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Blood Jan 2000Daclizumab, a humanized monoclonal IgG1 directed against the alpha chain of the interleukin-2 receptor (IL-2R), is a competitive inhibitor of IL-2 on activated... (Clinical Trial)
Clinical Trial
Daclizumab, a humanized monoclonal IgG1 directed against the alpha chain of the interleukin-2 receptor (IL-2R), is a competitive inhibitor of IL-2 on activated lymphocytes. To test the hypothesis that specific inhibition of activated lymphocytes in patients with ongoing acute graft-versus-host disease (GVHD) might ameliorate the process, we treated 43 patients with advanced or steroid-refractory GVHD with daclizumab. The first cohort of 24 patients was treated with daclizumab 1 mg/kg on days 1, 8, 15, 22, and 29. On day 43, the complete response (CR) rate was 29% (95% confidence interval [CI], 13%-51%). Survival on day 120 was 29% (95% CI, 13%-51%). A second cohort of 19 patients was treated with daclizumab 1 mg/kg on days 1, 4, 8, 15, and 22. For these patients, the CR rate on day 43 was 47% (95% CI, 24%-71%), and survival on day 120 was 53% (95% CI, 29%-76%). There were no infusion-related reactions and no serious side effects related to daclizumab. Following treatment, there was a reduction in serum concentrations of soluble IL-2R and peripheral blood CD3( + )25(+) lymphocytes, but these changes were not predictive of response. Daclizumab has substantial activity for the treatment of acute GVHD, and the second regimen evaluated is recommended for a controlled study. (Blood, 2000; 95:83-89)
Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Transfusion; Bone Marrow Transplantation; Child; Child, Preschool; Cohort Studies; Confidence Intervals; Daclizumab; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Male; Middle Aged; Receptors, Interleukin-2
PubMed: 10607689
DOI: No ID Found -
American Journal of Respiratory and... Nov 2008Airway inflammation in asthma is associated with increased activated CD25(+) T cells, IL-2, and soluble IL-2 receptors (IL-2Rs). (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Airway inflammation in asthma is associated with increased activated CD25(+) T cells, IL-2, and soluble IL-2 receptors (IL-2Rs).
OBJECTIVES
A randomized, double-blinded, placebo-controlled study was used to evaluate the safety and efficacy of daclizumab, a humanized IgG1 monoclonal antibody against the IL-2R alpha chain (CD25) of activated lymphocytes, in adults with moderate to severe persistent asthma.
METHODS
Patients with obstructive pulmonary functions, despite inhaled corticosteroids (ICS), were switched to equivalent dose inhaled triamcinolone acetate acetonide (TAA). Patients dependent on ICS were randomized (3:1) to daclizumab (intravenous loading dose, 2 mg/kg, then 1 mg/kg) or placebo every 2 weeks, added to stable-dose TAA through Week 12 (Treatment Period 1). Over Weeks 12-20 (Treatment Period 2), patients tapered TAA while on the study drug, and were followed for 16 weeks off the study drug.
MEASUREMENTS AND MAIN RESULTS
Among 115 evaluable patients (88 daclizumab, 27 placebo), groups had similar age, disease duration, and length of ICS use. During Treatment Period 1, daclizumab improved FEV(1) (daclizumab, 4.4 +/- 1.80% vs. placebo, 1.5 +/- 2.39%; P = 0.05), and reduced daytime asthma symptoms (P = 0.018) and short-acting inhaled beta(2)-agonist use (P = 0.009). Daclizumab treatment prolonged time to exacerbation (P = 0.024). Adverse events were evenly distributed between groups, although there were more serious adverse events in the patients treated with daclizumab.
CONCLUSIONS
Daclizumab improved pulmonary function and asthma control in patients with moderate to severe chronic asthma inadequately controlled on ICS. The mechanism of action likely involves inhibition of proinflammatory cytokine generation by IL-2R blockade in activated T cells. Clinical trial registered with www.clinicaltrials.gov (NCT00028288).
