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

Autor: Baumgartner CK; AbbVie, North Chicago, IL, USA. christina.baumgartner@abbvie.com., Ebrahimi-Nik H; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Ohio State University Comprehensive Cancer Center and Pelotonia Institute for Immuno-Oncology, Columbus, OH, USA., Iracheta-Vellve A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Pfizer, Groton, CT, USA., Hamel KM; AbbVie, North Chicago, IL, USA., Olander KE; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Davis TGR; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., McGuire KA; AbbVie, North Chicago, IL, USA., Halvorsen GT; AbbVie, North Chicago, IL, USA., Avila OI; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Patel CH; Calico Life Sciences, South San Francisco, CA, USA., Kim SY; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Kammula AV; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Muscato AJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Halliwill K; AbbVie, South San Francisco, CA, USA., Geda P; AbbVie, North Chicago, IL, USA.; Bristol Myers Squibb, Summit, NJ, USA., Klinge KL; AbbVie, North Chicago, IL, USA., Xiong Z; AbbVie, North Chicago, IL, USA.; Ipsen Biosciences, Cambridge, MA, USA., Duggan R; AbbVie, North Chicago, IL, USA., Mu L; AbbVie, North Chicago, IL, USA., Yeary MD; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Patti JC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Balon TM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Mathew R; AbbVie, South San Francisco, CA, USA., Backus C; AbbVie, South San Francisco, CA, USA., Kennedy DE; AbbVie, North Chicago, IL, USA., Chen A; AbbVie, North Chicago, IL, USA., Longenecker K; AbbVie, North Chicago, IL, USA., Klahn JT; AbbVie, North Chicago, IL, USA., Hrusch CL; AbbVie, North Chicago, IL, USA., Krishnan N; AbbVie, North Chicago, IL, USA.; Monte Rosa Therapeutics, Boston, MA, USA., Hutchins CW; AbbVie, North Chicago, IL, USA., Dunning JP; AbbVie, North Chicago, IL, USA., Bulic M; AbbVie, North Chicago, IL, USA., Tiwari P; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Dana-Farber Cancer Institute, Boston, MA, USA., Colvin KJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Chuong CL; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Kohnle IC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Rees MG; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Boghossian A; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ronan M; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Roth JA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wu MJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Suermondt JSMT; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Knudsen NH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Cheruiyot CK; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Sen DR; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Griffin GK; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Dana-Farber Cancer Institute, Boston, MA, USA., Golub TR; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Dana-Farber Cancer Institute, Boston, MA, USA., El-Bardeesy N; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Decker JH; AbbVie, North Chicago, IL, USA., Yang Y; AbbVie, North Chicago, IL, USA., Guffroy M; AbbVie, North Chicago, IL, USA., Fossey S; AbbVie, North Chicago, IL, USA., Trusk P; AbbVie, North Chicago, IL, USA., Sun IM; Calico Life Sciences, South San Francisco, CA, USA., Liu Y; Calico Life Sciences, South San Francisco, CA, USA., Qiu W; AbbVie, North Chicago, IL, USA., Sun Q; AbbVie, North Chicago, IL, USA., Paddock MN; Calico Life Sciences, South San Francisco, CA, USA., Farney EP; AbbVie, North Chicago, IL, USA., Matulenko MA; AbbVie, North Chicago, IL, USA., Beauregard C; Calico Life Sciences, South San Francisco, CA, USA.; Vir Biotechnology, San Francisco, CA, USA., Frost JM; AbbVie, North Chicago, IL, USA. jennifer.frost@abbvie.com., Yates KB; Broad Institute of MIT and Harvard, Cambridge, MA, USA. yates@broadinstitute.org.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org., Kym PR; AbbVie, North Chicago, IL, USA. phil.r.kym@abbvie.com., Manguso RT; Broad Institute of MIT and Harvard, Cambridge, MA, USA. rmanguso@mgh.harvard.edu.; Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Oct; Vol. 622 (7984), pp. 850-862. Date of Electronic Publication: 2023 Oct 04.
DOI: 10.1038/s41586-023-06575-7
Abstrakt: 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 1,2 . 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 immunity 3-6 . 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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