Following the recent approval of the first oral therapy for multiple sclerosis (MS), fingolimod, multiple other oral compounds, and also a number of monoclonal antibodies (mab) are currently in phase III clinical testing. One of these is daclizumab, a humanized mab against the interleukin-2 receptor alpha chain (IL2RA or CD25). Efficacy to block clinical and inflammatory activity of relapsing-remitting MS (RR-MS) has been shown for daclizumab in several small phase IIa studies and one large phase IIb clinical trial, and phase III testing is ongoing. Different from prior expectations about its mechanism of action that anticipated that daclizumab would block the activation and expansion of autoreactive T cells, we and others have shown that the expansion of regulatory natural killer (NK) cells, which express high levels of the marker CD56, appears to be the most important biological effect of CD25 blockade. From these data CD25 inhibition is one of the most promising upcoming treatments of RR-MS and possibly also other autoimmune conditions. Clinical and mechanistic data will be summarized in this short review.
"While T-cell activation requires, in addition to IL-2 stimulation, the engagement of the trimolecular complex and other costimulatory interactions between the antigen-presenting cell and the T cell, NK cells can be activated and expanded by IL-2 recognition alone via the intermediate affinity receptor R Milo http://tan.sagepub.com 9 [Martin, 2012]. However, high levels of IL-2 may be needed for this activation. "
[Show abstract][Hide abstract] ABSTRACT: Daclizumab is a humanized monoclonal antibody of the immunoglobulin G1 (IgG1) isotype that binds to the α-subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor expressed on activated T cells and CD4+CD25+FoxP3+ regulatory T cells. Based on the assumption that it would block the activation and expansion of autoreactive T cells that are central to the immune pathogenesis of multiple sclerosis (MS), daclizumab was tested in several small open-label clinical trials in MS and demonstrated a profound inhibition of inflammatory disease activity. Surprisingly, accompanying mechanistic studies revealed that the most important biological effect of daclizumab was rather a dramatic expansion and activation of immunoregulatory CD56(bright) natural-killer (NK) cells that correlated with treatment response, while there was no or only minor effect on peripheral T-cell activation and function. These CD56(bright) NK cells were able to gain access to the central nervous system in MS and kill autologous activated T cells. Additional and relatively large phase IIb clinical trials showed that daclizumab, as add-on or monotherapy in relapsing-remitting (RR) MS, was highly effective in reducing relapse rate, disability progression, and the number and volume of gadolinium-enhancing, T1 and T2 lesions on brain magnetic resonance imaging (MRI), and reproduced the expansion of CD56(bright) NK cells as a biomarker for daclizumab activity. Daclizumab is generally very well tolerated and has shown a favorable adverse event (AE) profile in transplant recipients. However, several potentially serious and newly emerging AEs (mainly infections, skin reactions, elevated liver function tests and autoimmune phenomena in several body organs) may require strict safety monitoring programs in future clinical practice and place daclizumab together with other new and highly effective MS drugs as a second-line therapy. Ongoing phase III clinical trials in RRMS are expected to provide definite information on the efficacy and safety of daclizumab and to determine its place in the fast-growing armamentarium of MS therapies.
"Daclizumab is a humanized monoclonal antibody specific for CD25 (the α subunit of the high-affinity interleukin-2 receptor) that is currently being evaluated as a potential treatment for RRMS . The phase II CHOICE study demonstrated that the addition of daclizumab to interferon beta (IFNβ) therapy significantly reduced new or newly-enlarging lesions on brain MRI in patients with RRMS who experienced MS disease activity while on IFNβ monotherapy . "
[Show abstract][Hide abstract] ABSTRACT: Patients with highly active relapsing-remitting multiple sclerosis (RRMS) are at greater risk for disease progression and may respond differently to MS therapeutics than those with less active disease. The current post hoc analysis evaluated the effects of daclizumab high-yield process (DAC HYP) vs. placebo in patients with highly active RRMS in the SELECT study. Highly active RRMS was defined as patients with ≥2 relapses in the year before randomization and ≥1 gadolinium-enhancing (Gd(+)) lesion at baseline. Because results were similar in the DAC HYP dose groups, data from the DAC HYP arms were pooled for analysis. Treatment with DAC HYP resulted in similar effects in highly active (n = 88) and less active (n = 506) RRMS patients. DAC HYP reduced the annualized relapse rate by 50 % and 51 % in the highly active (p = 0.0394) and less active (p < 0.0001) groups vs. placebo, respectively (interaction p = 0.82). DAC HYP reduced new/newly-enlarging T2 lesions (highly active RRMS 76 % reduction, p < 0.0001; less active RRMS 73 % reduction, p < 0.0001; interaction p = 0.18), the risk of having more Gd(+) lesions (highly active RRMS 89 % reduction, p < 0.0001; less active RRMS 86 % reduction, p < 0.0001; interaction p = 0.46), and sustained disability progression (highly active RRMS 88 % reduction, p = 0.0574; less active RRMS 46 % reduction, p = 0.0383; interaction p = 0.22) vs. placebo. DAC HYP efficacy was similar across the spectrum of MS disease activity as assessed prior to treatment initiation.
Journal of Neurology 12/2013; 261(2). DOI:10.1007/s00415-013-7196-4 · 3.38 Impact Factor
"Review of previous studies shows that various clusters of differentiation antigens (CDs, i.e. antigens present on leukocytes with particular lineage and differentiation stage) may be involved in the pathogenesis of MS. For instance, CD25 inhibition is suggested as a possible treatment for RRMS and some other autoimmune diseases . Or else, CD161 expression on CD8+ T cells may contribute to the MS pathogenesis . "
[Show abstract][Hide abstract] ABSTRACT: We aimed to evaluate the frequency of various types of B and T cells expressing CD21, CD32, and CD35 in multiple sclerosis (MS) clinical courses.
Peripheral blood mononuclear cell from 30 MS patients (17 relapsing remitting [RRMS], six secondary progressive [SPMS], and seven primary progressive MS [PPMS]) and 18 healthy subjects were analyzed. All patients were in acute attack. Healthy controls were matched for age and gender ratio. The frequencies of various subsets of B and T cells were determined using flow cytometry.
The frequency of CD4+T cells was lower in MS patients compared to control subjects (41.14 +/- 9.45% vs. 46.88 +/- 6.98%, respectively, P < 0.05). The CD32+ fraction of CD4+T cells and the CD21+ fraction of CD8+T cells were higher in MS patients (2.85 +/- 3.72% vs. 1.06 +/- 0.62% for CD32+CD4+T cells, 2.71 +/- 1.86% vs. 1.16 +/- 0.99% for CD21+CD8+T cells in MS patients and control subjects, respectively, P < 0.05). After dividing subjects by type of MS course, higher values of these two T cell subsets were found in SPMS patients compared to control subjects (P < 0.05). Further, RRMS patients had lower levels of CD32+CD4+T cells than SPMS patients and also they had lower levels of CD32+CD8+T cells than PPMS patients (P < 0.05). However, neither the expression of CD35 on T cells nor the various B cell subsets were statistically different between the compared groups.
Our findings demonstrate that T cell subsets expressing CD21 and CD32 may differ with respect to the presence or clinical forms of MS disease. By contrast, CD35+T cells and different subsets of B cells are not altered in various MS clinical courses.
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