Novel Phosphoinositide 3-Kinase d,g Inhibitor: Potent Anti-Inflammatory Effects and Joint Protection in Models of Rheumatoid Arthritis

Phosphoinositide 3-kinases g and d (PI3Kg and PI3Kd) are expressed in rheumatoid arthritis (RA) synovium and regulate innate and adaptive immune responses. We determined the effect of a potent PI3Kd,g inhibitor, IPI-145, in two preclinical models of RA. IPI-145 was administered orally in rat adjuvantinduced arthritis (AA) and intraperitoneally in mouse collageninduced arthritis (CIA). Efficacy was assessed by paw swelling, clinical scores, histopathology and radiography, and microcomputed tomography scanning. Gene expression and Akt phosphorylation in joint tissues were determined by quantitative real-time polymerase chain reaction and Western blot analysis. Serum concentrations of anti-type II collagen (CII) IgG and IgE were measured by immunoassay. T-cell responses to CII were assayed using thymidine incorporation and immunoassay. IPI-145 significantly reduced arthritis severity in both RA models using dosing regimens initiated before onset of clinical disease. Treatment of established arthritis with IPI-145 in AA, but not CIA, significantly decreased arthritis progression. In AA, histology scores, radiographic joint damage, and matrix metalloproteinase (MMP)-13 expression were reduced in IPI145–treated rats. In CIA, joint histology scores and expression of MMP-3 and MMP-13 mRNA were lower in the IPI-145 early treatment group than in the vehicle group. The ratio of anti-CII IgG2a to total IgG in CIA was modestly reduced. Interleukin-17 production in response to CII was decreased in the IPI-145–treated group, suggesting an inhibitory effect on T-helper cell 17 differentiation. These data show that PI3Kd,g inhibition suppresses inflammatory arthritis, as well as bone and cartilage damage, through effects on innate and adaptive immunity and that IPI145 is a potential therapy for RA.