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Article

The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients

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Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
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Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
Academic Editor: Beate Heissig
Int. J. Mol. Sci. 2021, 22(15), 8031; https://doi.org/10.3390/ijms22158031
Received: 18 June 2021 / Revised: 19 July 2021 / Accepted: 22 July 2021 / Published: 27 July 2021
In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide AαVal541, compared with healthy controls. Here, we analyzed the course of AαVal541 plasma levels during 4 weeks after a single iv dose of 240 mg/kg AAT in ten patients with genotype Z/Rare or Rare/Rare. To this end, we developed an immunoassay to measure AαVal541 in plasma and applied population pharmacokinetic modeling for AAT. The median AαVal541 plasma level before treatment was 140.2 nM (IQR 51.5–234.8 nM)). In five patients who received AAT for the first time, AαVal541 levels decreased to 20.6 nM (IQR 5.8–88.9 nM), and in five patients who already had received multiple infusions before, it decreased to 26.2 nM (IQR 22.31–35.0 nM). In 9 of 10 patients, AαVal541 levels were reduced to the median level of healthy controls (21.4 nM; IQR 16.7–30.1 nM). At 7–14 days after treatment, AαVal541 levels started to increase again in all patients. Our results show that fibrinopeptide AαVal541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy. View Full-Text
Keywords: alpha-1-antitrypsin deficiency; proteinase 3; alpha-1-antitrypsin augmentation therapy; biomarker alpha-1-antitrypsin deficiency; proteinase 3; alpha-1-antitrypsin augmentation therapy; biomarker
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MDPI and ACS Style

Schouten, I.G.M.; Mumford, R.A.; Moes, D.J.A.R.; Hiemstra, P.S.; Stolk, J. The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients. Int. J. Mol. Sci. 2021, 22, 8031. https://doi.org/10.3390/ijms22158031

AMA Style

Schouten IGM, Mumford RA, Moes DJAR, Hiemstra PS, Stolk J. The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients. International Journal of Molecular Sciences. 2021; 22(15):8031. https://doi.org/10.3390/ijms22158031

Chicago/Turabian Style

Schouten, Iris G.M., Richard A. Mumford, Dirk J.A.R. Moes, Pieter S. Hiemstra, and Jan Stolk. 2021. "The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients" International Journal of Molecular Sciences 22, no. 15: 8031. https://doi.org/10.3390/ijms22158031

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