Journal Article

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

Paddock, Marcia N., Geda, Prasanthi, Chuong, Cun Lan, Davis, Thomas G. R., Duggan, Ryan, Frost, Jennifer M., Rees, Matthew G., Dunning, Jax P., Wu, Meng-Ju, Kennedy, Domenick E., Roth, Jennifer A., Hrusch, Cara L., Kohnle, Ian C., Suermondt, Juliette S. M. T., Chen, Angeline, Muscato, Audrey J., Klinge, Kelly L., McGuire, Kathleen A., Griffin, Gabriel K., Cheruiyot, Collins K., Fossey, Stacey, Sun, Qi, Kim, Sarah Y., Decker, Joshua H., Farney, Elliot P., Yeary, Mitchell D., Matulenko, Mark A., Kammula, Ashwin V., Golub, Todd R., Baumgartner, Christina K., El-Bardeesy, Nabeel, Halvorsen, Geoff T., Ronan, Melissa, Balon, Tyler M., Krishnan, Navasona, Manguso, Robert T., Liu, Yue, Olander, Kira E., Colvin, Kayla J., Mathew, Rebecca, Backus, Carey, Klahn, Joseph T., Sen, Debattama R., Trusk, Patricia, Beauregard, Clay, Iracheta-Vellve, Arvin, Boghossian, Andrew, Longenecker, Kenton, Sun, Im-Meng, Ebrahimi-Nik, Hakimeh, Hutchins, Charles W., Halliwill, Kyle, Patel, Chirag H., Mu, Liang, Bulic, Marinka, Guffroy, Magali, Yates, Kathleen B., Knudsen, Nelson H., Avila, Omar I., Hamel, Keith M., Patti, James C., Qi

2023

Overview

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance 1 , 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 immunity 3 – 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. An orally bioavailable small-molecule active-site inhibitor of the phosphatases PTPN2 and PTPN1, ABBV-CLS-484, demonstrates immunotherapeutic efficacy in mouse models of cancer resistant to PD-1 blockade.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/58 / 13/1 / 13/106 / 13/21 / 13/31 / 13/51 / 14 / 14/34 / 38/39 / 38/91 / 42/41 / 59/5 / 60 APPLIED LIFE SCIENCES / 631/67/1059/2325 / 631/67/580 / 64/60 / 692/308/2778 / 96/1 / 96/31 / Animal models / Animals / Antibodies / Antigens / Bioavailability / Cancer / Cancer immunotherapy / CD8 antigen / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Cell culture / Cell growth / Clonal deletion / Design / Disease Models, Animal / Drug dosages / Drug Resistance, Neoplasm / Humanities and Social Sciences / Humans / Immune Checkpoint Inhibitors / Immune system / Immunity / Immunotherapy / Immunotherapy - methods / Inhibitors / Interferons - immunology / Killer Cells, Natural - drug effects / Killer Cells, Natural - immunology / Kinases / Lymphocytes / Lymphocytes T / Mice / multidisciplinary / Naphthalenes - pharmacology / Natural killer cells / Neoplasms - drug therapy / Neoplasms - enzymology / Neoplasms - immunology / Patients / PD-1 protein / Phosphatase / Phosphorylation / Plasma / preclinical research / Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors / Protein Tyrosine Phosphatase, Non-Receptor Type 2 - antagonists & inhibitors / Proteins / PTPN2 protein / Science / Science (multidisciplinary) / Signal transduction / Solid tumors / T cell receptors / Therapeutic targets / Thiadiazoles - pharmacology / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors / tumour immunology / Tyrosine