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Cold Spring Harbor Perspectives in... May 2019Daclizumab is a humanized monoclonal antibody that prevents formation of high-affinity interleukin (IL)-2 receptor (IL-2R). Because activated T cells up-regulate... (Review)
Review
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 CD56 natural killer (NK) cells. Activated CD56 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 -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.
Topics: Clinical Trials as Topic; Daclizumab; Humans; Immunoglobulin G; Immunosuppressive Agents; Killer Cells, Natural; Lymphocyte Activation; Multiple Sclerosis; T-Lymphocytes
PubMed: 29661806
DOI: 10.1101/cshperspect.a034470 -
Revista de Neurologia Apr 2018Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting... (Review)
Review
INTRODUCTION
Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The present review addresses how the drug was developed, the known mechanism of action of the drug and the up-to-date data of efficacy and safety.
DEVELOPMENT
Daclizumab has shown superiority in prevention of relapses against placebo and low-dose interferon beta-1a at a level that puts it on par with the rest of current first-line drugs. The effect on the progression of the disease and on neurodegeneration parameters, however, is not clear. On the other hand, it presents safety problems (mainly risk of autoimmunity phenomena including fulminant hepatopathy and encephalitis) that have supposed eventually its withdrawn from marketing. Daclizumab introduces a new mechanism of action through the blocking of a key interleukin in immune regulation and its effect on a population of cells with regulatory ability, such as the NK CD56(bright) cells.
CONCLUSIONS
Daclizumab has shown efficacy in slowing the inflammatory process of multiple sclerosis, although the appearance of potentially serious side effects has not allowed its use to significantly impact current clinical practice. The development of new drugs in multiple sclerosis must be contingent on maintaining or improving the risk-benefit profile with respect to those already in use.
Topics: Abnormalities, Drug-Induced; Antibodies, Monoclonal, Humanized; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Daclizumab; Drug Eruptions; Encephalitis; Female; Humans; Immunosuppressive Agents; Interferon beta-1a; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Killer Cells, Natural; Models, Immunological; Multicenter Studies as Topic; Multiple Sclerosis; Pregnancy; Pregnancy Complications; Safety-Based Drug Withdrawals; T-Lymphocyte Subsets
PubMed: 29645071
DOI: No ID Found -
Expert Opinion on Biological Therapy Oct 2007Daclizumab is a humanized monoclonal antibody which binds to the IL-2 receptor on activated lymphocytes and blocks the production of IL-2. Its use is well established in... (Review)
Review
Daclizumab is a humanized monoclonal antibody which binds to the IL-2 receptor on activated lymphocytes and blocks the production of IL-2. Its use is well established in solid organ transplantation as induction therapy, especially in high-risk patients where reduction or delayed dose of standard immunosuppression would be beneficial. It has been used effectively in both 2-dose and 5-dose regimens in conjunction with other standard immunosuppressive agents. The incidence of acute rejection appears reduced without increasing the rates of infection or post-transplant lympho-proliferative disorders. The agent is generally well tolerated in adults and children and there is no need for additional monitoring. Daclizumab has also been used outside the transplant arena in a variety of immune-mediated diseases with limited success.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Daclizumab; Drug Monitoring; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Organ Transplantation; Receptors, Interleukin-2; Recombinant Fusion Proteins; Treatment Outcome
PubMed: 17916050
DOI: 10.1517/14712598.7.10.1583 -
Neurodegenerative Disease Management Oct 2017Daclizumab is a monoclonal antibody that targets the α-chain of the IL-2 receptor. Results of Phase II and III clinical trials showed efficacy of daclizumab in... (Review)
Review
Daclizumab is a monoclonal antibody that targets the α-chain of the IL-2 receptor. Results of Phase II and III clinical trials showed efficacy of daclizumab in relapsing-remitting multiple sclerosis, with reduction of annualized relapse rate by 50-54% versus placebo and 45% versus intramuscular IFN-β-1a. Certain aspects of the immunomodulatory mode of action of daclizumab were only discovered during its clinical development, such as the expansion of a subpopulation of natural killer cells. In this article, we outline the putative mechanisms of action and the key clinical data on daclizumab, with a focus on the efficacy and safety profile. We also evaluate its potential role in future treatment algorithms of multiple sclerosis.
