Journal Article

Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist

Koyama, Shohei, Katakai, Yuko, Saijo, Shinobu, Narita, Hirotaka, Aoshi, Taiki, Sakurai, Kazuo, Kuroda, Etsushi, Yasutomi, Yasuhiro, Tetsutani, Kohhei, Hayashi, Masayuki, Kobiyama, Kouji, Mochizuki, Shinichi, Iwakura, Yoichiro, Coban, Cevayir, Akira, Shizuo, Ishii, Ken J.

2014

Overview

CpG DNA, a ligand for Toll-like receptor 9 (TLR9), has been one of the most promising immunotherapeutic agents. Although there are several types of potent humanized CpG oligodeoxynucleotide (ODN), developing “all-in-one” CpG ODNs activating both B cells and plasmacytoid dendritic cells forming a stable nanoparticle without aggregation has not been successful. In this study, we generated a novel nanoparticulate K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand schizophyllan (SPG), K3-SPG. In sharp contrast to K3 alone, K3-SPG stimulates human peripheral blood mononuclear cells to produce a large amount of both type I and type II IFN, targeting the same endosome where IFN-inducing D CpG ODN resides without losing its K-type activity. K3-SPG thus became a potent adjuvant for induction of both humoral and cellular immune responses, particularly CTL induction, to coadministered protein antigens without conjugation. Such potent adjuvant activity of K3-SPG is attributed to its nature of being a nanoparticle rather than targeting Dectin-1 by SPG, accumulating and activating antigen-bearing macrophages and dendritic cells in the draining lymph node. K3-SPG acting as an influenza vaccine adjuvant was demonstrated in vivo in both murine and nonhuman primate models. Taken together, K3-SPG may be useful for immunotherapeutic applications that require type I and type II IFN as well as CTL induction.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adjuvants / Adjuvants, Immunologic - pharmacology / agonists / animal models / Animals / Antigens / B lymphocytes / Biological Sciences / cell-mediated immunity / Cells / Cells, Cultured / Cellular biology / CpG Islands - genetics / Cytokines / Dendritic cells / Deoxyribonucleic acid / DNA / Enzyme-Linked Immunosorbent Assay / Humans / immunotherapy / Immunotherapy - methods / influenza / Interferon Inducers - pharmacology / Lectins, C-Type - genetics / Lectins, C-Type - metabolism / Leukocytes, Mononuclear - drug effects / Leukocytes, Mononuclear - metabolism / Ligands / lymph nodes / Macrophages / Mice / Mice, Inbred C57BL / Microscopy, Electron / mononuclear leukocytes / Nanoparticles / Nanoparticles - metabolism / oligodeoxyribonucleotides / Oligodeoxyribonucleotides - genetics / Oligodeoxyribonucleotides - metabolism / Oligodeoxyribonucleotides - pharmacology / Ova / Primates / schizophyllan / Sizofiran - metabolism / T lymphocytes / Toll-like receptor 9 / Toll-Like Receptor 9 - agonists / Vaccination / vaccines