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Marianne T Sweetser - One of the best experts on this subject based on the ideXlab platform.
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safety and tolerability profile of Daclizumab in patients with relapsing remitting multiple sclerosis an integrated analysis of clinical studies
Multiple sclerosis and related disorders, 2016Co-Authors: Ralf Gold, Jacob Elkins, Kimberly Umans, Steven J Greenberg, Marianne T Sweetser, Bhupendra Khatri, Peter MccroskeryAbstract:Abstract Background Daclizumab has been evaluated in multicentre, randomised, double-blind studies for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). Safety and tolerability are key considerations in MS treatment selection, as they influence adherence to medication. Objective Evaluate the safety of Daclizumab in patients with RRMS from an integrated analysis of six clinical studies. Methods Patients treated with at least one dose of subcutaneous Daclizumab 150 mg or 300 mg monthly in three completed and three ongoing clinical studies were included in this integrated analysis. Cumulative incidence of treatment-emergent adverse events (AEs) was the primary endpoint. Results This analysis included 2236 patients with 5214 patient-years of exposure to Daclizumab. The cumulative incidence of any AE was 84% and of any serious AE excluding MS relapse was 16%. The incidences of AEs when evaluated by 6-month intervals remained stable over the 6.5 years of maximum follow-up. Most AEs were mild or moderate in severity. An important safety concern associated with Daclizumab therapy involved hepatic AEs (16%) and serum transaminase elevations at least three times the upper limit of normal (10%), most of which were asymptomatic, self-limiting, and non-recurring. Cumulative incidences of cutaneous, infectious, and gastrointestinal AEs were 33%, 59%, and 25%, respectively; most events either resolved spontaneously or were treated successfully with standard medical interventions and did not result in discontinuation of treatment. Conclusion This integrated analysis demonstrates that treatment of RRMS with Daclizumab for periods of up to 6.5 years is associated with an acceptable safety profile with no evidence of cumulative toxicity over time.
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cutaneous adverse events in the randomized double blind active comparator decide study of Daclizumab high yield process versus intramuscular interferon beta 1a in relapsing remitting multiple sclerosis
Advances in Therapy, 2016Co-Authors: James G Krueger, Leon H Kircik, Firas Hougeir, Adam J Friedman, X You, Nisha Lucas, Steven J Greenberg, Marianne T SweetserAbstract:Cutaneous adverse events (AEs) have been observed in clinical studies of Daclizumab high-yield process (HYP) in relapsing-remitting multiple sclerosis (RRMS). Here, we report cutaneous AEs observed in the randomized, double-blind, active-comparator DECIDE study (ClinicalTrials.gov identifier, NCT01064401). DECIDE was a randomized, double-blind, active-controlled phase 3 study of Daclizumab HYP 150 mg subcutaneous every 4 weeks versus interferon (IFN) beta-1a 30 mcg intramuscular (IM) once weekly in RRMS. Treatment-emergent AEs were classified and recorded by investigators. Investigators also assessed the severity of each AE, and whether it met the criteria for a serious AE. Cutaneous AEs were defined as AEs coded to the Medical Dictionary for Regulatory Activities System Organ Class of skin and subcutaneous tissue disorders. The incidence, severity, onset, resolution, and management of AEs were analyzed by treatment group. Cutaneous AEs were reported in 37% of Daclizumab HYP-treated patients and 19% of IFN beta-1a-treated patients. The most common investigator-reported cutaneous AEs with Daclizumab HYP were rash (7%) and eczema (4%). Most patients with cutaneous AEs remained on treatment (Daclizumab HYP, 81%; IM IFN beta-1a, 90%) and had events that were mild or moderate (94% and 98%) and subsequently resolved (78% and 82%). Most patients with cutaneous AEs did not require treatment with corticosteroids or were treated with topical corticosteroids (Daclizumab HYP, 73%; IM IFN beta-1a, 81%). Serious cutaneous AEs were reported in 14 (2%) Daclizumab HYP patients and one (<1%) IM IFN beta-1a patient. There was an increased risk of cutaneous AEs with Daclizumab HYP. While physicians should be aware of the potential for serious cutaneous AEs, the typical cutaneous AEs were mild-to-moderate in severity, manageable, and resolved over time. Biogen and AbbVie Biotherapeutics Inc. ClinicalTrials.gov identifier, NCT01064401.
