Galectin‐3: an early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36 months

Anna Maria Riccio, Pierluigi Mauri, Laura De Ferrari, Rossana Rossi, Dario Di Silvestre, Louise Benazzi, Alessandra Chiappori, Roberto Walter Dal Negro, Claudio Micheletto, Giorgio Walter Canonica

Bronchial asthma is a heterogeneous disease characterized by three cardinal features: chronic inflammation, variable airflow obstruction, and airway hyperresponsiveness. Asthma has traditionally been defined using nonspecific clinical and physiologic variables that encompass multiple phenotypes and are treated with nonspecific anti-inflammatory therapies. Based on the modulation of airway remodeling after 12 months of anti-immunoglobulin E (IgE) treatment, we identified two phenotypes (omalizumab responder, OR; and non-omalizumab responder, NOR) and performed morphometric analysis of bronchial biopsy specimens. We also found that these two phenotypes were correlated with the presence/absence of galectin-3 (Gal-3) at baseline (i.e., before treatment). The aims of the present study were to investigate the histological and molecular effects of long-term treatment (36 months) with anti-IgE and to analyze the behavior of OR and NOR patients. All patients were treated with the monoclonal antibody anti-IgE omalizumab for 36 months. The bronchial biopsy specimens were evaluated using morphometric, eosinophilic, and proteomic analysis (MudPIT). New data were compared with previous data, and unsupervised cluster analysis of protein profiles was performed. After 36 months of treatment with omalizumab, reduction of reticular basement membrane (RBM) thickness was confirmed in OR patients (Gal-3-positive at baseline); similarly, the protein profiles (over 500 proteins identified) revealed that, in the OR group, levels of proteins specifically related to fibrosis and inflammation (e.g., smooth muscle and extracellular matrix proteins (including periostin), Gal-3, and keratins decreased by between 5- and 50-fold. Eosinophil levels were consistent with molecular data and decreased by about tenfold less in ORs and increased by twofold to tenfold more in NORs. This tendency was confirmed (p < 0.05) based on both fold change and DAVE algorithms, thus indicating a clear response to anti-IgE treatment in Gal-3-positive patients. Our results showed that omalizumab can be considered a disease-modifying treatment in OR. The proteomic signatures confirmed the presence of Gal-3 at baseline to be a biomarker of long-term reduction in bronchial RBM thickness, eosinophilic inflammation, and muscular and fibrotic components in omalizumab-treated patients with severe asthma. Our findings suggest a possible relationship between Gal-3 positivity and improved pulmonary function.