Antigen specific immunotherapeutics and -vaccines are considered as one of the most promising new developments in the search to cure cancer and induce tolerance in allergy patients. These therapies rehabilitate the immune system and prepare the human body to fight the disease. The main challenge in developing effective antigen-based immunotherapeutics is to efficiently target and trigger dendritic cells (DCs) in order to elicit a specific, potent, and long term immune response without adverse effects. Only then these types of treatments can be successfully applied in a clinical setting.
Pioneering research by Prof. Van Kooyk (DC4U/VUmc) has led to a novel targeting approach that has this potential. She discovered that some DC receptors have a high specificity for binding specific glycan structures. We have demonstrated in several national and international research projects that glycan structures can be used as probes to directly target DCs in tissue and thereby trigger and modulate a specific immune response.
The core of our technology is glycation of antigens to which we direct the immune response. Our GlycoDCTM technology can either potentiate or suppress the immune system via specific targeting of DC receptors by these glycan modified antigen conjugates. Glycation is the result of covalent binding of a peptide, protein or lipid molecule with a glycan molecule without the controlling action of an enzyme (compared to glycosylation, which includes the controlling action of an enzyme). Antigens of choice include tumor antigens, allergens, self-antigens and pathogen related antigens. Modification of these antigens by conjugation with a specific glycan structure enables specific targeting of certain DC receptors. This results in DC internalization, processing, MHC antigen presentation and antigen specific T-cell activation. Different glycans target specific but different DC receptors, leading to completely different DC processing, antigen presentation and T-cell response.
In this way our dendritic cell targeting technology enables opportunities for both immune stimulation and suppression by selection of the right combination of glycan and antigen / allergen. These selected combinations collectively present our GlycoDCTM technology.
Immune stimulating glycans:
We have identified glycans that can be covalently linked to antigens to target specific DC receptors with the purpose to boost the immune response. This specific targeting results in the instruction of T cells to potentiate CD8+T cells with cytotoxic potential, as well as CD4+T cells for help activity. This response is required for therapeutic cancer vaccines with strong anti-tumor potential.
Immune suppressing glycans:
We have identified inhibitory glycans which can be linked to antigens with the purpose to suppress the immune response by instructing DCs to differentiate and activate regulatory T-cells (Tregs). This approach is suitable for development of immunotherapeutics to treat allergy or autoimmune diseases.
GlycoDCTM compared to conventional approach.
Our approach differ from current antigen based immunotherapeutics and competitive approaches on a few important features:
- DC specific targeting: Glycated antigens target glycan-specific DC receptors, leading to specific DC internalization and antigen presentation. This enables directing the immune response to either stimulation or suppression. Naked peptides do not have this immune steering potential.
- Increased durability of the immune response: Naked short peptides derived from antigens can directly bind to MHC I molecules, which allows rapid stimulation of CD8+ T cells, but duration is short as turnover of MHC I molecules is rapid. Glycan-antigens target DC receptors, resulting in DC internalization, loading of peptide antigen on both MHC-I and MHC-II to present to both CD8+ and CD8+T cells. This guarantees both a potent and a durable anti-tumor response.
- Increased efficiency of the immune response: Glycated antigens have a considerable higher internalization potency compared to un-glycated antigens. This results in a longer antigen presentation and a more potent immune response.
- Lowering antigen dose: Current allergen based immunotherapeutics require high allergen doses to induce tolerance. Considerable lower and more potent doses can be administered using glycated allergens, which will improve both the efficacy and safety profile of the treatment