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.