The generation and characterization of antagonist RNA aptamers to human oncostatin M.
Oncostatin M (OSM) is a multifunctional member of the interleukin-6 cytokine family. OSM has been implicated as a powerful proinflammatory mediator and may represent a potentially important, novel therapeutic opportunity for treatment of established rheumatoid arthritis. To further investigate the role of OSM in inflammatory disorders, we have isolated a series of RNA aptamers that bind specifically to human OSM. The highest affinity aptamer, designated ADR58, has been characterized in a series of in vitro and cell based assays. ADR58 has an affinity of 7 nm for human OSM, and it can antagonize OSM binding to the gp130 receptor and specifically antagonize OSM mediated signaling. The aptamer has been truncated in length to 33 bases, all pyrimidine positions are substituted with 2' fluorine, and 14 of 18 purine positions have been substituted with 2' O-methyl to increase stability toward nucleases. This truncated, modified form of ADR58 retains complete affinity and functional activity for OSM. This aptamer may be used as a tool to further investigate the role of OSM in inflammatory disorders and may also have role as a therapeutic agent.
Rhodes
A
A
Molecular Discovery Department, Glaxo Wellcome Research and Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. adr7003@glaxowellcome.co.uk
Deakin
A
A
Spaull
J
J
Coomber
B
B
Aitken
A
A
Life
P
P
Rees
S
S
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000628:therapy; D001483:Base Sequence; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D051379:Mice; D008969:Molecular Sequence Data; D053683:Oncostatin M; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000502:physiology; D012313:RNA / Q000494:pharmacology*
D018836:Inflammation Mediators; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D053683:Oncostatin M; D012313:RNA