DLL3, or delta-like ligand 3, has emerged as a promising therapeutic target for specific malignancies. DLL3, which is generally not expressed in most normal tissues, is overexpressed in neuroendocrine malignancies such as small cell lung cancer (SCLC). Thus, targeting DLL3 provides an approach for more specific cancer treatment, particularly for neuroendocrine cancer patients who have few therapeutic options. DLL3 regulates the Notch signaling pathways, which control cell differentiation. In healthy tissues, DLL3 expression is strictly regulated. However, in cancer, abnormal DLL3 expression has been linked to tumor start and development. DLL3 is found in up to 80% of small cell lung cancer tumors but has little expression in normal adult tissues, making it a promising therapeutic target.
Pharmaceutical companies are developing targeted therapeutics for DLL3 using a variety of ways. Bispecific antibodies, primarily as T cell engagers, have advanced the most in clinical research and testing. Bispecific T cell engagers bridge the gap between cancer cells and immune cells by simultaneously connecting with both, diverting endogenous T-cell populations to cells expressing DLL3 and inducing tumor cell death. This method aids in initiating a focused attack on specific cancer cells while reducing collateral damage to healthy cells.
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Amgen created Tarlatamab utilizing its patented BiTE (bispecific T-cell engager) technology. In the phase 2 DeLLphi-301 trial, which assessed the objective response rate, duration of response, disease control rate, progression-free survival, and overall survival following Tarlatamab treatment, an objective response rate of 40% and disease control rate of 63% were found. All participants in the study had advanced-stage SCLC, and had received at least two lines of previous treatment, including platinum-doublet chemotherapy.
Based on these promising results, Amgen filed a biologics license application (BLA) at the US FDA for the treatment of patients with advanced small cell lung cancer (SCLC), which granted it Priority Review in December 2023, with the Prescription Drug User Fee Action date of June 12, 2024. Other approaches to DLL3 include cell therapies, such as Tianjin Medical University Cancer Institute and Hospital’s DLL3-CAR-NK cell therapy, and Legend Biotech’s LB2102, a DLL3-CAR-T cell therapy. Another example is antibody-drug conjugates, which paved the way for the development of DLL3 targeting therapies after studies using Rovalpituzumab Tesirine proved the anticancer effects of DLL3 targeting.
While most DLL3 targeted therapies are still in their early phases, Tartalamab has demonstrated promise thus far, as seen by its multiple designations. DLL3 targeted treatments have significant implications for cancer treatment, with the potential to succeed where previous therapies have failed. With further study and clinical trials, DLL3 targeted treatments have the potential to improve patient survival in neuroendocrine cancers.