Topics: Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Daclizumab; Humans; Immunoglobulin G; Immunologic Factors; Multiple Sclerosis
PubMed: 28849702
DOI: 10.2217/nmt-2017-0023 -
Drugs Mar 2017Daclizumab (Zinbryta; previously known as daclizumab high-yield process) is a therapeutic monoclonal antibody that has recently been approved for the treatment of... (Review)
Review
Daclizumab (Zinbryta; previously known as daclizumab high-yield process) is a therapeutic monoclonal antibody that has recently been approved for the treatment of relapsing forms of multiple sclerosis (MS) in adults. Daclizumab is a humanized IgG1 monoclonal antibody directed against CD25, the alpha subunit of the high-affinity interleukin-2 receptor. As demonstrated in the phase III DECIDE trial, once-monthly subcutaneous daclizumab was superior to once-weekly intramuscular interferon (IFN) β-1a in reducing the clinical relapse rate and radiological measures of disease in patients with relapsing-remitting MS. In addition, daclizumab has demonstrated efficacy in reducing disability progression and in improving health-related quality of life in patients with relapsing MS. Ongoing open-label clinical trials indicate that daclizumab's efficacy is maintained in the longer term (3 years or more). Daclizumab appears to be generally well tolerated, with adverse events of interest (including hepatic, infectious and cutaneous events) generally manageable with regular monitoring and/or standard therapies. The place of daclizumab in MS treatment remains to be fully determined. However, based on available evidence, daclizumab provides a useful alternative option to other currently available disease-modifying therapies in the treatment of relapsing MS.
Topics: Antibodies, Monoclonal, Humanized; Daclizumab; Drug Tolerance; Humans; Immunoglobulin G; Multiple Sclerosis, Relapsing-Remitting
PubMed: 28211007
DOI: 10.1007/s40265-017-0708-2 -
Drug and Therapeutics Bulletin Feb 2017▼Daclizumab (Zinbryta-Biogen Idec) is a new injectable disease-modifying drug licensed for the treatment of relapsing forms of multiple sclerosis (MS) in adults. It is... (Review)
Review
▼Daclizumab (Zinbryta-Biogen Idec) is a new injectable disease-modifying drug licensed for the treatment of relapsing forms of multiple sclerosis (MS) in adults. It is a humanised monoclonal antibody that modulates interleukin-2 signalling. Here, we review the evidence on daclizumab and consider its place in the management of MS.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Humans; Immunoglobulin G; Multiple Sclerosis, Relapsing-Remitting
PubMed: 28183723
DOI: 10.1136/dtb.2017.2.0454 -
Neurotherapeutics : the Journal of the... Oct 2017Daclizumab is a humanized monoclonal antibody directed towards CD25, the alpha subunit of the high-affinity interleukin (IL)-2 receptor. Daclizumab exerts its effects... (Review)
Review
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.
Topics: Animals; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Daclizumab; Humans; Immunoglobulin G; Immunosuppressive Agents; Interleukin-2; Multiple Sclerosis; Receptors, Interleukin-2; Treatment Outcome
PubMed: 28707278
DOI: 10.1007/s13311-017-0553-8 -
Neurotherapeutics : the Journal of the... Jan 2013Daclizumab is a humanized monoclonal antibody of IgG1 subtype that binds to the Tac epitope on the interleukin-2 (IL-2) receptor α-chain (CD25), thus, effectively... (Review)
Review
Daclizumab is a humanized monoclonal antibody of IgG1 subtype that binds to the Tac epitope on the interleukin-2 (IL-2) receptor α-chain (CD25), thus, effectively blocking the formation of the high-affinity IL-2 receptor. Because the high-affinity IL-2 receptor signaling promotes expansion of activated T cells in vitro, daclizumab was designed as a therapy that selectively inhibits T-cell activation. Assuming the previous statement, daclizumab received regulatory approval as add-on therapy to standard immunosuppressive regimen for the prevention of acute allograft rejection in renal transplantation. Based on its putative mechanism of action (MOA), daclizumab represented an ideal therapy for T-cell-mediated autoimmune diseases and was subsequently tested in inflammatory uveitis and multiple sclerosis (MS). In both of these diseases, daclizumab therapy significantly inhibited target organ inflammation. Mechanistic studies in MS demonstrated that the MOA of daclizumab is surprisingly broad and that the drug exerts unexpected effects on multiple components of the innate immune system. Specifically, daclizumab dramatically expands and activates immunoregulatory CD56(bright) NK cells, which gain access to the intrathecal compartment in MS and can kill autologous activated T cells. Daclizumab also blocks trans-presentation of IL-2 by mature dendritic cells to primed T cells, resulting in profound inhibition of antigen-specific T cells. Finally, daclizumab modulates the development of innate lymphoid cells. In conclusion, daclizumab therapy, which is currently in phase III testing for inflammatory MS, has a unique MOA that does not limit migration of immune cells into the intrathecal compartment, but rather provides multifactorial immunomodulatory effects with resultant inhibition of MS-related inflammation.
