BACKGROUND: Alpha-1 antitrypsin (AAT) deficiency is the most common genetic cause of emphysema. Chymotrypsin-like elastase 1 (CELA1) is a serine protease neutralized by AAT and is important in emphysema progression. METHODS: We evaluated potential toxicities of KF4 and its ability to prevent emphysema in AAT deficiency. We found Cela1 protein expression in mouse lungs, pancreas, small intestine, spleen, and bone marrow. In toxicity studies, mice treated with KF4 25mg/kg weekly for 4 weeks showed an elevation in blood urea nitrogen and slower weight gain compared to lower doses or equivalent dose immunoglobin G (IgG). By histologic grading of tissue injury of the lung, kidney, liver, and heart, there was some evidence of liver injury with KF4 25mg/kg, but in all tissues, injury was less than in control mice subjected to cecal ligation and puncture. In efficacy studies, KF4 doses as low as 0.5mg/kg reduced the lung elastase activity of RESULTS: In this injury model, CONCLUSION: While KF4 might be an alternative to AAT replacement, combined KF4 and AAT replacement does not confer additional benefit.