Superior activity of the type C class of ISS in vitro and in vivo across multiple species.
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.
Marshall
Jason D
JD
Dynavax Technologies Corporation, Berkeley, California 94710, USA. jmarshall@dvax.com
Fearon
Karen L
KL
Higgins
Debbie
D
Hessel
Edith M
EM
Kanzler
Holger
H
Abbate
Christi
C
Yee
Priscilla
P
Gregorio
Josh
J
Cruz
Tracy Dela
TD
Lizcano
Jennifer O
JO
Zolotorev
Alya
A
McClure
Hazel M
HM
Brasky
Kathleen M
KM
Murthy
Krishna K
KK
Coffman
Robert L
RL
Nest
Gary Van
GV
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
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