Preclinical Characterization of HPN536, a Trispecific, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors
| Autor: | Che-Leung Law, Holger Wesche, Timothy Yu, Richard J. Austin, Vaishnavi Ganti, Mary Ellen Molloy, Kathryn L. Strobel, Susan D. Jones, Purbasa Patnaik, Laurie Tatalick, A. Jones, Kenneth Sexton, Patrick A. Baeuerle, Wade Aaron, Lemon Bryan D |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cancer Research T cell T-Lymphocytes Serum albumin Apoptosis Mice SCID Lymphocyte Activation 03 medical and health sciences Mice 0302 clinical medicine Breast cancer Pharmacokinetics Antigens Neoplasm Mice Inbred NOD Neoplasms Tumor Cells Cultured Medicine Potency Animals Humans Mesothelin Cell Proliferation biology business.industry In vitro toxicology Single-Domain Antibodies medicine.disease Xenograft Model Antitumor Assays Tumor antigen Peptide Fragments Macaca fascicularis 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Female Immunotherapy business |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 27(5) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: 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. Experimental Design: 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). Results: 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. Conclusions: 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|