Delta-like ligand 3 and Cluster of differentiation 3 (DLL3–CD3)

DLL3–CD3 is a therapeutic target complex utilized by bispecific T-cell engagers (BiTEs) to treat neuroendocrine-derived malignancies, most notably small cell lung cancer (SCLC) [1, 3]. Delta-like ligand 3 (DLL3) is a Notch pathway ligand that is highly overexpressed on the surface of SCLC and other neuroendocrine tumor cells but is minimally present in healthy adult tissues [6, 13]. Cluster of differentiation 3 (CD3) is a protein complex on the surface of T-cells that is essential for T-cell receptor signaling and activation [4, 11]. By simultaneously binding to DLL3 on tumor cells and CD3 on T-cells, these therapeutic agents facilitate the formation of an artificial immunological synapse [3, 5]. This interaction triggers T-cell activation and the release of cytotoxic granules, such as perforin and granzymes, leading to the selective lysis of the cancer cells [4, 7]. Tarlatamab (Imdelltra) is the first FDA-approved drug targeting this complex, demonstrating significant clinical efficacy in patients with advanced SCLC [2, 14]. Other agents in development, such as BI 764532 and HPN328, also target this interaction to treat various neuroendocrine carcinomas [10, 15]. The primary safety concerns associated with this target include cytokine release syndrome (CRS) and neurotoxicity, which result from the potent activation of the immune system [13, 14].

Other names

DLL3/CD3DLL3-CD3 bispecific T-cell engagerDLL3-CD3 BiTEDLL3-CD3 TriTAC

Bispecific T-cell engager that simultaneously binds DLL3 on tumor cells and CD3 on T-cells, redirecting T-cells to kill the tumor cells [1, 3, 4].