The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis

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.

CD25 Identifies a Subset of CD4+FoxP3− TIL That Are Exhausted Yet Prognostically Favorable in Human Ovarian Cancer

“…Indeed, in renal transplantation and autoimmunity, the net effect of anti-CD25 antibody therapy is immune suppression not activation (22). Second, our findings might help to explain the positive clinical effects of IL2 in ovarian cancer, where a 25% response rate was achieved with intraperitoneal administration of IL2 as a monotherapy (26).…”

“…Although these agents have been shown to reduce the number of circulating Tregs in patients with cancer, and improve responses to tumor-specific vaccines, this has generally not resulted in major antitumor effects. Indeed, in the settings of transplantation and autoimmunity, these agents have proven efficacious at inhibiting T-cell responses rather than reversing immune suppression (22).…”

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

“…Daclizumab is a humanized IgG antibody targeting CD25 and thereby preventing the binding of IL-2 to its receptor, which is highly expressed on activated T lymphocytes and regulatory CD4 + CD25 + FoxP3 + T lymphocytes [74]. Daclizumab does not trigger cell depletion or interfere with CD25 receptor signaling itself.…”

Daclizumab

“…Daclizumab is composed of 2 humanized gamma-1 heavy chains and 2 humanized kappa light chains, with a molecular weight of approximately 144 kDa. 3,7 It binds to the Tac epitope on the alpha subunit (CD25) of the interleukin 2 (IL-2) receptor. 3,[6][7][8][9] CD25 is constitutively expressed at high levels on CD4 + CD25 + FoxP3 + regulatory T cells and at low levels on resting T cells.…”

“…3,7 It binds to the Tac epitope on the alpha subunit (CD25) of the interleukin 2 (IL-2) receptor. 3,[6][7][8][9] CD25 is constitutively expressed at high levels on CD4 + CD25 + FoxP3 + regulatory T cells and at low levels on resting T cells. CD25 expression is upregulated in resting T cells after they become activated, which allows for a greater capacity for IL-2 to bind.…”