Abstract 7322: LBL-058, A novel T cell engager conjugate (TEC) targeting DLL3 with dual tumor suppressive functions

Abstract Background: Small cell lung cancer (SCLC) is a highly malignant tumor and accounts for approximately 15% of lung cancer cases. The prognosis of invasive SCLC is poor, with a 5-year survival is 7%. SCLC has a high response to chemotherapy but tends to relapse and resist. In recent years, immune checkpoints have brought breakthroughs in first-line treatment and prolonged OS, but options after the second line are still lacking. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors, and its expression is limited in normal cells. Nowadays, many DLL3-targeting therapies are in development among them Tarlatamab, which is a T cell engager (TCE), has been approved by FDA for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy, at the same time several DLL3 targeting ADCs were also showing some promising results. Thus makes DLL3-targeting therapy an attractive strategy to treat SCLC. Methods: Here we report a T cell engager conjugate (TEC), LBL-058, comprised of a DLL3-targeted T cell engager conjugated to a novel topoisomerase I inhibitor (TOP1i) payload. Moreover, LBL-058 was designed with a higher affinity targeting DLL3 and a lower affinity targeting CD3 to avoid potential cytotoxicity to T cells mediated by binding to T cells. The binding affinity of LBL-058 to DLL3 and CD3 was determined with Fortebio, while the T cell based activity was measured using several cell-based assays including reporter gene and TDCC assays. Binding of LBL-058 to DLL3 or CD3 induced Internalization and cytotoxicity were also evaluated by several cell-based assays. The anti-tumor activity of LBL-058 was investigated in xenograft mouse model. Results: The affinity difference between CD3 and DLL3 has been fine-tuned, LBL-058 binds more easily to DLL3-positive cells. In CD3 reporter gene assay, LBL-058 could activate the NFAT reporter element through DLL3 antigen-dependent CD3 cross-linking. LBL-058 not only induce potent TDCC and T cell activation but also selectively deliver cytotoxicity payload to DLL3-positive tumor cells. In animal models, LBL-058 treatment induced durable tumor regression in xenograft tumor model. Conclusion: LBL-058 has the potential to be a First-In-Class DLL3-targeted TCE ADC, which combines the anti-tumor properties of TCE and ADC, and shows a potent and durable anti-tumor activity and is expected to provide clinical benefits for the treatment of patients with SCLC. Citation Format: Sun Jianming, Huang Xiao, Huang Jing, Zhang Peng, Ding Mi, Qin Yurong, Wu Guojin, Mi Ye, Yang Ye, Jordan Zhu, Yue Zhao, Shoupeng Lai, Xiaoqiang Kang, Hong Ling. LBL-058, A novel T cell engager conjugate (TEC) targeting DLL3 with dual tumor suppressive functions [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 7322.