Osunprotafib (ABBV-CLS-484) is a potent, orally bioavailable PTP1B/PTPN2 inhibitor in clinical trials for solid tumors. [1] Osunprotafib (ABBV-CLS-484) stimulates the tumor microenvironment and promotes natural killer cell and CD8 T cell function and enhances T cell anti-tumor immunity by enhancing JAK-STAT signaling and reducing T cell dysfunction. [2]

Osunprotafib (ABBV-CLS-484) dose-dependently increased STAT5 phosphorylation to similar levels in whole blood from healthy donors and cancer patients; Osunprotafib (ABBV-CLS-484) increased IFNγ-induced STAT1 phosphorylation and CXCL10 production in blood samples from healthy donors and cancer patients, suggesting that Osunprotafib (ABBV-CLS-484)-enhanced pathway engagement leads to enhanced downstream functional effects; Osunprotafib (ABBV-CLS-484) increased T cell activation and function in human whole blood, as indicated by dose-dependent increases in CD69 expression and IFNγ and TNF production after TCR stimulation; Osunprotafib (ABBV-CLS-484) inhibition of PTPN2/N1 enhances human immune cell activation. [2]

METHODS: Mice with systemic Ptpn2 deletion were administered oral doses of Osunprotafib (ABBV-CLS-484) at 3/10/100 mg/kg twice daily in an attempt to determine whether oral systemic inhibition of PTPN2/N1 could be a safe and effective immunotherapy
RESULTS Circulating chemokines, including CXCL10 and CXCL9, increased 2-3-fold at a dose of 10 mg kg-1 twice daily; a dose of 100 mg/kg twice daily resulted in significant Systemic immune activation, manifested by significant increases in circulating cytotoxic granzyme B (GZMB) CD8 T cells and cytokines such as CXCL10 and CXCL9.
METHODS: Animals with tumors were evaluated at doses of 50, 100, and 150 mg/kg-1 once daily and significant changes in body condition score or body weight were observed.
RESULTS No significant changes in body weight were observed with Osunprotafib (ABBV-CLS-484), which was tolerated in naive rats at doses up to 300 mg kg-1/day for 28 days. The most notable finding was a dose-dependent infiltration of immune cells in the kidneys, joints and liver, and it was also found that Osunprotafib (ABBV-CLS-484) has a relatively short half-life, allowing for rapid discontinuation of treatment, and thus faster than antibody-based therapies. effectively resolve inflammatory conditions. [2]