Abstract 3172: XYD-8006: A novel ADAM9-targeting dual-payload ADC demonstrates superior preclinical efficacy in gastrointestinal and lung cancer models

Abstract Background: A Disintegrin And Metalloproteinase 9 (ADAM9) is a cell surface protease implicated in growth factor shedding, integrin binding, and cell migration, processes critical for tumor progression, metastasis, and neovascularization. Its overexpression is correlated with poor prognosis in multiple solid tumors, and overexpressed in GI and lung cancers but limited in normal tissues, highlighting its potential as a therapeutic target. While Antibody-Drug Conjugates (ADCs) represent a transformative oncology modality, single-payload ADCs face limitations including, tumor heterogenecity, the emergence of payload resistance such as DXD/SN38. To address this, we developed XYD-8006, a ADAM9-targeting ADC equipped with dual-payload platform designed to enhance efficacy and overcome tumor heterogenecity and DXD/SN38 resistance. Methods: XYD-8006, a humanized anti-ADAM9 IgG1 monoclonal antibody conjugated with high hydrophilic linker to two distinct potent payloads: a microtubule inhibitor and a topoisomerase I inhibitor, with a controlled and specific Drug-to-Antibody Ratio (DAR). The molecule was evaluated for specificity, internalization efficiency, and in vitro/in vivo efficacy across a panel of ADAM9-high, -medium, and -low expressing tumor models. Results: XYD-8006 exhibited high specificity for ADAM9 with no observed cross-reactivity to paralog family members and demonstrated superior internalization efficiency. In vitro and in vivo study showed, XYD-8006 induced potent, synergistic tumor cell killing, significantly outperforming single-payload ADC controls. Notably, it achieved robust tumor growth inhibition and regression not only in ADAM9-high models but also in models with medium and low ADAM9 expression. XYD-8006 exhibited potent ADAM9-targeted cytotoxicity and tumor suppression, with a favorable pharmacokinetic and safety profile. Conclusion: XYD-8006 was designed to overcome key limitations of current ADC therapies. Its promising preclinical efficacy across gastrointestinal and lung cancers supports its further development, with an expected entry into clinical study in 2026. Citation Format: Weng Hang Ho, Pengfei Rong, Mengrui Zhao, Jun Li, Xidong Zhang, Hui Ding, Fangxing Ouyang, . XYD-8006: A novel ADAM9-targeting dual-payload ADC demonstrates superior preclinical efficacy in gastrointestinal and lung cancer models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3172.