Ustekinumab

Key points

Introduction

It can be argued that psoriasis is the most successfully treated immune-mediated disease and a promising example of the impact of translational research. Improved understanding of the pathophysiology of psoriasis in the late twentieth and early twenty-first century facilitated the evolution of treatments from nonspecific, immunosuppressive medications to novel targeted therapies. Several biologic agents have been developed for the treatment of psoriasis over the past decade. Biologics act with greater target specificity and generally have not demonstrated end-organ toxicities more commonly observed with other effective systemic agents. Although concern over adverse events (AEs; infections and malignancy) exists with some biological therapies, studies have shown that the risks are minimal and benefits are well documented. Targeted therapies, such as tumor necrosis factor (TNF)-α inhibitors, have considerably enhanced the treatment of moderate-to-severe plaque psoriasis and improved overall quality of life in psoriasis patients.

Ustekinumab is a human, monoclonal antibody that binds to the shared p40 subunit of interleukin (IL)-12 and IL-23. It was US Food and Drug Administration approved for the treatment of moderate-to-severe plaque psoriasis in 2009 and has proven to be a safe and efficacious treatment. Recommended dosing occurs at weeks 0, 4, and every 12 weeks thereafter ( Fig. 11.1 ). Infrequent dosing, high efficacy, and tolerability could positively affect adherence in psoriasis patients, who, in the past, have not treated their disease adequately.

Mechanism of action

Although monoclonal antibodies directed against TNFs proved to be effective in treating psoriasis, more specific targets were sought. Ustekinumab is a human immunoglobulin G _κ (IgG _κ ) monoclonal antibody that binds to the p40 protein subunit shared by IL-12 and IL-23 cytokines, preventing their interactions with the heterodimeric IL-12 receptor subunit. IL-12 and IL-23 are naturally occurring cytokines involved in inflammatory and immune responses. In transgenic mice, the overexpression of IL-12 has been linked to the development of inflammatory skin lesions; not surprisingly, lesional skin in psoriasis patients has demonstrated increased expression of IL-12 compared with nonlesional skin.

IL-12 and IL-23 are produced primarily by antigenic stimulation of dendritic cells and macrophages. IL-12 is composed of a p35 and a p40 subunit, the latter being largely expressed in psoriatic lesional skin; its receptor is made up of IL-12RB1 and IL-12R2 subunits. Binding of IL-12 to its receptor causes activation of a JAK-STAT signaling pathway, causing T cells to be assigned to the Th1 pathway and downstream secretion of its effector interferon-γ (IFN-γ).

IL-23 is composed of p19 and p40 subunits (both largely expressed in lesional skin). It binds to a receptor made of the IL-12RB1 and IL-23R subunits. Similar to IL-12, binding of the p40 subunit with IL-12RB1 and the p19 subunit with IL-23R signals through JAK-STAT signaling, activating STAT3 and causing a Th17-driven response.

Ustekinumab blocks IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) receptor complexes on the surface of natural killer and T cells. In vitro models showed ustekinumab equally disrupted the action of IL-12 and IL-23, blocking STAT 3,4 phosphorylation and ultimately IFN-γ, IL-22, and IL-17 production.

Pharmacokinetics

Similar to endogenous IgG, ustekinumab has an approximate half-life of 3 weeks. Peak serum concentration of ustekinumab occurred at approximately 13.5 days after a 45-mg dose and 7 days after a 90-mg dose. Steady-state drug concentrations were achieved by week 28. Ustekinumab is metabolized much the same as human IgG. An Fc receptor binds to IgG and carries it across the cell membrane to be degraded within the cell.