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P & T : a Peer-reviewed Journal For... Oct 2016Obeticholic acid (Ocaliva) for primary biliary cholangitis; sofosbuvir 400 mg/velpatasvir 100 mg (Epclusa) for chronic hepatitis C virus infection; and daclizumab...
Obeticholic acid (Ocaliva) for primary biliary cholangitis; sofosbuvir 400 mg/velpatasvir 100 mg (Epclusa) for chronic hepatitis C virus infection; and daclizumab (Zinbryta) for relapsing multiple sclerosis.
PubMed: 27756999
DOI: No ID Found -
Brain Sciences Jul 2017The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a... (Review)
Review
The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumb, ocrelizumab, alentuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS.
PubMed: 28686222
DOI: 10.3390/brainsci7070078 -
Nature Communications Aug 2023Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures...
Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes-including cell-type specific measures of granularity, nucleic acid content and reactivity-in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types-variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.
Topics: Genome-Wide Association Study; Proteomics; Microscopy; Transcription Factors; Causality
PubMed: 37596262
DOI: 10.1038/s41467-023-40679-y -
Multidisciplinary Respiratory Medicine 2015Patients with severe asthma or COPD have often a suboptimal symptom control due to inadequate treatment. A better understanding of pathogenetic mechanisms, phenotypes,... (Review)
Review
Patients with severe asthma or COPD have often a suboptimal symptom control due to inadequate treatment. A better understanding of pathogenetic mechanisms, phenotypes, endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen, or to open a way for new therapeutic target options. At the moment, the only biologic drug available in clinical practice is omalizumab. To overcome the limits of omalizumab, the research has focused on new monoclonal antibodies presenting higher avidity for IgE (e.g. ligelizumab and lumiximab) and ability to interact also with low affinity IgE receptor (FcϵRII). At present, many new biological drugs with different mechanisms of action and targets are matter of research. It is very important to identify the asthmatic phenotype in order to select the most appropriate drug for the individual patient. The most promising agents are targeted against cytokines of Th2 pattern and related receptors, such as IL-2 (daclizumab) and IL-13 (lebrikizumab) or IL-5 in patients with hypereosinophilia (mepolizumab, reslizumab and benralizumab). Other interesting drugs have as a target TNF-α or its soluble receptor (infliximab, golimumab and etanercept) or IL-1 (canakinumab), a cytokine with an important systemic proinflammatory action. Finally, the discovery of increased levels of C5a in the airways of asthmatic patients has led to the synthesis of a specific monoclonal antibody (eculizumab). Further help should come from the identification of biomarkers that can guide in choosing the best treatment for the individual patient, such as IgE for omalizumab or periostin for lebrikizumab.
PubMed: 25671117
DOI: 10.1186/2049-6958-10-1 -
Trends in Genetics : TIG Sep 2021Human leukocyte antigen (HLA)-encoded surface molecules present antigenic peptides to T lymphocytes and play a key role in adaptive immune responses. Besides their... (Review)
Review
Human leukocyte antigen (HLA)-encoded surface molecules present antigenic peptides to T lymphocytes and play a key role in adaptive immune responses. Besides their physiological role of defending the host against infectious pathogens, specific alleles serve as genetic risk factors for autoimmune diseases. For multiple sclerosis (MS), an autoimmune disease that affects the brain and spinal cord, an association with the HLA-DR15 haplotype was described in the early 1970s. This short opinion piece discusses the difficulties of disentangling the details of this association and recent observations about the functional involvement of not only one, but also the second gene of the HLA-DR15 haplotype. This information is not only important for understanding the pathomechanism of MS, but also for antigen-specific therapies.
