Treatment of rheumatoid arthritis with an anti‐CD4 monoclonal antibody

126

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.

“…The overall lack of serious toxicity of cM-T412 is consistent with similar observations following administration of other anti-CD4 MAbs in patients with RA (19,20).…”

Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 99%

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

Moreland

Bucy

Tilden

et al. 1993

126

“…The rapid improvemeiit, which may last for several months, is consistent with the results of murine antibody treatment in RA patients (8)(9)(10)(11).…”

Section: Discussionsupporting

confidence: 81%

“…In contrast to the studies with murine CD4 antibodies, the CD4+ T cell counts remained markedly suppressed for up to 12 months after treatment (8)(9)(10)(11). The mechanism of prolonged depletion of circulating CD4+ T cells is not yet understood.…”

Section: Discussionmentioning

confidence: 80%

Chimeric cd4 monoclonal antibody cm‐t412 as a therapeutic approach to rheumatoid arthritis

Lubbe

Reiter

Breedveld

et al. 1993

Objective. To investigate the effects of chimeric CD4 monoclonal antibody cM-T412 treatment in patients with rheumatoid arthritis (RA).Methods. Thirty-two RA patients received daily doses of 10,50, or 100 mg of cM-T412 intravenously for 7 days.Results. There was a sustained decrease in the number of CD4+ T lymphocytes in all patients. Those who received 50 mg and 100 mg of the antibody experienced significant reductions in disease activity.Conclusion. Treatment with cM-T412 appears to have a dose-dependent beneficial effect in RA patients. The clinical effects of cM-T412 are independent of the depressed numbers of circulating CD4+ T cells.A large body of evidence indicates that CD4+ T lymphocytes play a major role in the pathogenesis

“…Transgenic mice were identified by analysis of Pvu II-digested tail DNA. A J,2 probe hybridized with a 5.5-kilobase endogenous band in all mice, but also to a 7.7-kb band in V, 8 mice. All mice were female, homozygous for H-2""' , and were 8 weeks old at the beginning of the experiments.…”

Section: Methodsmentioning

confidence: 99%

T Cell Influence on Superantigen‐Induced Arthritis in MRL‐lpr/lpr Mice

Mountz

Zhou

Long

et al. 1994

Objective. To define the influence of the T cell receptor (TCR) and the lpr autoimmune gene on the induction and progression of superantigen-induced arthritis in V,8 transgenic MRL-lprllpr mice.Methods. The time to onset and the extent of synovial hyperplasia after the induction of arthritis by intraarticular injection of staphylococcal enterotoxin B (SEB) were compared in mice having T cells that bear the V, $ transgene alone (V@ TCR transgenic M R G +/+), the lpr gene without the Vs8 gene (nontransgenic MRL-lpr/lpr), both the Vs8 gene and the lpr gene Results. At day 30, increased synovial cells were observed in all SEB-treated mice, but the increase was greatest in the V@ transgenic MRGlprllpr mice. T cell involvement was indicated by the inability of either heat-denatured SEB or SEA to induce severe arthritis, the reduction in the severity of the arthritis on systemic treatment with CSA or anti-VgS, and the correlation of synovial hyperplasia with in vitro SEB reactivity of T cells.Conclusion. Theseobservations suggest that superantigens can induce chronic arthritis and that the induction and progression of the arthritis requires an underlying T cell defect in anergy induction in addition to exposure to the superantigen.