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Cells Jun 2020Alemtuzumab is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes... (Review)
Review
Alemtuzumab is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. It is currently used as an immune reconstitution therapy in patients with relapsing-remitting multiple sclerosis. Alemtuzumab treatment is an intermittent infusion that induces long-term remission of Multiple Sclerosis also in the treatment-free period. After the robust T and B cell depletion induced by alemtuzumab, the immune system undergoes radical changes during its reconstitution. In this review, we will discuss the current knowledge on the reconstitution of the lymphocyte repertoire after alemtuzumab treatment and how it could affect the development of side effects, which led to its temporary suspension by the European Medical Agency.
Topics: Alemtuzumab; Animals; Clinical Trials as Topic; Disease Models, Animal; Humans; Immune Reconstitution; Multiple Sclerosis; Translational Research, Biomedical
PubMed: 32503344
DOI: 10.3390/cells9061396 -
Arthritis Research & Therapy Apr 2022Primary systemic vasculitis (PSV) is a heterogeneous group of autoimmune conditions. There is an unmet need for alternative therapies that lead to sustained remission in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Primary systemic vasculitis (PSV) is a heterogeneous group of autoimmune conditions. There is an unmet need for alternative therapies that lead to sustained remission in patients with refractory disease. Alemtuzumab, an anti-CD52 antibody, depletes lymphocytes for prolonged periods and, in retrospective studies, has induced sustained, treatment-free remissions in patients with refractory/relapsing vasculitis but has raised safety concerns of infection and secondary autoimmunity. This phase IIb clinical trial aimed to assess the efficacy and safety of alemtuzumab, at two different doses, in inducing remission in refractory vasculitis patients.
METHODS
The ALEVIATE trial was a randomised, prospective, open-label, dose ranging clinical trial. Patients with refractory ANCA-associated vasculitis (AAV) or Behçet's disease (BD) were randomised to receive either 60 mg or 30 mg alemtuzumab. Treatments were administered at baseline and 6 months or earlier where clinically appropriate. A maximum of three treatments were allowed within the 12-month study period.
RESULTS
Twenty-three patients received at least one dose of alemtuzumab. Twelve had AAV, and 11 a diagnosis of BD. The median age was 40 years (range 28-44), with a prior disease duration of 61 months (42-103). Sixteen (70%) achieved either complete (6/23, 26%) or partial (10/23, 44%) response at 6 months. Eight (35%) maintained remission to the end of the trial without relapse. Ten severe adverse events were observed in 7 (30%) patients; 4 were related to alemtuzumab. There were no differences in clinical endpoints between the 60 and 30 mg alemtuzumab treatment groups.
CONCLUSION
In a selected group of refractory vasculitis patients, alemtuzumab led to remission in two thirds of patients at 6 months. Remission was maintained to 12 months in a third of the patients, and the safety profile was acceptable.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT01405807, EudraCT Number: 2009-017087-17. Registered on April 07, 2011.
Topics: Adult; Alemtuzumab; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Humans; Prospective Studies; Remission Induction; Retrospective Studies; Treatment Outcome
PubMed: 35365179
DOI: 10.1186/s13075-022-02761-6 -
CNS Drugs Nov 2021Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs)... (Review)
Review
Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs) has been approved for multiple sclerosis and related disorders such as neuromyelitis optica spectrum disorders, some of which are frequently also used in- or off-label to treat conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, myositis, and encephalitis. In this review, we focus on currently available immune therapeutics in neurology to explore their specific modes of action that might contribute to SID, with particular emphasis on their potential to induce secondary antibody deficiency. Considering evidence from clinical trials as well as long-term observational studies related to the patients' immune status and risks of severe infections, we delineate long-term anti-CD20 therapy, with the greatest data availability for rituximab, as a major risk factor for the development of SID, particularly through secondary antibody deficiency. Alemtuzumab and cladribine have relevant effects on circulating B-cell counts; however, evidence for SID mediated by antibody deficiency appears limited and urgently warrants further systematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk factors, individualized treatment protocols, and vaccination concepts. Immune supplementation employing Ig replacement therapy might reduce morbidity and mortality associated with SIDs in neurological conditions. In light of the broad range of existing and emerging therapies, the potential for SID warrants urgent consideration among neurologists and other healthcare professionals.
Topics: Age Factors; Alemtuzumab; Animals; Coinfection; Dimethyl Fumarate; Fingolimod Hydrochloride; Humans; Immunoglobulin G; Immunologic Factors; Immunosuppressive Agents; Immunotherapy; Infections; Natalizumab; Neurology; Risk Factors; Rituximab
PubMed: 34657228
DOI: 10.1007/s40263-021-00863-4 -
Annals of Clinical and Translational... Jun 2021Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS).... (Comparative Study)
Comparative Study
OBJECTIVE
Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS). This study aims to assess outcome differences in disease activity in MS patients treated either with aHSCT or alemtuzumab.
