Galectin-3 is elevated following nintedanib treatment

Background a Objective: Idiopathic pulmonary fibrosis (IPF) is a common and severe form of pulmonary fibrosis. Nintedanib, a triple angiokinase inhibitor, is approved for treating IPF and other progressive interstitial lung diseases (ILD). Galectin 3 (Gal-3) activates a variety of pro-fibrotic processes. Currently, the Gal-3 inhibitor (TD139 by Galecto) is being tested in phase-II clinical trials 9on-top9 of Nintedanib. Therefore, we evaluated the impact of Nintedanib on Gal-3 expression using in-vitro and in-vivo models, in addition to IPF patient samples. Methods: Gal-3 levels were evaluated in IPF and control tissue samples, primary human lung fibroblasts (HLFs) following Nintedanib treatment (10-100nM, qPCR and Western blot) and in a silica-induced-fibrosis mouse model with/without Nintedanib (0.021-0.21 mg/kg) by immunohistochemistry (IHC). Additionally, Gal-3 levels were analyzed in serum samples from 41 ILD patients with/without Nintedanib treatment by ELISA. Results: Nintedanib addition to HLFs resulted in significant elevations in Gal-3, pSTAT3, as well as IL-8 mRNA levels (pl0.05). Gal-3 expression was elevated in IPF tissue samples compared with non-IPF controls (pl0.05). IHC staining demonstrated stromal involvement with strong staining mainly in the alveolar macrophages. In the in-vivo mouse model, Gal-3 levels were increased following fibrosis induction and even further increased with the addition of Nintedanib, mostly in macrophages (pl0.05). Patients receiving Nintedanib presented with higher Gal-3 serum levels in comparison to those who did not (pl0.05). Conclusion: Nintedanib elevates Gal-3 levels in both experimental models, along with patient samples. These findings highlight the possibility of using combined inhibition therapy.