Immunological effects of high dose administration of anti-CD4 antibody in rheumatoid arthritis patients

Goldberg, Danièle; Morel, P; Chatenoud, Lucienne; Menkès, C J; Bertoye, P; Revillard, Jean‐Pierre; Bach, Jean‐François

doi:10.1016/0896-8411(91)90181-b

Cited by 71 publications

(20 citation statements)

References 31 publications

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“…The low incidence of immunogenicity of this chimeric MAb is similar to the experience with chimeric 17-1A (24) and chimeric MOV-18 (40). It is strikingly different than the experience with chimeric B72.3 (41), chimeric 14.18 (42), or mouse MAb (22,23). Thus, cM-T412 fits into the category of low V-region immunogenic molecules, which provides the opportunity for continuous or repetitive treatment schedules.…”

Section: Discussionmentioning

confidence: 95%

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

Moreland

Bucy

Tilden

et al. 1993

Arthritis & Rheumatism

126

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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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Section: Discussionmentioning

confidence: 95%

“…Pilot studies using several murine MAbs directed against human CD4 in patients with refractory RA have yielded promising results (17)(18)(19)(20)(21). A source of concern in some of these early trials has been the development of host antibody responses directed against the therapeutic M A b (22,23).…”

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

126

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“…the treatment of autoimmune diseases in experimental animal models (3,4), open-label studies were performed in patients with RA (5)(6)(7)(8)(9)(10)(11)(12). CD4 MAb treatment was well tolerated and induced a rapid amelioration of arthritis activity in the majority of the patients studied.…”

mentioning

confidence: 99%

A randomized, double‐blind, placebo‐controlled study of cd4 monoclonal antibody therapy in early rheumatoid arthritis

Lubbe¹,

Dijkmans²,

Markusse³

et al. 1995

Arthritis & Rheumatism

142

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Objective. To assess the efficacy of the CD4 monoclonal antibody (MAb) cM-T412 in the treatment of early rheumatoid arthritis (RA).Methods. Sixty patients were enrolled in a 6-week randomized, double-blind, placebo-controlled study investigating multiple dose regimens of cM-T412. Thirty patients subsequently were enrolled in a 9-month randomized, double-blind, placebo-controlled study investigating monthly single-dose adminiitrations of cM-T412.Results. Analysis of clinical parameters revealed no changes in arthritis activity in the groups that received CD4 MAb or the placebo group, and no difference between the groups, in either in the first or the second part of the study. The number of circulating CD4+ cells decreased substantially in the patients treated with CD4 MAb. Conclusion. CD4 MAb treatment of patients with early RA induced no therapeutic effect.Present understanding of the pathogenesis of rheumatoid arthritis (RA) is incomplete. However, accumulating evidence has indicated that the T lymphocyte orchestrates an autoimmune process (I). Therefore, surface antigens of T cells were suggested as possible targets for a specific immunotherapy .Monoclonal antibodies (MAb) against the CD4 molecule were shown to modulate the function of CD4+ T cells (2). Following the successful use of CD4 MAb in

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“…144 The cartilage destructive properties of IL-1 have been targeted by inhibition using either IL-1ra or a soluble IL-1 receptor fusion protein. 145 In general, anti-T cell therapies such as anti-CD4 146,147 have been disappointing until now but this may be due to the particular epitopes of CD4 which are targeted by these particular antibodies.…”

Section: Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

Immuno- and genetic therapy in autoimmune diseases

et al. 2000

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Animal models of autoimmune disease have been developed that mimic some aspects of the pathophysiology of human disease. These models have increased our understanding of possible mechanisms of pathogenesis at the molecular and cellular level and have been important in the testing, development and validation of new immunotherapies. The susceptibility to develop disease in the majority of these models is polygenic as is the case in humans. The exceptions to this rule are gene knock outs and transgenic models of particular genes which, in particular genetic backgrounds, have also contributed to the understanding of single gene function and their possible contribution to pathogenesis. Gene therapy approaches that target immune functions are being developed with encouraging results, despite the polygenic nature of these diseases. Basically this novel immuno-genetic therapy harnesses the knowledge of immunology with the myriad of biotechnological breakthroughs in vector design and delivery. Autoimmune disease is the result of genetic dysregulation which could be controlled by gene therapy. Here we summarize the genetic basis of these human diseases as well as some of the best characterized murine models. We discuss the strategies for their treatment using immunoand gene therapy. Genes and Immunity (2000) 1, 295-307.

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Immunological effects of high dose administration of anti-CD4 antibody in rheumatoid arthritis patients

Cited by 71 publications

References 31 publications

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

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

A randomized, double‐blind, placebo‐controlled study of cd4 monoclonal antibody therapy in early rheumatoid arthritis

Immuno- and genetic therapy in autoimmune diseases

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