METHODS
We conducted a monocentric registry-based cohort study by recording the clinical course (EDSS and relapses), MRI parameters (new T2 lesions), and neuropsychological assessment in all 19 MS patients receiving aHSCT, and all 21 patients receiving alemtuzumab between 2007 and 2018. We used survival analyses of no evidence of disease activity (NEDA) as the primary objective which was defined by no EDSS progression, no relapse, and no new T2 lesion on MRI. Secondary objectives were EDSS improvement and neurocognitive performance.
RESULTS
Both treatment groups were similar in respect of age, gender, disability, and neurocognitive performance except for significantly longer disease duration in the alemtuzumab group. Mean follow-up was 58.8 [range 29-140] months in the aHSCT group compared to 27.6 [range 11-52] months in the alemtuzumab-treated group. We observed significantly more patients maintaining NEDA in the aHSCT group (p = 0.048) compared to the alemtuzumab-treated patients. Furthermore, 37% of the aHSCT patients showed an improvement of EDSS compared to none in the alemtuzumab-treated group (p = 0.033). It is of note that cognitive function was significantly improved in the aHSCT-treated patients.
INTERPRETATION
aHSCT suppresses inflammatory activity more effectively than alemtuzumab and might enable improvement of overall disability and cognition in MS.
Topics: Adult; Alemtuzumab; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; Outcome Assessment, Health Care; Patient Acuity; Registries; Transplantation, Autologous; Young Adult
PubMed: 33949790
DOI: 10.1002/acn3.51366 -
Frontiers in Immunology 2023Alemtuzumab is a monoclonal antibody targeting CD52 on the surface of immune cells, approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS)....
Immune reconstitution following alemtuzumab therapy is characterized by exhausted T cells, increased regulatory control of proinflammatory T cells and reduced B cell control.
Alemtuzumab is a monoclonal antibody targeting CD52 on the surface of immune cells, approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). The purpose of this study was to analyze the repopulation of peripheral lymphocytes following alemtuzumab-induced lymphocyte depletion and investigate associations with disease activity and development of secondary autoimmunity. For this, blood samples were collected two years after initiation of alemtuzumab treatment and lymphocytes were subjected to a comprehensive flow cytometry analysis. Included in the study were 40 patients treated with alemtuzumab and 40 treatment-naïve patients with RRMS. Disease activity and development of secondary autoimmune disease was evaluated after three years of treatment. Our study confirms that alemtuzumab treatment profoundly alters the circulating lymphocyte phenotype and describes a reconstituted immune system characterized by T cell activation/exhaustion, an increased regulatory control of IL-17 producing effector T cells and CD20 T cells, and a reduced control of B cells. There were no obvious associations between immune cell subsets and disease activity or development of secondary autoimmune disease during treatment with alemtuzumab. Our results indicate that the reconstituted immune response is skewed towards a more effective regulatory control of MS-associated proinflammatory T cell responses. Also, the enlarged pool of naïve B cells together with the apparent decrease in control of B cell activity may explain why alemtuzumab-treated patients retain the ability to mount a humoral immune response towards new antigens.
Topics: Humans; T-Lymphocytes; Alemtuzumab; Immune Reconstitution; B-Lymphocytes; Multiple Sclerosis, Relapsing-Remitting
PubMed: 37744364
DOI: 10.3389/fimmu.2023.1249201 -
Experimental and Clinical... Feb 2016Successful attenuation of allograft rejection rate is a major clinical aspect in transplant. The CD52 binding monoclonal antibody CAMPATH1 or alemtuzumab, in this... (Review)
Review
Successful attenuation of allograft rejection rate is a major clinical aspect in transplant. The CD52 binding monoclonal antibody CAMPATH1 or alemtuzumab, in this aspect, shows a promise as an effective immunomodifier. This humanized monoclonal antibody efficiently depletes CD52-bearing mature B- and T lymphocytes from circulation and thereby causes transient lymphopenia, a condition for generalized immunosuppression. Alemtuzumab is an approved drug for the treatment of B cell chronic lymphocytic leukemia. However, its implication in transplant as nonsteroidal drug is a growing area of investigation. Here, we provided a brief account on alemtuzumab as an immunomodifier in allotransplant.
