MONOCLONAL ANTIBODIES TO CD4

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In almost a decade, a substantial body of evidence has accumulated that justified the construction of a “T cell paradigm” for rheumatoid arthritis (RA), and this model has formed the basis for trials of biologic therapies and other novel immunotherapies in the treatment of this disease. Since then impressive research efforts on the pathogenesis of RA discovered many new disease mechanisms illustrating the complexity and multicellular nature of the disease. It was shown that major inflammatory responses in arthritis are caused by interaction between activated monocyte/macrophages and synoviocytes.5, 14 At the same time, the thymus-derived lymphocyte (T cell) response in arthritis could be described in much more detail.15 T cell functions in human autoimmune diseases seemed to be much more complex than previously anticipated. The information provided by these lines of research now allows the construction of a better informed paradigm that describes how many pathologic cell-cell interactions transform the rheumatoid joint into a component of the lymphoid system in the middle of invasive and destructive connective tissue. To achieve the goal of interfering with those immunologic responses that drive arthritis, several components of the immune system can be targeted. In that respect, T cells are considered as attractive targets for monoclonal antibody (mAb) therapy in RA. However, the particular T cell subset that is reactive against inciting antigens has not been identified nor is the nature of the antigens inciting or perpetuating the arthritic process known. As a consequence, therapeutic approaches to date have been directed at T-cell subsets, in particular the CD4+ subset.

The strong association of human leukocyte antigens (HLA)-DR antigens with susceptibility and severity of RA forms the most convincing evidence that the CD4 subset of T cells is pivotal in the pathogenesis of RA since the CD4 receptor on T cells is known to bind to major histocompatibility complex (MHC) class II receptors on antigen processing cells, i.e. HLA-DR (Fig. 1).17, 59 Additional evidence supporting the role of CD4+ T cells in RA include the predominance of these cells in the synovial membrane and the increased expression of T-cell activation markers.49 Furthermore, passive transfer of disease to healthy animals can be achieved with CD4+ T cell clones from animals with experimental arthritis.19

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THE CD4 MOLECULE AND CD4 MONOCLONAL ANTIBODIES

Mature T cells comprise a number of functionally distinct subpopulations which are distinguished by function-associated surface membrane receptors. The CD4 molecule expressed on the helper/inducer T cell subset is a typical member of the immunoglobulin gene family, having an array of four extracellular domains. A hydrophobic transmembrane anchor, it acts as a coreceptor with the antigen-specific T-cell receptor (TCR), and plays a critical role in the activation of T cells and induction of

USE OF CD4-mAb IN ANIMAL MODELS

The first report of CD4-mAb-induced blockade of a host immune response described the diminished immune response to rat immunoglobulin in mice treated with rat CD4-mAb.10 In rodent systems, rejection of an allograft was prevented by administration of CD4-mAb that depleted T cells from the circulation. The efficacy of the treatment depended on the time of administration, just prior to engraftment, and the dosage given: greater than 5 mg mAb/kg body weight.47 Tolarized T cells could transfer their

Immunopharmacology

The serum level of circulating CD4-mAb after injection is a result of the applied dosage and the infusion rate. In the case of a chimerized CD4-mAb, unbound circulating CD4-mAb were only detected after injections of more than 10 mg.56 After the infusion of 20 mg, these levels peaked to 1 to 2 mg/l and were undetectable 24 hours later. With murine mAb, a half-life of 3 hours was measured; whereas a four- to six-fold longer half-life was reported for chimeric mAb.20, 28 The apparent T 1/2 of

CLINICAL EVALUATION

CD4-mAb treatment was mainly studied in RA patients refractory to conventional therapeutic regimens. The initial trials were of an open uncontrolled design, with the primary aim of assessing safety and objective biological effects. These studies used murine and chimeric mAb. More recent studies had a placebo-controlled design. To decrease immunogenicity and lymphocytopenia, nondepleting primatized as well as humanized antibodies were applied.

Interestingly, the dosages of CD4-mAb used in RA were

FUTURE PROSPECTS

Following the disappointing results of two controlled studies on the effect of depleting CD4-mAb in RA, encouraging results are now being presented by investigators that use nondepleting CD4-mAb. It is not yet clear as to what extent antibody characteristics determine the clinical observation. More information on the optimal characteristics for a therapeutic CD4-mAb would certainly allow a more appropriate usage of this therapeutic tool. Such information would also provide surrogate measures of

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    Address reprint requests to Ferdinand C. Breedveld, MD, Leiden University Medical Center, Department of Rheumatology, C4-R, Albinusdreef 2, 2300 RC Leiden, The Netherlands, [email protected]

    *

    Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

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