Abstract 7318: ZW209, a DLL3 targeted trispecific T cell engager with integrated CD28 co-stimulation, demonstrates safety and potent preclinical efficacy in models of small cell lung cancer

Abstract Small cell lung cancer (SCLC) is a highly aggressive and difficult-to-treat malignancy with limited treatment options. Delta-like ligand 3 (DLL3), a cell surface protein overexpressed in SCLC, has emerged as a promising therapeutic target. Bispecific T cell engagers (TCE) targeting DLL3, including tarlatamab which has received accelerated approval, have demonstrated anti-tumor activity in the clinic with an improved duration of response compared to current standard of care, including chemotherapy and immunotherapy. Despite these advances, we believe there is opportunity to improve the rate and depth of response as the clinical activity of bispecific T cell engagers may be limited by low T cell infiltration and poor T cell function characteristic of SCLC tumors, and by the emergence of treatment-related T cell anergy due to T cell stimulation via signal 1 (CD3) only. The incorporation of signal 2 co-stimulation, via CD28 signaling, has the potential to improve response rates by stimulating increased T cell activation, proliferation and survival. To address treatment challenges and enhance the durability and sustainability of T cell activation, we engineered ZW209, a trispecific co-stimulatory T cell engager (TriTCE Co-stim) that optimally engages CD3 and CD28 and redirects and enhances cytotoxic T cell responses to DLL3-expressing tumor cells while maintaining a desired safety profile. Our development candidate, ZW209, is designed to optimally engage CD3 and CD28 in an obligate cis manner, supported by a lack of T cell cross-linking and fratricide. The addition of CD28 co-stimulation in ZW209 demonstrated enhanced DLL3-dependent cytokine induction and T cell proliferation with improved antitumor activity relative to clinical bispecific TCEs benchmarks. In a serial, repeated challenge in vitro cytotoxicity assay, ZW209 displayed superior T cell fitness and anti-tumor activity to a bispecific control and clinical benchmark. In vivo, ZW209 exhibited potent anti-tumor activity in multiple humanized SCLC xenograft models. In aqueous and solid phase cytokine release assays, ZW209 exhibited minimal DLL3-independent cytokine production. Importantly, a ZW209 cynomolgus cross-reactive surrogate molecule displayed a favorable safety profile as it was well tolerated in non-human primates with repeat dosing at 10 mg/kg with no abnormal clinical signs. In summary, these preclinical data support that ZW209 promotes improved anti-tumor activity against DLL3-positive cancer cells relative to competitor bispecific TCEs. By integrating CD28 co-stimulation into our trispecific T cell engager, ZW209 has the potential to improve the rate and duration of response for better clinical outcomes. Citation Format: Desmond Lau, Peter Repenning, Diana Canals Hernaez, Alec Robinson, Diego Perez Escanda, John Zhang, Hamed Shirvani, Catherine Wu, Kurt Stahl, Aditi Deshmukh, Nichole Escalante, Mariana Rocha, Begonia Silva Moreno, Lisa Newhook, Purva Bhojane, Paul A. Moore, Nina E. Weisser, Thomas Spreter von Kreudenstein. ZW209, a DLL3 targeted trispecific T cell engager with integrated CD28 co-stimulation, demonstrates safety and potent preclinical efficacy in models of small cell lung cancer [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 7318.