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Daclizumab hyp versus interferon beta 1a in relapsing multiple sclerosis
The New England Journal of Medicine, 2015Co-Authors: Ludwig Kappos, Krzysztof Selmaj, John W. Rose, Heinz Wiendl, Eva Havrdova, Steven J Greenberg, Douglas L Arnold, Alexey Boyko, Michael Kaufman, Marianne T SweetserAbstract:BackgroundDaclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders. MethodsWe conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing–remitting multiple sclerosis to compare Daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate. ResultsThe annualized relapse rate was lower with Daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with Daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower w...
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Daclizumab high yield process in relapsing remitting multiple sclerosis selection a multicentre randomised double blind extension trial
Lancet Neurology, 2014Co-Authors: Ralf Gold, Xavier Montalban, Eva Havrdova, Ernstwilhelm Radue, Dusan Stefoski, Lakshmi Amaravadi, Manjit Mcneill, Marianne T SweetserAbstract:Summary Background In the SELECT trial, disease activity was reduced in patients with multiple sclerosis who received Daclizumab high-yield process (HYP) for 52 weeks. The primary aim of the SELECTION extension study was to assess the safety and immunogenicity of extended treatment with Daclizumab HYP. Methods A multicentre, randomised, double-blind, 52-week extension trial was done in 74 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, and the UK between Feb 13, 2009, and Oct 3, 2012. Eligible patients were aged 18–55 years, had relapsing-remitting multiple sclerosis, and had completed the SELECT study. Patients who received placebo in SELECT were randomly assigned (1:1) to receive 150 mg or 300 mg subcutaneous Daclizumab HYP every 4 weeks for 52 weeks (treatment initiation group); those who had received Daclizumab HYP were randomly assigned (1:1) to continue their present dose with (washout and re-initiation group) or without (continuous treatment group) a washout period of 20 weeks. All randomisation was done with a centralised, interactive voice-response system. Patients and personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug but had no interaction with patients. The primary endpoints were the safety and immunogenicity of Daclizumab HYP. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00870740. Findings 517 (91%) of 567 patients who completed the SELECT trial entered SELECTION, of whom 170 were in the treatment initiation group, 173 in the continuous treatment group, and 174 in the washout and re-initiation group. 11 patients in the treatment initiation group (6%), 13 in the continuous treatment group (8%), and ten in the washout and re-initiation group (6%) had any serious adverse event other than relapse of multiple sclerosis. One patient in the washout and re-initiation group (300 mg Daclizumab HYP) died because of autoimmune hepatitis; a contributory role of Daclizumab HYP could not be excluded. Seven patients tested positive for neutralising antidrug antibodies: one (1%) of 128 for whom data were available in the continuous treatment group (this patient also tested positive at SELECTION baseline), four (2%) in the treatment initiation group, and two (2%) of 129 in the washout and re-initiation group. Interpretation Adverse events and immunogenicity were not increased in the second year of continuous treatment with Daclizumab HYP or during treatment washout and re-initiation. These results support further assessment of Daclizumab HYP for relapsing-remitting multiple sclerosis. Funding Biogen Idec and AbbVie Biotherapeutics.
Thomas A Waldmann - One of the best experts on this subject based on the ideXlab platform.
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Intrathecal effects of Daclizumab treatment of multiple sclerosis.
Neurology, 2011Co-Authors: Bibiana Bielekova, Roland Martin, Thomas A Waldmann, Nancy Richert, Joan Ohayon, Henry F. Mcfarland, Matthew L. Herman, Gregg BlevinsAbstract: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 monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of Daclizumab on the intrathecal immune system. 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 CSF. Results: The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56 bright NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood. Conclusions: Daclizumab monotherapy 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. Classification of evidence: The study provides Class III evidence that Daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period.
