Delta-like ligand 3 and CD3 T-cell surface glycoprotein CD3 epsilon chain (DLL3/CD3)

Delta-like ligand 3 (DLL3) is a non-canonical Notch ligand that is highly overexpressed on the surface of small cell lung cancer (SCLC) and other neuroendocrine tumors, while remaining largely absent from healthy adult tissues (17, 21, 25). CD3 is a multi-subunit protein complex on T cells, specifically the epsilon chain (CD3e), which is essential for signal transduction and T-cell activation (3, 8, 24). The dual targeting of DLL3 on tumor cells and CD3 on T cells is the basis for bispecific T-cell engager (BiTE) therapies, which physically bridge cytotoxic T lymphocytes to malignant cells (6, 12, 14). This interaction facilitates the formation of an immunological synapse, leading to MHC-independent T-cell activation and the subsequent release of perforins and granzymes to induce tumor cell lysis (9, 15, 26). Tarlatamab (Imdelltra) is the first FDA-approved therapy utilizing this dual target for the treatment of extensive-stage SCLC (12, 15). Other agents in development, such as BI 764532 and the trispecific HPN328, aim to improve outcomes in recalcitrant neuroendocrine malignancies by leveraging this specific immune redirection (4, 5, 30).

Other names

Delta-like 3DLL3CD3eCD3 epsilonT-cell receptor complex subunit epsilonDLL3-CD3DLL3xCD3

Bispecific T-cell engager (BiTE) that simultaneously binds DLL3 on tumor cells and CD3 on T cells to form an immunological synapse, leading to MHC-independent T-cell activation and granzyme/perforin-mediated tumor cell lysis.