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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 -
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 -
Transplant International : Official... Jul 2013Strategies for induction in lung transplant recipients typically mirror those used in other solid organ transplant recipients. Polyclonal (Atgam, RATG) and monoclonal... (Review)
Review
Strategies for induction in lung transplant recipients typically mirror those used in other solid organ transplant recipients. Polyclonal (Atgam, RATG) and monoclonal (OKT3) T-cell depleting agents, IL-2 Receptor antagonists (basiliximab and daclizumab) have been used most commonly. In spite of evidence from ISHLT registry reports that induction reduces acute rejection and has a small benefit in freedom from bronchiolitis obliterans and long-term survival, other studies have been less convincing in terms of long-term benefit. Future iterations of induction strategy for lung transplant recipients will hopefully utilize tolerogenic approaches currently being tested in renal transplantation.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Bronchiolitis Obliterans; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Lymphocyte Depletion; Receptors, Interleukin-2
PubMed: 23701023
DOI: 10.1111/tri.12115 -
Transplant International : Official... Aug 2006Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated... (Clinical Trial)
Clinical Trial
Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.
Topics: Acute Disease; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Female; Graft Rejection; Humans; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Infections; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Safety; Tacrolimus
PubMed: 16827681
DOI: 10.1111/j.1432-2277.2006.00326.x -
MAbs 2012Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As...
Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As more mAbs become available to physicians and patients, keeping track of the number, types, production cell lines, antigenic targets, and dates and locations of approvals has become challenging. Data are presented here for 34 mAbs that were approved in either Europe or the United States (US) as of March 2012, and nimotuzumab, which is marketed outside Europe and the US. Of the 34 mAbs, 28 (abciximab, rituximab, basiliximab, palivizumab, infliximab, trastuzumab, alemtuzumab, adalimumab, tositumomab-I131, cetuximab, ibrituximab tiuxetan, omalizumab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, certolizumab pegol, golimumab, canakinumab, catumaxomab, ustekinumab, tocilizumab, ofatumumab, denosumab, belimumab, ipilimumab, brentuximab) are currently marketed in Europe or the US. Data for six therapeutic mAbs (muromonab-CD3, nebacumab, edrecolomab, daclizumab, gemtuzumab ozogamicin, efalizumab) that were approved but have been withdrawn or discontinued from marketing in Europe or the US are also included.
Topics: Animals; Antibodies, Monoclonal; Drug Approval; Europe; Humans; Immunotherapy; Marketing; Product Recalls and Withdrawals; United States
PubMed: 22531442
DOI: 10.4161/mabs.19931 -
Clinical and Experimental Immunology Mar 2014Monoclonal antibodies (mAbs) are used as therapeutics in a number of disciplines in medicine, such as oncology, rheumatology, gastroenterology, dermatology and... (Review)
Review
Monoclonal antibodies (mAbs) are used as therapeutics in a number of disciplines in medicine, such as oncology, rheumatology, gastroenterology, dermatology and transplant rejection prevention. Since the introduction and reintroduction of the anti-alpha4-integrin mAb natalizumab in 2004 and 2006, mAbs have gained relevance in the treatment of multiple sclerosis (MS). At present, numerous mAbs have been tested in clinical trials in relapsing-remitting MS, and in progressive forms of MS. One of the agents that might soon be approved for very active forms of relapsing-remitting MS is alemtuzumab, a humanized mAb against CD52. This review provides insights into clinical studies with the mAbs natalizumab, alemtuzumab, daclizumab, rituximab, ocrelizumab and ofatumumab.
Topics: Antibodies, Monoclonal; Humans; Immunologic Factors; Multiple Sclerosis
PubMed: 24001305
DOI: 10.1111/cei.12197 -
Degenerative Neurological and... 2016Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the central nervous system of a putative autoimmune etiology. Although the exact pathogenic... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the central nervous system of a putative autoimmune etiology. Although the exact pathogenic mechanisms underlying demyelination and axonal damage in MS are not fully understood, T-cells are believed to play a central role in the pathogenesis of the disease. Daclizumab is a humanized binding monoclonal antibody that binds to the Tac epitope on the α-subunit (CD25) of the interleukin-2 (IL-2) receptor, thus effectively blocking the formation of the high-affinity IL-2 receptor, which is expressed mainly on T-cells. A series of clinical trials in patients with relapsing MS demonstrated a profound effect of daclizumab on inflammatory disease activity and improved clinical outcomes compared with placebo or interferon-β, which led to the recent approval of daclizumab (Zinbryta) for the treatment of relapsing forms of MS. Enhancement of endogenous mechanisms of immune regulation rather than inhibition of effector T-cells might explain the effects of daclizumab in MS. These include expansion and improved function of regulatory CD56 NK cells, inhibition of the early activation of T-cells through blockade of IL-2 transpresentation by dendritic cells and reduction in the number of intrathecal proinflammatory lymphoid tissue inducer cells. The enhanced efficacy of daclizumab is accompanied by an increased frequency of adverse events and risks of serious adverse events, thus placing it as a second-line therapy and calling for the implementation of a strict risk management program. This review details the mechanisms of action of daclizumab, discusses its efficacy and safety in patients with MS, and provides an insight into the place of this novel therapy in the treatment of MS.
