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Pharmacodynamic effects of daclizumab in the intrathecal compartment

Mika Komori1, Peter Kosa1, Jason Stein1

  • 1Neuroimmunological Diseases Unit National Institute of Neurological Disorders and Stroke (NINDS) Bethesda Maryland.

Annals of Clinical and Translational Neurology
|July 12, 2017
PubMed

Insights

Daclizumab therapy reduced multiple sclerosis (MS) disease activity by decreasing inflammatory biomarkers in cerebrospinal fluid (CSF). Inhibition of myeloid lineage markers correlated with reduced MS progression, suggesting a key role in treatment response.

Area of Science:

  • Neuroimmunology
  • Clinical Pharmacology
  • Biomarker Research

Background:

  • Daclizumab therapy was previously shown to normalize cerebrospinal fluid (CSF) cellular abnormalities in multiple sclerosis (MS).
  • However, the effect of daclizumab on compartmentalized inflammation and its correlation with clinical response remained unclear.

Purpose of the Study:

  • To investigate whether daclizumab reverses compartmentalized inflammation in the central nervous system (CNS) in MS patients.
  • To determine if residual inflammation correlates with clinical response to daclizumab therapy.

Main Methods:

  • A longitudinal study of 40 MS patients treated with daclizumab for up to 16 years.
  • Assessment of MRI contrast-enhancing lesions (CELs), clinical scales, and CSF biomarkers to quantify residual disease activity.

Main Results:

  • Daclizumab treatment led to rapid and sustained reduction in CELs.
  • Significant decreases in CSF levels of T-cell activation marker CD27 and IgG index were observed.
  • CSF levels of IL-12p40, chitinase-3-like protein-1 (CHI3L1), and neurofilament light chain (NFL) were significantly reduced, with CHI3L1 inhibition correlating with reduced disease progression.

Conclusions:

  • Daclizumab exerts direct pharmacodynamic effects on immune cells within the CNS.
  • Inhibition of CSF myeloid lineage biomarkers is a stronger determinant of reduced clinical MS activity than inhibition of adaptive immunity biomarkers.
Abstract

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