KF4 Anti-Chymotrypsin-like Elastase 1 Antibody and Purified Alpha-1 Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine Alpha-1 Antitrypsin Deficiency

Abstract

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. Cela1-deficiency is protective in murine models of AAT-deficient emphysema. KF4 anti-CELA1 antibody prevented emphysema in porcine pancreatic elastase (PPE) and cigarette smoke models in wild-type mice.

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 AAT^-/- mice treated with 0.2 units of PPE.

Results: In this injury model, AAT^-/- mice treated with KF4 1mg/kg weekly, human purified AAT 60mg/kg weekly, and combined KF4 and AAT treatment had less emphysema than mice treated with IgG 1mg/kg weekly. However, the efficacy of KF4, AAT, or KF4 and AAT was similar.

Conclusion: While KF4 might be an alternative to AAT replacement, combined KF4 and AAT replacement does not confer additional benefit.

Keywords: COPD; alpha-1 antitrypsin; elastase; emphysema; protease.