Effect of intravenous alpha-1-antitrypsin augmentation therapy on a proteinase-3-generated AαVal541 in deficient patients

Iris G. M. Schouten, Richard A. Mumford, Abraham C. van der Linden, Dirk Jan A. R. Moes, Pieter S. Hiemstra, Jan Stolk

Background. In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as proteinase 3 (PR3) and elastase are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived footprint peptide AαVal541, compared to healthy controls (Newby et al, ERJ Open Res. 2019).
Aim and objectives. To analyse the course of AαVal541 in plasma over 4 weeks after a single iv dose of 240 mg/kg AAT in patients with genotype Z/Rare or Rare/Rare. 
Methods We developed a competitive immunoassay to measure AαVal541 in plasma. We assessed AaVal541 levels in healthy controls (n=20) and in patients before/after AAT augmentation (n=10).
Results. The average AαVal541 plasma level before treatment was 535.4 nM (range 46.9 - 4017.8 nM), and in all patients the level decreased within 1 day after receiving iv AAT. 
In the 5 patients who received AAT for the first time, the AαVal541 decreased to 42.0 nM (range 5.1 - 141.1 nM), 89.7% (SD 6.4%) of the baseline AαVal541 value. In the patients (n=5) who already received multiple infusions before, the AαVal541 decreased to 28.1 nM (range 21.9 - 38.0 nM), 68% (SD 13.8%) of baseline. In 9 of 10 patients, AαVal541 levels were reduced to the average level of healthy controls (27.9 nM ± 17.9 SD). At 7-14 days after treatment, AαVal541 levels started to increase again in all patients, reaching on average a level of 202.0 nM (range 15.3 - 1237.0 nM) at about 4 weeks after the AAT dose.
Conclusion. Fibrinopeptide AαVal541 may serve as a biochemical footprint to assess efficacy of in vivo inhibition of proteinase 3 activity in patients receiving intravenous AAT augmentation therapy. This opens opportunities for personalized tailored dosing.

Effect of intravenous alpha-1-antitrypsin augmentation therapy onproteinase-3-generated AαVal541 in deficient patients

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The Dutch Lung Congress aims to bring together everyone interested in research related to pulmonary diseases in the Netherlands.  We hope this event will provide opportunities for multidisciplinary interactions to enhance our approaches for addressing these challenging diseases.  Each session will include input from patients, clinical and basic and/or translational scientists discussing the latest information around the central themes chosen by the organizing committee.  One advantage of holding our congress as a virtual event this year is that we will have the opportunity to hear from world leading experts from all over the globe.  We hope you enjoy the programme the organizing committee have put together and will engage in dynamic discussions with all the speakers.

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<br>**Janette Burgess
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**More about the committee team:**:
[Barbro N. Melgert, PhD] (https://drive.google.com/file/d/1q_IIH3JvTivumCUzzsZGX7BgD41HxQmk/view?usp=sharing)
// [Bas Holverda, PhD] (https://drive.google.com/file/d/1QKXHmTTQjgs4OZVuM8doXU055S-fu_uU/view?usp=sharing)
// [Frits Franssen, PhD] (https://drive.google.com/file/d/1d7HRUJaqGuRFzkPN3SVgkbBfqFkDkWq2/view?usp=sharing)
// [Janette Burgess, PhD] (https://drive.google.com/file/d/1VHFlrEN6uCQGeeW3Lj4I8aTw7HsB0GFr/view?usp=sharing)
// [Michel van den Heuvel, PhD] (https://drive.google.com/file/d/1JeOEP8MHxiK_4lONr8UM2HaxdxpkAmA2/view?usp=sharing)
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// [Gimano Amatngalim, PhD] (https://drive.google.com/file/d/1fyVDDKARLNjRk_JZk8_GyhGMjmp6DWHp/view?usp=sharing)
// [Peter Kunst, PhD] (https://drive.google.com/file/d/1QhtB4nQezpAjbfUAcBnINc-Bm3Shy2Lf/view?usp=sharing)
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Effect of intravenous alpha-1-antitrypsin augmentation therapy onproteinase-3-generated AαVal541 in deficient patients

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