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.

Autor:	Devine AJ; Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States., Smith NJ; College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States., Joshi R; Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States., Brooks-Patton B; Northern Kentucky University, Highland Heights, Kentucky, United States., Dunham J; Northern Kentucky University, Highland Heights, Kentucky, United States., Varisco AN; University of Arkansas at Little Rock, Little Rock, Arkansas, United States., Goodman EM; University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States., Fan Q; Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States., Zingarelli B; Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States., Varisco BM; Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States.; College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States.; University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States.; Arkansas Children's Research Institute, Little Rock, Arkansas, United States.
Jazyk:	angličtina
Zdroj:	Chronic obstructive pulmonary diseases (Miami, Fla.) [Chronic Obstr Pulm Dis] 2024 Nov 26. Date of Electronic Publication: 2024 Nov 26.
DOI:	10.15326/jcopdf.2024.0535
Abstrakt:	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 a 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. We evaluated potential toxicities of KF4 and its ability to prevent emphysema in AAT deficiency. We found Cela1 protein expression in mouse lung, pancreas, small intestine, spleen, and bone marrow. In toxicity studies, mice treated with KF4 25 mg/kg weekly for four weeks showed an elevation in blood urea nitrogen and slower weight gain compared to lower doses or equivalent dose IgG. By histologic grading of tissue injury of the lung, kidney, liver, and heart, there was some evidence of liver injury with KF4 25 mg/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 0.5 mg/kg reduced the lung elastase activity of AAT-/- mice treated with 0.2 units of PPE. In this injury model, AAT-/- mice treated with KF4 1 mg/kg weekly, human purified AAT 60 mg/kg weekly, and combined KF4 and AAT treatment had less emphysema than mice treated with IgG 1 mg/kg weekly. However, the efficacy of KF4, AAT, or KF4 & AAT was similar. While KF4 might be an alternative to AAT replacement, combined KF4 and AAT replacement does not confer additional benefit. (JCOPDF © 2024.)
Databáze:	MEDLINE
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