Oncostatin M: Development of a Pleiotropic Cytokine

Author:

Loy James K.1,Davidson Thomas J.2,Berry Karen K.3,Macmaster John F.3,Danle Bharat2,Durham Stephen K.1

Affiliation:

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

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

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

Abstract

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-α (TNF-α) 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.

Publisher

SAGE Publications

Subject

Cell Biology,Toxicology,Molecular Biology,Pathology and Forensic Medicine

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