Research theme 3: Biomarker development for AATD-related lung disease to monitor treatment efficacy
Background: In recent years, a significant role for Proteinase 3 (PR3) in disease development has emerged, both in COPD and other chronic inflammatory conditions. Therefore, there is a need to investigate the importance of PR3 in disease development and hence its potential as a therapeutic target. Research into PR3 has largely been confined to its role as an autoantigen granulomatous
polyangiitis, but PR3 is involved in triggering inflammatory pathways, disrupting cellular signalling, degrading key structural proteins, and pathogen response. We aim to validate an ELISA for plasma fibrinopeptide Aa541 as a biomarker for personalized medical treatment of patients with pulmonary emphysema caused by rare inherited alpha-1-antitrypsine (AAT) deficiency. The strong association between the latter and symptomatic emphysema suggests the destruction of lung tissue by inflammatory proteases from neutrophils such as elastase and proteinase3 (PR3). We developed antibodies against PR3-specific cleavage sites present in fibrinogen and developed an ELISA to monitor emphysema progression by PR3. Validation against established quantitative imaging values of emphysema in a cross-sectional and long-term study will generate a commercially viable ELISA.
It will allow monitoring disease progression of emphysema prospectively. It also may reveal if newly detected AATD subjects are at risk of lung destruction by PR3 and available PR3 inhibitor treatment may be monitored using the ELISA to titrate the appropriate inhibitor dose for a given individual as personalised medicine. Finally, it will be of interest to investigate the predictive value of Aa541 plasma levels for lung tissue destruction, currently measured directly by CTscan-derived lung density, but with risk of radiation burden.
Users of our ELISA will be clinical chemistry labs of hospitals as well as pharma companies, and the results will be applied by clinicians and drug developers. Currently, there is no existing product that provides information like the Aa541 fibrinopeptide ELISA. Furthermore, Aa541 plasma levels in combination with lung density values for AATD emphysema may strengthen clinical decision making compared to lung density values alone.
Publikatie: The Course of AαVal541 as a Proteinase 3 specific neo-epitope after Alpha-1-Antitrypsin augmentation in severe deficient patients. Schouten IGM, Mumford RA, Moes DJAR, Hiemstra PS, Stolk J.Int J Mol Sci. 2021 Jul 27;22(15):8031. doi: 10.3390/ijms22158031. PMID: 34360796 Free PMC article.