An engineered human antibody to TNF (CDP571) for active Crohn's disease: A randomized double-blind placebo-controlled trial

Sandborn, William J.; Feagan, Brian G.; Hanauer, Stephen B.; Present, Daniel H.; Sutherland, Lloyd R.; Kamm, Michael A.; Wolf, Douglas C.; Baker, Jeffrey P.; Hawkey, Christopher J.; Archambault, A; Bernstein, Çharles N.; Novak, Claire; Heath, Patricia K.; Targan, Stephan R.

doi:10.1053/gast.2001.24042

Cited by 248 publications

(138 citation statements)

References 13 publications

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“…In a subsequent 24-week phase 2 study [103], CD patients were randomized to receive either CDP-571 10 mg/kg or 20 mg/kg IV and then redosed with 10 mg/kg CDP-571 or placebo every 8 or every 12 weeks. Only 32% of treated and 19% of placebo patients completed the study.…”

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

255

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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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

255

162

View full text Add to dashboard Cite

show abstract

“…Mitochondrial permeability is increased by Bak and Bax (proapoptotic) and maintained by Bcl-2 and Bcl-X L (antiapoptotic). Cytochrome C that has leaked out of the mitochondria forms a complex (the "apoptosome") with Apaf-1 and caspase 9, which is able to activate caspase 3. anti-inflammatory effects of 2 TNF-␣-neutralizing antibodies, infliximab and CDP571, 8,12 observed in a very similar population of patients with active Crohn's disease. Because etanercept has potent anti-inflammatory effects in rheumatoid arthritis, 13,14 the mechanisms of the therapeutic efficacy of TNF-binding molecules in Crohn's disease and rheumatoid arthritis seem to differ.…”

mentioning

confidence: 90%

Transmembrane TNF-α, induction of apoptosis, and the efficacy of TNF-targeting therapies in Crohn's disease

Deventer

2001

Gastroenterology

112

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“…Recent advances in drug development for IBD have involved the use of mAbs to inhibit specific proinflammatory cytokines, such as ILs, IFNs, and TNF-␣ (5,6). In particular, the anti-TNF-␣ Abs CDP571 and infliximab have been used clinically to treat Crohn's disease with some success (7)(8)(9). Major drawbacks of these new protein therapies are the narrow spectrum of inflammatory mediators that they regulate, their high costs of production, in vivo instability, poor bioavailability, limited routes of administration, and immunogenicity.…”

mentioning

confidence: 99%

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Woodruff¹,

Arumugam²,

Shiels³

et al. 2003

The Journal of Immunology

109

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The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-d-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-α levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-α inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.

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An engineered human antibody to TNF (CDP571) for active Crohn's disease: A randomized double-blind placebo-controlled trial

Cited by 248 publications

References 13 publications

TNFα blockade in human diseases: Mechanisms and future directions

TNFα blockade in human diseases: Mechanisms and future directions

Transmembrane TNF-α, induction of apoptosis, and the efficacy of TNF-targeting therapies in Crohn's disease

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

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