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Oncostatin M: Development of a Pleiotropic Cytokine

Department of Experimental Pathology, Bristol-Myers Squibb, Princeton, New Jersey

Thomas J. Davidson

Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York

Karen K. Berry

Animal Modeling, Bristol-Myers Squibb, Princeton, New Jersey

John F. Macmaster

Animal Modeling, Bristol-Myers Squibb, Princeton, New Jersey

Bharat Danle

Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York

Stephen K. Durham

Department of Experimental Pathology, Bristol-Myers Squibb, Princeton, New Jersey

Oncostatin M (OM) is a member of the interleukin-6 (IL-6) cytokine subfamily. The binding of OM to its receptor initiates signal transduction through JAK-signal transducers and activators of transcription (STAT) pathways and activates transcription activators through mitogen-activated protein (MAP) kinases. Results of in vitro assays documented that OM modulates cytokine expression and alters the production of proteases that down-regulate inflammation. Administration of OM to lipopolysaccharide (LPS)-challenged mice lowered serum tumor necrosis factor- (TNF-) levels and decreased the lethal effects of LPS administration. OM also reduced inflammation in animal models of human disease, including inflammatory bowel disease, antibody-induced arthritis, and experimental autoimmune encephalomyelitis. Preclinical safety studies have been conducted in the mouse and monkey. Mice were administered OM (subcutaneously) at 72, 360, or 1,560 µg/kg/day in a 2-wk toxicity study. Decreased body weights occurred at 1,560 µg/kg. Drug-related changes at 360 and 1,560 µg/kg consisted of dermal irritation at the injection site, leukopenia, and thymic lymphoid depletion; all changes were reversible following a 2-wk recovery period. In a 2-wk subcutaneous study in monkeys, OM was administered at 1, 5, 15, 45, or 150 µg/kg/day. At all doses there was reversible, transient inappetence and dermal irritation at the injection site. Drug-related changes at 5, 15, 45, and 150 µg/kg consisted of reversible elevations in both serum amyloid A and IL-6, and reversible thymic lymphoid depletion. Transient increases in body temperature occurred at 15, 45, and 150 µg/kg. The observed spectrum of immunomodulatory effects suggests that OM may have therapeutic utility in treating chronic inflammatory diseases.

Key Words: Interleukin-61 inflammation • anti-inflammatory • immunomodulatory • safety assessment

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