Daclizumab (anti-CD25) in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a typical CD4 T cell-mediated autoimmune disease of the central nervous system (CNS) that leads to inflammation, demyelination, axonal damage, glial scarring and a broad range of neurological deficits. While disease-modifying drugs with a good safety profile and moderate efficacy have been available for 20years now, a growing number of substances with superior therapeutic efficacy have recently been introduced or are in late stage clinical testing. Daclizumab, a humanized neutralizing monoclonal antibody against the -chain of the Interleukin-2 receptor (IL-2R, CD25), which had originally been developed and approved to prevent rejection after allograft renal transplantation, belongs to the latter group. Clinical efficacy and safety of daclizumab in MS has so far been tested in several smaller phase II trials and recently two large phase II trials (combined 912 patients), and has shown efficacy regarding reduction of clinical disease activity as well as CNS inflammation. A phase III clinical trial is ongoing till March 2014 (DECIDE study, comparison with interferon (IFN) -1a in RRMS). Furthermore, the existing safety data from clinical experience in kidney transplantation and in MS appears favorable. Apart from the promising clinical data mechanistic studies along the trials have provided interesting novel insights not only about the mechanisms of daclizumab treatment, but in general about the biology of IL-2 and IL-2 receptor interactions in the human immune system. Besides blockade of recently activated CD25+ T cells daclizumab appears to act through additional mechanisms including the expansion of immune regulatory CD56(bright) natural killer (NK) cells, the blockade of cross-presentation of IL-2 by dendritic cells (DC) to T cells, and the reduction of lymphoid tissue inducer cells.

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…This compound, originally developed for the treatment of leukemia, has been shown to be relatively well-tolerated and effective in MS [72]. However, IL-2 is critical to the production and function of Tregs, and daclizumab may potentially inhibit the function of these cells.…”

Challenges for Therapeutic Application of Pseudomonas Exotoxin-Based Immunotoxins

“…Many hematological malignancies express this receptor at a high level ranging from several hundred to a few thousand sites/cell. Daclizumab (trade name Zenapax) is a therapeutic humanized anti-Tac mAb antibody that is FDA approved to prevent rejection in organ transplantation and is undergoing clinical evaluation for treatment of multiple sclerosis [25][26][27]. ITs based on anti-Tac antibody fragments have been extensively studied by Ira Pastan's group and their collaborators since the early 1990s and have been evaluated in a number of clinical studies.…”

Mapping the effects of vitamin D in multiple sclerosis

“…Therefore, the molecular mechanisms leading to our observations are to be determined. The picture is even more complex, since a general promotion of CD25 expression in activated T cells by vitamin D may be detrimental: anti-CD25 targeted therapies are an efficacious treatment in RRMS [73][74] . Therefore, the interaction between anti-CD25 targeted therapies and vitamin D status remains to be investigated.…”

“…This high-affinity IL-2R complex is expressed on activated T cells and, therefore, the IL-2/IL-2R pathway is considered essential in T cell proliferation and survival [68][69][70][71][72] . This is underlined by the introduction of therapies that target CD25 in order to block expansion of pathogenic T cells in transplantation and autoimmune diseases [73] . These therapies have also have been found to be efficacious in relapsing remitting MS (RRMS) [73][74] .…”

“…This is underlined by the introduction of therapies that target CD25 in order to block expansion of pathogenic T cells in transplantation and autoimmune diseases [73] . These therapies have also have been found to be efficacious in relapsing remitting MS (RRMS) [73][74] . In the last decade of the previous century, however, CD25 was identified as a marker for regulatory T cells (Treg), both in rodents and in humans [75][76] .…”