An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

Abstract

Psoriasis is characterized by activation of T cells with a type 1 cytokine profile. IL-12 and IL-23 produced by APCs are essential for inducing Th1 effector cells. Promising clinical results of administration of an Ab specific for the p40 subunit of IL-12 and IL-23 (anti-IL-12p40) have been reported recently. This study evaluated histological changes and mRNA expression of relevant cytokines and chemokines in psoriatic skin lesions following a single administration of anti-IL-12p40, using immunohistochemistry and real-time RT-PCR. Expression levels of type 1 cytokine (IFN-γ) and chemokines (IL-8, IFN-γ-inducible protein-10, and MCP-1) were significantly reduced at 2 wk posttreatment. The rapid decrease of these expression levels preceded clinical response and histologic changes. Interestingly, the level of an anti-inflammatory cytokine, IL-10, was also significantly reduced. Significant reductions in TNF-α levels and infiltrating T cells were observed in high responders (improvement in clinical score, ≥75% at 16 wk), but not in low responders. Of importance, the levels of APC cytokines, IL-12p40 and IL-23p19, were significantly decreased in both responder populations, with larger decreases in high responders. In addition, baseline levels of TNF-α significantly correlated with the clinical improvement at 16 wk, suggesting that these levels may predict therapeutic responsiveness to anti-IL-12p40. Thus, in a human Th1-mediated disease, blockade of APC cytokines by anti-IL-12p40 down-regulates expression of type 1 cytokines and chemokines that are downstream of IL-12/IL-23, and also IL-12/IL-23 themselves, with a pattern indicative of coordinated deactivation of APCs and Th1 cells.

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

“…5A). IL-12p40 is a subunit in both IL-12 and IL-23 and is a novel drug target for the treatment of psoriasis (32)(33)(34). The induction was also observed in serum of TNFR1 KO mice (Fig.…”

“…Moreover, IL-12p40 levels were affected as well. IL-12p40 is a subunit shared by IL-12 and IL-23 and has recently been validated as a therapeutic target for psoriasis (32)(33)(34). Although IL-12 and IL-23 are not strictly known as typical type I IFN-induced genes, the presence of ISRE elements in the promoter regions for units p35, p40, and p19 have been described (55)(56)(57)(58)(59).…”

“…This is very interesting, because the complex biology underlying a disease is often multifactorial and requires a multifaceted approach, which can be achieved by combination therapies. Blocking both TNFR1 and IFNAR1 reduces activation of the IL-23/IL-17 axis during IMQ-mediated skin inflammation through reduction of IL-12p40 and IL-17F levels, two novel drug targets in psoriasis, Crohn's disease, and rheumatoid arthritis (34,(64)(65)(66)(67)(68)(69).…”

Psoriasis: Ustekinumab and Other Biologics in the Pipeline

“…IL-12, another heterodimeric cytokine, not only shares the p40 subunit with IL-23 but consists of the p35 subunit [28]. In fact, the pivotal role that the IL-23/ Th17 axis plays in psoriasis pathogenesis is reinforced by evidence that the mRNA levels of the subunit p19-unique to IL-23-were elevated in psoriasis lesional skin compared to non-lesional skin, whereas the levels for p35-a subunit distinct to IL-12-were not [29][30][31]. Importantly, the levels of IL-23 decreased in correlation to skin improvement and efficacy of various therapies-including phototherapy, cyclosporin A, and tumor necrosis factor-alpha (TNF-α) inhibitors-further crediting the role of IL-23 in psoriasis pathology and its utility as a therapeutic target [32][33][34].…”

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs

“…Ustekinumab prevents the interaction of these cytokines with the IL-12R 1 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).…”