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A protein that appears on the surface of small-cell lung cancer cells, now hit by a drug that pulls T cells onto them.
Delta-like ligand 3 is an inhibitory Notch ligand aberrantly surface-expressed in ~85% of small-cell lung cancer and neuroendocrine prostate cancer. The first DLL3 ADC (rovalpituzumab tesirine) failed; the T-cell engager tarlatamab (Imdelltra) succeeded, with a survival benefit in second-line SCLC (DeLLphi-304). Trispecifics and CAR-T follow.
In plain words · A protein that appears on the surface of small-cell lung cancer cells, now hit by a drug that pulls T cells onto them.
A protein that appears on the surface of small-cell lung cancer cells, now hit by a drug that pulls T cells onto them.
Normally intracellular Golgi protein; ASCL1-driven neuroendocrine lineage exposes it on the membrane.
6 products aim at DLL3: antibody-drug conjugates, bispecific antibodies and cell therapies. Because it sits on the outside of the cell, it can be reached from the bloodstream: antibodies flag the cell, ADCs deliver a toxin, radioligands deliver radiation, and CAR-T or bispecifics bring a T cell.
Tumour-associated overexpression: 5 cell-killing or cell-finding medicines (ZL-1310, DJI136, Obrixtamig and more) aim at the antigen, which HPA finds with no normal tissue stained high; the medicine relies on the tumour carrying more of it than the normal tissue it shares it with. HPA DLL3: RNA tissue enriched (brain 27 nTPM); blood lineage group enriched (B-cells 3 nTPM, T-cells 1 nTPM); no normal tissue stained high. Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Lung cancer (all types), Prostate cancer); Open Targets associates it with 1 specific cancer type at or above 0.5 (small cell lung carcinoma). (Rule 5 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas DLL3 tissue; Human Protein Atlas DLL3 pathology; Open Targets ENSG00000090932 associations
First described 2000. Earliest sequence paper UniProt cites for the protein: Bulman M.P. et al, Nat. Genet, 2000, "Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis". Source.
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Normally intracellular Golgi protein; ASCL1-driven neuroendocrine lineage exposes it on the membrane.
RNA: tissue enriched (brain 27 nTPM), detected in some normal tissues. Blood: group enriched (B-cells 3 nTPM, T-cells 1 nTPM).
No normal tissue stained high.
RNA cancer enhanced: Glioblastoma Multiforme 60 pTPM, Skin Cutaneous Melanoma 27 pTPM.
No cancer sample stained medium or high.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Small-cell lung cancer | 80-85% | IHC, any expression | Wikipedia | |
| Prostate cancer | 70-80% | Neuroendocrine prostate cancer only | Rare in adenocarcinoma | Wikipedia |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
DJI136 is an experimental CAR-T cell therapy from Novartis Pharmaceuticals in phase 2 trials for non-small-cell lung cancer, aimed at DLL3.
Obrixtamig is an antibody with two arms: one grabs DLL3, a protein on the surface of most neuroendocrine carcinomas, and the other grabs a T cell, pulling the killer cell onto the cancer. It is in a phase 3 trial for neuroendocrine carcinomas outside the lung.
Peluntamig is an experimental bispecific antibody from Phanes Therapeutics in phase 2 trials for non-small-cell lung cancer and neuroendocrine tumours, aimed at CD47 and DLL3.
Rovalpituzumab tesirine (Rova-T) was the first drug against DLL3 in small-cell lung cancer. AbbVie bought it for $5.8B and abandoned it after two failed phase 3 trials. The target later worked with a different weapon.
The first T-cell engager to improve survival in a common solid tumour, small-cell lung cancer.
ZL-1310 is an experimental antibody-drug conjugate from Zai Lab (Shanghai) in phase 3 trials for non-small-cell lung cancer, aimed at DLL3.
Patients with small-cell lung cancer that has relapsed after chemotherapy now have a drug that works far better than topotecan or lurbinectedin, and it is the first T-cell engager approved for a solid tumour. Treatment requires inpatient monitoring for the first doses because of cytokine release syndrome, which most centres now manage on a short-stay basis. It does not yet apply to first-line treatment, where trials are ongoing.
It offers the first credible explanation for why only a minority of small-cell patients get a durable benefit from checkpoint blockade, and it introduces subtype switching, which would mean retesting at relapse rather than typing once.
It is the reality check on the subtype model and it has a direct consequence for treatment: the DLL3-directed medicines are aimed at the neuroendocrine-high subtypes, and the POU2F3 and double-negative tumours will not express the target.
The organising framework for every small-cell lung cancer trial designed since. It is also why the slow progress in the disease is now attributed to treating four diseases as one rather than to the biology being intractable.
Why small-cell lung cancer has no targeted therapy in the conventional sense: it is built from the loss of TP53 and RB1, and the drugs that transformed non-small-cell disease inhibit gains rather than restore losses. The NOTCH result pointed at DLL3 and, eventually, at tarlatamab.
Query for this target: (TITLE:"DLL3" OR ABSTRACT:"DLL3") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about DLL3, not a curated reading list.
Shares Harpoon Therapeutics, Obrixtamig, DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer, Tarlatamab and the tag t-cell-engager-target.
Shares T-cell engagers (bispecific) and the tag t-cell-engager-target.
Shares Prostate cancer and the tag t-cell-engager-target.
Shares Prostate cancer and the tag t-cell-engager-target.
Shares Hospital Universitario 12 de Octubre, Resistance routes: how a blocked pathway comes back, T-cell engagers (bispecific) and the tag t-cell-engager-target.
Shares DeLLphi-305, DeLLphi-304, DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer, Tarlatamab.
Shares SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization, Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities, Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, Comprehensive genomic profiles of small cell lung cancer.
Shares Hallmark (2022): unlocking phenotypic plasticity, Cancer stem cells & phenotypic plasticity, Extrapulmonary neuroendocrine carcinoma, Neuroendocrine and small-cell prostate cancer.