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a role for interleukin 2 trans presentation in dendritic cell mediated t cell activation in humans as revealed by Daclizumab therapy
Nature Medicine, 2011Co-Authors: Simone C Wuest, Jehad H Edwan, Jayne F Martin, Sungpil Han, Justin S A Perry, Casandra M Cartagena, Eiji Matsuura, Dragan Maric, Thomas A WaldmannAbstract:Dendritic cells produce interleukin-2 (IL-2) and express the IL-2 receptor subunit CD25. Bibiana Bielekova and her colleagues show that dendritic cells, upon interacting with cognate T cells, secrete IL-2 into the immune synapse and use their CD25 to trans-present IL-2 to T cells, facilitating early IL-2 signaling in T cells. Inhibition of CD25 by the monoclonal antibody Daclizumab prevents T cell activation and may partly account for the therapeutic effects of Daclizumab in patients with multiple sclerosis.
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Effect of Anti-CD25 Antibody Daclizumab in the Inhibition of Inflammation and Stabilization of Disease Progression in Multiple Sclerosis
Archives of neurology, 2009Co-Authors: Bibiana Bielekova, Thomas A Waldmann, T. Howard, Amy N. Packer, Nancy Richert, Gregg Blevins, Joan Ohayon, Henry F. Mcfarland, Roland MartinAbstract:Background Several questions arise concerning the use of the anti-CD25 antibody Daclizumab to treat multiple sclerosis (MS). Objectives To answer the following 3 questions related to the efficacy of Daclizumab therapy in patients with MS: Is the therapeutic effect of Daclizumab dependent on combination with interferon beta? Is a higher dosage of Daclizumab more efficacious in patients with persistent disease activity? Can biomarkers predict full vs partial therapeutic response to Daclizumab? Design An open-label baseline vs treatment phase II clinical trial of Daclizumab in patients having MS with inadequate response to interferon beta. Three months of interferon beta treatment at baseline were followed by 5.5 months of interferon beta–Daclizumab combination therapy. If patients experienced more than 75% reduction of contrast-enhancing lesions (CELs) on brain magnetic resonance imaging at month 5.5 compared with baseline, Daclizumab was continued as monotherapy for 10 months. Otherwise, the dosage of Daclizumab was doubled. Setting Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. Patients Fifteen patients with MS receiving standard preparations of interferon beta who experienced more than 1 MS exacerbation or whose clinical disability increased in the preceding 12 months and who had at least 2 CELs on baseline brain magnetic resonance images. Intervention Daclizumab (1 mg/kg) as an intravenous infusion every 4 weeks in combination with interferon beta (months 0-5.5) and as monotherapy (months 6.5-15.5). Main Outcome Measures The primary outcome was the reduction of CELs among interferon beta monotherapy, interferon beta–Daclizumab combination therapy, and Daclizumab monotherapy. The secondary outcomes included immunologic biomarkers and changes in clinical disability. Results Overall, 5 of 15 patients (33%) experienced adverse effects of therapy. Two patients developed systemic adverse effects, and Daclizumab therapy was discontinued. Although Daclizumab monotherapy was efficacious in 9 of 13 patients with MS, interferon beta–Daclizumab combination therapy was necessary to stabilize disease activity in the other 4 patients. Daclizumab therapy led to 72% inhibition of new CELs and significant improvement in clinical disability. Pilot biomarkers (increase in CD56 bright natural killer cells and decrease in CD8 + T cells) were identified that can differentiate between full and partial Daclizumab responders. Conclusions Daclizumab monotherapy is effective in most patients who experienced persistent MS disease activity with interferon beta therapy. Interferon beta–Daclizumab combination therapy or higher dosages of Daclizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to Daclizumab monotherapy. Administration among a large patient sample during a longer period is needed to fully define the safety and long-term efficacy of Daclizumab as treatment for high-inflammatory MS. Trial Registration clinicaltrials.gov Identifier:NCT00001934
