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The Lancet. Neurology May 2014In 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... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adult; Antibodies, Monoclonal, Humanized; Daclizumab; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Female; Follow-Up Studies; Humans; Immunoglobulin G; Immunosuppressive Agents; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Time Factors; Treatment Outcome
PubMed: 24656609
DOI: 10.1016/S1474-4422(14)70039-0 -
Archives of Ophthalmology (Chicago,... Feb 2008To report the outcomes for daclizumab in the treatment of birdshot chorioretinopathy (BSCR) refractory to traditional immunomodulatory therapy (IMT).
OBJECTIVE
To report the outcomes for daclizumab in the treatment of birdshot chorioretinopathy (BSCR) refractory to traditional immunomodulatory therapy (IMT).
METHODS
We retrospectively reviewed medical records of 8 patients with BSCR whose disease was refractory to or who were intolerant of traditional IMT. All patients received 1 mg/kg of daclizumab intravenously at 2-week intervals initially at 1 referral uveitis practice. Main outcome measures were changes in visual acuity, vitreous inflammation, fluorescein angiographic pathologic features, electroretinography (ERG) parameters, concomitant IMT requirements, and adverse events.
RESULTS
Over a mean follow-up of 25.6 months, 7 patients had either stabilization or improvement in visual acuity of both eyes and complete resolution of vitreous inflammation. Six patients had resolution of vasculitis on fluorescein angiography. The ERG 30-Hz implicit times and the bright scotopic amplitudes worsened in some patients despite abolition of clinically evident inflammation. Four patients were able to discontinue all other IMT and remain inflammation free while receiving only daclizumab treatment. Two patients developed adverse effects that led to daclizumab treatment discontinuation.
CONCLUSIONS
Daclizumab therapy was effective in stabilizing vision and decreasing inflammation in most patients with BSCR. The ERG parameters continued to decline in some patients despite adequate inflammatory control. Regular serologic monitoring is critical to detect adverse events.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Chorioretinitis; Daclizumab; Electroretinography; Eye Diseases; Female; Fluorescein Angiography; HLA-A Antigens; Humans; Immunoglobulin G; Immunosuppressive Agents; Middle Aged; Retrospective Studies; Treatment Outcome; Visual Acuity; Vitreous Body
PubMed: 18268208
DOI: 10.1001/archophthalmol.2007.49 -
Minerva Urologica E Nefrologica = the... Mar 2003Acute rejection still remains a major problem in organ transplantation and is a significant risk factor for chronic rejection, and chronic rejection is one of the most... (Comparative Study)
Comparative Study Review
Acute rejection still remains a major problem in organ transplantation and is a significant risk factor for chronic rejection, and chronic rejection is one of the most important causes of late graft loss. Current new immunosuppressive drugs such as tacrolimus, rapamycin and mycophenolate mofetil have been developed to reduce acute rejection and to improve renal allograft survival. More recently, antihuman antibodies, either monoclonal or polyclonal, have been developed to use for induction therapy at the time of transplantation or to treat rejection. Daclizumab, a new engineered human immunoglobulin monoclonal antibody to the interleukin-2 receptor a-subunit was approved to prevent acute rejection after solid organ transplantation. Data from clinical trials show daclizumab to be well tolerated in solid organ transplantation. It does not increase the incidence of infection, including cytomegalovirus infection.
Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Calcineurin Inhibitors; Daclizumab; Drug Therapy, Combination; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Mycophenolic Acid; Pancreas Transplantation; Recombinant Fusion Proteins; Reoperation; Risk Factors; Time Factors
PubMed: 12773966
DOI: No ID Found -
Frontiers in Immunology 2022This study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren's syndrome (SS).
OBJECTIVE
This study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren's syndrome (SS).
METHODS
MS- and SS-related susceptibility genes and differentially expressed genes (DEGs) were identified by bioinformatics analysis based on genome-wide association studies (GWAS) and transcriptome data from GWAS catalog and Gene Expression Omnibus (GEO) database. Pathway enrichment, Gene Ontology (GO) analysis, and protein-protein interaction analysis for susceptibility genes and DEGs were performed. The drugs targeting common pathways/genes were obtained through Comparative Toxicogenomics Database (CTD), DrugBank database, and Drug-Gene Interaction (DGI) Database. The target genes of approved/investigational drugs for MS and SS were obtained through DrugBank and compared with the common susceptibility genes.