Topics: Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Daclizumab; Humans; Immunoglobulin G; Immunosuppressive Agents; Lymphocyte Activation; Multiple Sclerosis; T-Lymphocytes
PubMed: 23055048
DOI: 10.1007/s13311-012-0147-4 -
Experimental Neurology Dec 2014Multiple sclerosis (MS) is a typical CD4 T cell-mediated autoimmune disease of the central nervous system (CNS) that leads to inflammation, demyelination, axonal damage,... (Review)
Review
Multiple sclerosis (MS) is a typical CD4 T cell-mediated autoimmune disease of the central nervous system (CNS) that leads to inflammation, demyelination, axonal damage, glial scarring and a broad range of neurological deficits. While disease-modifying drugs with a good safety profile and moderate efficacy have been available for 20 years now, a growing number of substances with superior therapeutic efficacy have recently been introduced or are in late stage clinical testing. Daclizumab, a humanized neutralizing monoclonal antibody against the α-chain of the Interleukin-2 receptor (IL-2Rα, CD25), which had originally been developed and approved to prevent rejection after allograft renal transplantation, belongs to the latter group. Clinical efficacy and safety of daclizumab in MS has so far been tested in several smaller phase II trials and recently two large phase II trials (combined 912 patients), and has shown efficacy regarding reduction of clinical disease activity as well as CNS inflammation. A phase III clinical trial is ongoing till March 2014 (DECIDE study, comparison with interferon (IFN) β-1a in RRMS). Furthermore, the existing safety data from clinical experience in kidney transplantation and in MS appears favorable. Apart from the promising clinical data mechanistic studies along the trials have provided interesting novel insights not only about the mechanisms of daclizumab treatment, but in general about the biology of IL-2 and IL-2 receptor interactions in the human immune system. Besides blockade of recently activated CD25(+) T cells daclizumab appears to act through additional mechanisms including the expansion of immune regulatory CD56(bright) natural killer (NK) cells, the blockade of cross-presentation of IL-2 by dendritic cells (DC) to T cells, and the reduction of lymphoid tissue inducer cells.
Topics: Antibodies, Monoclonal, Humanized; Daclizumab; Humans; Immunoglobulin G; Interleukin-2 Receptor alpha Subunit; Multiple Sclerosis
PubMed: 24768797
DOI: 10.1016/j.expneurol.2014.04.015 -
Expert Review of Clinical Pharmacology Oct 2017The goal of the article is to review the mechanism of action and the use of daclizumab, a humanized monoclonal antibody (mAb) against the alpha subunit of the high... (Review)
Review
The goal of the article is to review the mechanism of action and the use of daclizumab, a humanized monoclonal antibody (mAb) against the alpha subunit of the high affinity interleukin-2 (IL-2) receptor, in the treatment of Multiple Sclerosis (MS). Areas covered: PubMed was searched for the terms 'daclizumab' and 'multiple sclerosis'. The mechanisms of action, pharmacokinetics and pharmacodynamics, major studies, side effects and drug interactions of daclizumab in MS are discussed. Expert commentary: Monthly daclizumab-beta [DAC-beta, formerly daclizumab high yield process (DAC HYP), approved as ZINBRYTA®, which has a different form and structure than an earlier form of daclizumab], is an effective and convenient treatment option for patients with relapsing forms of MS who have failed other treatment, or as a first-line option in highly active MS patients. IL-2 signaling modulation by daclizumab constitutes a novel mechanism of action which may also underlie the adverse and serious adverse events and risk profile of the drug that requires appropriate patient selection, monitoring and risk-mitigation programs.
Topics: Adult; Animals; Antibodies, Monoclonal, Humanized; Daclizumab; Drug Interactions; Humans; Immunoglobulin G; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Multiple Sclerosis, Relapsing-Remitting; Patient Selection
PubMed: 28803486
DOI: 10.1080/17512433.2017.1366854