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effective treatment of a murine model of adult t cell leukemia using depsipeptide and its combination with unmodified Daclizumab directed toward cd25
Blood, 2009Co-Authors: Jing Chen, Wei Ju, Meili Zhang, Thomas A WaldmannAbstract:Adult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus I (HTLV-1) and is an aggressive malignancy of CD4, CD25-expressing leukemia, and lymphoma cells. There is no accepted curative therapy for ATL. Depsipeptide, a histone deacetylase inhibitor, has demonstrated major antitumor effects in leukemias and lymphomas. In this study, we investigated the therapeutic efficacy of depsipeptide alone and in combination with Daclizumab (humanized anti-Tac) in a murine model of human ATL. The Met-1 ATL model was established by intraperitoneal injection of ex vivo leukemic cells into nonobese diabetic/severe combined immunodeficiency mice. Either depsipeptide, given at 0.5 mg/kg every other day for 2 weeks, or Daclizumab, given at 100 μg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of soluble IL-2R-α (sIL-2R-α) and soluble β2-microglobulin (β2μ) (P < .001), and prolonged survival of the leukemia-bearing mice (P < .001) compared with the control group. Combination of depsipeptide with Daclizumab enhanced the antitumor effect, as shown by both sIL-2R-α and β2μ levels and survival of the leukemia-bearing mice, compared with those in the depsipeptide or Daclizumab alone groups (P < .001). The significantly improved therapeutic efficacy by combining depsipeptide with Daclizumab supports a clinical trial of this combination in the treatment of ATL.
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Daclizumab anti tac zenapax in the treatment of leukemia lymphoma
Oncogene, 2007Co-Authors: Thomas A WaldmannAbstract:Daclizumab (Zenapax) identifies the alpha subunit of the interleukin-2 (IL-2) receptor and blocks the interaction of this cytokine with its growth factor receptor. The scientific basis for the choice of the IL-2 receptor alpha subunit as a target for monoclonal antibody-mediated therapy of leukemia/lymphoma is that very few normal cells express IL-2R alpha, whereas the abnormal T cells in patients with an array of lymphoid malignancies express this receptor. In 1997, Daclizumab was approved by the FDA for use in the prevention of renal allograft rejection. In addition, anti-Tac provided effective therapy for select patients with T-cell malignancies and an array of inflammatory autoimmune disorders. Finally, therapy with this antibody armed with (90)Y has led to clinical responses in the majority of patients with adult T-cell leukemia. These insights concerning the IL-2/IL-2 receptor system facilitated the development of effective Daclizumab antibody therapy for select patients with leukemia/lymphoma.
Roland Martin - One of the best experts on this subject based on the ideXlab platform.
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Anti-CD25 (Daclizumab) monoclonal antibody therapy in relapsing-remitting multiple sclerosis
Clinical Immunology, 2012Co-Authors: Roland MartinAbstract:Following the recent approval of the first oral therapy for multiple sclerosis (MS), fingolimod, multiple other oral compounds, and also a number of monoclonal antibodies (mab) are currently in phase III clinical testing. One of these is Daclizumab, a humanized mab against the interleukin-2 receptor alpha chain (IL2RA or CD25). Efficacy to block clinical and inflammatory activity of relapsing-remitting MS (RR-MS) has been shown for Daclizumab in several small phase IIa studies and one large phase IIb clinical trial, and phase III testing is ongoing. Different from prior expectations about its mechanism of action that anticipated that Daclizumab would block the activation and expansion of autoreactive T cells, we and others have shown that the expansion of regulatory natural killer (NK) cells, which express high levels of the marker CD56, appears to be the most important biological effect of CD25 blockade. From these data CD25 inhibition is one of the most promising upcoming treatments of RR-MS and possibly also other autoimmune conditions. Clinical and mechanistic data will be summarized in this short review. © 2011.
