Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
A Novel PI3Kinase / Inhibitor Suppresses Collagen-Induced Arthritis
Boyle1, David L., Rommel2, Christian, Topolewski1, Katharyn, Firestein1, Gary S.
The four members (a, b, g, and delta [d]) of the phosphoinositide 3-kinases (PI3K) family transduce a variety of receptor-mediated signals. However, the gamma and delta PI3K isoforms are primarily restricted to leukocytes and act independently to regulate cytokine, chemokine and immunoglobulin responses. The delta isoform is associated with many cell surface receptors while the gamma isoform exclusively associates with G-protein coupled receptors, such as chemokine receptors. While selective g and d inhibitors have potential for diseases like rheumatoid arthritis (RA), we hypothesized that combined inhibition would be especially effective. Therefore, we evaluated the effect of a dual PI3Kg/d (INK055) inhibitor on murine collagen induced arthritis.
DBA1/J mice (n=8/group) were immunized with bovine type II collagen in complete Freund's adjuvant and again on day 21 with type II collagen in PBS. On day 28, 5 mg of LPS in PBS was injected intraperitoneally. Paws were scored using a 04 scale, maximum 16 per animal. Animals were treated by gavage daily starting day 20 or 30 with vehicle, 30, or 60 mg/kg with a novel dual specific PI3K g/d inhibitor, INK055 (IC50: PI3Kd: 3.2nM, PI3Kg: 5.7nM, >600 for PI3Ka and PI3Kb). ELISA was performed to assess anti-type II collagen levels in serum. Quantitative PCR was used to determine the effect on ankle joints gene expression.
Initiating treatment with INK055 on day 20 in CIA significantly decreased disease severity by day 32 in both treatment groups (peak difference on day 36, vehicle 5.6±1.9, 30mg/kg 2.4±1.0, 60mg/kg 2.6±1.5; p<0.05). Serum anti-type II collagen antibody levels were unchanged in the low dose group and only modestly decreased in high dose group (Vehicle 200±3, 30mg/mg 180±20, 60mg/kg 143±12 mg/ml). MMP3 and MMP13 expression was significantly reduced in the ankles after treatment (MMP3 77±41, 46±12, 38±16 relative expression units in vehicle, 30mg/kg, 60mg/kg respectively). Treatment of established disease beginning on day 30 significantly decreased severity compared with vehicle with the peak effect on day 34 (see Figure) (vehicle 11.9±2, 30mg/kg 4.3±1.8, 60mg/kg 6.9±2.2; p<0.05). Anti type II collagen antibody levels were not affected in the delayed treatment study despite improved clinical arthritis (vehicle 151±17, 30mg/kg 125±19, 60mg/kg 152±18).
The dual PI3Kg/d inhibitor INK055 was effective as prophylactic therapy as well as in established arthritis. The modest effect on autoantibody production and benefit observed in established disease suggests that the mechanism is through an effect on innate immunity rather than antibody production. A dual specific PI3Kg/d inhibitor might be effective in rheumatoid arthritis while limiting systemic toxicity of a and b inhibitors.
To cite this abstract, please use the following information:
Boyle, David L., Rommel, Christian, Topolewski, Katharyn, Firestein, Gary S.; A Novel PI3Kinase / Inhibitor Suppresses Collagen-Induced Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :669