Activating strong anti-tumor immunity with PTPN2/PTPN1 inhibitor: AC484

BackgroundWhile immune checkpoint inhibitors are effective in some cancer patients, overcoming resistance is a substantial barrier, prompting the need for new therapeutic strategies. Protein tyrosine phosphatases PTPN2 and PTPN1 are key regulators of inflammation, and deleting their genes in tumor or immune cells significantly enhances anti-tumor immunity. However, targeting phosphatases, especially at their active sites, presents challenges as drug targets.MethodsThis study explores the biological impact of ABBV-CLS-484 (AC484), a pioneering, orally administered, potent inhibitor that specifically targets the active sites of PTPN2 and PTPN1. We conducted in vitro experiments to assess the effects of AC484 on interferon responses and activation of various immune cell types. Furthermore, we evaluated the efficacy of AC484 in various mouse tumor models including those that exhibit resistance to PD-1 inhibitors.ResultsOur in vitro experiments demonstrated that AC484 treatment significantly boosts interferon responses and activates multiple immune cell types. In resistant mouse models, AC484 alone elicited potent anti-tumor responses. Notably, AC484 was observed to stimulate the tumor microenvironment, enhancing the effectiveness of natural killer cells and CD8+ T cells.ConclusionsOur findings support the potential of PTPN2 and PTPN1 inhibition as a promising direction for cancer immunotherapy, currently being tested in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT04777994). Significantly, our research reveals that small-molecule inhibitors targeting internal immune regulators can achieve preclinical outcomes that match or surpass those of antibody-based immune checkpoint inhibitors. AC484 is, to our knowledge, the first active-site phosphatase inhibitor to enter clinical trials for cancer immunotherapy.Clinical trial identificationNCT04777994.Legal entity responsible for the studyBroad Institute of MIT and Harvard and AbbVie Inc and Calico Life Sciences.FundingAbbVie, Calico Life Sciences.DisclosureC.K. Baumgartner, K.M. Hamel, K.A. McGuire, E. Farney, M. Matulenko, J.M. Frost, P.R. Kym: Financial Interests, Institutional, Membership or affiliation: AbbVie. C.H. Patel, M. Paddock, C. Beauregard: Financial Interests, Institutional, Membership or affiliation: Calico Life Sciences. K. Yates, R.T. Manguso: Financial Interests, Institutional, Funding: Calico Life Sciences. All other authors have declared no conflicts of interest.