Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon β

Bielekova, Bibiana; Richert, Nancy; Howard, T.; Blevins, Gregg; Marković-Pleše, Silva; McCartin, Jennifer; Wuerfel, Jens; Ohayon, Joan; Waldmann, Thomas A.; McFarland, Henry F.; Martin, Roland

doi:10.1073/pnas.0402653101

Cited by 303 publications

(243 citation statements)

References 17 publications

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“…Daclizumab showed a profound inhibitory effect on brain inflammatory activity (78% reduction) and subsequent stabilization of disability progression (9). Both the inhibition of brain inflammation by daclizumab and reappearance of inflammation after cessation of the therapy developed gradually over a period of 2-3 months, consistent with the hypothesis that daclizumab induced gradual and prolonged immunomodulatory changes in vivo.…”

Section: Ultiple Sclerosis (Ms) Is An Inflammatory͞demyelinatingsupporting

confidence: 67%

“…However, this inhibition is dose-dependent and is fully reversible when daclizumab fails to saturate CD25-binding sites, which occurs in patients 6-8 weeks after cessation of daclizumab dosing (data not shown). Therefore, the sole inhibition of T cell function by daclizumab does not appear to explain the gradually developing and lasting therapeutic effect observed during a daclizumab trial in MS (9). In contrast, daclizumab therapy resulted in a gradual expansion of CD56 bright NK cells that correlated strongly with the decrease in brain inflammatory activity (Fig.…”

Section: Discussionmentioning

confidence: 91%

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Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Bielekova

Catálfamo

Reichert-Scrivner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Administration of daclizumab, a humanized mAb directed against the IL-2R␣ chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4 ؉ T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4 ؉ and CD8 ؉ T cells and significant expansion of CD56 bright natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56 bright NK cells and contraction of CD4 ؉ and CD8 ؉ T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56 bright NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.CD25 ͉ IL-2 ͉ immunoregulatory natural killer cells M ultiple sclerosis (MS) is an inflammatory͞demyelinating disease of the CNS that is one of the leading causes of neurological disability in young adults (1). It is believed that MS is a T cell-mediated autoimmune disease, and therefore the search for new therapies focuses on agents that affect lymphocyte function. Daclizumab (Zenapax), a humanized mAb that blocks the IL-2 binding site on the IL-2R␣ chain, CD25 (i.e., Tac epitope), is among these novel agents (2). The IL-2R complex is comprised of three subunits: IL-2R␣ (CD25), IL-2R␤ (CD122), and IL-2R␥ (CD132). CD122 and CD132 have intracellular signaling motifs and together form the intermediate-affinity (K dis Ϸ 0.1-1 nM) IL-2R. CD25 binds IL-2 with low (K dis Ϸ 10 nM) affinity, but when it associates with CD122͞CD132 it stabilizes the complex to form the highaffinity (K dis Ϸ 10 pM) receptor (3). CD25 is present at low levels in resting human T cells (with the exception of T regulatory cells) but is significantly up-regulated on activated T cells, enabling them to receive a high-affinity IL-2 signal (4). Therefore, it is believed that the blockade of CD25 will result in selective functional inhibition of activated T cells (5). Although it has been demonstrated that daclizumab (or the original murine anti-Tac mAb) inhibits early IL-2R signal transduction events (6, 7) and blocks T cell activation and expansion in vitro (8), a comprehensive characterization of its in vivo effects is still lacking.We recently concluded a phase II, open-label, baseline-versustreatment crossover trial of daclizumab in 10 MS patients with incomplete therapeutic response to IFN-␤. Daclizumab showed a profound inhibitory effect on brain inflammatory activity (78% reduction) and subsequent stabilization o...

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Section: Ultiple Sclerosis (Ms) Is An Inflammatory͞demyelinatingsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 91%

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Bielekova

Catálfamo

Reichert-Scrivner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

564

543

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“…Depleting anti-CD25 mAbs have already been used to target pathological cells in autoimmune mice and humans. For instance, similarly to what we observed in T͞R Ϫ animals, clinical trials testing the sustained usage of anti-CD25 mAb in combined therapies for multiple sclerosis gave promising results (34). On the other hand, and similarly to what we report here for the T͞R ϩ animals, a single anti-CD25 mAb administration targets T R and sets a time window where immunization protocols gain in efficiency, an approach explored to improve tumor therapies (35).…”

Section: Discussionsupporting

confidence: 48%

Foxp3⁺CD25^–CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion

Zelenay

Lopes-Carvalho

Caramalho

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Routine spin‐echo and gradient‐echo T1‐weighted images were collected following intravenous administration of 0.1 mmol/kg gadopentetate dimeglumine as described previously 13. CELs were quantified according to the consensus of two neurologists with neuroimmunology/MS subspecialty training (B.…”

Section: Methodsmentioning

confidence: 99%

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Komori

Kósa

Stein

et al. 2017

Ann Clin Transl Neurol

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ObjectiveIt 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.MethodsForty 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.ResultsRapid 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.InterpretationThese 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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Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon β

Cited by 303 publications

References 17 publications

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Foxp3⁺CD25^–CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion

Pharmacodynamic effects of daclizumab in the intrathecal compartment

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Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon β

Cited by 303 publications

References 17 publications

Regulatory CD56brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Regulatory CD56brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Foxp3+CD25–CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion

Pharmacodynamic effects of daclizumab in the intrathecal compartment

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Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Foxp3⁺CD25^–CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion