title: Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody.
abstract: Current dendritic cell (DC)-based vaccines are based on ex vivo-generated autologous DCs loaded with antigen prior to readministration into patients. A more direct and less laborious strategy is to target antigens to DCs in vivo via specific surface receptors. Therefore, we developed a humanized antibody, hD1V1G2/G4 (hD1), directed against the C-type lectin DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) to explore its capacity to serve as a target receptor for vaccination purposes. hD1 was cross-linked to a model antigen, keyhole limpet hemocyanin (KLH). We observed that the chimeric antibody-protein complex (hD1-KLH) bound specifically to DC-SIGN and was rapidly internalized and translocated to the lysosomal compartment. To determine the targeting efficiency of hD1-KLH, monocyte-derived DCs and peripheral blood lymphocytes (PBLs) were obtained from patients who had previously been vaccinated with KLH-pulsed DCs. Autologous DCs pulsed with hD1-KLH induced proliferation of patient PBLs at a 100-fold lower concentration than KLH-pulsed DCs. In addition, hD1-KLH-targeted DCs induced proliferation of naive T cells recognizing KLH epitopes in the context of major histocompatibility complex (MHC) classes I and II. We conclude that antibody-mediated targeting of antigen to DCs via DC-SIGN effectively induces antigen-specific naive as well as recall T-cell responses. This identifies DC-SIGN as a promising target molecule for DC-based vaccination strategies.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tacken
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
authors.forename: Karlijn
authors.initials: K
authors.lastname: Gijzen
authors.forename: Ben
authors.initials: B
authors.lastname: Joosten
authors.forename: Dayang
authors.initials: D
authors.lastname: Wu
authors.forename: Russell P
authors.initials: RP
authors.lastname: Rother
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Faas
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: Ruurd
authors.initials: R
authors.lastname: Torensma
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
mesh_terms: D000906:Antibodies / Q000627:therapeutic use*; D017951:Antigen Presentation / Q000276:immunology; D000941:Antigens / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006433:Hemocyanins / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007167:Immunotherapy / Q000379:methods; D037181:Lectins, C-Type / Q000737:chemistry / Q000276:immunology*; D015202:Protein Engineering; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000493:pharmacokinetics; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014612:Vaccines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000906:Antibodies; D000941:Antigens; D015815:Cell Adhesion Molecules; D006433:Hemocyanins; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D014612:Vaccines; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human; C032808:keyhole-limpet hemocyanin