학술논문
The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity
Document Type
Original Paper
Author
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.
Source
Nature: International weekly journal of science. 622(7984):850-862
Subject
Language
English
ISSN
0028-0836
1476-4687
1476-4687
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.
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.
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.