Abstract 3503: ZW171, a differentiated 2+1 T cell-engaging bispecific antibody with antitumor activity in a range of mesothelin-expressing cancers

Abstract Mesothelin (MSLN) is a tumor associated antigen overexpressed in many cancer indications and is an attractive target for immunotherapies including bispecific T cell engagers (TCE) and chimeric antigen receptor T (CART) cells. While MSLN-targeting immunotherapies have shown signs of clinical activity, their success has been hindered by dose-limiting toxicities associated with on-target off-tumor effects and cytokine release syndrome (CRS). To overcome these issues, we engineered ZW171, a MSLN-targeting TCE, with enhanced safety and antitumor activity. ZW171 is a 2+1 IgG1-like antibody, built with AzymetricTM and EFECTTM technologies, consisting of two MSLN binding domains and one low affinity CD3ε binding domain. We previously showed that the unique geometry and 2+1 design of ZW171 facilitates tumor selective binding and potent preferential killing of MSLN-mid and -high target cells, while sparing MSLN-low expressing target cells, and enhanced antitumor activity compared to other 2+1 TCE formats and the clinical benchmark HPN536 in MSLN-expressing PBMC-engrafted CDX models. To address the evolving clinical landscape and assess antitumor activity in additional indications and more translationally relevant models, we assessed ZW171 activity in advanced patient-derived organoid and xenograft models and benchmarked to other MSLN-targeting TCE including AMG 305, JNJ-79032421 and CT95. Additionally, activity in expanded MSLN-positive indications including pancreatic, endometrial, and gastric cancer, and the in the presence of soluble MSLN (sMSLN), which is observed in the serum of patients and can impede MSLN-targeted antibody-based therapies, was assessed in vitro. Ex vivo, ZW171 mediated potent tumor cell killing and T cell activation in patient-derived ovarian cancer organoid models. ZW171 induced complete tumor regressions in established patient-derived in vivo MSLN-positive non-small cell lung cancer and pancreatic cancer models. Comparison of ZW171 to AMG 305, JNJ-79032421 and CT95 showed reduced binding to T cells and equivalent or greater antitumor activity against MSLN-overexpressing cells. In vitro, ZW171 demonstrated potent MSLN-dependent killing in MSLN-positive indications including pancreatic, endometrial, and gastric cancer, and maintained activity in the presence of clinically relevant sMSLN concentrations observed in patient serum. Overall, ZW171 demonstrates differentiated and potent antitumor activity in a range of MSLN-expressing cancers. ZW171 is being evaluated in a Phase 1 clinical trial in MSLN-expressing solid tumors (NCT06523803). Citation Format: Nicole J. Afacan, Patricia Zwierzchowski, Wingkie Wong, Maya Poffenberger, Chayne Piscitelli, Thomas Spreter von Kreudenstein, Nina E. Weisser. ZW171, a differentiated 2+1 T cell-engaging bispecific antibody with antitumor activity in a range of mesothelin-expressing cancers [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 3503.