Abstract B030: Development of a novel antibody drug conjugate (ADC) targeting Nectin-2 on the surface of breast cancers

Abstract To find novel therapeutic targets in triple negative breast cancer, we performed cell surface proteomic profiling of cell lines. We identified Nectin-2, a cell adhesion molecule and immune regulator, that is over expressed in ∼70% of breast cancers relative to non-cancerous tissues as a promising target for ADC development. Using a human phage display Fab (fragment antigen-binding) library, we developed a high-affinity Fab against human Nectin-2, which we reformatted into a human IgG1 antibody (IgG-F1). The novel IgG-F1 binds Nectin-2 with high affinity (KD = 1 nM) and undergoes rapid internalization upon engagement. We also mapped the binding sites of F1 on Nectin-2 by Cryogenic electron microscopy analysis. To evaluate the therapeutic potential of this antibody, we generated ADCs using cleavable linkers with 3 different cytotoxic payloads (DM1, DXd, MMAE). The MMAE conjugated IgG-F1 demonstrated the highest in vitrocytotoxicity across a panel of breast cancer cell lines (IC50 range 1.24 - 11.76 nM). In an MDA-MB-468 xenograft model, this ADC also induced dose-dependent tumor regression and fully suppressed tumor growth in vivo at 10 mg/kg weekly dosing. In summary, we describe a novel ADC targeting Nectin-2 which exhibits selective tumor binding, efficient internalization, and potent anti-tumor activity in preclinical breast cancer models – supporting further development of anti-Nectin-2 therapeutics for human cancer treatment. Citation Format: Yueyue Wang, Naing Lin Shan, Xiaolong Zhu, Tongqing Li, Jiawei Dai, Hengyi Li, Florine Collin, Weiwei Wang, TuKiet T. Lam, Haiying Zhan, Kim RM. Blenman, Daryl E. Klein, Lajos Pusztai. Development of a novel antibody drug conjugate (ADC) targeting Nectin-2 on the surface of breast cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B030.