Toll-like receptor activation enhances cell-mediated immunity induced by an antibody vaccine targeting human dendritic cells.
Previously, we have successfully targeted the mannose receptor (MR) expressed on monocyte-derived dendritic cells (DCs) using a fully human MR-specific antibody, B11, as a vehicle to deliver whole protein tumor antigens such as the human chorionic gonadotropin hormone (hCGbeta). Since MRs play a role in bridging innate immunity with adaptive immunity we have explored several toll-like receptor (TLR)-specific ligands that may synergize with MR targeting and be applicable as adjuvants in the clinic. We demonstrate that antigen-specific helper and cytolytic T cells from both healthy donors and cancer patients were effectively primed with B11-hCGbeta-treated autologous DCs when a combination of one or several TLR ligands is used. Specifically, concomitant signaling of DCs via TLR3 with dsRNA (poly I:C) and DC TLR 7/8 with Resiquimod (R-848), respectively, elicited efficient antigen presentation-mediated by MR-targeting. We demonstrate that MR and TLRs contribute towards maturation and activation of DCs by a mechanism that may be driven by a combination of adjuvant and antibody vaccines that specifically deliver antigenic targets to DCs.
Ramakrishna
Venky
V
Celldex Therapeutics, Inc,, Phillipsburg, NJ 08865, USA. vramakrishna@celldextherapeutics.com
Vasilakos
John P
JP
Tario
Joseph D
JD
Berger
Marc A
MA
Wallace
Paul K
PK
Keler
Tibor
T
D000906:Antibodies / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002451:Cell Compartmentation / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D008024:Ligands; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*
D000906:Antibodies; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018997:Chorionic Gonadotropin, beta Subunit, Human; D016207:Cytokines; D000939:Epitopes; D007093:Imidazoles; D037181:Lectins, C-Type; D008024:Ligands; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D011070:Poly I-C; C402365:resiquimod