GS24-B047, a potential best-in-class DLL3-targeting T-cell engager with integrated costimulatory signal, for the treatment of small cell lung cancer

Background: Small cell lung cancer (SCLC) remains an aggressive malignancy with limited therapeutic options and poor prognosis, particularly in the relapsed/refractory settings. DLL3, a tumor-associated antigen highly expressed on SCLC cells with minimal expression in normal tissues, represents a promising therapeutic target. While T-cell engagers (TCEs) targeting DLL3 and CD3, such as Tarlatamab, have demonstrated clinical activity, maintaining T-cell function in the tumor microenvironment remains challenging, and improvements in progression-free survival (PFS) have been limited. GS24-B047 is a novel DLL3-targeting TCE that incorporates a proprietary costimulatory signal designed to enhance T cell activation and persistence, with the potential to improve clinical efficacy in SCLC patients. Methods: Binding activity and specificity of GS24-B047 to DLL3, CD3, and the costimulatory target were characterized by surface plasmon resonance (SPR), Octet biosensor, and flow cytometry. In vitro functional activity was assessed in co-culture assays with human PBMCs and DLL3-expressing SCLC cell lines, measuring T cell activation, cytokine release, and cytotoxicity. In vivo anti-tumor efficacy was evaluated in SCLC cell-derived xenograft (CDX) models with human immune system reconstitution. Results: GS24-B047 bound to DLL3 with sub-nanomolar affinity, recognizing a distinct, more membrane-proximal epitope as compared to Tarlatamab, and effectively mediated simultaneous engagement of DLL3 on tumor cells and CD3 on T cells. In vitro , GS24-B047 induced T cell activation, proliferation, and cytokine secretion, and exhibited potent cytotoxicity against DLL3-expressing SCLC cell lines (with EC 50 values in the picomolar range). GS24-B047 demonstrated a favorable therapeutic index with a high ratio of tumor cell killing to IL-6 release. The integrated costimulatory signal reduced markers of T-cell exhaustion as compared to a benchmark DLL3xCD3 TCE, supporting a more sustained T-cell response. In vivo , GS24-B047 treatment resulted in significant and durable tumor regression in multiple CDX models of SCLC, showing enhanced anti-tumor activity when compared to clinical benchmarks. Conclusion: GS24-B047 is a novel DLL3-targeting TCE with integrated costimulation that promotes potent and sustained anti-tumor immunity in preclinical SCLC models. Collectively, our data support GS24-B047 as a potential therapeutic candidate for SCLC and warrant further evaluation in IND-enabling studies.