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Intrathecal effects of Daclizumab treatment of multiple sclerosis.
Neurology, 2011Co-Authors: Bibiana Bielekova, Roland Martin, Thomas A Waldmann, Nancy Richert, Joan Ohayon, Henry F. Mcfarland, Matthew L. Herman, Gregg BlevinsAbstract: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 monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of Daclizumab on the intrathecal immune system. 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 CSF. Results: The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56 bright NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood. Conclusions: Daclizumab monotherapy 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. Classification of evidence: The study provides Class III evidence that Daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period.
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Effect of Anti-CD25 Antibody Daclizumab in the Inhibition of Inflammation and Stabilization of Disease Progression in Multiple Sclerosis
Archives of neurology, 2009Co-Authors: Bibiana Bielekova, Thomas A Waldmann, T. Howard, Amy N. Packer, Nancy Richert, Gregg Blevins, Joan Ohayon, Henry F. Mcfarland, Roland MartinAbstract:Background Several questions arise concerning the use of the anti-CD25 antibody Daclizumab to treat multiple sclerosis (MS). Objectives To answer the following 3 questions related to the efficacy of Daclizumab therapy in patients with MS: Is the therapeutic effect of Daclizumab dependent on combination with interferon beta? Is a higher dosage of Daclizumab more efficacious in patients with persistent disease activity? Can biomarkers predict full vs partial therapeutic response to Daclizumab? Design An open-label baseline vs treatment phase II clinical trial of Daclizumab in patients having MS with inadequate response to interferon beta. Three months of interferon beta treatment at baseline were followed by 5.5 months of interferon beta–Daclizumab combination therapy. If patients experienced more than 75% reduction of contrast-enhancing lesions (CELs) on brain magnetic resonance imaging at month 5.5 compared with baseline, Daclizumab was continued as monotherapy for 10 months. Otherwise, the dosage of Daclizumab was doubled. Setting Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. Patients Fifteen patients with MS receiving standard preparations of interferon beta who experienced more than 1 MS exacerbation or whose clinical disability increased in the preceding 12 months and who had at least 2 CELs on baseline brain magnetic resonance images. Intervention Daclizumab (1 mg/kg) as an intravenous infusion every 4 weeks in combination with interferon beta (months 0-5.5) and as monotherapy (months 6.5-15.5). Main Outcome Measures The primary outcome was the reduction of CELs among interferon beta monotherapy, interferon beta–Daclizumab combination therapy, and Daclizumab monotherapy. The secondary outcomes included immunologic biomarkers and changes in clinical disability. Results Overall, 5 of 15 patients (33%) experienced adverse effects of therapy. Two patients developed systemic adverse effects, and Daclizumab therapy was discontinued. Although Daclizumab monotherapy was efficacious in 9 of 13 patients with MS, interferon beta–Daclizumab combination therapy was necessary to stabilize disease activity in the other 4 patients. Daclizumab therapy led to 72% inhibition of new CELs and significant improvement in clinical disability. Pilot biomarkers (increase in CD56 bright natural killer cells and decrease in CD8 + T cells) were identified that can differentiate between full and partial Daclizumab responders. Conclusions Daclizumab monotherapy is effective in most patients who experienced persistent MS disease activity with interferon beta therapy. Interferon beta–Daclizumab combination therapy or higher dosages of Daclizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to Daclizumab monotherapy. Administration among a large patient sample during a longer period is needed to fully define the safety and long-term efficacy of Daclizumab as treatment for high-inflammatory MS. Trial Registration clinicaltrials.gov Identifier:NCT00001934
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Spotlight on anti-CD25: Daclizumab in MS
International MS journal, 2008Co-Authors: Sven Schippling, Roland MartinAbstract:Monoclonal antibodies are a promising new class of therapeutic agents that can be employed to target specific molecules of the immune system or any tissue. They are currently being tested in a number of clinical trials in autoimmune diseases such as multiple sclerosis (MS). One of these, the humanized monoclonal anti-CD25 antibody Daclizumab (Zenapax), is directed against the interleukin-2 (IL-2) receptor alpha chain (CD25) that is involved in clonal expansion of autoreactive T-cells by binding of its ligand IL- 2. Several years ago Daclizumab was approved for the prevention of renal allograft rejection. Following promising observations in uveitis, Daclizumab has since been tested in a number of small clinical trials in MS based on the rationale that blocking CD25 would prevent the expansion of autoreactive T-lymphocytes. Safety and efficacy data from the preliminary clinical exploration as well as findings about the mechanism of action of anti-CD25 treatment are reviewed here.
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regulatory cd56bright natural killer cells mediate immunomodulatory effects of il 2rα targeted therapy Daclizumab in multiple sclerosis
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Bibiana Bielekova, Thomas A Waldmann, Amy N. Packer, Henry F. Mcfarland, Marta Catalfamo, Susan Reichertscrivner, Magdalena Cerna, Pierre A Henkart, Roland MartinAbstract:Administration of Daclizumab, a humanized mAb directed against the IL-2Ralpha 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.
Bibiana Bielekova - One of the best experts on this subject based on the ideXlab platform.
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Daclizumab Therapy for Multiple Sclerosis.
Cold Spring Harbor perspectives in medicine, 2019Co-Authors: Bibiana BielekovaAbstract:Daclizumab is a humanized monoclonal antibody that prevents formation of high-affinity interleukin (IL)-2 receptor (IL-2R). Because activated T cells up-regulate high-affinity IL-2R and IL-2 is used to grow activated T cells in vitro, Daclizumab was envisioned to selectively inhibit activated T cells. However, the mechanism of action (MOA) of Daclizumab is surprisingly broad and it includes many unanticipated effects on innate immunity. Specifically, Daclizumab modulates the development of innate lymphoid cells, leading to expansion of immunoregulatory CD56bright natural killer (NK) cells. Activated CD56bright NK cells migrate to the intrathecal compartment in multiple sclerosis (MS) and regulate autoreactive T cells via cytotoxicity. Finally, Daclizumab also restricts initial steps of T-cell activation by blocking trans-presentation of IL-2 by dendritic cells to antigen-specific T cells. In conclusion, Daclizumab has complex immunomodulatory effects with resultant inhibition of central nervous system inflammation in MS.
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Pharmacodynamic effects of Daclizumab in the intrathecal compartment
Annals of clinical and translational neurology, 2017Co-Authors: Mika Komori, Andrew Blake, Peter Kosa, Jason Stein, Vivian Zhao, Jamie Cherup, James P Sheridan, Bibiana BielekovaAbstract: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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Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis
Annals of clinical and translational neurology, 2015Co-Authors: Yen Chih Lin, Paige Winokur, Andrew Blake, Elena Romm, Bibiana BielekovaAbstract:Objective Novel treatments such as natalizumab and fingolimod achieve their therapeutic efficacy in multiple sclerosis (MS) by blocking access of subsets of immune cells into the central nervous system, thus creating nonphysiological intrathecal immunity. In contrast, Daclizumab, a humanized monoclonal antibody against the alpha chain of the IL-2 receptor, has a unique mechanism of action with multiple direct effects on innate immunity. As cellular intrathecal abnormalities corresponding to MS have been well defined, we asked how Daclizumab therapy affects these immunological hallmarks of the MS disease process. Methods Nineteen subpopulations of immune cells were assessed in a blinded fashion in the blood and 50-fold concentrated cerebrospinal fluid (CSF) cell pellet in 32 patients with untreated relapsing-remitting MS (RRMS), 22 Daclizumab-treated RRMS patients, and 11 healthy donors (HDs) using 12-color flow cytometry. Results Long-term Daclizumab therapy normalized all immunophenotyping abnormalities differentiating untreated RRMS patients from HDs. Specifically, strong enrichment of adaptive immune cells (CD4+ and CD8+ T cells and B cells) in the CSF was reversed. Similarly, Daclizumab controlled MS-related increases in the innate lymphoid cells (ILCs) and lymphoid tissue inducer cells in the blood and CSF, and reverted the diminished proportion of intrathecal monocytes. The only marker that distinguished Daclizumab-treated MS patients from HDs was the expansion of immunoregulatory CD56bright NK cells. Interpretation Normalization of immunological abnormalities associated with MS by long-term Daclizumab therapy suggests that this drug's effects on ILCs, NK cells, and dendritic cell-mediated antigen presentation to CD4+ and CD8+ T cells are critical in regulating the MS disease process.
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Daclizumab-induced adverse events in multiple organ systems in multiple sclerosis
Neurology, 2014Co-Authors: Shiv Saidha, Bibiana Bielekova, Joan Ohayon, Irene Cortese, Peter A. Calabresi, Scott D. NewsomeAbstract:Objective: To report 3 patients with multiple sclerosis (MS) who presented with Daclizumab-related adverse events (AEs) in multiple organ systems. Methods: A retrospective chart review was performed of patients with MS who had clinical and histopathologic findings suggestive of Daclizumab-induced AEs between 2004 and 2010 at the Johns Hopkins MS Clinic. This study met criteria for exemption from review from the institutional review board. Results: Of 20 total patients with MS who had been treated with Daclizumab, 3 patients with clinical and histopathologic findings suggestive of Daclizumab-induced AEs were identified. All patients were treated with Zenapax (1 mg/kg monthly IV infusions) outside of a clinical trial setting. Clinical manifestations after a mean treatment duration of 20 months consisted of diffuse rash and alopecia, diffuse lymphadenopathy, and breast nodules. Tissue histopathology demonstrated lymphocytic infiltrates with CD56-expressing cells in 2 patients (lymph node, breast nodule). On Daclizumab discontinuation, the rash/alopecia and diffuse lymphadenopathy resolved, while the breast nodules stabilized. Conclusions: Daclizumab-induced AEs can occur in various organ systems after a relatively prolonged duration of exposure and require clinician awareness. Future studies are needed to better understand the relationship between natural killer cells and Daclizumab-related AEs.
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Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis.
Multiple sclerosis (Houndmills Basingstoke England), 2013Co-Authors: Ying Zhang, Bibiana Bielekova, M Mcclellan, Lyubov Efros, D Shi, Mt Tang, Vladimir Vexler, James SheridanAbstract:Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating Daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between Daclizumab and reductions in HLA-DR + -activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which Daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the Daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4 + T cells and FoxP3 + Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A Daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to Daclizumab inhibition of IL-2 signaling.
John W. Rose - One of the best experts on this subject based on the ideXlab platform.
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consistent efficacy of Daclizumab beta across patient demographic and disease activity subgroups in patients with relapsing remitting multiple sclerosis
Multiple sclerosis and related disorders, 2017Co-Authors: John W. Rose, Ludwig Kappos, Gavin Giovannoni, Krzysztof Selmaj, Heinz Wiendl, Ralf Gold, Eva Havrdova, Jun Zhao, Katherine Riester, Claire L TsaoAbstract:Abstract Background Daclizumab beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with Daclizumab beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) interferon beta-1a. Objectives To determine if the efficacy of Daclizumab beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups. Methods In the SELECT study, patients received Daclizumab beta 150 or 300 mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received Daclizumab beta 150 mg administered subcutaneously every 4 weeks for 96–144 weeks, and were compared with patients who received IM interferon beta-1a 30 µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous interferon beta-1a use. Results Treatment with Daclizumab beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with interferon beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of Daclizumab beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with Daclizumab beta treatment compared with placebo or interferon beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs). Conclusions These findings suggest that treatment with Daclizumab beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS.
