PMID- 34360796
OWN - NLM
STAT- MEDLINE
DCOM- 20210908
LR  - 20210908
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 15
DP  - 2021 Jul 27
TI  - The Course of AalphaVal541 as a Proteinase 3 Specific Neo-Epitope after 
      Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients.
LID - 10.3390/ijms22158031 [doi]
LID - 8031
AB  - 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 AalphaVal541, compared with healthy controls. Here, we 
      analyzed the course of AalphaVal541 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 AalphaVal541 in plasma and applied 
      population pharmacokinetic modeling for AAT. The median AalphaVal541 plasma level 
      before treatment was 140.2 nM (IQR 51.5-234.8 nM)). In five patients who received 
      AAT for the first time, AalphaVal541 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, AalphaVal541 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, AalphaVal541 levels started to increase again in all 
      patients. Our results show that fibrinopeptide AalphaVal541 may serve as a 
      biochemical footprint to assess the efficacy of in vivo inhibition of PR3 
      activity in patients receiving intravenous AAT augmentation therapy.
FAU - Schouten, Iris G M
AU  - Schouten IGM
AD  - Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 
      ZA Leiden, The Netherlands.
FAU - Mumford, Richard A
AU  - Mumford RA
AD  - Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 
      ZA Leiden, The Netherlands.
FAU - Moes, Dirk Jan A R
AU  - Moes DJAR
AUID- ORCID: 0000-0003-3219-253X
AD  - Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 
      Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
FAU - Hiemstra, Pieter S
AU  - Hiemstra PS
AUID- ORCID: 0000-0002-0238-5982
AD  - Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 
      ZA Leiden, The Netherlands.
FAU - Stolk, Jan
AU  - Stolk J
AD  - Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 
      ZA Leiden, The Netherlands.
LA  - eng
GR  - 2019/Stichting AIR/
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
DEP - 20210727
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Epitopes)
RN  - 0 (SERPINA1 protein, human)
RN  - 0 (alpha 1-Antitrypsin)
RN  - EC 3.4.21.76 (Myeloblastin)
SB  - IM
MH  - Adult
MH  - Epitopes/*blood
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Myeloblastin/*antagonists & inhibitors/blood
MH  - Severity of Illness Index
MH  - alpha 1-Antitrypsin/*blood
MH  - *alpha 1-Antitrypsin Deficiency/blood/drug therapy
PMC - PMC8347723
OTO - NOTNLM
OT  - alpha-1-antitrypsin augmentation therapy
OT  - alpha-1-antitrypsin deficiency
OT  - biomarker
OT  - proteinase 3
COIS- The funders had no role in the design of the study; in the collection, analyses, 
      or interpretation of data; in the writing of the manuscript; or in the decision 
      to publish the results.
EDAT- 2021/08/08 06:00
MHDA- 2021/09/09 06:00
PMCR- 2021/07/27
CRDT- 2021/08/07 01:07
PHST- 2021/06/18 00:00 [received]
PHST- 2021/07/19 00:00 [revised]
PHST- 2021/07/22 00:00 [accepted]
PHST- 2021/08/07 01:07 [entrez]
PHST- 2021/08/08 06:00 [pubmed]
PHST- 2021/09/09 06:00 [medline]
PHST- 2021/07/27 00:00 [pmc-release]
AID - ijms22158031 [pii]
AID - ijms-22-08031 [pii]
AID - 10.3390/ijms22158031 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Jul 27;22(15):8031. doi: 10.3390/ijms22158031.