Back to the future: oral targeted therapy for RA and other autoimmune diseases

Abstract

The molecular biology revolution coupled with the development of monoclonal antibody technology enabled remarkable progress in rheumatology therapy, comprising an array of highly effective biologic agents. With advances in understanding of the molecular nature of immune cell receptors came elucidation of intracellular signalling pathways downstream of these receptors. These discoveries raise the question of whether selective targeting of key intracellular factors with small molecules would add to the rheumatologic armamentarium. In this Review, we discuss several examples of this therapeutic strategy that seem to be successful, and consider their implications for the future of immune-targeted treatments. We focus on kinase inhibitors, primarily those targeting Janus kinase family members and spleen tyrosine kinase, given their advanced status in clinical development and application. We also summarize other targets involved in signalling pathways that might offer promise for therapeutic intervention in the future.

Figures

Figure 1. The role of Janus kinases (Jaks) in signaling by Type I/II cytokine receptors

Cytokines are structurally diverse and bind to structurally distinct receptors. One major class of cytokines are those that bind receptors belonging to the Type I/II family. These include many, but not all interleukins, interferons, colony and stimulating factors, as well as growth hormone, prolactin, and erythropoietin. Of note, IL-1, IL-17 and TNF do not signal by the Jak-Stat pathway. Shown here are the signal transduction pathways stemming from the IL-2 receptor in T cells culminating in the activation of the of signal transducer and activator of transcription 5, MAPK, and mTOR serine/ threonine kinase. The Raf-Ras-MAPK pathway is linked to cytokine receptors like the IL-2 receptor by adapter molecules such as SHC, Grb2 and SOS. IL-2 and other cytokines also activate PDK1 and PKB (Akt) leading to activation of mTor. In this regard, it is useful to note that although the term Jak-Stat pathway is frequently used, other pathways are also activated. As best we can tell, these pathways are also dependent upon Jaks; although, this is an area that deserves further research. Tyrosine kinases are indicated in red and serine threonine kinases are indicated in blue. The effect of various jakinibs is depicted. mTor inhibitors are also shown.

Figure 2. Usage of different Jaks by various cytokines

In considering the mechanism of action of different jakinibs it is useful to keep in mind the dependence of different cytokines on the various Jaks. Jak3 has the most selective function. As best we can tell, it associates uniquely with the common γ chain, γc. This cytokine receptor subunit is used by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Inhibition of Jak3 therefore blocks signaling by these cytokines. Common γ chain cytokines also utilize Jak1, so agents that block Jak1 will also block IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. In contrast to Jak3, Jak1 is used by a number of other cytokine those that use gp130 (IL-6 and related cytokines), interferons, and IL-10-family cytokines. Like Jak1, Jak2 is important for signaling by an array of cytokines including IFNγ, IL-6, and other cytokines. Jak2 is important for signal by IL-3, IL-5 and GM-CSF. It is especially critical for erythropoietin (EPO), thrombopoietin (TPO), and growth hormone (GH). Thus, inhibitors that block Jak1 and Jak2 interfere with signaling by many proinflammatory cytokines, but also interfere with EPO signaling and thus can cause anemia. Tyk2 also contributes to IL-6 and IL-10 signaling and is especially important for the actions of IFNα/β. At present, there are no Tyk2 inhibitors in clinical use.

Figure 3. The proximal signalling events in response to the B cell receptor activation

A number of key immune receptors are structurally similar. Such receptors include the B cell receptor, T cell receptor and Fc receptors. These receptors are referred to as multichain immune recognition receptors and are just 3 of many different receptors in this family that trigger activation of immune cells. In the case of the B cell receptor, antigen binding activates Src family kinases such as Lyn, which phosphorylate receptor subunits. This allows the recruitment of Syk and activation of these membrane-proximal tyrosine kinases lead to phosphorylation of adapter molecules including SLP-76, GADS and LAT. This in turn activates Btk, phospholipase Cγ, and Ras. In this manner, second messengers like diacyglycerol and inositol trisphosphate are produced and downstream kinases including PKC, Raf, MEK, and Erk are activated. The actions of various inhibitors are depicted. Tyrosine and lipid kinases are indicated in red, serine/ threonine kinases indicated in blue.