Multivalent glycopeptide dendrimers for the targeted delivery of antigens to dendritic cells

• Published in: Molecular immunology Vol. 53; no. 4; pp. 387 - 397
• Main Authors: García-Vallejo, Juan J., Ambrosini, Martino, Overbeek, Annemieke, van Riel, Wilhelmina E., Bloem, Karien, Unger, Wendy W.J., Chiodo, Fabrizio, Bolscher, Jan G., Nazmi, Kamran, Kalay, Hakan, van Kooyk, Yvette
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2013
• Subjects: Amino Acid Sequence; Animals; Antigen Presentation; Biological Transport; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - immunology; Cell Proliferation; Cell surface molecules; Dendrimers - chemical synthesis; Dendrimers - pharmacology; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Drug Carriers - chemical synthesis; Drug Carriers - pharmacology; Glycopeptides - chemical synthesis; Glycopeptides - immunology; Glycopeptides - pharmacology; Human; Humans; K562 Cells; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Lysosomes - drug effects; Lysosomes - immunology; Mice; Molecular Sequence Data; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Rodent; Human; Dendritic cells; LeX, Y,a,orb; MR; DC-SIGN; CLR; Cell surface molecules; Rodent; PAMAM; DC
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2012.09.012

► Multivalent antigen presentation improves delivery through DC-SIGN. ► 16–32 glycan units are the optimal multivalency for DC-SIGN targeting. ► DC-SIGN mediated uptake results in robust CD4 and CD8T cell responses.
Dendritic cells are the most powerful type of antigen presenting cells. Current immunotherapies targeting dendritic cells have shown a relative degree of success but still require further improvement. One of the most important issues to solve is the efficiency of antigen delivery to dendritic cells in order to achieve an appropriate uptake, processing, and presentation to Ag-specific T cells. C-type lectins have shown to be ideal receptors for the targeting of antigens to dendritic cells and allow the use of their natural ligands – glycans – instead of antibodies. Amongst them, dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) is an interesting candidate due to its biological properties and the availability of its natural carbohydrate ligands. Using Leb-conjugated poly(amido amine) (PAMAM) dendrimers we aimed to characterize the optimal level of multivalency necessary to achieve the desired internalization, lysosomal delivery, Ag-specific T cell proliferation, and cytokine response. Increasing DC-SIGN ligand multivalency directly translated in an enhanced binding, which might also be interesting for blocking purposes. Internalization, routing to lysosomal compartments, antigen presentation and cytokine response could be optimally achieved with glycopeptide dendrimers carrying 16–32 glycan units. This report provides the basis for the design of efficient targeting of peptide antigens for the immunotherapy of cancer, autoimmunity and infectious diseases.