Mouse/human chimeric monoclonal antibody in man: kinetics and immune response.

LoBuglio, Albert F.; Wheeler, Richard; Trang, John M.; Haynes, Amy; Rogers, Kim R.; Harvey, Elizabeth B.; Sun, Lee K.; Ghrayeb, John; Khazaeli, M. B.

doi:10.1073/pnas.86.11.4220

Cited by 438 publications

(137 citation statements)

References 20 publications

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“…Chimeric antibodies have shown a considerable variation in immunogenicity. 14 The human engineered anti-TNFa antibody CDP571 has previously been shown to induce only low concentrations of an IgM type anti-idiotype response with a weak response in IgG. 7 This is in keeping with the pharmacokinetic data showing a long half-life.…”

Section: Discussionmentioning

confidence: 56%

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: 56%

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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“…The immune response to cM-T412 was assessed by a double-antigen radiometric assay, as previously described (24,29), with serum samples obtained prior to treatment and at 7, 14, and 28 days, and at 2, 4, and 6 months postinfusion. The assay utilized murine M-T412-coated beads and '251-labeled chimeric M-T412 as the radioactive probe.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have indicated the lower immunogenicity of a chimeric MAb (versus an intact murine MAb) in tumor therapy (24 …”

mentioning

confidence: 99%

Use of a chimeric monoclonal anti‐CD4 antibody in patients with refractory rheumatoid arthritis

Moreland

Bucy

Tilden

et al. 1993

Arthritis & Rheumatism

127

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Objectives. To evaluate the safety, immunogenicity, and biologic effects of chimeric monoclonal anti‐CD4 (cM‐T412) in patients with refractory rheumatoid arthritis (RA), and to obtain preliminary data on the clinical response to this treatment.Methods. Twenty‐five patients with active refractory RA were treated with incremental doses (10 to 700 mg) of cM‐T412 in an open‐label, escalating‐dose phase I trial.Results. Infusion with cM‐T412 was followed by an immediate, rapid decline in CD4+ T cells. The level of circulating CD4+ T cells remained depressed in most patients even at 6 months posttreatment. Following antibody infusion, proliferative responses of peripheral blood lymphocytes to mitogens and antigens were determined; mitogen and antigen responses were decreased compared with pretreatment responses. Mitogen responses tended to return to baseline values more rapidly than did responses to antigen. Adverse events included fever (19 patients), which was associated with myalgias, malaise, and asymptomatic hypotension; these symptoms were self‐limited and appeared to correlate with transient elevations in interleukin‐6. No significant human antibody response to the cM‐T412 variable region was detected; only 2 patients developed transiently low levels of antibodies reactive with cM‐T412. Significant clinical improvement, defined as ≥50% decrease in tender joint counts compared with baseline, was noted in 43% of patients at 5 weeks and 33% at 6 months following cM‐T412 infusion.Conclusions. Treatment of refractory RA with cM‐T412 appears to be safe and is associated with sustained decreases in circulating CD4+ T cell counts and depressed in vitro T cell responses. No significant human antichimeric antibody response was detected. Nonblinded assessment of clinical end points suggests that treatment with cM‐T412 may have beneficial effects in these patients with refractory RA. A double‐blind clinical trial is warranted to determine its clinical efficacy in treating RA.

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“…Development of host antibody responses directed against the therapeutic MAb had previously raised concerns about the long-term usefulness of murine MAb (27,28). To overcome this problem, chimeric MAb that exhibit lower immunogenecity compared with the parent murine MAb have been developed (29). We have previously reported on the use of a chimeric anti-CD4 MAb, cM-T412, in a phase I trial, in patients with refractory RA (30,31).…”

mentioning

confidence: 99%

Double‐blind, placebo‐controlled multicenter trial using chimeric monoclonal anti‐cd4 antibody, cm‐t412, in rheumatoid arthritis patients receiving concomitant methotrexate

Moreland

Pratt

Mayes

et al. 1995

Arthritis & Rheumatism

100

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Objective. To evaluate the clinical response to and safety of single and repeat doses of a chimeric anti-CD4 monoclonal antibody, cM-T412, in patients with rheumatoid arthritis (RA) concomitantly treated with a stable regimen of low-dose methotrexate.Methods. Sixty-four patients with refractory RA, who were already receiving stable doses of methotrexate, were randomized into a multicenter, double-blind, placebo-controlled trial to receive 3 monthly treatments with either a placebo, or 5,10, or 50 mg cM-T412, given intravenously.Results. Using 250% improvement in swollen joint counts as a criterion for clinical response, 13%, 13%, 18%, and 13% of patients receiving 50, 10, or 5 mg cM-T412, or the placebo, respectively, exhibited a

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Mouse/human chimeric monoclonal antibody in man: kinetics and immune response.

Cited by 438 publications

References 20 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

Use of a chimeric monoclonal anti‐CD4 antibody in patients with refractory rheumatoid arthritis

Double‐blind, placebo‐controlled multicenter trial using chimeric monoclonal anti‐cd4 antibody, cm‐t412, in rheumatoid arthritis patients receiving concomitant methotrexate

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