A novel tri-specific T-cell engager, DLL3-TOPAbody, has demonstrated promising antitumor efficacy and enhanced immune response in preclinical studies targeting DLL3-expressing tumors, according to data presented at the 2024 SITC Annual Meeting.
The innovative therapeutic compound showed robust activity in both in vitro and in vivo studies, specifically designed to address the limitations of current treatments for small cell lung cancer (SCLC) and other DLL3-expressing tumors.
Mechanism and Design Features
DLL3-TOPAbody represents a new generation of immunotherapy, combining three crucial components: a membrane-proximal epitope of DLL3, a fine-tuned 4-1BB antibody, and an anti-CD3 antibody with disabled Fc effector function. This design enables the agent to simultaneously target cancer cells and stimulate T-cell responses while maintaining a manageable safety profile.
The compound's architecture was specifically engineered to achieve high affinity and specificity against tumor targets, while ensuring target-dependent T-cell activation and balanced CD3 and 4-1BB signaling for sustained therapeutic activity.
Significant Preclinical Findings
Laboratory studies revealed that DLL3-TOPAbody effectively induced DLL3-dependent cytokine release and proliferation of both CD8- and CD4-positive T cells. The agent demonstrated potent tumor cell lysis in DLL3-positive cells while maintaining well-balanced binding activity across its target proteins.
In mouse models, the therapy showed remarkable results:
- Significant tumor growth inhibition in a dose-dependent manner
- Marked increase in CD8-positive T-cell infiltration
- Notable transformation of "cold" tumors into "hot" tumors
- Statistically significant improvements in both invasive margin (P < .05) and central tumor regions (P < .001)
Safety and Development Outlook
Initial safety assessments through cytokine release assays showed promising results, with interleukin-6 release occurring primarily in the presence of target cells and minimal release in their absence. This suggests a potentially favorable safety profile for clinical application.
"This approach has the potential to improve clinical outcomes for patients with SCLC, particularly those with poorly infiltrated tumors," noted Dr. Lei Fang and colleagues in their poster presentation. The research team reported that preliminary chemistry, manufacturing, and control developability assessments indicated good molecular stability.
Clinical Context and Future Directions
The development of DLL3-TOPAbody comes at a crucial time in SCLC treatment advancement. While other DLL3-targeted therapies like tarlatamab-dlle (Imdelltra) have shown success, receiving FDA accelerated approval in May 2024, there remains an unmet need in addressing poor T-cell infiltration in the tumor microenvironment.
The research team anticipates submitting an investigational new drug application for DLL3-TOPAbody in the first half of 2025, potentially offering a new treatment option for patients with SCLC and other DLL3-expressing tumors.