RESULTS
Based on GWAS data, we found 14 hub common susceptibility genes (, , , , , , , , , , , , , and ), with 8 drugs targeting two or more than two genes, and 28 common susceptibility pathways, with 15 drugs targeting three or more than three pathways. Based on transcriptome data, we found 3 hub common DEGs (, , ) with 3 drugs and 10 common risk pathways with 435 drugs. "JAK-STAT signaling pathway" was included in common susceptibility pathways and common risk pathways at the same time. There were 133 overlaps including JAK-STAT inhibitors between agents from GWAS and transcriptome data. Besides, we found that and , identified as hub common susceptibility genes, were the targets of daclizumab and glatiramer that were used for MS, indicating that daclizumab and glatiramer may be therapeutic for SS.
CONCLUSION
We observed the shared mechanism of MS and SS, in which JAK-STAT signaling pathway played a vital role, which may be the genetic and molecular bases of comorbidity of MS with SS. Moreover, JAK-STAT inhibitors were potential therapies for MS and SS, especially for their comorbidity.
Topics: Computational Biology; Daclizumab; Genome-Wide Association Study; Glatiramer Acetate; HLA-DRB1 Chains; Humans; Multiple Sclerosis; Sjogren's Syndrome; Transcriptome
PubMed: 35356004
DOI: 10.3389/fimmu.2022.857014 -
Multiple Sclerosis (Houndmills,... Feb 2009Daclizumab is a humanized monoclonal antibody (mAb) that blocks the interleukin-2 receptor alpha subunit (IL-2R-alpha chain; CD25) expressed on activated T cells leading... (Clinical Trial)
Clinical Trial
BACKGROUND
Daclizumab is a humanized monoclonal antibody (mAb) that blocks the interleukin-2 receptor alpha subunit (IL-2R-alpha chain; CD25) expressed on activated T cells leading to the inhibition of T-cell expansion, thus strongly reduces brain inflammation in patients with multiple sclerosis (MS). Another mechanism is significant expansion of CD56 (bright) natural killer (NK) cells that in turn inhibit T-cell survival.
OBJECTIVE
At the Partners MS center, we have been using Daclizumab in an open-label fashion in patients who fail first line therapy or non-standard immunosuppressive treatment. Our aim was to assess its safety and tolerability in our patient population.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome; Young Adult
PubMed: 19136546
DOI: 10.1177/1352458508097468 -
Medizinische Monatsschrift Fur... Jun 2014
Review
Topics: Antibodies, Monoclonal, Humanized; Daclizumab; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Multiple Sclerosis
PubMed: 25051810
DOI: No ID Found -
Progress in Transplantation (Aliso... Mar 2000Transplant professionals have the dual responsibility of achieving acceptable clinical outcomes and controlling costs. One approach transplant centers have used to... (Review)
Review
Transplant professionals have the dual responsibility of achieving acceptable clinical outcomes and controlling costs. One approach transplant centers have used to control transplant-related costs has been to decrease patients' length of stay, and thus it has decreased significantly in the last 6 years. This reduction in resource consumption has been accomplished by increased efficiency in providing transplantation services, expanding the number of outpatient services available, and integrating new technologies. Future cost containment measures by payers, especially Medicare, will continue to require that transplant centers manage resources and meet financial objectives while achieving acceptable clinical outcomes. Daclizumab, a new immunosuppressive drug, is used as an example in this article, which assesses its value in helping meet resource management and financial goals.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cost Control; Daclizumab; Health Resources; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Length of Stay; Medicare; Reimbursement Mechanisms; United States
PubMed: 10941323
DOI: 10.1177/152692480001000105 -
Frontiers in Immunology 2020Daclizumab beta is a humanized monoclonal antibody that binds to CD25 and selectively inhibits high-affinity IL-2 receptor signaling. As a former treatment for relapsing...
Daclizumab beta is a humanized monoclonal antibody that binds to CD25 and selectively inhibits high-affinity IL-2 receptor signaling. As a former treatment for relapsing forms of multiple sclerosis (RMS), daclizumab beta induces robust expansion of the CD56 subpopulation of NK cells that is correlated with the drug's therapeutic effects. As NK cells represent a heterogeneous population of lymphocytes with a range of phenotypes and functions, the goal of this study was to better understand how daclizumab beta altered the NK cell repertoire to provide further insight into the possible mechanism(s) of action in RMS. We used mass cytometry to evaluate expression patterns of NK cell markers and provide a comprehensive assessment of the NK cell repertoire in individuals with RMS treated with daclizumab beta or placebo over the course of 1 year. Treatment with daclizumab beta significantly altered the NK cell repertoire compared to placebo treatment. As previously reported, daclizumab beta significantly increased expression of CD56 on total NK cells. Within the CD56 NK cells, treatment was associated with multiple phenotypic changes, including increased expression of NKG2A and NKp44, and diminished expression of CD244, CD57, and NKp46. These alterations occurred broadly across the CD56 population, and were not associated with a specific subset of CD56 NK cells. While the changes were less dramatic, CD56 NK cells responded distinctly to daclizumab beta treatment, with higher expression of CD2 and NKG2A, and lower expression of FAS-L, HLA-DR, NTB-A, NKp30, and Perforin. Together, these data indicate that the expanded CD56 NK cells share features of both immature and mature NK cells. These findings show that daclizumab beta treatment is associated with unique changes in NK cells that may enhance their ability to kill autoreactive T cells or to exert immunomodulatory functions.
Topics: Adult; Aged; Aged, 80 and over; CD4-Positive T-Lymphocytes; CD56 Antigen; Cohort Studies; Daclizumab; Female; Humans; Immunosuppressive Agents; Killer Cells, Natural; Male; Mass Spectrometry; Middle Aged; Multiple Sclerosis; Receptors, Natural Killer Cell; Young Adult
PubMed: 32391016
DOI: 10.3389/fimmu.2020.00714 -
Bone Marrow Transplantation Jan 2006Daclizumab, a humanized IL-2 receptor antagonist, has been found to be safe and effective in adults with refractory graft-versus-host disease (GVHD); however, data... (Clinical Trial)
Clinical Trial
Daclizumab, a humanized IL-2 receptor antagonist, has been found to be safe and effective in adults with refractory graft-versus-host disease (GVHD); however, data describing its efficacy for refractory GVHD in children are limited. We report a series of 14 children who were treated with daclizumab for severe acute and/or chronic corticosteroid refractory GVHD. Patients were treated with 2 mg/kg weekly for 8 weeks followed by 1 mg/kg weekly for 4 weeks. Nine of 14 patients responded to daclizumab as measured by improvement of GVHD symptoms, and the ability to substantially wean corticosteroid dose. Five of 11 patients with acute GVHD had complete symptom resolution, and 2/11 had a partial response. Two of four patients with chronic GVHD had complete symptom resolution. In these patients, daclizumab was only effective in treating skin GVHD. Seven of the nine patients who had a complete or partial response eventually had recurrence of GVHD; however, the GVHD was less severe and no longer corticosteroid refractory. There was no infusional toxicity, and no infections that could be attributable to the drug. Daclizumab is a relatively safe and effective medication for corticosteroid refractory GVHD in children and larger studies are needed to evaluate its role in treatment.
Topics: Acute Disease; Adolescent; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Chronic Disease; Daclizumab; Disease-Free Survival; Drug Resistance; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Male; Recurrence; Remission Induction; Stem Cell Transplantation; Transplantation, Homologous
PubMed: 16247417
DOI: 10.1038/sj.bmt.1705199 -
Cancer Biotherapy & Radiopharmaceuticals May 2020Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a...
Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma.
Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6-574.6 MBq Y-daclizumab and the fourth patient receiving two doses of 580.9-566.1 MBq Y-daclizumab followed by high-dose chemotherapy and ASCT. All 4 evaluable patients treated with Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5-7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and Y-daclizumab provided strong enough β emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong β irradiation killed normal cells in the tumor microenvironment. Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of Y-daclizumab into the preconditioning regimen for refractory and relapsed HL patients with high-dose BEAM chemotherapy and ASCT provided sustained CRs in the 4 patients studied. Two of these patients were highly refractory to multiple prior treatments with bulky disease at entry into this study, including 1 patient who never entered a remission and had failed 6 different therapeutic regimens. Despite the small number of patients treated in this study, the sustained clinical benefit in these patients indicates a highly effective treatment. The daclizumab was directed primarily not at HRS cells themselves but toward nonmalignant T cells rosetting around malignant cells. Y provided strong β emissions that killed antigen nonexpressing tumor cells at a distance by a crossfire effect. Furthermore, the strong β radiation killed normal cells in the tumor microenvironment that nurtured the malignant cells in the lymphomatous mass. The present study supports expanded analysis of Y-daclizumab as part of the regimen of ASCT in patients with refractory and relapsed HL.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Daclizumab; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Male; Melphalan; Transplantation, Autologous
PubMed: 32275165
DOI: 10.1089/cbr.2019.3298