Preclinical safety evaluation of the dipeptidyl peptidase 3 inhibiting antibody Procizumab in rodents and non-human primates.

The cytosolic protease dipeptidyl peptidase 3 (DPP3) is released into the circulation upon profound cellular stress. In the bloodstream, circulating DPP3 (cDPP3) rapidly degrades several important mediators of vascular tone. The cDPP3-antagonizing antibody Procizumab (PCZ) improved outcome in animal models of shock. This study aimed to establish the safety and tolerability of PCZ across relevant animal species. In the first study, mice received vehicle (n = 72), 37.5 (n = 114), 75 (n = 114), or 150 (n = 126) mg/kg of PCZ intravenously on days 1, 2, 13, and 14. In the second study, cynomolgus monkeys received vehicle (n = 10), 40 (n = 6), 120 (n = 6), or 350 (n = 10) mg/kg of PCZ intravenously on days 1, 2, 13 and 14. Toxicokinetic analyses demonstrated instant and dose-dependent peak concentrations. PCZ was eliminated relatively fast compared to other monoclonal antibodies and administration resulted in an instant reduction of cDPP3 enzyme activity, confirming the intended pharmacodynamic mechanism-of-action. Apart from fully reversible, non-dose-dependent increases of enzymes aspartate aminotransferase, alanine aminotransferase, and creatinine kinase in monkeys, and decreased rarefaction of the cytoplasm of hepatocytes in treated mice compared to the control group, toxicologic analyses showed no test item-related effects. In both studies, no mortality, moribund condition or any other adverse histopathological findings were attributed to PCZ therapy. These findings demonstrate that intravenous, repeated administration of high doses of PCZ was well tolerated in mice and cynomolgus monkeys. Results of this study were followed by a Phase 1 safety assessment of PCZ in humans, with single-administration clinical doses of 3, 6, and 12 mg/kg (NCT06331884).