Galectin Therapeutics

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, irreversible and ultimately fatal disease characterized by progressive scaring (fibrosis) of the lungs. Affecting older adults, it targets the tissue between the lungs alveoli and the bloodstream, severely compromising gas exchange leading to worsening dyspnoea (difficulty breathing). It is associated with a poor prognosis, with several retrospective longitudinal studies suggesting a median survival of 2-3 years from the time of diagnosis (1). There is no known cause of IPF (thus the term “idiopathic” – a disease/condition which arises spontaneously or for which cause is unknown) however it is believed to arise through a combination of environmental exposures (e.g. cigarette smoking, metal dusts, farming that lead to repetitive alveolar cell damage) (1) and genetic predisposition (2) – for example, TERT and MUC5B, involved in host defence, cell-cell adhesion and DNA repair, have been identified to contribute to the risk of developing pulmonary fibrosis (3). This leads to increased fibroblast recruitment and proliferation within the lungs of IPF sufferers, causing excessive deposition of the extracellular matrix and progressive scarring.

Two drugs have been FDA-approved for the treatment of IPF. Nintedanib is an intracellular inhibitor of multiple tyrosine kinases (vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF)) which have been implicated in the pathogenesis of IPF (4). Pirfenidone has a different mechanism of action, exhibiting its anti-fibrotic effects through a reduction in fibroblast activation, proliferation and TGF-beta induced collagen production (5). Both drugs can be taken orally but do carry side effects which can often lead to withdrawal from treatment, with nintedanib associated with diarrhea, and pirfenidone associated with nausea and rash.

Other drugs have undergone trails for IPF (e.g. azathioprine, an immunosuppressant, and N-acetylcysteine, a prodrug to L-cysteine, a precursor to the antioxidant glutathione) (6) however a systematic review has suggested that few treatments have shown any significant improvement for sufferers (7). No cure exists, and, at best, nintedanib and pirfenidone can only halt disease progression. Seeing as lung transplantation is the only intervention known to prolong life (8), it is therefore essential that novel therapeutic targets should be identified for the treatment of IPF.

A potential therapeutic target for the treatment of IPF is Galectin-3. Galectin-3 (gal-3), is a ß-galactoside binding protein consisting of a carbohydrate-recognition-binding domain (CRD) and an N-terminal, separated by a collagen-like domain. It has been shown to be elevated in bronchoalveolar lavage fluid (BALF) of patients with IPF and is highly expressed by alveolar macrophages in IPF patients (9). Increased galectin-3 expression and secretion is also a feature of alternative macrophage activation (10) and is believed to contribute towards the progression of fibrosis (11) – see figure 1. Expressed in myeloid cells (particularly monocytes and macrophages), fibroblasts, epithelial and endothelial cells, gal-3 is believed to drive IPF by inducing fibroblast migration and collagen synthesis (9), increased TNF and IL-8 production in macrophages (leading to prolonged inflammation and alveolar tissue injury) (11) and TGF-ß-induced activation of fibroblasts/myofibroblasts (12). Using in-vivo models of pulmonary fibrosis (TGF-ß and bleomycin-induced pulmonary fibrosis), Mackinnon et al demonstrated that fibrosis was dramatically reduced in mice deficient for gal-3 and identified it as “an important regulator of lung fibrosis”, providing “a proof of principle for gal-3 inhibition as a potential novel therapeutic strategy for IPF” (12).

Gal-3 has also been shown to be pro-inflammatory via its effects on neutrophil activation, neutrophil cell death (13), monocyte/macrophage recruitment (14) and its ability to act as a damage associated molecular pattern (DAMP) to induce inflammation (15). As such, gal-3 inhibition may be beneficial in a range of diseases, not just IPF.

In March 2017, Swedish based Galecto Biotech announced the successful completion of its phase Ib/IIa clinical trial of inhaled TD139 for the treatment of IPF. The new drug demonstrated “ground-breaking results for patients suffering from IPF”. A modified disaccharide, TD139 is an “ultra-potent gal-3 inhibitor that specifically blocks the binding of gal-3 to carbohydrate structures”, capable of blocking “various biological actions of gal-3 which include modulation of immune processes and pro-fibrotic activity” (Galecto Biotech). Preclinical studies have shown it is capable of attenuating late-stage progression of lung fibrosis following bleomycin (12). TD139 offers the advantage of blocking both intracellular and extracellular gal-3 however is not well absorbed orally and must be given parentally (inhalation for the treatment of IPF). Galecto Biotech are currently developing other “highly potent and selective galectin modulators for fibrosis, inflammation and other serious diseases” (Galecto Biotech) and have an ongoing research collaboration with the University of Edinburgh, UK, led by Dr. Alison Mackinnon.

