Delta-like protein 3 and T-cell surface glycoprotein CD3 epsilon chain interface (DLL3-CD3ε)

Delta-like protein 3 (DLL3) is a Notch pathway ligand that is typically localized to the Golgi apparatus in normal tissues but is highly overexpressed on the cell surface of small cell lung cancer (SCLC) and other neuroendocrine tumors (Saunders et al., 2015). T-cell surface glycoprotein CD3 epsilon chain (CD3ε) is a critical component of the T-cell receptor (TCR) complex involved in signal transduction and T-cell activation (Giffin et al., 2021). The DLL3–CD3ε interface represents the functional interaction site created by bispecific T-cell engagers (BiTEs) or trispecific antibodies. By simultaneously binding to DLL3 on malignant cells and CD3ε on cytotoxic T cells, these therapeutics bypass the requirement for major histocompatibility complex (MHC) class I recognition. This proximity induces T-cell activation, secretion of perforins and granzymes, and subsequent apoptosis of the DLL3-positive tumor cells (Giffin et al., 2021). This target interface is a major focus in the development of immunotherapies for recalcitrant neuroendocrine malignancies, with tarlatamab receiving FDA approval in 2024 for SCLC (FDA, 2024).

Other names

DLL3-CD3 complexDLL3/CD3εDelta-like ligand 3/CD3 epsilonDLL3-CD3 interface

Bispecific T-cell redirection: The drug binds to DLL3 on the surface of tumor cells and CD3ε on T cells, facilitating the formation of an artificial immunological synapse that triggers T-cell activation and tumor cell lysis.