TD139

TD139 is a novel high-affinity inhibitor of the galectin-3 carbohydrate binding domain (Kd = 14 nM)^[6].The antifibrotic potential of TD139 centres around the inhibition of the recruitment and expansion of Gal-3-secreting macrophages that drive local myofibroblast activation^[7].

In Mice Primary Alveolar Epithelial Cells ,TD139 blocked TGF-β1-induced phosphorylation of β-catenin. TD139 reduced TGF-β1-induced translocation of β-catenin to the nucleus, and most β-catenin was retained on the cell surface^[3].TD139 has been shown pre-clinically to exhibit effects on all of the key IPF cell types: modulating macrophage phenotype/Gal-3 expression and fibroblast activation, reducing the effects of key profibrotic growth factors that act on myofibroblasts, and inhibiting epithelial–mesenchymal transition^[5,6].

In the lungs of WT mice treated with TD139 there was marked reduction in fibrosis and β-catenin activation accompanied by decreased galectin-3 expression. TD139 produced a significant decrease in total lung collagen, TD139 also decreased β-catenin activation in vivo as quantified, galectin-3 inhibition via TD139 can block the active fibrotic phase after bleomycin-induced lung injury^[3].In mice, Inhibition of Gal3 by TD139 prevented the expression of proinflammatory cytokines in microglia, TD139 treatment ameliorated the clinical and histological manifestations of EAU^[2].TD139 also suppressed microvascular thrombosis to protect the heart from myocardial ischaemia-reperfusion injury in ApoE-/- mice^[1].

In clinical trials,TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression^[4].

References:
[1]: Chen Y, Fu W, et,al. Galectin 3 enhances platelet aggregation and thrombosis via Dectin-1 activation: a translational study. Eur Heart J. 2022 Feb 15:ehac034. doi: 10.1093/eurheartj/ehac034. Epub ahead of print. PMID: 35165707.
[2]: Liu Y, Zhao C, et,al. Galectin-3 regulates microglial activation and promotes inflammation through TLR4/MyD88/NF-kB in experimental autoimmune uveitis. Clin Immunol. 2022 Mar;236:108939. doi: 10.1016/j.clim.2022.108939. Epub 2022 Feb 1. PMID: 35121106.
[3]: Mackinnon AC, Gibbons MA, et,al. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012 Mar 1;185(5):537-46. doi: 10.1164/rccm.201106-0965OC. Epub 2011 Nov 17. PMID: 22095546; PMCID: PMC3410728.
[4]: Hirani N, MacKinnon AC, et,al. Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2021 May 27;57(5):2002559. doi: 10.1183/13993003.02559-2020. Erratum in: Eur Respir J. 2022 Apr 14;59(4): PMID: 33214209; PMCID: PMC8156151.
[5]: N. Hirani, L. Nicol, A.C. et,al. TD139, A Novel Inhaled Galectin-3 Inhibitor for The Treatment of Idiopathic Pulmonary Fibrosis (IPF). Results from The First in (IPF) Patients Study., QJM: An International Journal of Medicine, Volume 109, Issue suppl_1, September 2016, Page S16, https://doi.org/10.1093/qjmed/hcw127.003
[6]: Delaine T, Collins P, et,al. Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition. Chembiochem. 2016 Sep 15;17(18):1759-70. doi: 10.1002/cbic.201600285. Epub 2016 Aug 12. PMID: 27356186.
[7]: MacKinnon AC, Farnworth SL, et,al. Regulation of alternative macrophage activation by galectin-3. J Immunol. 2008 Feb 15;180(4):2650-8. doi: 10.4049/jimmunol.180.4.2650. PMID: 18250477.