Topics: Genome-Wide Association Study; HLA Antigens; HLA-DR Serological Subtypes; Haplotypes; Humans; Multiple Sclerosis; T-Lymphocytes
PubMed: 34006391
DOI: 10.1016/j.tig.2021.04.012 -
Journal of Thoracic Disease Aug 2014Lung transplantation can be a life-saving procedure for those with end-stage lung diseases. Unfortunately, long term graft and patient survival are limited by both acute... (Review)
Review
Lung transplantation can be a life-saving procedure for those with end-stage lung diseases. Unfortunately, long term graft and patient survival are limited by both acute and chronic allograft rejection, with a median survival of just over 6 years. Immunosuppressive regimens are employed to reduce the rate of rejection, and while protocols vary from center to center, conventional maintenance therapy consists of triple drug therapy with a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative agents [azathioprine (AZA), mycophenolate, sirolimus (srl), everolimus (evl)], and corticosteroids (CS). Roughly 50% of lung transplant centers also utilize induction therapy, with polyclonal antibody preparations [equine or rabbit anti-thymocyte globulin (ATG)], interleukin 2 receptor antagonists (IL2RAs) (daclizumab or basiliximab), or alemtuzumab. This review summarizes these agents and the data surrounding their use in lung transplantation, as well as additional common and novel therapies in lung transplantation. Despite the progression of the management of lung transplant recipients, they continue to be at high risk of treatment-related complications, and poor graft and patient survival. Randomized clinical trials are needed to allow for the development of better agents, regimens and techniques to address above mentioned issues and reduce morbidity and mortality among lung transplant recipients.
PubMed: 25132971
DOI: 10.3978/j.issn.2072-1439.2014.04.23 -
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 -
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 -
BMC Gastroenterology Oct 2023Therapeutic options for ulcerative colitis (UC) have increased since the introduction of biologics a few decades ago. Due to the wide range of biologics available,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Therapeutic options for ulcerative colitis (UC) have increased since the introduction of biologics a few decades ago. Due to the wide range of biologics available, physicians have difficulty in selecting biologics and do not know how to balance the best drug between clinical efficacy and safety. This study aimed to compare the efficacy and safety of biologics in treating ulcerative colitis.
METHODS
In this study, eight electronic databases (PubMed, Web of Science, Cochrane, Embase, Sinomed, China National Knowledge Infrastructure, Chongqing VIP Information, and WanFang Data) were searched to collect eligible studies without language restrictions. Retrieved 1 June 2023, from inception. All articles included in the mesh analysis are randomised controlled trials (RCTs). The inclusion of drugs for each outcome was ranked using a curved surface under cumulative ranking (SUCRA). Higher SUCRA scores were associated with better outcomes, whereas lower SUCRA scores were associated with better safety. This study has registered with PROSPERO, CRD42023389483.
RESULTS
Induction Therapy: Among the biologic therapies evaluated for induction therapy, vedolizumab demonstrated the highest efficacy in achieving clinical remission (OR vs daclizumab, 9.09; 95% CI, 1.01-81.61; SUCRA 94.1) and clinical response. Guselkumab showed the lowest risk of recurrence of UC (SUCRA 94.9%), adverse events resulting in treatment discontinuation (SUCRA 94.8%), and serious infections (SUCRA 78.0%). Maintenance Therapy: For maintenance therapy, vedolizumab ranked highest in maintaining clinical remission (OR vs mesalazine 4.36; 95% CI, 1.65-11.49; SUCRA 89.7) and endoscopic improvement (SUCRA 92.6). Infliximab demonstrated the highest efficacy in endoscopic improvement (SUCRA 92.6%). Ustekinumab had the lowest risk of infections (SUCRA 92.9%), serious adverse events (SUCRA 91.3%), and serious infections (SUCRA 67.6%).
CONCLUSION
Our network meta-analysis suggests that vedolizumab is the most effective biologic therapy for inducing and maintaining clinical remission in UC patients. Guselkumab shows promise in reducing the risk of recurrence and adverse events during induction therapy. Infliximab is effective in improving endoscopic outcomes during maintenance therapy. Ustekinumab appears to have a favorable safety profile. These findings provide valuable insights for clinicians in selecting the most appropriate biologic therapy for UC patients.
Topics: Humans; Colitis, Ulcerative; Infliximab; Biological Products; Ustekinumab; Network Meta-Analysis; Biological Factors
PubMed: 37803294
DOI: 10.1186/s12876-023-02938-6