Galectin Therapeutics, a biotechnology company based in Georgia, USA, are developing novel gal-3 inhibitors for the treatment of chronic liver disease (non-alcoholic steatohepatitis [NASH] with cirrhosis), skin diseases (dermatitis, psoriasis) and cancer (advanced melanoma and other malignancies). Several clinical trials are ongoing and a recent work has demonstrated GR-MD-02 improves survival and immune function following cancer (16). Galectin Therapeutics gal-3 inhibitor, GR-MD-02 is a “proprietary galactoarabino-rhamnogalacturonan polysaccharide polymer, comprised predominantly of galacturonic acid, galactose, arabinose, rhamnose and smaller amounts of other sugars” (Galectin Therapeutics). Capable of binding both galectins-1 & 3 (but with greater affinity for gal-3), GR-MD-02 has the disadvantage of only targeting extracellular galectins unlike Galecto Biotech’s TD139. However, as GR-MD-02 is a polysaccharide as opposed to TD138 disaccharide, it is capable of binding 5 molecules of gal-3 per drug molecule and has a broader binding area of amino acids of gal-3 (17). Recent data however has cast doubts on the potency and selectivity of such complex carbohydrates against gal-3 (18). Despite this, mouse models of pulmonary fibrosis have shown similar levels of effect with GR-MD-02 vs. TD139 (17). Both drugs are modified carbohydrates, therefore are inexpensive to manufacture and have low toxicity potentially compared to other drugs that may produce toxic metabolites (17).

GlycoMimetics, a biotechnology company based in Maryland, United States, have developed several high-potency, selective, small molecule “glycomimetic” antagonists of galecin-3 for the treatment of fibrosis and cancer. Having demonstrated anti-fibrotic activity in the bleomycin-induced pulmonary fibrosis in-vivo model, GlycoMimetics molecules can be administered intravenously, topically (delivered to the lungs via an inhaler) or even subcutaneously.

As opposed to using small molecular pharmacological inhibitors, iTeos Therapeutics (Charleroi, Belgium) are developing a galecin-3 antagonist monoclonal antibody for the treatment of cancer.

Gal-3 has also been found to play a role in many other forms of fibrosis, including liver, vascular, cardiac and systemic sclerosis (11). Numerous preclinical and clinical trials are ongoing. Chen et al (2017) found that Galecto Biotech’s TD139 could ameliorate pathological corneal angiogenesis as well as fibrosis (18). An ongoing clinical trial (clinical trial identifier NCT01960946) investigating the effects of Modified Citrus Pectin (MCP) in people with hypertension and elevated galectin-3 levels is currently underway (https://clinicaltrials.gov/ct2/show/NCT01960946) after it was shown inhibiting gal-3 reduced atherosclerotic lesions in apoE-deficient mice (19). Modified Citrus Pectin was found to modulate gal-3 activity by tightly binding to its CRD (19).

Neuropathic pain following peripheral nerve injury is a chronic clinical problem often experienced by diabetics that is poorly responsive to analgesics. It has been hypothesised that galecin-3’s pro-inflammatory ability to activate lymphocytes, macrophages and microglia may contribute and prolong neuroinflammation. Ma et al (2016) demonstrated that galectin-3 inhibition could suppress inflammation and attenuate neuropathic pain following spinal nerve ligation (20).

Gal-3 has also been implicated in the pathogenesis of cancer. As well as being used as a potential biomarker due to its high expression within cancers (21), gal-3 promotes tumour angiogenesis and metastasis (22). Is has also been shown to suppress CD8+ T-cell ability to recognize and destroy cancer cells through its binding LAG-3 (23). GlycoMimetics are currently testing the ability of their novel small molecular galectin-3 antagonist to restore immune anti-cancer function.

Conclusions

Current treatments for idiopathic pulmonary fibrosis are limited – no cure exists and few interventions show a significant effect on the disease. Galectin-3, shown to be upregulated in areas of fibrosis, could provide a novel therapeutic target not just for patients suffering from IPF, but a range of other diseases. Manufactured from modified carbohydrates, gal-3 inhibitors have the potential to be made cheaply, with little toxicity.

References:

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