Structural Basis for the Dual Recognition of IL-12 and IL-23 by Ustekinumab

Luo, Jinquan; Wu, Sheng‐Jiun; Lacy, Eilyn R.; Orlovsky, Yevgeniya; Baker, Audrey; Teplyakov, A.; Obmolova, Galina; Heavner, George A.; Richter, Hans-Thomas; Benson, Jacqueline

doi:10.1016/j.jmb.2010.07.046

Cited by 91 publications

(73 citation statements)

References 48 publications

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“…Therefore, it was concluded that UST would both neutralize the IL12/23 pathway and decrease expression of skin homing and activation markers [33]. In another study, x-ray crystallography demonstrated that UST binds with nearly equal affinity to the p40 component of both IL12 and IL23 [34].…”

Section: Ustekinumabmentioning

confidence: 99%

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

Mortezavi

Ritchlin

2015

Curr Treat Options in Rheum

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Section: Ustekinumabmentioning

confidence: 99%

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

Mortezavi

Ritchlin

2015

Curr Treat Options in Rheum

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“…IL-23 is composed of p19 and p40 subunits, and the IL-23 receptor also has two chains: IL-12Rb1 in combination with IL-23R. Ustekinumab (Stelara), a monoclonal antibody developed by Janssen Pharmaceuticals and approved by the FDA in 2010 for the treatment of moderate to severe plaque psoriasis, binds to the shared p40 subunit of IL-12 and IL-23 (Benson et al, 2011), thereby neutralizing the cytokines' bioactivity and subsequent molecular signaling pathways (Luo et al, 2010). However the impact of decreasing free circulating IL-12 and IL-23 levels on drug metabolizing enzymes is currently unknown.…”

mentioning

confidence: 99%

Interleukins-12 and -23 Do Not Alter Expression or Activity of Multiple Cytochrome P450 Enzymes in Cryopreserved Human Hepatocytes

et al. 2013

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Psoriasis is a T-cell-mediated autoimmune disease involving the skin. Two cytokines, interleukin-12 (IL-12) and IL-23 have been shown to play a pivotal role in the pathogenesis of the disease. Ustekinumab (Stelara) is a therapeutic monoclonal antibody (mAb) targeted against the p40 shared subunit of . Recently the ability of therapeutic proteins (TP) including mAbs that target either cytokines directly (e.g., Pegasys; peginterferon a-2a) or their respective cell surface receptors [e.g., tocilizumab (Actemra); anti IL-6R] to desuppress cytochrome P450 (P450) enzymes in vitro and in the clinic, has been demonstrated. In the present study the ability of IL-12 and IL-23 to suppress multiple P450 enzymes was investigated in vitro using six separate lots of cultured human hepatocytes. Following exposure of 10 ng/ml IL-12 and IL-23 for 48 hours, either alone or in combination, no change in CYP2B6, 2C9, 2C19, or 3A4 gene expression or functional activity was observed. None of the untreated hepatocyte donors showed appreciable expression of the IL-12 or IL-23 receptors. Similar results were seen with whole human liver samples. Exposure of hepatocytes to IL-12 and/or IL-23, known P450 suppressors (IL-6 and tumor necrosis factor-a) or known P450 inducers (b-naphthoflavone, phenobarbital, and rifampicin) did not appreciably alter the expression of the IL-12 and IL-23 receptors either. Finally, in contrast to the positive control IL-6, expression of the acute phase C-reactive protein was unaltered following IL-12 and/or IL-23 treatment. Together, these data suggest a negligible propensity for IL-12 or IL-23 to directly alter P450 enzymes in human hepatocytes. IntroductionThe ability of therapeutic proteins (TP) that target cytokines to potentially mediate drug interactions through alterations in drug metabolizing enzymes is a growing concern in drug development (Huang et al., 2010). Patients with inflammatory disease often have increased circulating or local cytokine levels including interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and interferon-gamma, which have all been shown to alter cytochrome P450 (P450) metabolic enzyme levels in the liver (Morgan, 2009). The TP treatment that neutralizes one or more of these cytokines could result in patients experiencing rebound metabolic enzyme levels, leading to decreased comedication exposure and potentially therapeutic failure. As an example, recent clinical studies by Schmitt et al., (2011) showed significantly decreased simvastatin (Zocor) exposure in rheumatoid arthritis patients receiving tocilizumab, an anti-human IL-6 receptor mAb. The decreased exposure was linked to changes in CYP3A4 expression reported by the same group following anti-IL-6R treatment in the presence and absence of tocilizumab in cultured human hepatocytes (Zhang et al., 2009).Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the population (Christophers, 2001;Nestle et al., 2009). Pathogenesis of psoriasis involves a complex interplay of various cytokines, incl...

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“…38,39 Based on a crystal structure of ustekinumab Fab region complexed with human IL-12, the binding epitope for ustekinumab is located in the D1 domain of the p40 subunit, which is spatially distant from IL-12p35 and IL-23p19. 33 Mutational analysis confirmed amino acid residues within D1 that were required for ustekinumab binding. Through isothermal titration calorimetry analysis, ustekinumab was shown to bind IL-12 and IL-23 equally, with the expected 2:1 antigen-to-antibody stoichiometry.…”

Section: Role Of Interleukin-12 and Interleukin-23 In Immune-mediatedmentioning

confidence: 89%

“…This was later confirmed by elucidation of the ustekinumab fragment antigen binding (Fab)/IL-12 co-crystal structure. 33 IL-12 binds to a heterodimeric receptor complex consisting of IL-12 receptor (IL-12R) β1 and IL-12Rβ2 chains expressed on the surface of T cells or NK cells (Fig. 4).…”

Section: Ustekinumab Mechanism Of Actionmentioning

confidence: 99%