Pharmacodynamic effects of daclizumab in the intrathecal compartment

Abstract

Objective

It was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.

Methods

Forty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open-label clinical trials. MRI contrast-enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease.

Results

Rapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant (P < 0.0001) decreases in CSF levels of T-cell activation marker CD27 and IgG index. Interleukin 2 (IL-2) CSF levels increased from baseline levels during treatment, consistent with reduced IL-2 consumption by T cells, as a consequence of daclizumab's saturation of high-affinity IL-2 receptors. CSF levels of IL-12p40, chitinase-3-like protein-1 (CHI3L1), chemokine C-X-C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression.

Interpretation

These observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.

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