Randomised controlled trial of CDP571 antibody to tumour necrosis factor-α in Crohn's disease

STACK, W. A; Mann, Steven; Roy, Abhik; Heath, Patricia K.; Sopwith, Mark; Freeman, Jan G.; Holmes, G. K. T.; Long, Rose G.; Forbes, Alastair; Kamm, Michael A.

doi:10.1016/s0140-6736(97)80083-9

Cited by 379 publications

(177 citation statements)

References 17 publications

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“…It seems likely that either repeat dosing or a higher initial dose would be needed to provide further maintenance of this bene®cial effect. Good results have also been reported with this antibody in a small placeboblinded study in Crohn's disease 12 and with another TNFa antibody in Crohn's disease 6 as well as in rheumatoid arthritis. In rheumatoid arthritis repeat dosing has been used successfully without any signi®-cant clinical problems related to antibody development or allergic reaction.…”

Section: Discussionmentioning

confidence: 81%

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

Evans

Clarke

Heath

et al. 1997

Aliment Pharmacol Ther

130

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Background:Tumour Necrosis Factor‐alpha (TNFα) is a pro‐inflammatory cytokine whose expression is increased in the colonic mucosa of patients with active ulcerative colitis. TNFα antibodies have been shown to be beneficial in animal models of bowel inflammation and in Crohn's disease but have not previously been studied in ulcerative colitis.Methods:Patients with mild/moderate ulcerative colitis were treated openly with a single intravenous infusion of 5 mg/kg of an engineered human IgGγ4 antibody CDP571 and monitored for 8 weeks.Results:Fifteen patients entered the study, eight males and seven females, with a mean age of 44 years. Eleven had left‐sided disease, four extensive disease and six patients were steroid‐unresponsive. The treatment was well tolerated and plasma half‐life of CDP571 was ≈7 days. There was a significant reduction from 6.7 to 4.6 (P = 0.023) in the mean Powell–Tuck score by 1 week post‐infusion and a reduction to 5.5 was seen at 2 weeks (P = 0.218). Significant but modest reductions also occurred in erythrocyte sedimentation rate and serum C reactive protein in the first 2 weeks. Mean Interleukin‐6 plasma concentrations fell from 6.9 to 5.4 pg/mL by week 1, and to 6.1 pg/mL by week 2 (NS). Reductions in sigmoidoscopic score and number of liquid stools were noted but failed to reach statistical significance.Conclusion:A consistent improvement in disease activity was seen in the initial 2 weeks after infusion and the treatment was well tolerated. These promising results support the testing of CDP571 in a larger controlled trial.

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Section: Discussionmentioning

confidence: 81%

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

Evans

Clarke

Heath

et al. 1997

Aliment Pharmacol Ther

130

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“…CDP-571-In a short-term, double-blind, placebo-controlled study, CDP-571, a humanized IgG4 anti-TNF Ab, was given as a single 5 mg/kg dose to 31 patients with moderate to severe CD [102]. At 2 weeks after the infusion, the median CDAI fell from 263 to 167 in the CDPtreated group, and the change was insignificant in the placebo-treated group.…”

Section: Developing 'Smart' Tnfα Antagonists Newer Anti-tnf Agents Inmentioning

confidence: 99%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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“…Several exogenous factors, such as bacterial cell wall components, viruses or dietary products, are thought to initiate and/or perpetuate a sequence of chronic immune processes that are not down-regulated appropriately in genetically predisposed individuals and that may lead to intestinal mucosal injury [1][2][3]. Cytokines, such as tumour necrosis factor (TNF)-a and interleukin (IL)-1, play a major role in the development of IBD [4][5][6][7][8][9][10][11]. TNF-a and IL-1 b induce synthesis of chemokines, including IL-8, a potent neutrophil chemoattractant [12,13].…”

Section: Introductionmentioning

confidence: 99%

Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease

Ludwiczek

Vannier

Borggraefe

et al. 2004

Clinical and Experimental Immunology

126

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SUMMARYInterleukin (IL)-1 is a key mediator in the pathogenesis of inflammatory bowel disease (IBD). Naturally occurring IL-1 modulators include IL-1 receptor antagonist (IL-1Ra), IL-1 soluble receptor Type I (IL1sRI), IL-1sRII and IL-1 receptor accessory protein (AcP). Systemic and mucosal levels of IL-1 soluble receptors remain unknown in IBD. Plasma or colonic tissues were obtained from 185 consecutive unselected patients with Crohn's disease (CD) or ulcerative colitis (UC) and from 52 control subjects. Plasma and colonic explant culture supernatants were assessed for IL-1 a , IL-1 b , IL-1Ra, IL-1sRI and IL-1sRII. Plasma IL-1Ra levels were higher in UC (+93%) than in healthy subjects. IL-1 a and IL-1 b were not detected. IL-1sRII levels were marginally lower in CD ( -10%) and UC ( -9%), whereas IL1sRI levels were elevated in CD (+28%) only. Plasma IL-1sRI levels correlated positively ( P < 0·01) with Crohn's disease activity index ( r = 0·53), C-reactive protein ( r = 0·46) and a 1-acid glycoprotein ( r = 0·42). In colonic explant cultures, IL-1 a and IL-1Ra levels were elevated in non-lesional (+233% and +185% respectively) and lesional CD (+353% and +1069%), lesional UC (+604% and +1138%), but not in non-lesional UC. IL-1 b was elevated in lesional UC (+152%) and CD (+128%). In contrast, IL-1sRII levels were elevated in non-lesional CD (+65%), but remained unchanged in lesional CD, nonlesional and lesional UC. IL-1sRI levels did not differ between patient and control groups. These results indicate that (i) the proinflammatory moiety IL-1sRI is a systemic marker of inflammation and activity in CD and (ii) local shedding of the functional antagonist IL-1sRII may dampen colonic inflammation in CD, but not in UC.

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Randomised controlled trial of CDP571 antibody to tumour necrosis factor-α in Crohn's disease

Cited by 379 publications

References 17 publications

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

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

TNFα blockade in human diseases: Mechanisms and future directions

Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease

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