Abstract LB266: VBC229: A novel DLL3-targeting biparatopic T-cell engager-topoisomerase I inhibitor fusion molecule for depth and duration of response in small-cell lung cancer

Abstract Small cell lung cancer (SCLC) is an aggressive, smoking related neuroendocrine carcinoma with rapid growth, early metastasis, and frequent relapse after initial chemotherapy. It remains a lethal disease with limited treatment options and poor long term survival. In recent years, biologic therapies have emerged as a transformative approach in SCLC. Notably, DLL3 - a target highly expressed in SCLC - has spurred the development of novel modalities. Here we present that VBC229, a first-in-class DLL3-targeting T-cell engager-topoisomerase I inhibitor (TCE-TOPO1i) fusion molecule, is designed to achieve deeper and more durable responses through the dual mechanism therapeutic modality. This strategy synergistically achieves improved efficacy while prolonging tumor control - directly addressing the core limitations of current SCLC biological regimens. VBC229’s molecular design integrates three key innovations: a. a proprietary CD3-binding arm showing potent on-target cytotoxicity while limiting excessive T-cell activation. b. a biparatopic DLL3-targeting architecture with enhanced efficacy against DLL3-positive tumor cells. c. a proprietary linker, minimizing peripheral payload release while avoiding detectable cytotoxicity against PBMCs, thereby enhancing the safety profile. More importantly, in the preclinical studies, VBC229 demonstrated the superior therapeutic window comparing to Tarlatamab (Amgen’s CD3×DLL3 TCE) - with greater antitumor activity but no excessive T-cell activation and CRS, especially with no detectable payload-induced cytotoxicity against PBMCs. Current development activities include CMC process optimization and dose-range-finding (DRF) toxicity studies, with an IND application scheduled for submission in H1 2027. In summary, VBC229 combines a differentiated antibody architecture and an innovative linker design, demonstrating promising preclinical efficacy and safety as a first-in-class candidate for SCLC clinical development. Citation Format: Wei (Vivian) Wang, Xuekun Zhang, Kevin Yin, Man Xu, Jim Li, Jian Tang, Xingguang Lin, Yingchun Wang, Yanwei Wang, Xin Li, Delong Zhang, Jing Li. VBC229: A novel DLL3-targeting biparatopic T-cell engager-topoisomerase I inhibitor fusion molecule for depth and duration of response in small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB266.