Synthesis and immunological activities of novel agonists of toll-like receptor 9.
Novel agonists of TLR9 with two 5'-ends and synthetic immune stimulatory motifs, referred to as immune modulatory oligonucleotides (IMOs) are potent agonists of TLR9. In the present study, we have designed and synthesized 15 novel IMOs by incorporating specific chemical modifications and studied their immune response profiles both in vitro and in vivo. Analysis of the immunostimulatory profiles of these IMOs in human and NHP cell-based assays suggest that changes in the number of synthetic immunostimulatory motifs gave only a subtle change in immune stimulation of pDCs as indicated by IFN-alpha production and pDC maturation while the addition of self-complementary sequences produced more dramatic changes in both pDC and B cell stimulation. All IMOs induced cytokine production in vivo immediately after administration in mice. Representative compounds were also compared for the ability to stimulate cytokine production in vivo (IFN-alpha and IP-10) in rhesus macaques after intra-muscular administration.
Struthers
Mary
M
Merck Research Labratories, P.O. Box 2000, Rahway, NJ 07065, USA.
Bett
Andrew J
AJ
Wisniewski
Thomas
T
Dubey
Sheri A
SA
Precopio
Melissa
M
Jiang
Weiwen
W
Sun
Zhenhua
Z
Wang
Hao
H
Nowak
Ireneusz
I
Putta
Mallikarjuna R
MR
Yu
Dong
D
Tang
Jimmy X
JX
Kandimalla
Ekambar R
ER
Agrawal
Sudhir
S
Casimiro
Danilo R
DR
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D011744:Pyrimidinones / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists*
D016898:Interferon-alpha; D009841:Oligonucleotides; D011744:Pyrimidinones; D013844:Thiazoles; D051217:Toll-Like Receptor 9; C041057:5(4'-hydroxybenzylidenoimino)-3-methylisothiazolo(5,4-d)pyrimidine-(7H)-4,6-dione