Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis.
BACKGROUND
CP-690550 is a small molecule inhibitor of Janus kinase 3 (JAK3), a critical enzyme in the signaling pathway of multiple cytokines (interleukin (IL)-2, -7, -15 and -21) that are important in various T cell functions including development, activation and homeostasis. The purpose of this study was to evaluate CP-690550 in murine collagen-induced (CIA) and rat adjuvant-induced (AA) models of rheumatoid arthritis (RA).


METHODS
CIA and AA were induced using standard protocols and animals received the JAK3 inhibitor via osmotic mini-pump infusion at doses ranging from 1.5-15 mg/kg/day following disease induction. Arthritis was assessed by clinical scores in the CIA models and paw swelling monitored using a plethysmometer in the AA model until study conclusion, at which time animals were killed and evaluated histologically.


RESULTS
CP-690550 dose-dependently decreased endpoints of disease in both RA models with greater than 90% reduction observed at the highest administered dose. An approximate ED50 of approximately 1.5 mg/kg/day was determined for the compound based upon disease endpoints in both RA models examined and corresponds to CP-690550 serum levels of 5.8 ng/ml in mice (day 28) and 24 ng/ml in rats (day 24). The compound also reduced inflammatory cell influx and joint damage as measured histologically. Animals receiving a CP-690550 dose of 15 mg/k/d showed no histological evidence of disease.


CONCLUSIONS
The efficacy observed with CP-690550 in CIA and AA suggests JAK3 inhibition may represent a novel therapeutic target for the treatment of RA.
Milici
Anthony J
AJ
Pfizer Global Research and Development, MS#8220-2235, Groton, CT 06340, USA. anthony.j.milici@pfizer.com
Kudlacz
Elizabeth M
EM
Audoly
Laurent
L
Zwillich
Samuel
S
Changelian
Paul
P
D000276:Adjuvants, Immunologic; D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology*; D003094:Collagen / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010880:Piperidines; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D003094:Collagen; D053616:Janus Kinase 3