DLL-3 as a Novel Target for Possible Lung Cancer Therapeutics

The Notch pathway is highly maintained to regulate cell proliferation, cell fate, differentiation, cell boundary construction, cell death, and several processes of growth and development in all metazoans. Delta‐like canonical Notch ligand 3 (DLL3) is a member of the Notch receptor ligand family and takes part in the Notch signaling pathway. High expression of DLL3 has been identified in small cell lung cancer and certain neuroendocrine tumors, while it is seldom observed in healthy normal tissues. This finding triggers the interest of developing DLL3 into a new target in cancer therapeutics, and some researchers have commenced their investigation on targeting DLL-3 for precision lung cancer treatment.

Human DLL3 consists of a DSL domain, an intracellular domain, and six epidermal growth factor-like domains. As a single transmembrane protein, it has 619 amino acids that allow it to adhere to the cell surface, and is commonly expressed in the Golgi apparatus. However, different from other Notch ligands, when overexpressed, DLL3 will show up on the cell surface. The most important thing is that DLL3 does not bind to the Notch receptor but works as a cell-autonomous Notch signaling inhibitor.

Recent research has shown that DLL3 is significantly expressed on the surface of small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC). And the ADC drug targeting DLL3, ROVA-T, is believed to be promising in treating SCLC and LCLNEC. Inhibition of DLL3 can prevent the development of SCLC and LCNEC and ultimately lead to apoptosis. Moreover, DLL3 has been identified as the direct downstream target of a transcription factor related to the development of pulmonary neuroendocrine cells, called ASCL1. This discovery provides evidence that DLL3 is associated with neuroendocrine carcinogenesis, notably the type related to lung cancer.

Several therapeutics targeting DLL3 have been developed, such as bispecific antibodies (bsAbs), cell therapy, antibody-coupled drugs (ADCs), monoclonal antibodies, and bispecific T-cell conjugates (BiTE), and most of them have proven to be effective in clinical trials. In addition, near-infrared immunotherapy that leverages antibody photosensitizer conjugates has been proposed to irradiate and finally damage cancer cells. Bispecific T‐cell engager (BiTE), as a new immunotherapy technique, was also developed to redirect T-cells in a patient's body to kill tumor cells. Based on this theory, chimeric antigen receptor T-cell (CAR-T) therapy that genetically transforms T cells and directs them to express tumor antigen-specific chimeric receptors to attack and kill the target cells is another significant attempt.

Despite these advancements, there is still a demand for novel lung cancer drugs targeting DLL3. Therefore, many DLL3 protein products are offered by worldwide biotech companies to facilitate the development of novel lung cancer therapeutics targeting DLL3. Most of these protein products are available in multiple species including humans, rats, mice, rhesus macaque, and Cynomolgus for cross-examination. Additional tags such as His, His and Avi, Fc, and Avi-tag are also required to develop new drugs in different experimental situations.

In summary, Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. Despite high rates of response to first-line chemotherapy and radiotherapy, patients with extensive-stage disease eventually relapse, and very few patients survive more than 5 years from diagnosis. Treatment options for recurrent or refractory disease are limited, and the treatments that do exist are associated with significant treatment-related toxicities. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. It is therefore being explored as a potential therapeutic target in SCLC. Here, we review the preclinical and clinical evidence for targeting DLL3 in SCLC and discuss several DLL3-specific therapies being developed for the treatment of SCLC: the antibody-drug conjugate rovalpituzumab tesirine, the bispecific T cell engager immuno-oncology therapy AMG 757, and the chimeric antigen receptor T cell therapy AMG 119.