Daclizumab, an IL-2 modulating antibody for treatment of multiple sclerosis

Abstract

Daclizumab is a monoclonal antibody specific for the IL-2R α chain (CD25). Daclizumab has been observed to have multiple mechanisms of action, which may contribute to beneficial effects in immune-related disease and particularly in relapsing and remitting multiple sclerosis (RRMS). These include inhibition of activated immune cells, increase of regulatory natural killer cells, effects on dendritic cells, inhibition of innate lymphoid tissue inducer cells and altered responses involving IL-2 transpresentation. The antibody has shown considerable promise in open-label and early Phase II clinical trials when used as a monotherapy, or in combination with IFN-β. In recently completed randomized trials in RRMS, treatment with daclizumab monotherapy compared with placebo resulted in clinically meaningful and statistically significant reductions in relapses, active lesions on brain MRI and slowing of disability progression. A large Phase III trial in RRMS is ongoing.

Keywords::

• antibody
• CD25
• DAC HYP
• daclizumab
• IL-2
• multiple sclerosis

Financial & competing interests disclosure

Sponsorship for the evaluation of DAC HYP as possible treatment of RRMS is a collaboration between AbbVie Biotherapeutics (a subsidiary of AbbVie Inc.) and Biogen Idec. The study design, conduct, analysis and financial support of the controlled clinical trials described in this manuscript were provided by AbbVie Biotherapeutics and Biogen Idec. JP Sheridan and RR Robinson are employees of AbbVie Biotherapeutics. JW Rose is an employee of University of Utah, Department of Neurology and the Veterans Administration Salt Lake City Health Care System. JW Rose is a member of the Medical Advisory Board for the DECIDE trial, a Phase III trial of DAC HYP. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Multiple mechanisms directly and indirectly related to preventing IL-2 association with the CD25 subunit of high-affinity IL-2 receptors likely contribute toward daclizumab’s (DAC) activity in relapsing – remitting multiple sclerosis.

• A potential biomarker, CD56^bright natural killer cell counts post-treatment, was confirmed in a controlled clinical trial and may be useful in monitoring effects of DAC.

• The SELECT trial confirmed that DAC high-yield process monotherapy (subcutaneous) reduces relapse rate and occurrence of MRI lesions, and a tertiary end point suggested an effect on disability progression.

• Adverse events in DAC studies include potential immune-related events including skin events (rash) and hepatic events, and increased infections.

• The ongoing Phase III DECIDE trial compares DAC high-yield process versus IFN-β-1a in a multinational, randomized, multi-center trial.