Delta-like ligand 3 (DLL3)–T-cell surface glycoprotein CD3 epsilon chain (CD3ε) (DLL3–CD3ε)

Delta-like ligand 3 (DLL3) is a Notch pathway ligand that is aberrantly expressed on the surface of neuroendocrine tumors, such as small cell lung cancer (SCLC), while remaining largely absent in healthy adult tissues [1, 6]. CD3 epsilon (CD3ε) is a key component of the T-cell receptor complex involved in signal transduction and T-cell activation [2, 7]. The DLL3–CD3ε target represents a bispecific approach where a therapeutic agent simultaneously binds to DLL3 on malignant cells and CD3ε on cytotoxic T cells [4, 8]. This dual binding facilitates the formation of an immunological synapse, bypassing the need for traditional MHC-mediated antigen presentation and triggering T-cell-mediated lysis of the tumor cells [7, 10]. This mechanism is the basis for several clinical-stage bispecific T-cell engagers, including the FDA-approved drug tarlatamab, which has demonstrated efficacy in treating relapsed or refractory SCLC [8, 11]. Clinical challenges associated with this target include the management of cytokine release syndrome (CRS) and neurotoxicity, which result from systemic T-cell activation [8, 11]. Despite these challenges, the high tumor selectivity of DLL3 makes the DLL3–CD3ε axis a promising frontier for treating aggressive neuroendocrine malignancies [5, 9].

Other names

DLL3/CD3DLL3-CD3Delta-like 3-CD3 epsilonDLL3-CD3eDLL3-CD3 epsilon

Bispecific T-cell engagement leading to redirected T-cell mediated cytotoxicity