title: Superior activity of the type C class of ISS in vitro and in vivo across multiple species.
abstract: CpG-C are a novel class of CpG motif-containing immunostimulatory sequences (ISS) that includes both a 5'-TCG element and a CpG-containing palindrome. CpG-C drive all known ISS activities and, in particular, are potent enhancers of IFN-alpha from plasmacytoid dendritic cells (PDCs). In our examination of CpG-C sequence requirements, we determined that optimal IFN-alpha-inducing activity could be achieved with longer palindromes. Longer palindromes also correlated with maintenance of the double-stranded (ds) form despite concentration and pH changes, indicating a preference for ds oligodeoxynucleotides (ODNs) by the ISS-induced signaling mechanism for IFN-alpha synthesis. This correlation did not hold for all arms of the ISS-induced immune response, since we did not observe increased B cell activity with the longer palindrome CpG-C ODNs. We further demonstrated that CpG-C retained activity in an in vitro primate system and induced the expression of several cytokines and IFN-alpha-inducible genes when CpG-C were administered in vivo to mice and primates. In conclusion, we have shown CpG-C to exert several types of immune functions across multiple species, and this novel class is thus an attractive candidate for ISS-based therapeutic strategies.
authors.affiliation: Dynavax Technologies Corporation, Berkeley, California 94710, USA. jmarshall@dvax.com
authors.forename: Jason D
authors.initials: JD
authors.lastname: Marshall
authors.forename: Karen L
authors.initials: KL
authors.lastname: Fearon
authors.forename: Debbie
authors.initials: D
authors.lastname: Higgins
authors.forename: Edith M
authors.initials: EM
authors.lastname: Hessel
authors.forename: Holger
authors.initials: H
authors.lastname: Kanzler
authors.forename: Christi
authors.initials: C
authors.lastname: Abbate
authors.forename: Priscilla
authors.initials: P
authors.lastname: Yee
authors.forename: Josh
authors.initials: J
authors.lastname: Gregorio
authors.forename: Tracy Dela
authors.initials: TD
authors.lastname: Cruz
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Lizcano
authors.forename: Alya
authors.initials: A
authors.lastname: Zolotorev
authors.forename: Hazel M
authors.initials: HM
authors.lastname: McClure
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Brasky
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Murthy
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.forename: Gary Van
authors.initials: GV
authors.lastname: Nest
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008198:Lymph Nodes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D064547:Myxovirus Resistance Proteins; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology*; D010215:Papio; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D051017:Apoptosis Regulatory Proteins; C000592162:C792 oligodeoxynucleotide; C408982:CPG-oligonucleotide; D016207:Cytokines; C484289:IFIT2 protein, human; D016898:Interferon-alpha; D015850:Interleukin-6; D064547:Myxovirus Resistance Proteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma; D019204:GTP-Binding Proteins