Topics: Alemtuzumab; Allografts; Animals; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Neoplasm; CD52 Antigen; Glycoproteins; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Organ Transplantation; Treatment Outcome
PubMed: 26862819
DOI: No ID Found -
Seminars in Hematology Apr 2008The introduction of the monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52) has revolutionized the treatment of chronic lymphocytic leukemia (CLL).... (Review)
Review
The introduction of the monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52) has revolutionized the treatment of chronic lymphocytic leukemia (CLL). Both antibodies were first studied as single agents in relapsed CLL, but rituximab is increasingly used in combination chemoimmunotherapy regimens in previously untreated patients. Phase II studies demonstrated that the addition of rituximab to fludarabine-based chemotherapy improves complete response (CR) rates and prolongs progression-free survival (PFS), but a long-term survival benefit has not been shown. Alemtuzumab is less commonly used, due to the greater likelihood of infusion toxicity, as well as hematologic and immune toxicities. Subcutaneous (SC) administration significantly reduces infusion toxicity, but hematologic and infectious complications, most notably cytomegalovirus (CMV) reactivation, still occur with SC dosing. Alemtuzumab's unique clinical properties include its clinical activity in relapsed CLL patients with del(17p13) and its ability to eradicate minimal residual disease (MRD) in bone marrow. Its use as consolidation therapy to eradicate MRD after nucleoside analog therapy is under active study. Several investigational monoclonal antibodies are in preclinical or clinical studies, most notably lumiliximab (anti-CD23) and ofatumumab (HuMax CD20), and are briefly discussed in this review.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Disease Progression; Disease-Free Survival; Drugs, Investigational; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Pentostatin; Rituximab; Vidarabine
PubMed: 18381104
DOI: 10.1053/j.seminhematol.2008.02.001 -
Therapeutic Drug Monitoring Aug 2017Multiple sclerosis is a heterogenous disease. Although several EMA-approved disease-modifying treatments including biopharmaceuticals are available, their efficacy is... (Review)
Review
Multiple sclerosis is a heterogenous disease. Although several EMA-approved disease-modifying treatments including biopharmaceuticals are available, their efficacy is limited, and a certain percentage of patients are always nonresponsive. Drug efficacy monitoring is an important tool to identify these nonresponsive patients early on. Currently, detection of antidrug antibodies and quantification of biological activity are used as methods of efficacy monitoring for interferon beta and natalizumab therapies. For natalizumab and alemtuzumab treatments, drug level quantification could be an essential component of the overall disease management. Thus, utilization and development of strategies to determine treatment response are vital aspects of multiple sclerosis management given the tremendous clinical and economic promise of this tool.
Topics: Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Biological Factors; Drug Monitoring; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; Treatment Outcome
PubMed: 28328761
DOI: 10.1097/FTD.0000000000000393 -
Neurology Sep 2017To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy.
OBJECTIVE
To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy.
METHODS
In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed.
RESULTS
Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3-5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1-5: -0.48%, -0.22%, -0.10%, -0.19%, -0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter.
CONCLUSIONS
Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Atrophy; Brain; Disability Evaluation; Follow-Up Studies; Humans; Immunologic Factors; Kaplan-Meier Estimate; Multiple Sclerosis, Relapsing-Remitting; Organ Size; Time Factors; Treatment Outcome
PubMed: 28835403
DOI: 10.1212/WNL.0000000000004354 -
Therapeutic Drug Monitoring Feb 2023Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein expressed on most lymphocytes, subsequently inducing complement-mediated and...
BACKGROUND
Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein expressed on most lymphocytes, subsequently inducing complement-mediated and antibody-mediated cytotoxicity. Owing to its ability to induce profound immune depletion, alemtuzumab is frequently used in patients before allogeneic hematopoietic stem cell transplantation to prevent graft rejection and acute graft-versus-host disease. In this clinical context, a stable immunoassay with high sensitivity and specificity to determine alemtuzumab levels is essential for performing pharmacokinetic and pharmacodynamic analyses; however, the available methods have several limitations. Here, we report the successful development and validation of an efficient and highly sensitive enzyme-linked immunosorbent assay technique based on commercially available reagents to quantify alemtuzumab in human serum or plasma.
METHODS
This enzyme-linked immunosorbent assay technique was developed and validated in accordance with the European Medicines Agency guidelines on bioanalytical method validation.
RESULTS
The assay sensitivity (lower limit of quantification) is 0.5 ng·mL -1 , and the dynamic range is 0.78-25 ng·mL -1 . To accommodate quantification of peak concentration and concentrations below the lympholytic level (<0.1 mcg·mL -1 ), patients' serum samples were prediluted 20-400 times according to the expected alemtuzumab concentration. The overall within-run accuracy was between 96% and 105%, whereas overall within-run precision (coefficient of variation) was between 3% and 9%. The between-run assessment provided an overall accuracy between 86% and 95% and an overall coefficient of variation between 5% and 14%.
CONCLUSIONS
The developed assay provides accurate insight into alemtuzumab exposure and its effects on the clinical response to treatment, which is key to optimizing treatment strategies.
Topics: Humans; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Graft vs Host Disease; Enzyme-Linked Immunosorbent Assay
PubMed: 36150715
DOI: 10.1097/FTD.0000000000001037