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

Michael A Campos, Patrick Geraghty, Gregory Holt, Eliana Mendes, Paul R Newby, Shuren Ma, Landy V Luna-Diaz, Gerard M Turino, Robert A Stockley, Michael A Campos, Patrick Geraghty, Gregory Holt, Eliana Mendes, Paul R Newby, Shuren Ma, Landy V Luna-Diaz, Gerard M Turino, Robert A Stockley

Abstract

Rationale: 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.Objectives: 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.Methods: 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.Measurements and Main Results: 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-Val360), 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.Conclusions: 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).

Keywords: alpha-1 antitrypsin deficiency; antiinflammatory; dosing; immunomodulation.

Figures

Figure 1.
Figure 1.
Summary of study procedures. AAT = alpha-1 antitrypsin; DD = double dose; SD = standard dose.
Figure 2.
Figure 2.
Trough serum AAT levels. For definition of abbreviations, seeFigure 1.
Figure 3.
Figure 3.
Activity of serine proteases in BAL fluid (BALF) (elastase activity, cathepsin G) and plasma (Aα-Val360). Eight subjects with AAT (alpha-1 antitrypsin) deficiency and chronic obstructive pulmonary disease on standard dose (SD) therapy (60 mg/kg/wk; Zemaira, CSL Behring) underwent BALF and plasma sampling after 4 weeks of SD, 4 weeks of double-dose (DD), and finally 4 weeks of SD therapy. (A) Elastase and cathepsin G activity were measured in BALF. (B) Aα-Val360 was measured in plasma. Representative immunoblot for neutrophil elastase in BALF sample from one subject. Graphs are represented as individual subject response to AAT therapy; each measurement performed three times (n = 8 per group). NE = neutrophil elastase.
Figure 4.
Figure 4.
Changes in desmosine (DES) and isodesmosine (IDES) levels in (A) BAL fluid (BALF) and (B) plasma. Eight subjects with AAT (alpha-1 antitrypsin) deficiency and chronic obstructive pulmonary disease on standard dose (SD) therapy (60 mg/kg/wk; Zemaira, CSL Behring) underwent BALF and plasma sampling after 4 weeks of SD, 4 weeks of double-dose (DD), and finally 4 weeks of SD therapy. DES/IDES levels were measured in (A) BALF and (B) plasma. Graphs are represented as individual subject response to AAT therapy; each measurement performed three times (n = 8 per group). Month 1: SD, 60 mg/kg/wk. Month 2: DD, 120 mg/kg/wk. Month 3: SD, 60 mg/kg/wk.
Figure 5.
Figure 5.
BAL fluid (BALF) concentrations of several ILs and related cytokines were significantly reduced after 120 mg/kg/wk dosing of AAT (alpha-1 antitrypsin). Eight subjects with AAT deficiency and chronic obstructive pulmonary disease on standard dose (SD) therapy (60 mg/kg/wk; Zemaira, CSL Behring) underwent BALF and plasma sampling after 4 weeks of SD, 4 weeks of double-dose (DD), and finally 4 weeks of SD therapy. BALF levels were determined by Luminex assays. Graphs are represented as individual subject BALF concentrations; each measurement performed three times (n = 8 per group). bFGF = basic fibroblast growth factor; CCL = chemokine (C-C motif) ligand; GM-CSF = granulocyte–macrophage colony–stimulating factor; M-CSF = macrophage colony–stimulating factor; MIF = macrophage migration inhibitory factor; MIP = macrophage inflammatory protein; NK = natural killer; TNF = tumor necrosis factor.

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