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CpG oligonucleotides as immunotherapeutic adjuvants: innovative applications and delivery strategies
Journal article   Open access   Peer reviewed

CpG oligonucleotides as immunotherapeutic adjuvants: innovative applications and delivery strategies

Aliasger K Salem and George J Weiner
Advanced drug delivery reviews, Vol.61(3), pp.193-194
2009
DOI: 10.1016/j.addr.2008.12.003
PMCID: PMC2667912
PMID: 19166888
url
http://doi.org/10.1016/j.addr.2008.12.003View
Open Access

Abstract

Cytosine–phosphorothioate–guanine oligodeoxynucleotides (CpG ODN) have shown significant potential for treatment of a wide variety of diseases including cancer. CpG ODN can be used either as a standalone molecule or as an adjuvant to other therapies. CpG ODN with sequence patterns like those found in bacterial DNA activate potent cell-mediated immune responses [1,2]. The specific sequence motif present in bacterial DNA that is responsible for triggering these immune responses is the unmethylated CpG dinucleotide flanked by two 5′ purines and two 3′ pyrimidines [1–4]. CpG ODN are taken up by cells via adsorptive endocytosis and bind to the toll-like receptor 9 (TLR9) present within the endosomes in the intracellular compartment of B cells and plasmacytoid dendritic cells [5–7]. The binding triggers an immunostimulatory cascade inducing the maturation, differentiation and proliferation of multiple immune cells including B and T lymphocytes, macrophages, natural killer cells and monocytes/ macrophages that produce interleukin 1, 6,12 and 18, interferon-γ and tumor necrosis factor-α [8–10]. In contrast to anti-sense therapeutics which requires continuous and prolonged exposure to the therapeutic nucleotide, the effects of CpG ODN can last for long periods of time even after a brief exposure. On the other hand, the duration, location, and formulation of CpG ODN therapy can have a profound effect on the immune response, and on the resulting therapeutic effects. This variability in immunologic and therapeutic response is not surprising given that CpG ODN can enhance antigen presentation, improve cellular killing mediated by T cells or NK cells, increase phagocytosis, increase production of cytokines that have anti-tumor effects or initiate proapoptotic effects on malignant cells that express TLR9. Which of these mechanisms is most important therapeutically depends on many factors including the underlying condition being treated, the state of the immune system, the selection of other agents used in combination with CpG ODN, the route of administration and the formulation of the therapy. It is therefore to be expected that the efficacy of CpG ODN can be substantially improved using a range of drug delivery systems. This theme issue of Advanced Drug Delivery Reviews is to provide a comprehensive summary of the therapeutic potential of CpG ODN in a range of diseases and cancer models and the drug delivery systems that are being developed to further enhance CpG ODN adjuvant efficacy. Vollmer and Krieg provide a strong current overview of CpG ODN as a TLR9 agonist and its therapeutic potential [1,11–13].

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