Treatment of ulcerative colitis with an engineered human anti‐TNFα antibody CDP571

Evans, Richard C.; Clarke, Lane L.; Heath, Patricia K.; Stephens, Sue; Morris, A. I.; Rhodes, JM

doi:10.1046/j.1365-2036.1997.00251.x

Cited by 130 publications

(69 citation statements)

References 10 publications

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“…In our studies, we observed a dose-dependent fluid accumulation following direct injection of mice with TNF. Clinically, blocking TNF with mAb's (Infliximab) has been known to prevent diarrhea symptoms in patients with IBD (2,33). Similarly, we found that in mice, blocking TNF prior to T cell activation prevented fluid accumulation almost completely.…”

Section: Discussionsupporting

confidence: 57%

T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase

et al. 2002

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Inflammatory bowel disease (IBD) is associated with mucosal T cell activation and diarrhea. We found that T cell activation with anti-CD3 mAb induces profound diarrhea in mice. Diarrhea was quantified by intestinal weight-to-length (wt/l) ratios, mucosal Na+/K+-ATPase activity was determined and ion transport changes were measured in Ussing chambers. Anti-CD3 mAb increased jejunal wt/l ratios by more than 50% at 3 hours, returning to base line after 6 hours. Fluid accumulation was significantly reduced in TNF receptor-1 (TNFR-1–/–), but not IFN-γ knockout mice. Anti-CD3 mAb decreased mucosal Na+/K+-ATPase activity, which was blocked by anti-TNF mAb and occurred to a lesser degree in TNFR-1–/– mice. Neither α nor β subunits of Na+/K+-ATPase decreased in abundance at 3 hours. Intestinal tissue from anti-CD3–treated mice exhibited increased permeability to mannitol at 1 hour and decreases in electroneutral Na+ absorption, Na+-dependent glucose absorption, and cAMP-stimulated anion secretion at 3 hours. Furthermore, enteral fluid accumulation was observed in CFTR–/– mice, indicating a minor role of active anion secretion. These data suggest that diarrhea in IBD is due to TNF-mediated malabsorption rather than to secretory processes. T cell activation induces luminal fluid accumulation by increasing mucosal permeability and reducing epithelial Na+/K+-ATPase activity leading to decreased intestinal Na+ and water absorption

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Section: Discussionsupporting

confidence: 57%

T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase

et al. 2002

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“…La segunda línea de evidencia proviene del tratamiento de animales de experimentación con CU idiopática con anticuerpos anti-TNF (CDP571). Dicho tratamiento conduce a aumento de peso y una mejoría histológica de la inflamación mucosa (21).…”

Section: Discussionunclassified

“…A second line of evidence is supplied by the experimental treatment of animals with idiopathic UC using anti-TNF-α antibodies (CDP571). Such treatment is followed by weight gain and a partial reversal of histological mucosal changes (21).…”

Section: Discussionmentioning

confidence: 99%

Infliximab induces clinical, endoscopic and histological responses in refractory ulcerative colitis

Bermejo

López-Sanromán²,

Hinojosa

et al. 2004

Rev. esp. enferm. dig.

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Background: infliximab is a monoclonal antiTNF-α antibody that has repeatedly shown to be effective in the management of Crohn's disease. However, data are scarce about its efficacy in ulcerative colitis.Aim: to describe the joint experience of three Spanish hospitals in the use of infliximab in patients with active refractory ulcerative colitis.Patients and methods: we present seven cases of ulcerative colitis (6 with chronic active disease despite immunosuppressive therapy, and one with acute steroid-refractory ulcerative colitis) treated with infliximab 5 mg/kg of body weight. Clinical response was evaluated by means of the Clinical Activity Index at 2, 4 and 8 weeks after initial infusion. Biochemical (erythrocyte sedimentation rate and C-reactive protein), endoscopic, and histological changes were also assessed.Results: mean age of patients was 45.8 ± 17 years (range 23-77); 4 were female. No adverse effects were recorded. Inflammatory activity diminished significantly in 6 of 7 patients (85.7%; CI 95%: 42-99%) both from a clinical (p = 0.01) and biochemical (p <0.05) point of view. Five out of six patients (83.3%; 36-99%) with corticosteroid-dependent disease could be successfully weaned off these drugs. Five patients were endoscopicly controlled both before and after therapy, and a positive endoscopic and histological response could be recorded in all of them.Conclusion: infliximab may be an effective and safe therapy for some patients with ulcerative colitis refractory to other forms of therapy, although controlled studies are needed to assess its role in the general management of this disease.

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“…CDP571, an immunoglobulin G4 humanized monoclonal anti-TNF-antibody showed a slight and short lived reduction in clinical activity of UC [234]. It proved to be less effective than infliximab and further clinical development of CDP571 for the treatment of CD has been discontinued (see review [194]).…”

Section: Inhibition Of Pro-inflammatory Cytokines 3211 Inhibitorsmentioning

confidence: 99%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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Treatment of ulcerative colitis with an engineered human anti‐TNFα antibody CDP571

Cited by 130 publications

References 10 publications

T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase

T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase

Infliximab induces clinical, endoscopic and histological responses in refractory ulcerative colitis

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

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