A Randomized Trial of Ustekinumab, a Human Interleukin-12/23 Monoclonal Antibody, in Patients With Moderate-to-Severe Crohn's Disease

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Gastroenterology (Impact Factor: 16.72). 07/2008; 135(4):1130-41. DOI: 10.1053/j.gastro.2008.07.014
Source: PubMed

ABSTRACT Interleukin-12 and interleukin-23 are inflammatory cytokines implicated in Crohn's disease pathophysiology. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12/23.
We performed a double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohn's disease (population 1). Patients were given subcutaneous placebo at weeks 0-3, then ustekinumab at weeks 8-11; subcutaneous ustekinumab at weeks 0-3, then placebo at weeks 8-11; intravenous placebo at week 0, then ustekinumab at week 8; or intravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an open-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2).
In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and 6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (P < .05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in patients given ustekinumab through week 8 compared with placebo.
Ustekinumab induced a clinical response in patients with moderate-to-severe Crohn's disease, especially in patients previously given infliximab.

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Available from: William J Sandborn, Sep 29, 2015
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    • "Safety data for ustekinumab are available for more than 3,000 patients enrolled in clinical trials evaluating use of the drug in psoriasis, psoriatic arthritis, multiple sclerosis, and CD.19 In the two published CD trials, the proportion of patients with at least one adverse event through week 8 was slightly higher in the placebo group (Phase IIA) and similar among the study groups (Phase IIB).16,26 In the Phase IIA study in CD, serious adverse events occurred in three of 53 patients (6%) in the placebo group compared to two of 51 patients (4%) in the ustekinumab group through week 8. "
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    ABSTRACT: The advent of anti-tumor necrosis factor (TNF)-α therapy has been a major advance in the medical management of Crohn's disease (CD). However, a significant proportion of patients with CD do not respond adequately to treatment with these agents. Primary and secondary nonresponse to anti-TNFα therapy represents a common clinical challenge, and highlights the need for the development of additional medication options for CD. The proinflammatory cytokines interleukin (IL)-12 and IL-23 are thought to play a key role in the pathogenesis of CD, and serve as a potential target for additional biologic therapies. Monoclonal antibodies targeting IL-12/23 have shown efficacy in animal models of colitis, and are currently being studied in Phase III clinical trials of CD. This review focuses on ustekinumab, a fully human immunoglobulin G1 monoclonal antibody, which blocks activity of IL-12 and IL-23 through binding the p40 subunit, and describes the current efficacy and safety data for ustekinumab in patients with CD.
    Clinical and Experimental Gastroenterology 05/2014; 7(1):173-179. DOI:10.2147/CEG.S39518
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    • "However, the underlying pathogenic mechanisms have not been thoroughly investigated . Monoclonal antibody (mAb) against the IL-12/23p40 subunit has proved clinical effect in CD patients [18] [19], and we have previously demonstrated that anti-IL-12/23p40 mAb ameliorates colitis in PAC IL-10 k.o. mice [15]. "
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    ABSTRACT: Piroxicam administration is a method for induction of enterocolitis in interleukin-10 knockout (IL-10 k.o.) mice. The piroxicam-accelerated colitis (PAC) IL-10 k.o. model combines a dysregulated immune response against the gut microbiota with a decreased mucosal integrity. The predictive validity and pathogenic mechanisms of the model have not been thoroughly investigated. In this study, IL-10 k.o. mice received piroxicam in the chow, and model qualification was performed by examining the efficacy of prophylactic anti-IL-12/23p40 monoclonal antibody (mAb), anti-TNFα mAb, cyclosporine A (CsA) and oral prednisolone treatment. To evaluate cell involvement in the disease pathogenesis, specific cell subsets were depleted by treatment with anti-CD4 mAb, anti-CD8 mAb or clodronate-encapsulated liposomes. T cell receptor co-stimulation was blocked by CTLA4-Ig. Cytokine profiling ELISAs and calprotectin immunohistochemistry were performed on colon tissue. Treatments with anti-IL-12/23p40 mAb and CsA prevented disease in PAC IL-10 k.o. mice and reduced IFNγ, IL-17A, MPO and calprotectin levels in colon. Anti-TNFα mAb treatment caused amelioration of selected clinical parameters. No effect of prednisolone was detected. Depletion of CD8(+) cells tended to increase mortality, whereas treatment with anti-CD4 mAb or CTLA4-Ig had no significant effect on disease development. Clodronate liposome treatment induced a loss of body weight; nevertheless macrophage depletion was associated with a significant reduction in colonic pathology. In conclusion, reference drugs with known efficacy in severe inflammatory bowel disease were efficacious in the PAC IL-10 k.o. model. Our data indicate that in this model macrophages are a main driver of colitis, whereas CD4(+) cells are not.
    International immunopharmacology 05/2014; 21(1). DOI:10.1016/j.intimp.2014.04.017 · 2.47 Impact Factor
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    • "Increasing evidence suggests that type 1 helper T (Th1) and interleukin (IL)-17 producing helper T (Th17) cells are important mediators of inflammation in IBD [7,8]. Th1- and Th17-type cytokines are highly expressed in inflamed mucosa in IBD patients, and inhibition of these cytokines leads to remission of human IBD and murine dextran sulfate sodium (DSS)-induced colitis model [9-13]. The involvement of Th17 cells in the pathogenesis of IBD is also supported by recent genome-wide association studies, indicating that genes involved in Th17 differentiation are associated with susceptibility to IBD [14]. "
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    ABSTRACT: Although some bacterial strains show potential to prevent colitis, their mechanisms are not fully understood. Here, we investigated the anti-colitic mechanisms of Bifidobacterium longum subsp. infantis JCM 1222(T), focusing on the relationship between interleukin (IL)-17A secreting CD4(+) T cells and intestinal epithelial costimulatory molecules in mice. Oral administration of JCM 1222(T) to mice alleviated dextran sulfate sodium (DSS)-induced acute colitis. The expression of type 1 helper T (Th1)- and IL-17 producing helper T (Th17)-specific cytokines and transcriptional factors was suppressed by JCM 1222(T) treatment. Intestinal epithelial cells (IECs) from colitic mice induced IL-17A production from CD4(+) T cells in a cell-cell contact-dependent manner, and this was suppressed by oral treatment with JCM 1222(T). Using blocking antibodies for costimulatory molecules, we revealed that epithelial costimulatory molecules including CD80 and CD40, which were highly expressed in IECs from colitic mice, were involved in IEC-induced IL-17A response. Treatment of mice and intestinal epithelial cell line Colon-26 cells with JCM 1222(T) decreased the expression of CD80 and CD40. Collectively, these data indicate that JCM 1222(T) negatively regulate epithelial costimulatory molecules, and this effect might be attributed, at least in part, to suppression of IL-17A in DSS-induced colitis.
    PLoS ONE 11/2013; 8(11):e79735. DOI:10.1371/journal.pone.0079735 · 3.23 Impact Factor
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