title: Design of synthetic oligoribonucleotide-based agonists of Toll-like receptor 3 and their immune response profiles in vitro and in vivo.
abstract: Double-stranded RNA of viral origin and enzymatically synthesized poly I:C act as agonists of TLR3 and induce immune responses. We have designed and synthesized double-stranded synthetic oligoribonucleotides (dsORNs) which act as agonists of TLR3. Each strand of dsORN contains two distinct segments, namely an alignment segment composed of a heteronucleotide sequence and an oligo inosine (I) or an oligo cytidine (C) segment. We report here the results of studies of dsORNs containing varying lengths and compositions of alignment and oligo I/oligo C segments. dsORNs of 50-mer length with a 15-mer alignment segment and a 35-mer oligo I/oligo C segment form stable duplexes under physiological conditions and induce TLR3-mediated immune responses. dsORNs activated the IRF3 signaling pathway in J774 cells, induced production of cytokines, including IFN-β, IFN-α, IP-10, IL-12 and IL-6, in murine and human cell-based assays and also induced multiple cytokines following systemic administration in mice and non-human primates.
authors.affiliation: Idera Pharmaceuticals, Inc., 167 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Lan
authors.forename: Daqing
authors.initials: D
authors.lastname: Wang
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Bhagat
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Philbin
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.forename: Jimmy X
authors.initials: JX
authors.lastname: Tang
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Putta
authors.forename: Tim
authors.initials: T
authors.lastname: Sullivan
authors.forename: Nicola
authors.initials: N
authors.lastname: La Monica
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.forename: Sudhir
authors.initials: S
authors.lastname: Agrawal
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009843:Oligoribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016415:Sequence Alignment; D051196:Toll-Like Receptor 3 / Q000819:agonists*
chemical_list: D009843:Oligoribonucleotides; D051196:Toll-Like Receptor 3