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

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...

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Autores principales: Schouten, Iris G. M., Mumford, Richard A., Moes, Dirk Jan A. R., Hiemstra, Pieter S., Stolk, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347723/
https://www.ncbi.nlm.nih.gov/pubmed/34360796
http://dx.doi.org/10.3390/ijms22158031
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author Schouten, Iris G. M.
Mumford, Richard A.
Moes, Dirk Jan A. R.
Hiemstra, Pieter S.
Stolk, Jan
author_facet Schouten, Iris G. M.
Mumford, Richard A.
Moes, Dirk Jan A. R.
Hiemstra, Pieter S.
Stolk, Jan
author_sort Schouten, Iris G. M.
collection PubMed
description 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.
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spelling pubmed-83477232021-08-08 The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients Schouten, Iris G. M. Mumford, Richard A. Moes, Dirk Jan A. R. Hiemstra, Pieter S. Stolk, Jan Int J Mol Sci Article 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. MDPI 2021-07-27 /pmc/articles/PMC8347723/ /pubmed/34360796 http://dx.doi.org/10.3390/ijms22158031 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schouten, Iris G. M.
Mumford, Richard A.
Moes, Dirk Jan A. R.
Hiemstra, Pieter S.
Stolk, Jan
The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients
title The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients
title_full The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients
title_fullStr The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients
title_full_unstemmed The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients
title_short The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients
title_sort course of aαval541 as a proteinase 3 specific neo-epitope after alpha-1-antitrypsin augmentation in severe deficient patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347723/
https://www.ncbi.nlm.nih.gov/pubmed/34360796
http://dx.doi.org/10.3390/ijms22158031
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