Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys

• Published in: Nucleic acid therapeutics Vol. 26; no. 1; p. 10
• Main Authors: Hirota, Masao, Murakami, Ikuo, Ishikawa, Yuichi, Suzuki, Tomoki, Sumida, Shun-ichiro, Ibaragi, Shigeru, Kasai, Hayato, Horai, Naoto, Drolet, Daniel W, Gupta, Shashi, Janjic, Nebojsa, Schneider, Daniel J
• Format: Journal Article
• Language: English
• Published: United States 01-02-2016
• Subjects: Amino Acid Sequence; Animals; Aptamers, Peptide - chemistry; Arthritis, Experimental - chemically induced; Arthritis, Experimental - prevention & control; Cells, Cultured; Collagen - adverse effects; Female; Humans; Interleukin-6 - blood; Interleukin-6 - chemistry; Macaca fascicularis; Molecular Sequence Data; Phosphorylation; Sequence Homology, Amino Acid; STAT3 Transcription Factor - metabolism; T-Lymphocytes - metabolism
• ISSN: 2159-3345
• DOI: 10.1089/nat.2015.0567

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.