Synthetic agonists of Toll-like receptors 7, 8 and 9

Biochem Soc Trans. 2007 Dec;35(Pt 6):1461-7. doi: 10.1042/BST0351461.

Abstract

TLRs (Toll-like receptors) are a family of innate immune receptors that induce protective immune responses against infections. Single-stranded viral RNA and bacterial DNA containing unmethylated CpG motifs are the ligands for TLR7 and TLR8 and 9 respectively. We have carried out extensive structure-activity relationship studies of DNA- and RNA-based compounds to elucidate the impact of nucleotide motifs and structures on these TLR-mediated immune responses. These studies have led us to design novel DNA- and RNA-based compounds, which act as potent agonists of TLR9 and TLR7 and 8 respectively. These novel synthetic agonists produce different immune response profiles depending on the structures and nucleotide motifs present in them. The ability to modulate TLR-mediated immune responses with these novel DNA- and RNA-based agonists in a desired fashion may allow targeting a broad range of diseases, including cancers, asthma, allergies and infections, alone or in combination with other therapeutic agents, and their use as adjuvants with vaccines. IMO-2055, our first lead candidate, is a TLR9 agonist that is currently in clinical evaluation in oncology patients. A second candidate, IMO-2125, is also a TLR9 agonist that has been shown to induce high and sustained levels of IFN (interferon) in non-human primates and is being evaluated in HepC-infected human subjects.

Publication types

  • Review

MeSH terms

  • Animals
  • CpG Islands / immunology
  • DNA, Bacterial / chemical synthesis
  • DNA, Bacterial / pharmacology
  • DNA, Bacterial / therapeutic use
  • Humans
  • Interferons / drug effects
  • Interferons / immunology
  • Ligands
  • RNA, Viral / chemical synthesis
  • RNA, Viral / pharmacology
  • RNA, Viral / therapeutic use
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 7 / immunology
  • Toll-Like Receptor 8 / agonists*
  • Toll-Like Receptor 8 / immunology
  • Toll-Like Receptor 9 / agonists*
  • Toll-Like Receptor 9 / immunology

Substances

  • DNA, Bacterial
  • Ligands
  • RNA, Viral
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptor 9
  • Interferons