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Asthma; Daclizumab; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Immunoglobulin G; Immunosuppressive Agents; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Kaplan-Meier Estimate; Male; Middle Aged; Pneumonia; T-Lymphocytes
PubMed: 18787222
DOI: 10.1164/rccm.200708-1200OC -
Journal of the American Society of... Jun 2009Nondepleting anti-CD25 monoclonal antibodies (daclizumab) and depleting polyclonal antithymocyte globulin (Thymoglobulin) both prevent acute rejection, but these... (Comparative Study)
Comparative Study Randomized Controlled Trial
Nondepleting anti-CD25 monoclonal antibodies (daclizumab) and depleting polyclonal antithymocyte globulin (Thymoglobulin) both prevent acute rejection, but these therapies have not been directly compared in a high-risk, HLA-sensitized renal transplant population. We randomly assigned 227 patients, who were about to receive a kidney graft from a deceased donor, to either Thymoglobulin or daclizumab if they met one of the following risk factors: current panel reactive antibodies (PRA) >30%; peak PRA >50%; loss of a first kidney graft from rejection within 2 yr of transplantation; or two or three previous grafts. Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and steroids. Compared with the daclizumab group, patients treated with Thymoglobulin had a lower incidence of both biopsy-proven acute rejection (15.0% versus 27.2%; P = 0.016) and steroid-resistant rejection (2.7% versus 14.9%; P = 0.002) at one year. One-year graft and patient survival rates were similar between the two groups. In a comparison of rejectors and nonrejectors, overall graft survival was significantly higher in the rejection-free group (87.2% versus 75.0%; P = 0.037). In conclusion, among high-immunological-risk renal transplant recipients, Thymoglobulin is superior to daclizumab for the prevention of biopsy-proven acute rejection, but there is no significant benefit to one-year graft or patient survival.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Biopsy; Daclizumab; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Risk Factors; Treatment Outcome
PubMed: 19470677
DOI: 10.1681/ASN.2008101037 -
Multiple Sclerosis and Related Disorders Jan 2017Patient-reported outcomes (PROs) provide information on treatment effects from the patient's perspective that complement outcomes on clinical measures. In DECIDE,... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Patient-reported outcomes (PROs) provide information on treatment effects from the patient's perspective that complement outcomes on clinical measures. In DECIDE, daclizumab demonstrated superior efficacy in reducing relapses, 24-week confirmed disability progression, and brain lesions (assessed by magnetic resonance imaging [MRI]) versus intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis.
OBJECTIVE
To examine the impact of daclizumab versus interferon beta-1a on PROs in DECIDE.
METHODS
DECIDE was a randomized, double-blind, active-controlled, phase 3 study comparing daclizumab 150mg subcutaneous every 4 weeks with interferon beta-1a 30mcg intramuscular once weekly. The 29-item Multiple Sclerosis Impact Scale (MSIS-29) and EuroQoL 5-Dimensions (EQ-5D) were assessed at baseline and every 24 weeks. Mean changes from baseline were analyzed using analysis of covariance models. Individual items for the MSIS-29 physical (PHYS) and psychological (PSYCH) subscales were analyzed post hoc.
RESULTS
Daclizumab treatment resulted in greater mean improvements relative to baseline in MSIS-29 PHYS and PSYCH scores starting at week 24 that persisted over 96 weeks. Mean improvements from baseline in MSIS-29 PHYS and PSYCH scores were significantly greater for daclizumab versus intramuscular interferon beta-1a at week 96. Daclizumab-treated patients showed steady improvements in EQ-5D health utility index and EQ-5D visual analog scale scores over the study period, with significantly greater improvements versus intramuscular interferon beta-1a at week 96 (p=0.0048 and p=0.0006, respectively).
CONCLUSIONS
Improvements in patient-reported physical and psychological functioning and general health status with daclizumab compared with intramuscular interferon beta-1a are consistent with outcomes on clinical and brain MRI lesion measures in DECIDE (NCT01064401).
Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Daclizumab; Double-Blind Method; Humans; Immunoglobulin G; Immunologic Factors; Interferon beta-1a; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Patient Reported Outcome Measures; Time Factors; Young Adult
PubMed: 28104250
DOI: 10.1016/j.msard.2016.11.005 -
Bone Marrow Transplantation Mar 2009GVHD remains a serious complication after allogeneic SCT. We describe 13 paediatric patients treated with daclizumab for refractory acute GVHD (aGVHD). After 30 days of...
GVHD remains a serious complication after allogeneic SCT. We describe 13 paediatric patients treated with daclizumab for refractory acute GVHD (aGVHD). After 30 days of daclizumab administration, all patients with cutaneous aGVHD reached complete response. Among patients with gastrointestinal disease, 50 and 30% had complete and partial response, respectively, whereas 11 and 55% of patients with hepatic aGVHD achieved CR and PR, respectively. Overall, complete (46%) and partial (46%) responses were demonstrated in 92% of our patients, whereas the remaining patients (8%) were nonresponders. No life-threatening infectious episodes were recorded within 100 days from transplant in this selected group of paediatric patients. Overall 46% of patients were alive at a median of 461 days from SCT, but 50% of them developed chronic GVHD. In our experience, daclizumab proved to be a useful and safe treatment for refractory and steroid-resistant/dependent aGVHD, in particular for cutaneous and low-moderate intestinal involvement.
Topics: Acute Disease; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Daclizumab; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Transplantation, Homologous
PubMed: 18850021
DOI: 10.1038/bmt.2008.331 -
Actas Dermo-sifiliograficas 2008In recent years, a series of new drugs have been developed through the application of molecular biology. These drugs act by blocking specific molecules of the immune... (Review)
Review
[Off-label use of biologic agents in the treatment of dermatosis, part 2: etanercept, efalizumab, alefacept, rituximab, daclizumab, basiliximab, omalizumab, and cetuximab].
In recent years, a series of new drugs have been developed through the application of molecular biology. These drugs act by blocking specific molecules of the immune system and have been developed to act on specific targets that play an important role in the pathophysiology of the diseases in which their therapeutic use has now been approved. Over time, experience has been accumulated in the use of these drugs in the treatment of skin diseases for which they have not been approved but in which the pathophysiology suggests that they could also be effective. The use of these drugs is increasing in difficult-to-treat cases of skin diseases for which the drugs are not approved. The second part of this review of off-label use of biologic agents in dermatology considers the use of etanercept, efalizumab, alefacept, rituximab, basiliximab, omalizumab, and cetuximab.
Topics: Alefacept; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Basiliximab; Biological Products; Cetuximab; Daclizumab; Drug Approval; Etanercept; Humans; Immunoglobulin G; Omalizumab; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Rituximab; Skin Diseases
PubMed: 18206084
DOI: 10.1016/s0001-7310(08)74612-x -
American Journal of Transplantation :... Jul 2015We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG,... (Comparative Study)
Comparative Study Observational Study Randomized Controlled Trial
We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG-treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high-immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts.
Topics: Adult; Animals; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Daclizumab; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Rabbits; Risk Factors
PubMed: 25707875
DOI: 10.1111/ajt.13191 -
Alimentary Pharmacology & Therapeutics Sep 2010The role of interleukin 2 (IL-2) receptor antibodies to avoid the nephrotoxic effects of calcineurin inhibitors in the early post-liver transplant (LT) period is not...
BACKGROUND
The role of interleukin 2 (IL-2) receptor antibodies to avoid the nephrotoxic effects of calcineurin inhibitors in the early post-liver transplant (LT) period is not well defined.
AIM
To examine the use of daclizumab induction in LT recipients with renal insufficiency.
