title: Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys.
abstract: Interleukin-6 (IL-6) is a potent mediator of inflammatory and immune responses, and a validated target for therapeutic intervention of inflammatory diseases. Previous studies have shown that SL1026, a slow off-rate modified aptamer (SOMAmer) antagonist of IL-6, neutralizes IL-6 signaling in vitro. In the present study, we show that SL1026 delays the onset and reduces the severity of rheumatoid symptoms in a collagen-induced arthritis model in cynomolgus monkeys. SL1026 (1 and 10 mg/kg), administered q.i.d., delayed the progression of arthritis and the concomitant increase in serum IL-6 levels compared to the untreated control group. Furthermore, SL1026 inhibited IL-6-induced STAT3 phosphorylation ex vivo in T lymphocytes from human blood and IL-6-induced C-reactive protein and serum amyloid A production in human primary hepatocytes. Importantly, SOMAmer treatment did not elicit an immune response, as evidenced by the absence of anti-SOMAmer antibodies in plasma of treated monkeys. These results demonstrate that SOMAmer antagonists of IL-6 may be attractive agents for the treatment of IL-6-mediated diseases, including rheumatoid arthritis.
authors.affiliation: 1 Otsuka Pharmaceutical Co., Ltd. , Tokushima, Japan .
authors.forename: Masao
authors.initials: M
authors.lastname: Hirota
authors.affiliation: 1 Otsuka Pharmaceutical Co., Ltd. , Tokushima, Japan .
authors.forename: Ikuo
authors.initials: I
authors.lastname: Murakami
authors.affiliation: 1 Otsuka Pharmaceutical Co., Ltd. , Tokushima, Japan .
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: 1 Otsuka Pharmaceutical Co., Ltd. , Tokushima, Japan .
authors.forename: Tomoki
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: 1 Otsuka Pharmaceutical Co., Ltd. , Tokushima, Japan .
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Sumida
authors.affiliation: 1 Otsuka Pharmaceutical Co., Ltd. , Tokushima, Japan .
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ibaragi
authors.affiliation: 2 Shin Nippon Biomedical Laboratories, Ltd. , Drug Safety Research Laboratories, Kagoshima, Japan .
authors.forename: Hayato
authors.initials: H
authors.lastname: Kasai
authors.affiliation: 2 Shin Nippon Biomedical Laboratories, Ltd. , Drug Safety Research Laboratories, Kagoshima, Japan .
authors.forename: Naoto
authors.initials: N
authors.lastname: Horai
authors.affiliation: 3 SomaLogic, Inc. , Boulder, Colorado.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Drolet
authors.affiliation: 3 SomaLogic, Inc. , Boulder, Colorado.
authors.forename: Shashi
authors.initials: S
authors.lastname: Gupta
authors.affiliation: 3 SomaLogic, Inc. , Boulder, Colorado.
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Janjic
authors.affiliation: 3 SomaLogic, Inc. , Boulder, Colorado.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schneider
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D052158:Aptamers, Peptide / Q000737:chemistry*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D002478:Cells, Cultured; D003094:Collagen / Q000009:adverse effects*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood* / Q000737:chemistry; D008252:Macaca fascicularis; D008969:Molecular Sequence Data; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D052158:Aptamers, Peptide; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D003094:Collagen