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 A alpha Val541, compared with healthy controls. Here, we analyzed the course of A alpha Val541 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 A alpha Val541 in plasma and applied population pharmacokinetic modeling for AAT. The median A alpha Val541 plasma level before treatment was 140.2 nM (IQR 51.5-234.8 nM)). In five patients who received AAT for the first time, A alpha Val541 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, A alpha Val541 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, A alpha Val541 levels started to increase again in all patients. Our results show that fibrinopeptide A alpha Val541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy.

Automated summary

In AATD, neutrophil serine proteases are insufficiently inhibited, leading to higher levels of fibrinogen-derived peptide A alpha Val541 in plasma. An analysis on AAT treatment in patients with AATD showed a decrease in A alpha Val541 levels, suggesting its potential as a biochemical marker for assessing PR3 activity inhibition efficacy.