Abstract 5161: Preclinical evaluation of CD3/DLL3 bispecific antibody in syngeneic and humanized mouse models for solid tumor treatment

In solid tumors, the number of T cells is limited, and immunosuppressive cells in the tumor microenvironment, such as cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), can inhibit T cell activity. Additionally, T cells in solid tumors often exist in a state of exhaustion, reducing the effectiveness of treatments. Delta-like 3 (DLL3) is abnormally highly expressed in various tumor cell lines and primary tumor tissues, particularly showing a significant increase in neuroendocrine tumors (NETs) and small cell lung cancer (SCLC). In SCLC, the expression of DLL3 is closely associated with poor prognosis in patients. Tarlatamab is the first approved bispecific T cell engager (BiTE) therapy for the treatment of solid tumors and is the bispecific antibody (BsAb) that targets DLL3. This BiTE works by directing T cells to the vicinity of small cell lung cancer cells and activating them to eliminate tumor cells. While the powerful therapeutic effects of Tarlatamab are being highlighted, there is also a consideration for more effective assessment of bispecific antibodies. Appropriate preclinical evaluation models can provide critical data support for subsequent clinical trials of CD3/DLL3 bispecific antibodies, aiding in the understanding of their potential and mechanisms in therapy. Biocytogen successfully developed a cell line B-hDLL3 B16-F10 that expresses human DLL3. B-hDLL3 B16-F10 cell line can bind to CD3/DLL3 BsAb Tarlatamab analog (in house) and is capable of forming tumors in C57BL/6 mice and B-hCD3E/hCD28 mice after injected. When B-hDLL3 B16-F10 cells are subcutaneously implanted in B-hCD3EDG mice, the Tarlatamab analog (in house) significantly inhibits tumor growth. In PBMC-reconstituted B-NDG mice implanted with human tumor cell line SHP-77, Tarlatamab analog (in house) almost completely suppresses tumor growth. These results indicate that both preclinical animal models can be used to evaluate the in vivo efficacy of the CD3/DLL3 BsAb treatment. Citation Format: Ravneet Chhabra, Chong Li, Shuangshi Liu, Qiang Liu, Liu Yang, Hui Xu. Preclinical evaluation of CD3/DLL3 bispecific antibody in syngeneic and humanized mouse models for solid tumor treatment [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 5161.