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

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.

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

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

Nature, 2023, vol. 622, issue 7984, 850-862

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06575-7

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