The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.
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Baumgartner Christina K, Ebrahimi-Nik Hakimeh, Iracheta-Vellve Arvin, Hamel Keith M, Olander Kira E, Davis Thomas G R, McGuire Kathleen A, Halvorsen Geoff T, Avila Omar I, Patel Chirag H, Kim Sarah Y, Kammula Ashwin V, Muscato Audrey J, Halliwill Kyle, Geda Prasanthi, Klinge Kelly L, Xiong Zhaoming, Duggan Ryan, Mu Liang, Yeary Mitchell D, Patti James C, Balon Tyler M, Mathew Rebecca, Backus Carey, Kennedy Domenick E, Chen Angeline, Longenecker Kenton, Klahn Joseph T, Hrusch Cara L, Krishnan Navasona, Hutchins Charles W, Dunning Jax P, Bulic Marinka, Tiwari Payal, Colvin Kayla J, Chuong Cun Lan, Kohnle Ian C, Rees Matthew G, Boghossian Andrew, Ronan Melissa, Roth Jennifer A, Wu Meng-Ju, Suermondt Juliette S M T, Knudsen Nelson H, Cheruiyot Collins K, Sen Debattama R, Griffin Gabriel K, Golub Todd R, El-Bardeesy Nabeel, Decker Joshua H, Yang Yi, Guffroy Magali, Fossey Stacey, Trusk Patricia, Sun Im-Meng, Liu Yue, Qiu Wei, Sun Qi, Paddock Marcia N, Farney Elliot P, Matulenko Mark A, Beauregard Clay, Frost Jennifer M, Yates Kathleen B, Kym Philip R, Manguso Robert T
Аннотация
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.