Preclinical Characterization of HPN536, a Trispecific, T-Cell–Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors
Open Access
- 1 March 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 27 (5), 1452-1462
- https://doi.org/10.1158/1078-0432.ccr-20-3392
Abstract
Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers. We designed HPN536, a 53-kDa, trispecific, T-cell–activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ϵ on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP). HPN536 binds to MSLN-expressing tumor cells and to CD3ϵ on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans. HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).Keywords
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Funding Information
- Harpoon Therapeutics, Inc
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