SBIR-STTR Award

Obesity-associated insulin resistance is a hallmark of type 2 diabetes (T2D) and plays a central role in metabolic syndrome. Numerous studies suggest a firm connection between obesity-induced inflammation and insulin resistance mediated by macrophages and other immune cells. A recent elegant study by Olefsky and his team [Cell publication PMID: 27814523 ] shows that galectin-3 (Gal3), a beta-galactoside-binding lectin, is a macrophage-derived instigator of “insulin resistance and impaired glucose tolerance”, associated with obesity- induced T2D. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. The study shows that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These fundamental observations elucidate a novel role of Gal3 that promotes obesity-mediated inflammation (macrophage-derived Gal3) and insulin resistance and suggest that specific inhibition of Gal3 may represent a promising therapeutic strategy to restore insulin sensitivity. Our scientific premise is that we have developed a very potent Gal3 antagonist, named TFD100, from a natural dietary source [PNAS publication, PMID 23479624]. TFD100 specifically targets Gal3 with picomolar affinity – the affinity is so high (10-100-fold more) to counteract Gal3’s natural affinity to its intrinsic ligands such as IR. In our preliminary studies, Gal3 inhibited IR activation of the engineered CHO/IR/IRS-1 cells, which was reversed by TFD100. Our research team has extensive expertise in a relevant mouse model of T2D – a high fat diet (HFD)-induced model in C57BL/6 (B6) . We demonstrated increased expression of Gal3 in liver of HFD fed mice compared to that of low fat diet (LFD) fed mice. Gal3 is also high in obese mice. Moreover, Gal3 levels in sera of T2D patients are found significantly linked with indices of insulin resistance. Based on the preliminary data we hypothesize that that specific inhibition of Gal3 with TFD100 will interfere with Gal3-IR interactions on myocytes, adipocytes and hepatocytes and thereby restore insulin sensitivity. We will test this hypothesis in the following specific aim: Investigate the therapeutic utility of TFD100 for treating T2D in a relevant mouse model. First we will determine TFD100’s ability to impede Gal3-mediated cellular insulin resistance. Various cells such as adipocytes, myocytes, hepatocytes, and engineered CHO/IR/IRS-1 cells will be treated with TFD100 and determine its effect on IR activation, signaling, and glucose uptake. Next, we will determine TFD100’s ability to treat HFD-induced obesity, insulin resistance, and T2D in both male and female mice. After drug (TFD100) treatment, glucose and insulin tolerance (primary endpoint) will be measured. For other endpoints, resolution of inflammation and restoration of insulin signaling will be measured by the frequency of pro-inflammatory biomarkers (gene and protein) in blood, liver, muscle and fat. This also includes determination of changes in pro-inflammatory immune cell frequencies such as polarization of macrophages. This study, for the first time, will explore the therapeutic utility of a very potent natural compound that outcompetes Gal3’s intrinsic interaction with the IR to reverse insulin resistance.

Public Health Relevance Statement:
Project Narrative Galectin-3 (Gal3) promotes insulin resistance of type 2 diabetes by interacting with the insulin receptor (IR). The objective of this project is to use a natural high affinity Gal3 antagonist to restore insulin sensitivity by interfering Gal3-IR interactions.

Project Terms:
Adipocytes; Adult; Affinity; Agreement; American; Animal Model; base; Binding; Biological Markers; Blood; Body Weight; Cause of Death; cell bank; Cells; Clinical Trials; Data; Diabetes Mellitus; Diet; Disease; Dose; Engineering; experimental study; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Frequencies; Future; Galactose Binding Lectin; Galectin 3; Gene Proteins; Genetic; Glucose Intolerance; glucose tolerance; glucose uptake; Goals; Heart Diseases; Hepatocyte; High Fat Diet; Hormones; Immune; immunoregulation; impaired glucose tolerance; improved; indexing; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; insulin sensitivity; insulin signaling; insulin tolerance; Investigational Drugs; Licensing; Ligands; Link; Liver; loss of function; macrophage; male; Malignant Neoplasms; Measures; Mediating; Metabolic syndrome; Modeling; mouse model; Mus; Muscle; Muscle Cells; Names; Non-Insulin-Dependent Diabetes Mellitus; novel; Obese Mice; Obesity; Outcome Study; Pancreas; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; phase 1 study; Phase I Clinical Trials; Play; Prediabetes syndrome; primary endpoint; Production; Publications; Publishing; Receptor Activation; Receptor Signaling; Research; Resolution; restoration; Role; Signal Transduction; Source; Technology; Testing; Therapeutic; Time; Toxic effect; United States

Obesity-mediated insulin resistance is a hallmark of type 2 diabetes (T2D), which accounts for ~90% of alldiabetes. Despite many drugs that are available to treat T2D, there is no FDA-approved drug that directlyworks on the insulin receptor (IR) to overcome insulin resistance. Recent studies show that galectin-3 (Gal3)can bind directly to the IR and inhibit downstream IR signaling causing insulin resistance and impaired glucosetolerance in obesity-induced T2D. Our scientific premise is that we have developed a very potent Gal3antagonist, TFD100, from a natural dietary source. The primary objective of this Phase II proposal is tocomplete the preclinical studies required for our IND submission to the FDA to enable the initiation of a first-in-human Phase 1 clinical trial. Successful completion of our proposed aims will achieve a significant valueinflection point for the company, positioning us well for either partnering or a capital raise. The proposed research embodies technological innovation in two areas: 1) This will be the first FDA-approved biologic therapeutics based on a natural carbohydrate compound; 2) TFD100's picomolar affinityto Gal3 has many advantages including overcoming the common saturation issue related to antigenicity. Ananticipated corollary benefit of the proposed studies includes the elucidation of novel lectin-mediated molecularmechanisms of cell-cell or cell-extracellular matrix (ECM) interactions that modulate IR signaling in T2D. Thisknowledge will be fundamental to opening-up new carbohydrate-based approaches to T2D treatments. We have successfully completed Phase 1 studies. In studies with cells, Gal3 inhibited IR/IRS-1 activation,which was reversed by TFD100. In high fat diet (HFD) animal model, TFD100 treatment significantly improvedglucose tolerance and insulin tolerance compared to the vehicle-treated animals. After analyzing our results,we are excited to continue our drug development. TFD100 is a biologic drug and we believe that TFD100 willlikely be distributed as a solution in the prefilled cartridge to be taken by T2D patients at home similar to non-invasive SC injection of insulin or Ozempic. To enhance the scientific rigor, we plan to ascertain SCadministered TFD100's ability to treat T2D in HFD model, and to complete relevant IND-enabling experimentsin the following specific aims: 1) Determine PK/PD of TFD100; 2) Ascertain efficacy of SC administeredTFD100 to treat HFD induced obesity, insulin resistance and T2D, and 3) GLP production of TFD100 forfuture toxicology studies. The proposed activities will be either performed by expert contractual collaboratorsor will be guided by an exceptional consultant team with specialized industry expertise in biologics productdevelopment, regulation, and clinical development. The outcomes of these studies will lead to the submissionof IND to the FDA followed by a Phase 1 clinical trial.

Public Health Relevance Statement:
Project Narrative Galectin-3 promotes insulin resistance of type 2 diabetes by interacting with the insulin receptor. GlycoMantra's commercial goal is to develop a high-affinity galectin-3 antagonist to restore insulin sensitivity. During this funding period, we will complete the critical path preclinical studies required for our IND submission to the FDA to enable the initiation of a first-in-human Phase 1 clinical trial.

Project Terms: