Research: Effects of Dacluzimab in the CNS

Bielekova et al. Intrathecal effects of daclizumab treatment of multiple sclerosis.Neurology. 2011 Nov [Epub]

OBJECTIVES
We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS), who were suboptimal responders to interferon-β and that this response correlated with expansion of CD56(bright) NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab reduces CEL in MSers with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system (within the cerebrospinal fluid in the brain).

METHODS: Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and cerebrospinal fluid (CSF).

RESULTS: The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in MS Scripps Neurologic Rating Scale, and Expanded Disability Status Scale outcomes. There was significant expansion of CD56(bright) Natural Killer cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios . Surprisingly, CD25 epitope was equally blocked on the immune cells in the CSF and in peripheral blood.

CONCLUSIONS: Daclizumab therapy inhibits formation of MS plaques in patients with RRMS and immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment.

Daclizumab is in late stage development for MS, These studies suggest either that the antibody penetrates the brain and down regulates the immune response. Alternatively it is possible that it inhibits NK activity in the blood and these then traffic into the brain. However this study indicates that this molecule can inhibit brain immune responses.

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