Hommes, D. W. et al. Fontolizumab, a humanised anti-interferon γ antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease. Gut 55, 1131-1137

Department Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, the Netherlands.
Gut (Impact Factor: 14.66). 09/2006; 55(8):1131-7. DOI: 10.1136/gut.2005.079392
Source: PubMed


Interferon gamma is a potent proinflammatory cytokine implicated in the inflammation of Crohn's disease (CD). We evaluated the safety and efficacy of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe CD.
A total of 133 patients with Crohn's disease activity index (CDAI) scores between 250 and 450, inclusive, were randomised to receive placebo or fontolizumab 4 or 10 mg/kg. Forty two patients received one dose and 91 patients received two doses on days 0 and 28. Investigators and patients were unaware of assignment. Study end points were safety, clinical response (decrease in CDAI of 100 points or more), and remission (CDAI < or =150).
There was no statistically significant difference in the primary end point of the study (clinical response) between the fontolizumab and placebo groups after a single dose at day 28. However, patients receiving two doses of fontolizumab demonstrated doubling in response rate at day 56 compared with placebo: 32% (9/28) versus 69% (22/32, p = 0.02) and 67% (21/31, p = 0.03) for the placebo, and 4 and 10 mg/kg fontolizumab groups, respectively. Stratification according to elevated baseline C reactive protein levels resulted in a decreased placebo response and pronounced differences in clinical benefit. Two grade 3 adverse events were reported and were considered to be related to CD. One death (during sleep) and one serious adverse event (an elective hospitalisation) occurred, both considered unrelated.
Treating active CD with fontolizumab was well tolerated and resulted in increased rates of clinical response and remission compared with placebo.

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Available from: János Lonovics, Oct 05, 2015
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    • "In 6 clinical studies reviewed (Danese and others 2008), IFN types do not appear promising in ulcerative colitis treatment. Similarly, early promise for anti-IFNG therapy in Crohn's disease (Hommes and others 2006) has not been borne out by subsequent studies (Reinisch and others 2010). Despite these inauspicious clinical results, other IFN activity-associated molecules require examination as therapeutic possibilities. "
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    ABSTRACT: The therapeutic efficacy of interferons (IFNs) in ulcerative colitis is minimal. However, IFN activity-associated molecules have been inadequately investigated. Appendicitis and appendectomy (AA), when done while young, protect against colitis development later. Our novel murine AA model protects against colitis. This therapeutic target-identifying study enumerates IFN activity-associated molecules involved in this protection. Mice with 2 laparotomies were controls (sham-sham/SS). Distal colons were harvested (4 AA-group colons and 4 SS-group colons). Microarray-analysis/reverse transcriptase-polymerase chain reaction-validation was done from RNA from each (3-days/28-days-post-AA). Gene set enrichment analysis (GSEA) software was used to analyze distal colonic gene sets associated with 46 IFN activity-related genes. More AA-upregulated gene sets were associated with IFIT1, IFIT2, IFIT3, IRF7, IFI35, and IFI44 (False Discovery Rate-FDR <5% and P<0.001), although only IFIT1, IFIT2, IFIT3, and IFI44 showed individual gene upregulation (P<0.05). More AA-downregulated gene sets were associated with IRF1, IRF2, IRF4, IRF8, IRF9, IRF2BP1, IFRD1, IFRD2, and IFIH1 (FDR <5%/P<0.001); although only IRF2BP1 showed individual gene downregulation (P<0.05). There was significant upregulation (P<0.05) of IFNZ; and downregulation of IRF2BP2 and IFI30, despite no major associated GSEA differences. IFIT1, IFIT2, IFIT3, and IFI44, with profound AA-induced individual/GSEA upregulation, and their immunomodulatory/ antiproliferative activity, are the best molecules to investigate therapeutic potential. IRF4, IRF8, IRF2BP1, IFRD1, and IFRD2, owing to their profound AA-induced gene set downregulation, and because of their diverse lymphocytic activity, are good targets to competitively inhibit or to treat with exogenous products in knockout animals.
    Journal of Interferon & Cytokine Research 09/2014; DOI:10.1089/jir.2014.0091 · 2.00 Impact Factor
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    • "In the same series, another group was treated with anti-TNF-α and showed similar improvement to those treated with anti-IFN-y (Sigidin et al., 2001). Interestingly, anti-TNF-α treatment is now an FDA approved treatment for RA, while anti-IFN-γ is still under investigation for treatment of Crohn's disease (Hommes et al., 2006; Ishimaru et al., 2008). "
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    ABSTRACT: Dry eye is an inflammatory disease that results from activation of innate inflammatory pathways in resident ocular surface cells, as well as cytokines produced by recruited T helper (Th) cells. Cytokines produced by the infiltrating Th cells alter the normal cytokine balance on the ocular surface and cause ocular surface epithelial pathology. Changes in levels of Th cytokines on the ocular surface have been measured in dry eye and the biological effects of these cytokines have been documented in experimental culture and mouse model systems. The Th2 cytokine IL-13 has a homeostatic role in promoting goblet cell differentiation. In contrast, The Th1 cytokine IFN-γ antagonizes IL-13 and promotes apoptosis and squamous metaplasia of the ocular surface epithelia. The Th17 cytokine, IL-17 promotes corneal epithelial barrier disruption. The ocular surface epithelium expresses receptors to all of these Th cytokines. Therapies that maintain normal IL-13 signaling, or suppress IFN- γ and IL-17 have potential for treating the ocular surface disease of dry eye.
    Experimental Eye Research 09/2013; 117. DOI:10.1016/j.exer.2013.08.013 · 2.71 Impact Factor
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    • "Antibodies designed to block IFN-γ activity have been effective in the treatment of chronic inflammatory disorders such as rheumatoid arthritis and Crohn’s disease [23,24]. Antagonizing the IFN-γ pathway has been investigated in the context of AMD. "
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    ABSTRACT: Age-related macular degeneration (AMD) is a neurodegenerative disease characterized by retinal cell atrophy, and/or choroidal neovascularization in the macula and constitutes the most common cause of blindness among the elderly in industrialized countries. The management of AMD is constrained by our insufficient knowledge of its underlying mechanisms. Recent studies point towards an emerging involvement of interferon-gamma (IFN-γ), a soluble cytokine associated with innate and adaptive immunity. IFN-γ promotes proinflammatory responses by activating proinflammatory cytokines and chemokines, thereby recruiting immune cells such as macrophages and T cells. On the other hand, IFN-γ modulates inflammatory response by upregulating anti-inflammatory factors or inhibiting development of immune cells related to autoimmune response. The complex role of IFN-γ in AMD pathogenesis is intriguing and worth further investigation in terms of therapeutic development.
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