Table 2.
Targeted Pathway (Therapeutic Modality) |
Biological Activity | Human Disease(s) (Refs)* | Animal Model (Refs) |
---|---|---|---|
Calcineurin (CsA, FK-506=tacrolimus) | Prevent T cell activation and proliferation by inhibiting the Ca2+/calmodulindependent protein phosphatase, calcineurin | Effective in various types of uveitis, often used as corticosteroid sparing agents | Rat EAU, monkey EAU |
mTOR signaling (rapamycin=sirolimus, everolimus) | Interferes with mTOR signaling: inhibits T cell activation by modulating signaling pathways of IL-2, IL-4, and IL-15; promotes Treg induction | Systemic pilot study and local Tx in Phase III clinical trial indicate efficacy (Nguyen et al., 2013) | Rat EAU (Roberge et al., 1993); Mouse EAU (Hennig et al., 2012) |
TNF-α (infliximab, adalimumab, etanercept) | Chimeric, fully humanized Abs to TNF-α (inflixi- and adalimumab, respectively) and TNFR-IgG Fc fusion protein (etanercept). The antibodies neutralize soluble and membrane bound forms of TNF-α; fusion protein binds to TNFR and prevents signaling. | Infliximab, and more recently adalimumab, show good efficacy in JIA; Etanercept appears not useful for treatment of uveitis. | Rat and mouse EAU models (Dick et al., 2004; Dick et al., 1996; Sartani et al., 1996) |
IL-6 (tocilizumab) | Antibody to IL-6R; blockade of the receptor prevents IL-6 signaling; inhibition of direct proinflammatory effects of IL-6 and indirect such as induction of Th17 response | Effective in uveitis patients who failed anti TNF-α therapy | Mouse EAU (Haruta et al., 2011; Hohki et al., 2010) |
IL-1 (anakinra, rilonacept, gevokizumab) | Recombinant IL-1RA (Anakinra) blocks binding of IL-1 to its receptor; engineered IL-1R-Fc fusion protein (Rilonacept) and monoclonal Ab Gevokizumab bind to and neutralize IL-1 | Uveitis associated with resistant Behçet’s disease or with CINCA syndrome respond to Anakinra. Rilonacept and Gevokizumab clinical trials pending. | Mouse EAU (Lim et al., 2005; Su et al., 2005) |
IFN type 1 (IFN-α,IFN-β) | Recombinant human IFN-α and IFN-β: mechanism of action poorly defined | Extensive experience in various types of uveitis more with IFN-α than with IFN-β. Especially effective in Behçet's disease. | (Stubiger et al., 2003; Sun et al., 2011; Suzuki et al., 2002) |
IL-2 (daclizumab) | Antibody to CD25 (IL-2Rα chain): blockade of high-affinity IL-2R; associated with emergence of suppressive CD56-bright NK cells. | Strikingly effective in several small, open-label trials in various types of uveitis, but a randomized, placebo controlled trial for Behçet's disease did not show good efficacy | Rat EAU (Higuchi et al., 1991; Nussenblatt, 2002) |
CTLA-4 (ligand of CD80 and CD86) (abatacept) | CTLA-4-Ig fusion protein: prevents effective costimulation of T cells by antigenpresenting cells, by blocking the CD80 and CD86 molecules. | Recent reports indicate that abatacept is highly effective in JIA associated uveitis even in cases where the disease was refractory to immunosuppressive agents and TNF inhibitors | Rat EAU (Verwaerde et al., 2003) |
IL-12/IL-23 p40 (ustekinumab) | Ab to IL-12/23 p40 subunit: inhibits Th1 and Th17 lineage commitment | Behçet’s disease single case report (Baerveldt et al., 2013). Clinical trial pending (NCT01647152). | Mouse EAU (Tarrant et al., 1998; Yoshimura et al., 2009) |
IL-17 (secukinumab= AIN457) | Monoclonal Ab to IL-17; IL-17 neutralization | An open label trial from Novartis reports efficacy in a mix of chronic intermediate, posterior, and pan uveitis (Hueber et al., 2010) but several placebo controlled trials in Behçet's disease did not meet primary efficacy criteria (Dick et al., 2013) | Mouse EAU (Luger et al., 2008) |
CD-20 (rituximab) | Antibody to the CD20 molecule: depletion of B cells. Mechanisms may include reduction of B cell produced Abs and cytokines (IL-6) and elimination of antigen presentation by B cells to disease associated T lymphocytes. | Effective in uveitis and scleritis associated with different systemic syndromes, which was refractory to other treatments, e.g., Wegener’s granulomatosis, Sjogren’s syndrome and JIA | Mouse experimental autoimmune encephalomyelitis (Barr et al., 2012; Monson et al., 2011) |
CD52 (altemtuzumab= Campath1) | Antibody to CD52: Depletion of T cells. New T cells may be “reprogrammed” for tolerance | Relatively few patients treated, but efficacy reported in various types of uveitis including Behçet's disease | Humanized SCID mice (de Kroon et al., 1996; Watanabe et al., 2006) |
If other references are not cited, the reader is referred to the following comprehensive recent reviews on biologics in uveitis: (Heiligenhaus et al., 2010; Heo et al., 2012; Larson et al., 2011; Leung and Thorne, 2013; Servat et al., 2012; Takeuchi, 2013).