DLL3/CD3 T-cell Engager
A bridge between DLL3-expressing tumor cells and cytolytic T cells
DLL3/CD3 T-cell engager
Our delta-like canonical Notch ligand 3/cluster of differentiation 3 (DLL3/CD3) T-cell engager* acts as a bridge that directs the activity of cytolytic T cells selectively to DLL3-expressing tumors.1-3
Clinical trials (monotherapy): our DLL3/CD3 T-cell engager is being investigated in patients with small cell lung cancer (SCLC) and other neuroendocrine carcinomas (NECs).4-6
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
Role of DLL3
DLL3 is an inhibitory Notch ligand that is expressed in tumors with a neuroendocrine origin, such as small-cell lung cancer (SCLC) and glioblastoma multiforme– but not in normal adult tissue.7‒9 Notch pathway signaling is involved in a variety of development processes, including the development of pulmonary neuroendocrine cells.8 DLL3 expression inhibits Notch signaling, which is downregulated during neuroendocrine tumor growth.8
About our DLL3/CD3 T-cell engager
Mechanism of action
Our compound acts as a T-cell engager with an extended half-life.1 The DLL3/CD3 T-cell engager directs the activity of cytolytic T cells selectively to DLL3-expressing tumors.1-3
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 cytolytic synapse.1,2
Preclinical studies have demonstrated the antitumor activity of the DLL3/CD3 T-cell engager in a range of DLL3-positive tumor models.2,3
T-cell engager mechanism of action1-3
CD3, cluster of differentiation 3; DLL3, delta-like canonical Notch ligand 3.
Watch the 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.2 Preclinical evidence supports the combination of the DLL3/CD3 T-cell engager with PD-1 inhibitors (such as ezabenlimab) in order to revert this upregulation.1,2
Clinical development
Preclinical results have shown that DLL3/CD3 monotherapy potently inhibited tumor growth in DLL3-positive SCLC xenograft models in a dose-dependent 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.2
Our DLL3/CD3 T-cell engager is being evaluated as a monotherapy in patients with SCLC and NECs in Phase I and II studies.4,5
DLL3/CD3 T-cell engager clinical trial
Trial number | Phase | Treatment | Patient population | Status** |
---|---|---|---|---|
II | BI 764532 monotherapy | Relapsed/refractory SCLC and other relapsed/refractory epNECs | Not yet recruiting | |
1 | BI 764532 monotherapy | Advanced SCLC and other NECs expressing DLL3 | Recruiting |
**As of August 2023.
CD3, cluster of differentiation 3; DLL3, delta-like canonical Notch ligand 3; epNEC, extrapulmonary neuroendocrine carcinoma; NEC, neuroendocrine carcinoma; SCLC, small-cell lung cancer.
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OUR PIPELINE
PIPELINE STRATEGIES
Boehringer Ingelheim. Data on file.
Hipp S, et al. Clin Cancer Res. 2020;26:5258–5268.
Wermke M, et al. ASCO 2021. Poster TPS8588.
ClinicalTrials.gov. NCT05882058. http://clinicaltrials.gov/ct2/show/NCT05882058 (Accessed: August 2023).
ClinicalTrials.gov. NCT04429087. http://clinicaltrials.gov/ct2/show/NCT04429087 (Accessed: August 2023).
Wermke M, et al. ASCO 2023. Abstract 8502.
National Center for Biotechnology Information. DLL3 delta like canonical Notch ligand 3 [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/10683 (Accessed: January 2023).
Owen DH, et al. J Hematol Oncol. 2019;12(1):61.
Saunders LR, et al. Sci Transl Med, 2015;7(302):302ra136.
This is an investigational compound and has not been approved. Its safety and efficacy have not been established.