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

Journal Article · · Nature (London)
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  1. AbbVie, North Chicago, IL (United States)
  2. Broad Institute of MIT and Harvard, Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States)
  3. Calico Life Sciences, San Francisco, CA (United States)
  4. AbbVie, South San Francisco, CA (United States)
  5. Broad Institute of MIT and Harvard, Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States); Dana-Farber Cancer Institute, Boston, MA (United States)
  6. Broad Institute of MIT and Harvard, Cambridge, MA (United States)
  7. Massachusetts General Hospital, Boston, MA (United States)
  8. Broad Institute of MIT and Harvard, Cambridge, MA (United States); Dana-Farber Cancer Institute, Boston, MA (United States)
+ Show Author Affiliations
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. 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. 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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
2470124
Journal Information:
Nature (London), Journal Name: Nature (London) Journal Issue: 7984 Vol. 622; ISSN 0028-0836
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

60 APPLIED LIFE SCIENCES
cancer immunotherapy
preclinical research
tumour immunology