Psoriasis is a common autoimmune skin disease (occurring in 2-3% of the population) that is characterized by inflammation, increased keratinocyte hyperproliferation, and altered epidermal differentiation. Cytokines interleukin (IL)-12 and IL-23 secreted by antigen presenting cells (macrophages and dendritic cells) are thought to play a major role in the immune reaction of this disease by activating NK cells and CD4+ T cells. The two cytokines are heterodimeric and both consist of the same p40 subunit and a distinguishing subunit (p35 and p19 respectively). After secretion by antigen presenting cells, these two cytokines activate NK-cells and T-cells. IL-12 binds to receptors IL-12Rβ1 and IL-12Rβ2 on Th1-cells; IL-23 targets receptors IL-12Rβ1 and IL-23R on Th17-cells. After binding, signal transduction is activated resulting in production of inflammatory mediators such as interleukins and interferon and differentiation and proliferation of immune cells. (see graphic below)
Ustekinumab is a fully human IgG1κ monoclonal antibody (MW of approx. 150kD) that binds with high affinity to this p40 protein subunit. Ustekinumab inhibits the bioactivity of IL-12 and IL-23 by preventing these cytokines from binding to their IL-12Rβ1 receptor expressed on natural killer (NK) cells and CD4+ T cells. Signal transduction and subsequent cytokine secretion does not occur after this binding. In this manner, ustekinumab interrupts the immune cascade responsible for the pathologic process in psoriasis.
Ustekinumab is highly specific and shows no cross-reactivity to structurally related proteins. It cannot bind to IL-12 or IL-23 that is already bound to the IL-12Rβ1R. Thus, it is unlikely that ustekinumab evokes complement- or antibody-mediated cytotoxicity of receptor-bearing cells.
Ustekinumab is administered by subcutaneous injection in a frequency of once every 12 weeks after a starting dose and a second dose after 1 month.
Due to its mechanism of action, ustekinumab has the potential to increase the risk of (respiratory) infections and reactivate latent infections, especially of tuberculosis. Patients with chronic infections or a history of recurrent infection should be monitored carefully. Other effects of ustekinumab in life-long immunosuppression include risk of malignancy, cardiovascular side effects, antibody formation and psychiatric disorders (depression).
Ustekinumab is indicated for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to or are intolerant to other systemic therapies including ciclosporin, methotrexate and psoralen plus ultra-violet A light (PUVA). Since ustekinumab targets cytokines which are involved in other immune diseases, its indication might be extended to other inflammatory conditions like Crohn’s disease, rheumatoid arthritis, ulcerative colitis.
EPAR of ustekinumab.