Background
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].
参考文献:
[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.
TD139 是半乳糖凝集素 3 碳水化合物结合域的新型高亲和力抑制剂 (Kd = 14 nM)[6]。TD139 的抗纤维化潜力主要集中在抑制募集和扩张驱动局部肌成纤维细胞活化的 Gal-3 分泌巨噬细胞[7]。
在小鼠原代肺泡上皮细胞中，TD139 阻断了 TGF-β1 诱导的 β-连环蛋白磷酸化。 TD139 减少了 TGF-β1 诱导的 β-catenin 向细胞核的易位，并且大部分 β-catenin 保留在细胞表面[3]。TD139 已在临床前显示对所有细胞均有影响关键 IPF 细胞类型:调节巨噬细胞表型/Gal-3 表达和成纤维细胞活化，减少作用于肌成纤维细胞的关键促纤维化生长因子的作用，抑制上皮-间质转化[5,6] .
在用 TD139 处理的 WT 小鼠的肺中，纤维化和 β-连环蛋白活化明显减少，同时半乳糖凝集素 3 表达减少。 TD139 显着降低了肺部胶原蛋白总量，TD139 还降低了体内 β-catenin 的量化激活，通过 TD139 抑制 galectin-3 可以阻断博来霉素诱导的肺损伤后的活性纤维化阶段[3] .在小鼠中，TD139 抑制 Gal3 阻止了小胶质细胞中促炎细胞因子的表达，TD139 治疗改善了 EAU 的临床和组织学表现[2]。TD139 还抑制微血管血栓形成以保护心脏免受心肌损伤ApoE-/-小鼠缺血再灌注损伤[1].
在临床试验中，TD139 在健康受试者和 IPF 患者中是安全且耐受性良好的。它被证明可以抑制支气管肺泡灌洗巨噬细胞上的 Gal-3 表达，并以协同方式减少与 IPF 进展相关的血浆生物标志物[4]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Mice Primary Alveolar Epithelial Cells
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Preparation Method
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Primary alveolar epithelial cells from wild-type (WT) mice were plated and treated with transforming growth factor (TGF)-β1 in the presence or absence of 10 μM TD139
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Reaction Conditions
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10 μM TD139
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Applications
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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.
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| Animal experiment [1]: |
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Animal models
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C57/Bl6 mice
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Preparation Method
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Mice were given bleomycin intratracheally and then saline or 10 μg TD139 was instilled into the lungs on Days 18, 20, 22, and 24 and lungs were harvested on Day 26
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Dosage form
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10 μg TD139 on Days 18, 20, 22, and 24
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Applications
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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.
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参考文献:
[1]. Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T. 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.
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