ABSTRACT
Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.
Subject(s)
Immunotherapy , Neoplasms , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatase, Non-Receptor Type 2 , Animals , Humans , Mice , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Disease Models, Animal , Drug Resistance, Neoplasm , Immune Checkpoint Inhibitors , Immunotherapy/methods , Interferons/immunology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 2/antagonists & inhibitors , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunologyABSTRACT
In preclinical studies of pharmaceutical agents, the beagle dog is a commonly used model for the detection of cardiotoxicity. Incidental findings, postmortem changes, and artifacts must be distinguished histopathologically from test item-related findings in the heart. In this retrospective analysis, cardiac sections from 88 control beagles (41 male, 47 female; ages 5-18 months) in preclinical studies were examined histopathologically. The most common finding was thickening of the tunica media of intramural coronary arteries, most likely a postmortem change. The second most common finding was the presence of vacuoles within Purkinje fibers. Dilated lymphatic and blood vessels at the insertion of chordae tendineae were noted more commonly in males than in females and were considered a normal anatomic feature. Mesothelial-lined papillary fronds along the epicardial surface of the atria were present in several dogs, as were small infiltrates of inflammatory cells usually within the myocardium. In summary, control beagles' hearts frequently have incidental findings that must be differentiated from test item-related pathologic changes. Historical control data can be useful for the interpretation of incidental and test item-related findings in the beagle heart.
Subject(s)
Dog Diseases/chemically induced , Dog Diseases/pathology , Heart/drug effects , Myocardium/pathology , Animals , Control Groups , Dogs , Female , Male , Toxicity Tests/methodsABSTRACT
In mice, hyaline droplets in renal proximal tubules have been associated with histiocytic sarcoma but have not been reported with lymphoma. Tissues from CD-1 mice in a 2-year carcinogenicity bioassay were examined microscopically. Twenty-five mice with hyaline droplets in renal tubules were identified. Immunohistochemistry to detect IgA, IgG, IgM, lysozyme, albumin, CD3, and CD79a was performed on kidneys of 21 affected mice. Hyaline droplets were present in the kidneys of 11 mice with lymphoma (1 male, 10 female), of which 1 female also had histiocytic sarcoma. Hyaline droplets were also present in 7 other mice with histiocytic sarcoma, 2 with chronic progressive nephropathy, 3 with renal cortical tubular necrosis, and 2 with granulocytic leukemia. Five of the 11 lymphomas were CD3+, indicating a T lymphocyte origin. Hyaline droplets in mice with lymphoma did not stain for IgA, IgG, or IgM, except in one questionable case. Results of other immunohistochemical stains were inconclusive. Although the droplet composition could not be determined immunohistochemically, the study findings indicate that renal tubular hyaline droplets may be associated with lymphoma in mice.