Abstract 2655: DB-1323, a next-generation mesothelin targeting antibody-drug conjugate, demonstrated anti-tumor activity and favorable safety profile in pre-clinical models

Abstract Background: Mesothelin (MSLN) is highly expressed in many hard-to-treat solid tumors and is associated with metastasis, poor progression-free survival and lower overall survival. Despite 25 years of drug- development efforts across modalities, no MSLN-directed therapy has been approved, hampered by on-/off-target toxicities, intra-tumoral antigen heterogeneity, poor internalization of MSLN-antibody complexes, and soluble MSLN “sink” effects. DB-1323 is a MSLN-ADC composed of a novel fully human anti-MSLN immunoglobulin G1 (IgG1) monoclonal antibody, covalently conjugated to a proprietary DNA topoisomerase I inhibitor via a maleimide-tetrapeptide cleavable linker. In the present study, we evaluated the efficacy and safety of DB-1323 in comprehensive preclinical models. Methods: Binding affinity of the anti-MSLN antibody to MSLN-expressing cells was quantified by flow cytometry. Cytotoxicity was assessed in MSLN-positive pancreatic cancer cells. Anti-tumor activity was tested in MSLN-positive pancreatic and ovarian cancer xenograft models compared to that of anetumab ravtansine and other MSLN ADCs. The pharmacokinetics and safety profile were also evaluated in cynomolgus monkeys. Results: DB-1323 showed high affinity to both Human and Cyno MSLN without detectable off-target binding. DB-1323 has unique MSLN binding characteristics (fast on/off kinetics) that allow it to evade soluble MSLN while maintaining high avidity for MSLN on the surface of tumor cells. DB-1323 has faster and more extensive internalization than anetumab ravtansine, especially in the presence of physiologically relevant soluble MSLN concentrations. In vitro, DB-1323 retained cytotoxicity towards MSLN-expressing pancreatic cancer cells in the presence of soluble MSLN. It also showed dose-dependent anti-tumor activity in a pancreatic cancer xenograft model and ovarian cancer patient-derived xenograft model. Moreover, DB-1323 showed stronger tumor growth inhibition than that of anetumab ravtansine at the same dose. The systemic exposure AUC0-last and Cmax of DB-1323 and total antibody increased dose proportionally from 1mg/kg to 10mg/kg with low free payload in serum. DB-1323 also showed good safety profile with highest non-severely toxic dose (HNSTD) of 60mg/kg in cynomolgus monkeys. Conclusions: DB-1323 overcomes historical MSLN-targeting liabilities through unique rapid-on/off binding, efficient internalization, and potent topoisomerase I inhibition, delivering superior tumor eradication versus at well-tolerated doses. These data support clinical evaluation of DB-1323 for patients with MSLN expressing tumors. Citation Format: Haiqing Hua, Xi Li, Jun Yao, Tao Cheng, Junjie Yang, Xinyue Chen, Sang Pil Lee, Jiyong Shin, Yunseon Choi, Gisun Baek, Alexandre Joyeux, Jung Chae Lee. DB-1323, a next-generation mesothelin targeting antibody-drug conjugate, demonstrated anti-tumor activity and favorable safety profile in pre-clinical 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 2655.