Molloy et al. engineered HPN328, a trispecific DLL3-targeting T cell engager with extended half-life via serum albumin binding. HPN328 induced a potent dose-dependent killing of DLL3-expressing SCLC lines in vitro, concomitant with T cell activation and cytokine release. HPN328 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys, and led to T cell recruitment and antitumor activity in a xenograft tumor model. In an immunocompetent mouse model expressing a human CD3ε epitope, HPN328 induced potent antitumor activity and protected against tumor rechallenge, even with hDLL3-negative parental tumor cells.
Contributed by Shishir Pant
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 tri-specific 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 CD3_ 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 pharmacokinetic 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.
Author Info: (1) Harpoon Therapeutics, South San Francisco, United States. (2) Harpoon Therapeutics, South San Francisco, United States. (3) Gilead Sciences (United States), Foster City, CA, Un
Author Info: (1) Harpoon Therapeutics, South San Francisco, United States. (2) Harpoon Therapeutics, South San Francisco, United States. (3) Gilead Sciences (United States), Foster City, CA, United States. (4) Harpoon Therapeutics, South San Francisco, United States. (5) Harpoon Therapeutics, South San Francisco, United States. (6) Harpoon Therapeutics, South San Francisco, United States. (7) Harpoon Therapeutics, South San Francisco, United States. (8) Harpoon Therapeutics, South San Francisco, United States. (9) Harpoon Therapeutics, South San Francisco, United States. (10) Tizona Therapeutics, san francisco, california, United States. (11) Harpoon Therapeutics, South San Francisco, United States. (12) Harpoon Therapeutics, South San Francisco, United States. (13) Harpoon Therapeutics, South San Francisco, United States. (14) Harpoon Therapeutics, South San Francisco, CA, United States. (15) Harpoon Therapeutics, South San Francisco, United States. (16) Harpoon Therapeutics, South San Francisco, United States. (17) Harpoon Therapeutics, South San Francisco, United States. (18) Harpoon Therapeutics, South San Francisco, United States. (19) Harpoon Therapeutics, South San Francisco, United States. (20) Harpoon Therapeutics, South San Francisco, United States. (21) Harpoon Therapeutics, South San Francisco, United States. (22) University of California, San Francisco, San Francisco, CA, United States. (23) Harpoon Therapeutics, South San Francisco, United States. (24) Harpoon Therapeutics, South San Francisco, CA, United States. (25) Harpoon Therapeutics, Austin, Texas, United States. (26) Abacus Bioscience, Seattle, WA, United States. (27) Genentech, Inc., South San Francisco, United States. (28) Harpoon Therapeutics, South San Francisco, United States. (29) Harpoon Therapeutics, South San Francisco, CA, United States.
