The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial

• Published in: American journal of respiratory and critical care medicine Vol. 200; no. 3; pp. 318 - 326
• Main Authors: Campos, Michael A, Geraghty, Patrick, Holt, Gregory, Mendes, Eliana, Newby, Paul R, Ma, Shuren, Luna-Diaz, Landy V, Turino, Gerard M, Stockley, Robert A
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.08.2019
• Subjects: Adolescent; Adult; Aged; alpha 1-Antitrypsin - administration & dosage; alpha 1-Antitrypsin Deficiency - complications; alpha 1-Antitrypsin Deficiency - drug therapy; Apoptosis; Chemokines; Chronic obstructive pulmonary disease; Clinical trials; Cytokines; Dose-Response Relationship, Drug; Drug dosages; Emphysema; Feasibility Studies; Female; Humans; Inflammation; Male; Medicine; Middle Aged; Neutrophils; Original; Pilot Projects; Prospective Studies; Pulmonary Disease, Chronic Obstructive - diagnosis; Pulmonary Disease, Chronic Obstructive - etiology; Pulmonary Disease, Chronic Obstructive - therapy; Trypsin Inhibitors - administration & dosage; Young Adult; United Kingdom > UK; Florida; New York; immunomodulation; alpha-1 antitrypsin deficiency; antiinflammatory; dosing
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201901-0010OC

Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven. To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy. Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained. DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val ), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers. Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421).