Therapeutic applications of synthetic CpG oligodeoxynucleotides as TLR9 agonists for immune modulation.
Vertebrate toll-like receptors (TLRs) sense invading pathogens by recognizing bacterial and viral structures and, as a result, activate innate and adaptive immune responses. Ten human functional TLRs have been reported so far; three of these (TLR7, 8, and 9) are expressed in intracellular compartments and respond to single-stranded nucleic acids as natural ligands. The pathogen structure selectively recognized by TLR9 in bacterial or viral DNA was identified to be CpG dinucleotides in specific sequence contexts (CpG motifs). Short phosphorothioate-stabilized oligodeoxynucleotides (ODNs) containing such motifs are used as synthetic TLR9 agonists, and different classes of ODN TLR9 agonists have been identified with distinct immune modulatory profiles. The TLR9-mediated activation of the vertebrate immune system suggests using such TLR9 agonists as effective vaccine adjuvants for infectious disease, and for the treatment of cancer and asthma/allergy. Immune activation by CpG ODNs has been demonstrated to be beneficial in animal models as a vaccine adjuvant and for the treatment of a variety of viral, bacterial, and parasitic diseases. Antitumor activity of CpG ODNs has also been established in numerous mouse models. In clinical vaccine trials in healthy human volunteers or in immunocompromised HIV-infected patients, CpG ODNs strongly enhanced vaccination efficiency. Most encouraging results in the treatment of cancers have come from human phase I and II clinical trials using CpG ODNs as a tumor vaccine adjuvant, monotherapy, or in combination with chemotherapy. Therefore, CpG ODNs represent targeted immune modulatory drugs with a broad range of potential applications.
Jurk
Marion
M
Coley Pharmaceutical GmbH, Dusseldorf, Germany.
Vollmer
Jörg
J
D000818:Animals; D002986:Clinical Trials as Topic; D003141:Communicable Diseases / Q000628:therapy; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D009369:Neoplasms / Q000628:therapy; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000627:therapeutic use*; D012130:Respiratory Hypersensitivity / Q000628:therapy; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000235:genetics; D014611:Vaccination / Q000379:methods
C408982:CPG-oligonucleotide; D007155:Immunologic Factors; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9