1. HPN328, a Trispecific T Cell-Activating Protein Construct Targeting DLL3-Expressing Solid Tumors.
- Author
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Molloy ME, Aaron WH, Barath M, Bush MC, Callihan EC, Carlin K, Cremin M, Evans T, Guerrero MG, Hemmati G, Hundal AS, Lao L, Laurie P, Lemon BD, Lin SJ, O'Rear J, Patnaik P, Sotelo Rocha S, Santiago L, Strobel KL, Valenzuela LB, Wu CH, Yu S, Yu TZ, Anand BS, Law CL, Sun LL, Wesche H, and Austin RJ
- Subjects
- Humans, Animals, Mice, T-Lymphocytes immunology, T-Lymphocytes metabolism, Intracellular Signaling Peptides and Proteins metabolism, Intracellular Signaling Peptides and Proteins genetics, Cell Line, Tumor, Macaca fascicularis, Xenograft Model Antitumor Assays, Neoplasms drug therapy, Neoplasms immunology, Neoplasms metabolism, Neoplasms pathology, Female, Membrane Proteins metabolism
- Abstract
Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC is highly aggressive, and limited therapeutic options lead to poor prognosis for patients. HPN328 is a trispecific T cell-activating construct (TriTAC) consisting of three binding domains: a CD3 binder for T-cell engagement, an albumin binder for half-life extension, and a DLL3 binder for tumor cell engagement. In vitro assays, rodent models, and non-human primates were used to assess the activity of HPN328. HPN328 induces potent dose-dependent killing of DLL3-expressing SCLC cell lines in vitro, concomitant with T-cell activation and cytokine release. In an NCI-H82 xenograft model with established tumors, HPN328 treatment led to T-cell recruitment and anti-tumor activity. In an immunocompetent mouse model expressing a human CD3ε epitope, mice previously treated with HPN328 withstood tumor rechallenge, demonstrating long-term anti-tumor immunity. When repeat doses were administered to cynomolgus monkeys, HPN328 was well tolerated up to 10 mg/kg. Pharmacodynamic changes, such as transient cytokine elevation, were observed, consistent with the expected mechanism of action of T-cell engagers. HPN328 exhibited linear pharmacokinetics in the given dose range with a serum half-life of 78 to 187 hours, supporting weekly or less frequent administration of HPN328 in humans. Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3-expressing malignancies., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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