Our DLL3/CD3 T-cell engager is being evaluated in Phase I and II clinical trials in patients with small cell lung cancer (SCLC) and other neuroendocrine carcinomas (NECs)^3–10

DLL3/CD3 T-cell engager clinical trials

DLL3/CD3 T-cell engager mechanism of action

Our compound acts as a T-cell engager with an extended half-life that selectively directs the activity of cytolytic T cells to DLL3-expressing tumors.^1–3,11

The pharmacological effect of the DLL3/CD3 T-cell engager depends on its ability to bind simultaneously to CD3 on T-cells and to DLL3 expressed on tumor cells, resulting in the formation of a major histocompatibility complex (MHC)-independent cytolytic synapse.^1–3

Preclinical studies have demonstrated the antitumor activity of the DLL3/CD3 T-cell engager in a range of DLL3-positive tumor models.^1,11 In preclinical studies, DLL3/CD3 monotherapy potently inhibited tumor growth in DLL3-positive SCLC xenograft models in a dose- and time-dependent manner. It also modulated the inflammatory environment in the tumor tissue by redirecting CD4-positive and CD8-positive T-cell cytotoxicity toward DLL3-postitive SCLC cells, without affecting DLL3-negative target cells.¹
 

DLL3/CD3 T-cell engager mechanism of action^2,3,11

Watch the DLL3/CD3 T-cell engager mechanism of action animation

Combination therapy

The binding of the DLL3/CD3 T-cell engager to CD3 may lead to programmed cell death protein-1 (PD-1) upregulation in activated T-cells and programmed death ligand-1 upregulation on malignant cells.¹ Preclinical evidence supports the combination of the DLL3/CD3 T-cell engager with PD-1 inhibitors (such as ezabenlimab) in order to inhibit this upregulation.^1,2

DLL3 is an inhibitory Notch ligand that is expressed in tumors with a neuroendocrine origin, such as small-cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinoma (epNEC), and large cell neuroendocrine carcinoma of the lung (LCNEC-L), but not in normal adult tissue.^3,12‒15 Notch pathway signaling is involved in a variety of development processes, including the development of pulmonary neuroendocrine cells.¹³ DLL3 expression inhibits Notch signaling, which is downregulated during neuroendocrine tumor growth.¹³

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
CD3, cluster of differentiation 3; DLL3, delta-like canonical Notch ligand 3; epNEC, extrapulmonary neuroendocrine carcinoma; LCNEC-L, large cell neuroendocrine carcinoma of the lung; MHC, major histocompatibility complex; NEC, neuroendocrine carcinoma; PD-1, programmed cell death protein-1; SCLC, small cell lung cancer.