Inhibitor-Mediated Programming of Glycoforms (IMProGlyco)

For the public, carbohydrates are best known for providing energy, but there are other types of carbohydrates in the body. Their task include being building blocks and providing protection.

Known examples of these types of carbohydrates are heparin (carbohydrate-based anticoagulant), hyaluronic acid (carbohydrate-based lubricant and also found in beauty creams) and ABO blood groups (red blood cell glycocalyx).

In the pharmaceutical industry, biological drugs for the treatment of cancer have become a success story. For the treatment of other types of cancer, immuno-reinforced cell therapy, so-called car-T cell treatment, has shown to be promising.

We are now participating in an EU-led consortium that will develop methods to change the cell's carbohydrate making machinery. The purpose is that biological drugs and CAR-T cell treatment can be made even more effective.

More about the project

The project will develop cellular inhibitors of glycosyltransferases to enable manipulation of the glycosylation of glycoproteins. The aim is to provide designed glycosylation for recombinant glycoprotein production of biologics and for efficient cell therapy (CAR-T). The inhibitors can be implemented to next generation precision medicine in for instance cancer treatment.

Our vision is to have impact through the precise manipulation of the glycans (carbohydrates) on cells and recombinant glycoproteins that will enable the discovery and production of the next generation of therapies for cancer, neurodegeneration and other disease families.

The glycans that are present on most proteins and cells have a substantial impact on their biological functions, yet the untemplated nature of their synthesis leads to inherent heterogeneity in both their structure and activity. This heterogeneity is very difficult to control, making it impossible to generate defined glycan ensembles with optimal activity using current technology.

Method

The project will adopt a radically new approach to manipulate cellular glycans. We will develop the delivery of computationally defined mixtures of enzyme-specific inhibitors to the site of glycan biosynthesis in the cell to tune the activity of glycosyltransferases.

Our approach, termed Inhibitor-Mediated Programming of Glykoforms (IMProGlyco) will provide an effective strategy to manipulate the glycosylation machinery and thereby generate proteins with defined ensembles of glycans. It will enable the production of precision glycan engineered therapeutic proteins and vaccines.

Moreover, shaping cellular glycan profiles will aid discovery science to uncover glycan functions and improve therapeutic cells, such as those used in Chimeric Antigen Receptors cell Therapy (CAR-T). Our technology will be adaptable and expandable into other cell types and organisms allowing glycan shaping in all areas of eukaryotic cell biology to enable new biotechnological applications and fundamental studies of biology.