MONOCLONAL ANTIBODIES TO CD4
Section snippets
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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1,25-dihydroxyvitamin D3-3-bromoacetate, a novel vitamin D analog induces immunosuppression through PI3K/Akt/mTOR signaling cascade
2013, International ImmunopharmacologyCitation Excerpt :Herein, we observed that the T-cell antimitotic effect of BE is significantly more than that of Vit-D, which is in line with BE's more anticancer effect [20,22]. Therapeutic targeting of CD4+ T cells in autoimmune diseases has led to improvement of disease activity, but with side effects of persistent CD4+ T-cell depletion [69–72], including increase susceptibility to infections. To our best knowledge, to date, only one study showed that memory T cells are more sensitive to the antimitotic effect of Vit-D compared to naïve T cells [67].
Monoclonal antibodies in the treatment of rheumatoid arthritis: toward a therapeutic revolution
2006, Comptes Rendus - BiologiesEvaluating the validity of animal models for research into therapies for immune-based disorders
2004, Drug Discovery TodayCD20-Mimotope Peptide Active Immunotherapy in Systemic Lupus Erythematosus and a Reappraisal of Vaccination Strategies in Rheumatic Diseases
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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]
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Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands