title: Potent CpG oligonucleotides containing phosphodiester linkages: in vitro and in vivo immunostimulatory properties.
abstract: Bacterial and synthetic DNAs, containing CpG dinucleotides in specific sequence contexts, activate the vertebrate immune system. Unlike phosphorothioate (PS) CpG DNAs, phosphodiester (PO) CpG DNAs require either palindromic sequences and/or poly(dG) sequences at the 3(')-end for activity. Here, we report 'PO-immunomers' having two PO-CpG DNA molecules joined through their 3(')-ends. These PO-imunomers permitted us, for the first time, to assess immunostimulatory properties of PO-CpG DNAs in vitro and in vivo without the need for palindromic and/or poly(dG) sequences. In medium containing 10% fetal bovine serum, PO-immunomers were more resistant than PO-CpG DNAs to nucleases. Compared to PS-CpG DNA in BALB/c and C3H/HeJ mice spleen cell culture assays, PO-immunomers showed increased IL-12 secretion and minimal amounts of IL-6 secretion. PO-immunomers activated NF-kappa B and induced cytokine secretion in J774 cell cultures. In addition, PO-immunomers showed antitumor activity in nude mice bearing human breast (MCF-7) and prostate (DU145) cancer xenografts.
authors.affiliation: Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.forename: Fu-Gang
authors.initials: FG
authors.lastname: Zhu
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Bhagat
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
authors.forename: Sudhir
authors.initials: S
authors.lastname: Agrawal
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D004795:Enzyme Stability; D007111:Immunity, Cellular / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D016207:Cytokines; D016328:NF-kappa B; D009841:Oligonucleotides; D003851:Deoxyribonucleases