**4. IL-12/IL-23 inhibitors**

A third class of biologics classified as IL-12/IL-23 inhibitors has been developed for treating psoriasis. These two cytokines, mainly produced by activated dendritic cells, lead to differentiation of Th cells into the Th1 and Th17 subsets, respectively (Nestle et al, 2009). Moreover, elevated levels of IL-12 and IL-23 have been observed in psoriatic skin lesions (Yawalcar et al, 2009). Currently, ustekinumab is FDA- and EMA-approved for the treatment of chronic plaque psoriasis, whereas briakinumab, has recently had its approval application withdrawn in the US and Europe to conduct further analysis and clinical trials (Centocor Ortho Biotech, 2009; Kurzeia et al, 2011).

#### **4.1 Ustekinumab**

Ustekinumab is a fully human monoclonal antibody that binds to the p40 subunit that is shared by IL-12 and IL-23 (Centocor Ortho Biotech, 2009). IL-12 activates natural killer and T cell responses, including CD4+ T cell differentiation toward the Th1 phenotype, while IL-23 leads to Th17 differentiation, regulates T memory cells, and activates macrophages to maintain chronic autoimmune inflammation (Aggarwal et al, 2003; Trinchieri, 2003). Ustekinumab prevents the interaction of these cytokines with the IL-12Rβ1 receptor, neutralizing their immune-mediated responses. A single administration of anti-IL-12p40 demonstrated significant changes in psoriatic skin lesions after 2 weeks, including the reduction of a type 1 cytokine (IFN-) and chemokines (IL-8, IFN--inducible protein-10, and MCP-1), and a decrease of TNF and infiltrating T cells (Toichi et al, 2006).

Ustekinumab was approved by the FDA in September 2009 for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy (Centocor Ortho Biotech, 2009). Early-stage clinical trials have also demonstrated its therapeutic potential in psoriatic arthritis (Gottlieb et al, 2009).