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Daclizumab: Development, Clinical Trials, and Practical Aspects of Use in Multiple Sclerosis.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2017Co-Authors: Laura E. Baldassari, John W. RoseAbstract:Daclizumab is a humanized monoclonal antibody directed towards CD25, the alpha subunit of the high-affinity interleukin (IL)-2 receptor. Daclizumab exerts its effects via multiple mechanisms, including reduction of IL-2-mediated lymphocyte activation and upregulation of CD56–bright natural killer cells. Intravenous Daclizumab (Zenapax™) was initially approved for prevention of rejection in renal transplant. In subsequent early testing, followed by larger-scale phase II and phase III trials, both intravenous and subcutaneous Daclizumab have demonstrated clinical efficacy in the treatment of multiple sclerosis. The subcutaneous Daclizumab prepared by high-yield process was utilized in the advanced phase II and phase III trials (SELECT and DECIDE). High-yield process Daclizumab is now approved by the US Food and Drug Administration for relapsing-remitting multiple sclerosis, and is now formally termed Daclizumab beta (DAC-beta; Zinbryta™). In this review, the early development of anti-IL-2 receptor alpha monoclonal antibodies and the properties of IL-2 and its receptor are discussed, and diverse mechanisms of action for Daclizumab are presented. Results of the CHOICE, SELECT, and DECIDE clinical trials are discussed in detail. Adverse events observed in clinical trials included cutaneous reactions, liver enzyme elevations, infections, and autoimmune phenomena. DAC-beta is a monthly, patient-administered subcutaneous injection that requires enrollment in a safety monitoring (REMS) program for monthly liver function testing. Prescribers should be aware of the potential adverse events, as early recognition and management is important, particularly in cutaneous and hepatic reactions. Continued clinical experience with DAC-beta, including observations from the REMS program, will define its place in the armamentarium of immunotherapeutics for relapsing-remitting multiple sclerosis.
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relapsingremitting
2016Co-Authors: Monica A. Rojas, Noel G. Carlson, Thomas L. Miller, John W. RoseAbstract:Daclizumab therapy i
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Daclizumab hyp versus interferon beta 1a in relapsing multiple sclerosis
The New England Journal of Medicine, 2015Co-Authors: Ludwig Kappos, Krzysztof Selmaj, John W. Rose, Heinz Wiendl, Eva Havrdova, Steven J Greenberg, Douglas L Arnold, Alexey Boyko, Michael Kaufman, Marianne T SweetserAbstract:BackgroundDaclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders. MethodsWe conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing–remitting multiple sclerosis to compare Daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate. ResultsThe annualized relapse rate was lower with Daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with Daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower w...
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Daclizumab phase II trial in relapsing and remitting multiple sclerosis MRI and clinical results
Neurology, 2007Co-Authors: John W. Rose, James Burns, J. Bjorklund, Julia Klein, Hilary E. Watt, Noel G. CarlsonAbstract:Objective: Daclizumab is an interleukin 2 receptor α chain specific humanized monoclonal antibody that has shown promising therapeutic effects in multiple sclerosis (MS). Daclizumab treatment in patients with relapsing and remitting MS was administered to determine effects on MRI and clinical outcomes. Methods: Patients with MS on interferon (IFN) therapy but with continuing relapses and contrast enhancing lesions (CEL) were selected. Patients were evaluated with monthly MRI scans and clinical rating scales starting 3 months prior to treatment and then at 0.5 to 27.5 months during treatment. Daclizumab (1 mg/kg IV) was administered twice in the first month (initiated and administered again in 2 weeks), followed by treatments every 4 weeks. IFN was continued until 5.5 months after Daclizumab was initiated. Patients were then placed on Daclizumab monotherapy. Patients with recurrent CEL were restarted on IFN with Daclizumab therapy at (1.5 mg/kg IV) every 28 days. Results: Nine patients qualified for inclusion and completed the trial. Efficacy measured by both total CEL and new CEL ( p p p Conclusion: Daclizumab was effective in reducing contrast enhancing lesions and improving clinical scores in patients with relapsing and remitting multiple sclerosis with active disease not controlled by interferon therapy. These results provide evidence for long-term efficacy and support further clinical development of Daclizumab.
