Delta-like ligand 3 (DLL3) (DLL3)

Delta-like ligand 3 (DLL3) is a type I transmembrane protein and a non-canonical ligand in the Notch signaling pathway [21, 22]. Unlike other Notch ligands that activate signaling in adjacent cells, DLL3 primarily functions as an inhibitor by sequestering Notch receptors in the Golgi apparatus or through cis-inhibition on the same cell membrane [22, 24]. While DLL3 expression is negligible in most healthy adult tissues, it is aberrantly overexpressed on the cell surface in high-grade neuroendocrine tumors, most notably small cell lung cancer (SCLC), where it is driven by the transcription factor ASCL1 [3, 16, 20]. This highly selective expression pattern makes DLL3 an exceptional candidate for targeted oncology therapies [11, 17]. Tarlatamab is a first-in-class bispecific T-cell engager (BiTE) designed to exploit this selectivity by simultaneously binding to DLL3 on tumor cells and CD3 on T cells [1, 2, 4]. This dual engagement facilitates the formation of an immunological synapse, leading to T-cell activation and the subsequent release of perforins and granzymes to lyse the target cancer cells [3, 5]. Beyond SCLC, DLL3-targeted strategies including tarlatamab are being investigated for other neuroendocrine-derived malignancies such as prostate and thyroid cancers [6, 13, 14]. Clinical use of these agents requires careful management of immune-related adverse events, particularly cytokine release syndrome and neurotoxicity [8, 13].

Other names

Delta-like protein 3SCDO1Delta-like 3Notch ligand DLL3

T-cell redirection via bispecific binding to DLL3 on tumor cells and CD3 on T cells, facilitating the formation of an immunological synapse that induces T-cell activation and MHC-independent tumor cell lysis [1, 2, 3].