Delta-like protein 3 (DLL3) (DLL3)

Delta-like protein 3 (DLL3) is a Notch pathway ligand that is predominantly localized in the Golgi apparatus and on the cell surface, where it acts as an inhibitory ligand to Notch receptors in cis (UniProt: O75780). While its expression is highly restricted in healthy adult tissues, it is significantly upregulated in small cell lung cancer (SCLC) and other high-grade neuroendocrine tumors, often driven by the transcription factor ASCL1 (PubMed: 30232139). This tumor-specific expression profile makes DLL3 a highly attractive target for various modalities, including bispecific T-cell engagers (BiTEs), antibody-drug conjugates (ADCs), and CAR-T cell therapies (PubMed: 37861218). Peluntamig (also known as tarlatamab or AMG 757) is a first-in-class BiTE designed to bridge DLL3-expressing cancer cells with CD3-positive T-cells, inducing potent T-cell activation and subsequent tumor cell lysis (ClinicalTrials.gov: NCT05060341). Clinical development of DLL3-targeted agents has shown promise in treating refractory SCLC, though management of immune-related adverse events like cytokine release syndrome remains a key clinical consideration (NEJM: 389(22)).

Other names

Delta-like ligand 3Drosophila Delta homolog 3SCDO1Delta3DLL-3

Peluntamig (Tarlatamab) is a bispecific T-cell engager (BiTE) that simultaneously binds to DLL3 on the surface of tumor cells and the CD3 epsilon subunit on T-cells (PubMed: 37861218). This interaction creates a cytolytic synapse, leading to the release of perforins and granzymes from T-cells, which results in the apoptosis of the DLL3-expressing target cell (ClinicalTrials.gov: NCT05060341).