bystander killing effect. In cynomolgus monkeys, AMB304 was well- tolerated with no significant adverse events at tolerable doses. Its stable linker chemistry minimized payload release, and it showed favorable pharmacokinetics, supporting its clinical potential. Conclusion: This study demonstrates that AMB304 is potent ADC with significant anticancer efficacy and an excellent safety profile. Moreover, its superior stability in plasma enhances its potential for clinical treatment. Therefore, AMB304 could be developed as a targeted therapy for advanced solid tumors with high target expression. Citation Format: Do-Hyun Nam, Yeong-Woo Kim, Byeongkwi Min, Wonsik Jung, Eunsuk Choi, Jungsu Shin, Nam-Gu Her. AMB304: A next generation ADC with topo I inhibitor, demonstrating robust preclinical efficacy against target overexpression tumors and high tolerability in non-human primate (NHP) [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 5463.