Reinisch, W. et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn’s disease. Gut 55, 1138-1144

Universitaetsklinik Innere Medizin IV, Abteilung Gastroenterologie and Hepatologie, Vienna, Austria.
Gut (Impact Factor: 14.66). 09/2006; 55(8):1138-44. DOI: 10.1136/gut.2005.079434
Source: PubMed


This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease (CD).
Forty five patients with a CD activity index (CDAI) of 250-450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates.
Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn's disease endoscopic index of severity (p = 0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry.
Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested.

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    • "Fontolizumab) was not beneficial in CD patients. [9]–[10] These disappointing results could rely on the fact that the CD-associated tissue lesions are driven by multiple and disconnected inflammatory pathways, which are not fully inhibited by Fontolizumab. Indeed, the inflamed gut of CD patients is also massively infiltrated with a distinct subset of Th cells, termed Th17 cells, which over-express the transcription factors retinoic acid-related orphan receptor (ROR)-γt and RORα, produce IL-17A, IL-17F, IL-21, IL-22, and IL-26, and are negatively regulated by IFN-γ. "
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    ABSTRACT: Crohn's Disease (CD)-associated inflammation is supposed to be driven by T helper (Th)1/Th17 cell-derived cytokines, even though there is evidence that the mucosal profile of cytokine may vary with the evolution of the disease. We aimed at comparing the pattern of effector cytokines in early and established lesions of CD. Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with (early lesions) or without post-operative recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (established lesions). Inflammatory cell infiltrate was examined by immunofluorescence and cytokine expression was analysed by real-time PCR, flow-cytometry and ELISA. Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of T cells and macrophages, elevated levels of Th1-related cytokines and TNF-α and slightly increased IL-17A expression. Transition from this stage to endoscopic recurrence was marked by abundance of Th1 cytokines, marked increase in IL-17A, and induction of IL-6 and IL-23, two cytokines involved in the control of Th17 cell responses. In samples with established lesions, there was a mixed Th1/Th17 response with no TNF-α induction. Expression of IL-4 and IL-5 was up-regulated in both early and established lesions even though the fraction of IL-4-producing cells was lower than that of cells producing either interferon-γ or IL-17A. Distinct mucosal profiles of cytokines are produced during the different phases of CD. A better understanding of the cytokines temporally regulated in CD tissue could help optimize therapeutic interventions in CD.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "Similarly, no significant clinical response has been documented in active CD patients treated with fontolizumab, an anti-IFN-g antibody (Hommes et al., 2006; Reinisch et al., 2006, 2010), as well as in patients receiving apilimod mesylate , an oral inhibitor of IL-12/IL-23 synthesis (Sands et al., 2010) (Figure 1). The reason why anti-Th1 cytokine therapy has failed in CD remains unknown. "
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    ABSTRACT: Gut inflammation occurring in patients with inflammatory bowel diseases (IBD) is associated with an excessive immune response that is directed against constituents of the normal bacterial flora and results in the production of large amounts of inflammatory cytokines. Anti-cytokine compounds, such as the neutralizing TNF antibodies, have been employed with clinical success in patients with IBD. However, nearly half of IBD patients are refractory to such treatments, response can wane with time, and anti-TNF treatment can associate with severe side effects and/or development/exacerbation of extra-intestinal immune-mediated pathologies. These observations, and the demonstration that, in IBD, the pathological process is also characterized by defects in the production and/or activity of counter-regulatory cytokines, have boosted further studies aimed at delineating novel strategies to combat the IBD-associated tissue-damaging immune response.
    Preview · Article · Aug 2011 · British Journal of Pharmacology
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    • "Patients with inherited and acquired HLH have very high IFNg serum levels during the active disease (Henter et al, 1991; Mazodier et al, 2005; Nagasawa et al, 2008; Osugi et al, 1997; Takada et al, 2003 and our own unpublished observations). An anti-human IFNg antibody (fontolizumab) has been shown to be safe in clinical trials in Crohn's disease (Hommes et al, 2006; Reinisch et al, 2006). In addition, fontolizumab's therapeutic effects have been documented in patients with inflammatory skin diseases and in a clinical trial of patients with corneal transplant rejection (Skurkovich et al, 2002; Skurkovich & Skurkovich, 2005). "
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    ABSTRACT: Hereditary haemophagocytic lymphohistiocytosis (HLH) is a fatal inflammatory disease and treatments currently may lead to serious side effects. There is a pressing need for effective, less toxic treatments for this disease. Previous reports have suggested that interferon gamma (IFNgamma) has a role in the pathogenesis of HLH. Here, we report that blocking IFNgamma had a therapeutic effect in two different murine models of human hereditary HLH (perforin-deficient and Rab27a-deficient mice, both infected with lymphocytic choriomeningitis virus). Therapeutic administration of an anti-IFNgamma antibody induced recovery from haemophagocytosis in both genetic models, as evidenced by increased survival in perforin-deficient mice and correction of blood cytopenia, moderation of body temperature changes, decreased cytokinaemia, restoration of splenic architecture and reduced haemophagocytosis in the liver of both murine models. Involvement of the central nervous system in Rab27a-deficient mice was prevented by anti-IFNgamma therapy. Hepatic T-cell infiltrates and virus persisted, with no detectable harm during the time course of these studies. These data strongly suggest that neutralization of IFNgamma could be used in humans to safely alleviate the clinical manifestations of haemophagocytosis.
    Full-text · Article · May 2009 · EMBO Molecular Medicine
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