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

Author

Listed:
  • Christina K. Baumgartner

    (AbbVie)

  • Hakimeh Ebrahimi-Nik

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Ohio State University Comprehensive Cancer Center and Pelotonia Institute for Immuno-Oncology)

  • Arvin Iracheta-Vellve

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Pfizer)

  • Keith M. Hamel

    (AbbVie)

  • Kira E. Olander

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Thomas G. R. Davis

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Kathleen A. McGuire

    (AbbVie)

  • Geoff T. Halvorsen

    (AbbVie)

  • Omar I. Avila

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Chirag H. Patel

    (Calico Life Sciences)

  • Sarah Y. Kim

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Ashwin V. Kammula

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Audrey J. Muscato

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Kyle Halliwill

    (AbbVie)

  • Prasanthi Geda

    (AbbVie
    Bristol Myers Squibb)

  • Kelly L. Klinge

    (AbbVie)

  • Zhaoming Xiong

    (AbbVie
    Ipsen Biosciences)

  • Ryan Duggan

    (AbbVie)

  • Liang Mu

    (AbbVie)

  • Mitchell D. Yeary

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • James C. Patti

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Tyler M. Balon

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Rebecca Mathew

    (AbbVie)

  • Carey Backus

    (AbbVie)

  • Domenick E. Kennedy

    (AbbVie)

  • Angeline Chen

    (AbbVie)

  • Kenton Longenecker

    (AbbVie)

  • Joseph T. Klahn

    (AbbVie)

  • Cara L. Hrusch

    (AbbVie)

  • Navasona Krishnan

    (AbbVie
    Monte Rosa Therapeutics)

  • Charles W. Hutchins

    (AbbVie)

  • Jax P. Dunning

    (AbbVie)

  • Marinka Bulic

    (AbbVie)

  • Payal Tiwari

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Dana-Farber Cancer Institute)

  • Kayla J. Colvin

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Cun Lan Chuong

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Ian C. Kohnle

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Matthew G. Rees

    (Broad Institute of MIT and Harvard)

  • Andrew Boghossian

    (Broad Institute of MIT and Harvard)

  • Melissa Ronan

    (Broad Institute of MIT and Harvard)

  • Jennifer A. Roth

    (Broad Institute of MIT and Harvard)

  • Meng-Ju Wu

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Juliette S. M. T. Suermondt

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Nelson H. Knudsen

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Collins K. Cheruiyot

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Debattama R. Sen

    (Massachusetts General Hospital)

  • Gabriel K. Griffin

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Todd R. Golub

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Nabeel El-Bardeesy

    (Massachusetts General Hospital)

  • Joshua H. Decker

    (AbbVie)

  • Yi Yang

    (AbbVie)

  • Magali Guffroy

    (AbbVie)

  • Stacey Fossey

    (AbbVie)

  • Patricia Trusk

    (AbbVie)

  • Im-Meng Sun

    (Calico Life Sciences)

  • Yue Liu

    (Calico Life Sciences)

  • Wei Qiu

    (AbbVie)

  • Qi Sun

    (AbbVie)

  • Marcia N. Paddock

    (Calico Life Sciences)

  • Elliot P. Farney

    (AbbVie)

  • Mark A. Matulenko

    (AbbVie)

  • Clay Beauregard

    (Calico Life Sciences
    Vir Biotechnology)

  • Jennifer M. Frost

    (AbbVie)

  • Kathleen B. Yates

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Philip R. Kym

    (AbbVie)

  • Robert T. Manguso

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

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.

Suggested Citation

  • Christina K. Baumgartner & Hakimeh Ebrahimi-Nik & Arvin Iracheta-Vellve & Keith M. Hamel & Kira E. Olander & Thomas G. R. Davis & Kathleen A. McGuire & Geoff T. Halvorsen & Omar I. Avila & Chirag H. P, 2023. "The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity," Nature, Nature, vol. 622(7984), pages 850-862, October.
  • Handle: RePEc:nat:nature:v:622:y:2023:i:7984:d:10.1038_s41586-023-06575-7
    DOI: 10.1038/s41586-023-06575-7
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    Cited by:

    1. Eduardo H. Gilglioni & Ao Li & Wadsen St-Pierre-Wijckmans & Tzu-Keng Shen & Israel Pérez-Chávez & Garnik Hovhannisyan & Michela Lisjak & Javier Negueruela & Valerie Vandenbempt & Julia Bauzá-Martinez , 2024. "PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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