PubMed: 30050372
DOI: 10.2147/DNND.S85747 -
Deutsches Arzteblatt International Dec 2016Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system. There are at least 150 000 persons with MS in Germany. Recent years have... (Review)
Review
BACKGROUND
Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system. There are at least 150 000 persons with MS in Germany. Recent years have seen the approval of new drugs against.
METHODS
This article is based on pertinent literature retrieved by a selective search in PubMed as well as on documentation of relevant risks and adverse effects in "red hand letters" (information bulletins from pharmaceutical companies to physicians about adverse drug effects) and elsewhere, along with data provided by the German Multiple Sclerosis Competence Network.
RESULTS
In recent years, there have been major advances enabling better, more individualized treatment of patients with MS. Physicians must, however, give due consideration to potentially severe or even life-threatening adverse drug effects. These can include, for example, transaminase elevation (hepatotoxicity), cardio- and nephrotoxicity, or lympho- and leukopenia with a variable risk of infection. Among patients taking natalizumab, the cumulative risk of developing progressive multifocal leukencephalopathy (PML) may be 1:100 or higher, depending on the individual risk profile. Rare cases of PML have also been seen under treatment with fingolimod and dimethyl fumarate. Moreover, any type of immunosuppressive treatment can, at least theoretically, increase the risk of malignant disease. Secondary autoimmune diseases can arise as well: approximately 35% of patients treated with alemtuzumab develop autoimmune thyroid disease within two years, and 2% of patients who take daclizumab have severe autoimmune dermatological side effects. Teriflunomide, fingolimod, natalizumab, mitoxantrone, interferon β1-a/b, and daclizumab can all damage the liver. There are also psychiatric, reproductive, and vaccineassociated risks and side effects that must be considered.
CONCLUSION
Newer drugs for MS have enabled more effective treatment, but are also associated with a higher risk of side effects. Interdisciplinary risk management is needed.
Topics: Germany; Humans; Immunosuppressive Agents; Multiple Sclerosis; Risk Management
PubMed: 28130920
DOI: 10.3238/arztebl.2016.0879 -
Scientifica 2013With the introduction of interferon- β 1b in 1993 as the first FDA-approved treatment for multiple sclerosis, the era of treatment of this incurable disease began, and... (Review)
Review
With the introduction of interferon- β 1b in 1993 as the first FDA-approved treatment for multiple sclerosis, the era of treatment of this incurable disease began, and its natural course was permanently changed. Currently, seven different treatments for patients with multiple sclerosis with different mechanisms of action and dissimilar side effect profiles exist. These medications include interferon- β 1a intramuscular (Avonex), interferon- β 1a subcutaneous (Rebif), interferon- β 1b subcutaneous (Betaseron/Extavia), glatiramer acetate (Copaxone), natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio), and mitoxantrone (Novantrone). In addition, a large number of clinical trials are being conducted to assess the safety and efficacy of various experimental agents in patients with multiple sclerosis, including alemtuzumab, dimethyl fumarate, laquinimod, rituximab, daclizumab, and cladribine. In this paper, the author presents a concise and comprehensive review of present and potential treatments for this incurable disease.
PubMed: 24278770
DOI: 10.1155/2013/249101 -
Journal of Immunology Research 2015In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not... (Review)
Review
In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4(+) regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naïve CD4(+) T cells to CD4(+) regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4(+) regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance. .
Topics: Animals; Antigens, Viral; Autoantigens; Autoimmunity; Hepatitis, Autoimmune; Hepatitis, Viral, Human; Humans; Immune Tolerance; Immunotherapy; Liver; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory
PubMed: 26106627
DOI: 10.1155/2015/479703