Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor

Abstract

IntroductionAn array of chronic inflammatory diseases, including Crohn disease, psoriasis, rheumatoid arthritis, and multiple sclerosis, cause widespread and severe health problems. These and other immune diseases can be considered to have a predominantly T helper cell type 1 (Th1) bias. Although injectable biologic treatments such as antibodies and soluble protein that block TNF-␣ have provided significant clinical benefit, there is still a high unmet medical need, particularly for a safe targeted drug that can be taken orally.Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) composed of 2 independently regulated protein subunits, p35 and p40. IL-12 plays a central role in the immune response by bridging innate resistance and antigen-specific adaptive immunity. 1 It is produced from phagocytic cells and antigen-presenting cells, in particular macrophages and dendritic cells, upon stimulation with bacteria, bacterial products such as lipopolysaccharide (LPS), and intracellular parasites. 2,3 The well-documented biologic functions of IL-12 are the induction of interferon-␥ (IFN-␥) expression from T and natural killer (NK) cells 4,5 and the differentiation of naive T cells toward a Th1-cell type. 6,7 IL-12 also appears to be critical in the expansion and maintenance of the Th1 phenotype. [8][9][10] IL-23, a more recently discovered member of the IL-12 family, also promotes Th1 response, but has distinct functions from IL-12. IL-23 is required for the generation of effector memory T cells. 11 IL-23 is also needed for the generation of IL-17-producing T cells, which play a significant role in the inflammatory response. 12 Through these activities, IL-23 plays a critical role in chronic inflammatory diseases.Although the inflammatory effector function of Th1 is essential for the clearance of intracellular pathogens, the excessive production of proinflammatory cytokines leads to serious tissue damage typical of organ-specific autoimmunity, 13,14 including type 1 diabetes, 15 multiple sclerosis, 16,17 rheumatoid arthritis, 18,19 inflammatory bowel disease, 20 psoriasis, 21 and sepsis. 22 IL-12/IL-23 has been validated as an attractive clinical target by a number of studies. Mice lacking the gene encoding the p40 subunit shared by IL-12 and IL-23 or lacking the IL-23-specific subunit p19 have proven the integral role of IL-12/IL-23 to the pathogenesis of these disorders, implying that blockade of the cytokines could be effective in the treatment of a variety of autoimmune diseases. 21,[23][24][25][26][27][28] Monoclonal antibodies to the IL-12/23 p40 subunit have been shown to be effective in human clinical trials in patients with Crohn disease and psoriasis. 29,30 While antibodies against IL-12/IL-23 could provide significant medical benefit, a small-molecule IL-12/IL-23 inhibitor that could be administered orally would be highly desirable. Although some compounds weakly or nonselectively inhibit IL-12, there are no potent and selective small-molecule IL-12 inhibitors. To find an effective inhibitor against the...

PIKfyve, a Class III Lipid Kinase, Is Required for TLR-Induced Type I IFN Production via Modulation of ATF3

“…PIKfyve-mediated PI(3,5)P 2 signaling has been shown to play a critical role in multiple biological processes by regulating endosomal trafficking, such as GLUT4 translocation, retroviral budding (12,13), autophagy (14), and neurodegeneration. Recently, we revealed that PIKfyve is the molecular target of apilimod (15), which is the first clinically evaluated small-molecule IL-12/IL-23 antagonist (16,17). We have shown that apilimod specifically binds to PIKfyve and inhibits its activity, which in turn silences TLR-induced IL-12/IL-23 production.…”

Prospective new biological therapies for rheumatoid arthritis

“…This drug has been successfully tested in patients with Crohn's disease, and a phase II clinical trial in patients with RA is currently in progress (32). A selective antagonist of a chemokine receptor CCR5, maraviroc, was well tolerated, without severe adverse events; however, due to lack of efficacy, the phase II clinical trial in patients with RA was terminated at the end of 2008.…”

Is there a future for small molecule drugs in the treatment of rheumatic diseases?

“…[24]. Preclinical studies [25 ] of STA-5326 demonstrated successful IL-12/IL-23 inhibition and suppression of Th1-dependent immune response. In the murine model of inflammatory bowel disease, STA-5326 inhibited the production of IFN-g and the development of histopathologic changes in the colon, suggesting potential benefit of this compound for the treatment of Th1-dependent autoimmune inflammatory diseases.…”