METHODS
Between 2002 and 2005, 62 patients (median pre-LT creatinine 2.4 mg/dL, IQR 1.9-3.7) received daclizumab induction with tacrolimus being administered when serum creatinine was <2.0 mg/dL. A concurrent comparison group (n = 221, 2002-2005) received tacrolimus-based immunosuppression without daclizumab (median pre-LT creatinine 1.1 mg/dL, IQR 0.9-1.4). A second historical comparison group (n = 103, 1995-2005) not receiving daclizumab was matched to the daclizumab patients by pre-LT serum creatinine (2.2 mg/dL, IQR 1.8-3.1). All patients received mycophenolate mofetil and steroids.
RESULTS
Serum creatinine improved in the daclizumab group (-1.0 mg/dL, IQR -2.2 to -0.4) and worsened in the concurrent comparison group (+0.2 mg/dL, IQR 0-0.5) from pre-LT to 4 months. However, there was no difference when daclizumab group was compared with the historical comparison group matched on pre-LT creatinine (median change: -0.8 mg/dL vs. -0.7 mg/dL). Daclizumab induction was not associated with improvement in renal function at 4 months (P = 0.34) after adjusting for pre-LT creatinine, age, gender, hepatitis C status and simultaneous liver kidney transplantation.
CONCLUSION
The incremental benefit offered by induction therapy with IL-2 receptor antibodies to preserve renal function is questionable.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Case-Control Studies; Daclizumab; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Retrospective Studies
PubMed: 20659283
DOI: 10.1111/j.1365-2036.2010.04408.x -
The New England Journal of Medicine Jun 1998
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Cyclosporine; Daclizumab; Europe; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; United States
PubMed: 9616069
DOI: 10.1056/NEJM199806043382317 -
Transplant Immunology Nov 2000Daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor (R) alpha-chain, is a promising new immunosuppressant in transplantation. As its exact...
Daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor (R) alpha-chain, is a promising new immunosuppressant in transplantation. As its exact mechanism of action has remained unclear, we examined its short-term effects on primary human T lymphocytes expressing the high-affinity IL-2R. Daclizumab exposure for 20 min neither affected T cell viability nor their surface expression of the IL-2R alpha-, beta-, or gamma-chains. However, after IL-2 stimulation (200 U/ml, 20 min), immunoblots of cell lysates demonstrated attenuation of the IL-2-induced tyrosine phosphorylation of 65-75 kDa proteins by Daclizumab, but not by isotype controls. Since this is the molecular weight of the IL-2R beta- and gamma-chains, which are both tyrosine-phosphorylated by IL-2, we next examined the effect of Daclizumab on their IL-2-induced tyrosine phosphorylation. In immunoblots of IL-2R beta- and gamma-chain-immunoprecipitates the tyrosine phosphorylation of both chains by IL-2, but not by IL-15, was attenuated in the presence of Daclizumab. Furthermore, co-immunoprecipitation experiments showed that Daclizumab inhibited the IL-2-induced association of these chains, a prerequisite for their mutual tyrosine phosphorylation. Lastly, we demonstrated that Daclizumab inhibits the receptor-downstream induction of the IL-2-activated DNA-binding protein STAT5 in gel shift assays. We conclude that Daclizumab directly and specifically interferes with IL-2 signaling at the receptor level by inhibiting the association and subsequent phosphorylation of the IL-2R beta- and gamma-chains induced by ligand binding. Under our experimental conditions, Daclizumab had no effects on cell viability, and it did not modulate the surface expression of the IL-2R alpha-, beta-, or gamma-chains.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; DNA-Binding Proteins; Daclizumab; Humans; Immunoglobulin G; Immunosuppressive Agents; In Vitro Techniques; Interleukin-2; Mice; Milk Proteins; Phosphorylation; Receptors, Interleukin-2; STAT5 Transcription Factor; Signal Transduction; T-Lymphocytes; Trans-Activators; Transplantation Immunology; Tyrosine
PubMed: 11147695
DOI: 10.1016/s0966-3274(00)00021-6