HPN328, a Trispecific T Cell-Activating Protein Construct Targeting DLL3-Expressing Solid Tumors.

Area of Science:

• Oncology
• Immunotherapy
• Pharmacology

Background:

• Small cell lung cancer (SCLC) is aggressive with limited treatment options.
• Delta-like ligand 3 (DLL3) is a promising target, present in over 70% of SCLC.
• Novel therapeutic strategies are needed to improve patient prognosis.

Purpose of the Study:

• To evaluate the preclinical efficacy and safety of HPN328, a DLL3-targeted trispecific T cell-activating construct (TriTAC).
• To assess HPN328's mechanism of action, including T-cell activation and anti-tumor responses.
• To determine the pharmacokinetic profile and tolerability of HPN328.

Main Methods:

• In vitro assays using DLL3-expressing SCLC cell lines.
• In vivo studies in rodent xenograft and immunocompetent models.
• Non-human primate studies for pharmacokinetic and safety assessments.

Main Results:

• HPN328 demonstrated potent, dose-dependent killing of SCLC cells and T-cell activation in vitro.
• Established tumors showed significant anti-tumor activity and T-cell recruitment upon HPN328 treatment.
• Long-term anti-tumor immunity was observed in a rechallenge model.
• HPN328 was well-tolerated in cynomolgus monkeys with predictable pharmacokinetics supporting infrequent dosing.

Conclusions:

• HPN328 exhibits strong preclinical efficacy and a favorable safety profile.
• The drug's mechanism involves potent T-cell mediated tumor cell killing.
• HPN328 represents a promising therapeutic candidate for DLL3-expressing malignancies, with a Phase 1/2 trial ongoing.