Efficacy, in vivo safety, and PK/PD studies for novel, oral, highly selective PTPN2/1 inhibitor (ZE00-0388)

PTPN2 inhibition is a novel immuno-oncology approach: by releasing an intracellular “brake” it increases cytokine responsiveness (e.g., IFN-gamma/JAK-STAT), boosts antigen presentation, and enhances T-cell cytotoxicity, helping to overcome immune evasion in tumors resistant to PD-1 blockade. Our development candidate ZE00-0388 demonstrates potential best-in-class profile: Nanomolar potency with high selectivity for PTPN2/1 over other phosphatases, predictable PK/PD with sustained exposure above EC50, and proven target engagement. ZE00-0388 shows favorable bioavailability in all species, with best translation expected from dog to human. The combination of anti-mPD-1 and ZE00-0388 exhibited remarkable dose-dependent anti-tumor efficacy against the subcutaneous MC38 colon model. Solo treatments with ZE00-0388 demonstrated tumor growth inhibition of 81% and in combination with anti-mPD-1 complete regression of tumor in 50% of animals. ZE00-0388 has a very favorable safety profile with tolerated doses significantly above pre-clinical proof-of-concept efficacious doses, which indicates that ZE00-0388 should have a very broad therapeutic window.