The Therapeutic Effects of an Engineered Human Anti-Tumour Necrosis Factor Alpha Antibody (Cdp571) in Rheumatoid Arthritis

Rankin, Elizabeth; Choy, Ernest; Kassimos, Dimitrios; Kingsley, Gabrielle; Sopwith, A. M.; Isenberg, David; Panayi, G. S.

doi:10.1093/rheumatology/34.4.334

Cited by 229 publications

(95 citation statements)

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“…infusion of CDP870, followed by a single open-label infusion, certolizumab significantly reduced inflammation and improved symptoms in RA patients [97]. Clinical improvement (ACR20 response) was comparable to that of ETA [98] and INF [96,99]. Certolizumab was very well tolerated in the study and had an extended duration of action after one or more i.v.…”

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

confidence: 79%

“…PEG increases its circulating half-life to approximately 14 days, which is that of a whole Ab [96], and it is much longer than the half-life of unconjugated Fab' fragments. This Ab has been developed to address the concerns that some toxicity associated with INF and ADA might be due to Fc-associated effects on complement activation and ADCC.…”

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

confidence: 99%

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

confidence: 79%

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

View full text Add to dashboard Cite

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“…Anti-CDP571 response was minimal and similar to that seen in other studies using CDP571 in humans. 7,11 Small increases in antibodies to the idiotype portion only of CDP571 were seen in 11 of the 15 patients, and the presence of anti-idiotype was not associated with a reduced clinical response. Ten patients completed the study.…”

Section: Resultsmentioning

confidence: 95%

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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“…Although IL-1 and TNF␣ share many biologic actions that are relevant in RA (4)(5)(6), research in animal models of arthritis suggests that IL-1 is the dominant cartilagedestructive cytokine (7). The biologic effects of both cytokines are modulated in vivo by naturally occurring protein inhibitors (8,9), and both have become prime targets for biologic therapy in RA (10)(11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Long‐term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin‐1 receptor antagonist) in patients with rheumatoid arthritis: Extension phase of a randomized, double‐blind, placebo‐controlled trial

Nuki¹,

Bresnihan²,

Bear³

et al. 2002

Arthritis & Rheumatism

200

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Objective. To demonstrate the long-term efficacy of anakinra, a human recombinant interleukin-1 receptor antagonist, in patients with rheumatoid arthritis (RA), and to assess the long-term safety of anakinra at different daily doses.Methods. The efficacy and safety of anakinra were previously demonstrated in a double-blind, placebocontrolled, 24-week evaluation in 472 patients with active RA. Of 345 patients who completed the placebocontrolled phase of the study, 309 continued in a 52-week, multicenter, double-blind, parallel-group extension phase of the study. Patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24 weeks of the extension phase (48 weeks total therapy), using the American College of Rheumatology composite score (ACR20), its components, and radiographs of the hands and wrists. Safety was assessed in all 472 patients over the entire 52-week extension phase (76 weeks total exposure).Results. A total of 218 patients completed the extension phase. Of the 91 patients who withdrew prematurely, 46 did so following adverse events, and 26 withdrew because of lack of efficacy. Among patients receiving anakinra who entered the extension phase, the level of improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24 and 46% at week 48, and this effect was consistent across all dose groups. The durability of the response to anakinra was further demonstrated in an evaluation of the sustained ACR20 response, which was similar during the first and second 24-week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued taking anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were originally receiving placebo and then were randomized to all doses of anakinra. Anakinra was well tolerated for 76 weeks. The only side effects that appeared to be treatment-related were skin reactions at the injection site. There was no evidence of decreased tolerance, an increased number of withdrawals, or an increased incidence of clinical complications associated with extended anakinra therapy.Conclusion. The clinical benefits of treatment with daily self-administered subcutaneous injections of anakinra in a cohort of patients with active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks. These observations support the long-term use of anakinra for the treatment of patients with RA.

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The Therapeutic Effects of an Engineered Human Anti-Tumour Necrosis Factor Alpha Antibody (Cdp571) in Rheumatoid Arthritis

Cited by 229 publications

References 0 publications

TNFα blockade in human diseases: Mechanisms and future directions

TNFα blockade in human diseases: Mechanisms and future directions

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

Long‐term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin‐1 receptor antagonist) in patients with rheumatoid arthritis: Extension phase of a randomized, double‐blind, placebo‐controlled trial

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