Delivery of antigen to CD40 induces protective immune responses against tumors.
Ligation of CD40 induces maturation of dendritic cells (DC) and could be a useful target for vaccines. In this study, we have constructed two types of Ab-based vaccine constructs that target mouse CD40. One type is a recombinant Ab with V regions specific for CD40 and has defined T cell epitopes inserted into its C region. The other type is a homodimer, each chain of which is composed of a targeting unit (single-chain fragment variable targeting CD40), a dimerization motif, and an antigenic unit. Such proteins bound CD40, stimulated maturation of DC, and enhanced primary and memory T cell responses. When delivered i.m. as naked DNA followed by electroporation, the vaccines induced T cell responses against MHC class II-restricted epitopes, Ab responses, and protection in two tumor models (myeloma and lymphoma). Two factors apparently contributed to these results: 1) agonistic ligation of CD40 and induction of DC maturation, and 2) delivery of Ag to APC and presentation on MHC class II molecules. These results highlight the importance of agonistic targeting of Ag to CD40 for induction of long-lasting and protective immune responses.
Schjetne
Karoline W
KW
Institute of Immunology, University of Oslo and Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway.
Fredriksen
Agnete B
AB
Bogen
Bjarne
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000097:blood; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000819:agonists*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D049109:Cell Proliferation; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D010954:Plasmacytoma / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D019444:Vaccines, DNA
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D019496:Cancer Vaccines; D011994:Recombinant Proteins; D019444:Vaccines, DNA