Fontolizumab, a humanised anti-interferon   antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease

Abstract

Introduction: Interferon c 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 c antibody, in patients with moderate to severe CD. Methods: 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 (150).Results: 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. Conclusion: Treating active CD with fontolizumab was well tolerated and resulted in increased rates of clinical response and remission compared with placebo.

TL1A (TNFSF15) Regulates the Development of Chronic Colitis by Modulating Both T-Helper 1 and T-Helper 17 Activation

“…IFN-γ from T H 1 cells and IL-17 from T H 17 cells are both key mediators in several autoimmune diseases and IBD. 5,6,20,21 In DSS-treated mice, IFN-γ, IL-17, and TNF-α mRNA ( Figure 1E) and protein ( Figure 1F) expressions were significantly higher than in untreated mice. However, IL-4 produced by T H 2 cells was rarely detectable in this model (data not shown).…”

“…CD has been characterized as having a T cell helper (T H ) 1 and T H 17 cytokine pattern, and antibodies to both interferon (IFN)-γ and p40 (interleukin (IL)-12/23) can treat subsets of CD patients. 5,6 TL1A, a recently identified tumor necrosis factor (TNF)-like factor, is the only known ligand for death receptor (DR) 3 which is primarily expressed on activated lymphocytes. 7 TL1A is expressed on endothelial cells, lymphocytes, plasma cells, monocytes, and DCs.…”

Interferon-γ Axis in Graft Arteriosclerosis

“…136 Similarly, a humanized monoclonal antibody directed against IFN-␥ is well tolerated by patients with Crohn's disease and has a beneficial effect on disease activity. 137,138 Besides neutralizing antibodies or similar strategies with soluble cytokine receptors, we have recently demonstrated that the IFN-␥ axis may be inhibited in an experimental model of GA by preventing IP-10 binding to low-affinity glycosaminoglycan (GAG) sites on vascular cells and consequently decreasing the transendothelial migration and arterial recruitment of CXCR3 ϩ T H 1 cells. 139 Currently, there is a great deal of interest by a number of groups in developing synthetic GAG derivatives capable of competitively binding cytokines and chemokines 140 and in producing modified chemokines with an alteration in the GAG-binding site such that they do not oligomerize on EC surfaces.…”

Cytokines and their Role in Health and Disease: A Brief Overview

“…Disease Targets IFN-α Hepatitis B and C [5] IFN-β Multiple sclerosis [5] IFN-γ Chronic granulomatous disease [38], Crohn's disease [65], Multidrug resistant tuberculosis [42] TNF-α Rheumatoid arthritis [30,31], Sepsis [32], Refractory asthma [33], Psoriasis [2] G-CSF Idiopathic neutropenia, Congenital neutropenia, Febrile neutropenia, Leukemic neutropenia, Aplastic neutropenia [37], Bone marrow suppression [5] GM-CSF Bone marrow suppression, Crohn's disease [5] IL-2 Metastatic melanoma, Renal cell carcinoma [46] IL-4 Asthma [43] IL-5 Asthma [44] IL-6 Rheumatic diseases [34] IL-10 Crohn's disease, Ulcerative colitis [2], Psoriasis, Rheumatoid arthritis [5] IL-11 Crohn's disease, Ulcerative colitis, Psoriasis, Rheumatoid arthritis [2] IL-13 Asthma [2,45] Erythropoietin Anaemia, Bone marrow failure [5] HER2-Specific Monoclonal Antibody Adenocarcinoma of stomach, Breast cancer [35,36] …”