title: Multivalent glycopeptide dendrimers for the targeted delivery of antigens to dendritic cells.
abstract: 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 Le(b)-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.
authors.affiliation: Department of Molecular Cell Biology & Immunology, Faculty of Medicine, VU University Medical Center, Amsterdam, The Netherlands. jj.garciavallejo@vumc.nl
authors.forename: Juan J
authors.initials: JJ
authors.lastname: García-Vallejo
authors.forename: Martino
authors.initials: M
authors.lastname: Ambrosini
authors.forename: Annemieke
authors.initials: A
authors.lastname: Overbeek
authors.forename: Wilhelmina E
authors.initials: WE
authors.lastname: van Riel
authors.forename: Karien
authors.initials: K
authors.lastname: Bloem
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: Unger
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiodo
authors.forename: Jan G
authors.initials: JG
authors.lastname: Bolscher
authors.forename: Kamran
authors.initials: K
authors.lastname: Nazmi
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001692:Biological Transport; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D050091:Dendrimers / Q000138:chemical synthesis* / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000494:pharmacology; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D008247:Lysosomes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D050091:Dendrimers; D004337:Drug Carriers; D006020:Glycopeptides; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C104700:PAMAM Starburst