Development of a Janus Kinase Inhibitor Prodrug for the Treatment of Rheumatoid Arthritis

This is the authors' abstract. We don't add key points for this paper.

While highly efficacious in treating rheumatoid arthritis (RA), the approved Janus kinase (JAK) inhibitor, Tofacitinib (Tofa, CP-690 550), has dose-dependent toxicities that limit its clinical application. In this study, we have examined whether a prodrug design that targets arthritic joints would enhance Tofa's therapeutic efficacy, which may provide an opportunity for future development of safer Tofa dosing regimens. A prodrug of Tofa (P-Tofa) was synthesized by conjugating the drug to the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer via an acid cleavable carbamate linker. The therapeutic efficacy of a single dose of P-Tofa was compared to the dose-equivalent daily oral administration of Tofa in an adjuvant-induced arthritis (AA) rat model. Saline treated AA rats and age-matched healthy rats were used as controls. Observational analyses support the superior and sustained efficacy of a single dose P-Tofa treatment compared to the dose-equivalent daily Tofa administration in ameliorating joint inflammation. Micro-CT and histological analyses demonstrated that the P-Tofa treatment provided a structural preservation of the joints better than that of the dose-equivalent Tofa. Optical imaging, immunohistochemistry, and fluorescence-activated cell sorting analyses attribute P-Tofa's superior therapeutic efficacy to its passive targeting to arthritic joints and inflammatory cell-mediated sequestration. In vitro cell culture studies reveal that the P-Tofa treatment produced sustained the inhibition of JAK/STAT6 signaling in IL-4-treated murine bone marrow macrophages, consistent with a gradual subcellular release of Tofa. Collectively, a HPMA-based nanoscale prodrug of P-Tofa has the potential to enhance the therapeutic efficacy and widen the therapeutic window of Tofa therapy in RA.