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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 -
Neurology(R) Neuroimmunology &... Mar 2020The use of alemtuzumab, a humanized monoclonal anti-CD52 antibody has changed the therapy of highly active relapsing-remitting MS (RRMS). Alemtuzumab infusion depletes...
OBJECTIVE
The use of alemtuzumab, a humanized monoclonal anti-CD52 antibody has changed the therapy of highly active relapsing-remitting MS (RRMS). Alemtuzumab infusion depletes most lymphocytes in peripheral blood, whereas differential recovery of immune cells, probably those with a less CNS-autoreactive phenotype, is supposed to underlie its long-lasting effects. To determine whether alemtuzumab significantly reduces immunoglobulin levels in blood and CSF of treated patients, we analyzed blood and CSF samples of 38 patients with MS treated with alemtuzumab regarding changes in immunoglobulin levels.
METHODS
Blood and CSF samples of patients were collected at the beginning of alemtuzumab treatment and at 12, 24, and 36 months after the first administration of the drug. Specimens were analyzed regarding immunoglobulin concentrations in blood and CSF.
RESULTS
We observed significant and dose-dependent reductions of immunoglobulin levels (IgG, IgM, and IgA) in serum and CSF 12 and 24 months following 2 courses of alemtuzumab. Patients with persistent or returning disease activity who were treated with a third course of alemtuzumab exhibited even further decrease in IgG levels compared with matched controls treated twice. Here, alemtuzumab-treated patients with IgG levels below the lower limits of normal were more susceptible to pneumonia, sinusitis, and otitis, whereas upper respiratory tract and urinary tract infections were not associated therewith.
CONCLUSIONS
Our results suggest to monitor IgG levels for safety reasons in patients treated with alemtuzumab-in particular when additional treatment courses are required-and to consider preventive action in critical cases.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that for patients with RRMS alemtuzumab reduces immunoglobulin levels.
Topics: Adolescent; Adult; Alemtuzumab; Female; Follow-Up Studies; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologic Factors; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Young Adult
PubMed: 31826986
DOI: 10.1212/NXI.0000000000000654 -
Transplant Infectious Disease : An... Dec 2023
Topics: Humans; Histoplasmosis; Alemtuzumab; Histoplasma; Antifungal Agents
PubMed: 37323093
DOI: 10.1111/tid.14089 -
Transplantation Reviews (Orlando, Fla.) Apr 2022Kidney transplantation has evolved over the years from transplants between identically matched donors and recipients to successfully transplanting allografts across... (Review)
Review
Kidney transplantation has evolved over the years from transplants between identically matched donors and recipients to successfully transplanting allografts across virtually any degree of donor-recipient human leukocyte antigen mismatch and ABO-incompatibility. Integral to these improved outcomes has been the development and deployment of a range of immunosuppressive agents. The addition of monoclonal and polyclonal antibodies as a standard part of overall immunosuppression has led to the improved outcomes by providing a robust and focused protection during the first few months of transplantation when allografts are most vulnerable to immune-mediated injury. Alemtuzumab is a recombinant anti-CD52 pan-lymphocyte depleting monoclonal antibody that has been in use for kidney transplantation since the late 1990s. Despite the many years of experience with alemtuzumab, its utilisation in the UK has remained relatively restrained. This may be due to a lack of high-level evidence to support its safety and efficacy in transplantation. Also, long-term outcomes have not been addressed by existing studies. Nevertheless, available evidence suggests that alemtuzumab is associated with a lower risk of acute rejection within the first year of transplantation while exhibiting a comparable safety profile to non-lymphocyte depleting agents. Despite the current economic advantages of alemtuzumab (available free of cost on a named transplant recipient basis), its use in UK transplant centres has remained limited, variating from non-use, through usage in selected high immunologic risk subjects, to use as routine induction immunosuppression. This review discusses the current use of alemtuzumab for immunosuppression induction in kidney transplantation. It describes its evolution from development to its present application in kidney transplantation and reviews the evidence underpinning its utilisation. The role of alemtuzumab in the immunosuppressive protocols individual UK kidney transplant centres is also described.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation
PubMed: 35151219
DOI: 10.1016/j.trre.2022.100686 -
Multiple Sclerosis (Houndmills,... Jan 2020Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk.
OBJECTIVE
To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials.
METHODS
CAMMS223 and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion.
RESULTS
Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials.
CONCLUSION
Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.
Topics: Adult; Alemtuzumab; Female; Follow-Up Studies; Humans; Immunologic Factors; Incidence; Interferon beta-1a; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Purpura, Thrombocytopenic, Idiopathic
PubMed: 30785358
DOI: 10.1177/1352458518816612 -
Current Neurology and Neuroscience... Sep 2016Alemtuzumab is a humanised anti-CD52 monoclonal antibody approved for use in active, relapsing multiple sclerosis (MS). Administration results in a rapid depletion of... (Review)
Review
Alemtuzumab is a humanised anti-CD52 monoclonal antibody approved for use in active, relapsing multiple sclerosis (MS). Administration results in a rapid depletion of circulating lymphocytes with a subsequent beneficial immune reconstitution. Early open-label experience and recent clinical trials have demonstrated a dramatic effect on relapse rates as well as a positive effect on radiological disease outcomes and disability measures. Despite a mechanism of action that results in profound lymphopaenia, opportunistic infections are rarely seen and no excess association with malignancy has been identified. However, acquired autoimmune disease (AID) is a common adverse event following treatment, necessitating rigorous monitoring in order to facilitate prompt detection and management. Despite this issue, a unique dosing schedule and durability of effect make alemtuzumab a welcome addition to currently available treatment options for MS.
Topics: Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Autoimmunity; Clinical Trials as Topic; Humans; Multiple Sclerosis; Neoplasms; Recurrence
PubMed: 27485945
DOI: 10.1007/s11910-016-0685-y -
European Journal of Neurology Apr 2021Blood pressure (BP) changes during alemtuzumab infusions are poorly understood. The aim of this study was to examine BP changes during alemtuzumab infusions in persons...
BACKGROUND AND PURPOSE
Blood pressure (BP) changes during alemtuzumab infusions are poorly understood. The aim of this study was to examine BP changes during alemtuzumab infusions in persons with multiple sclerosis (PwMS).
METHODS
This was a retrospective cohort review of systolic (S) and diastolic (D) BP in PwMS receiving alemtuzumab.
RESULTS
Thirty-one patients were identified; 22 (64.5%) were women. Mean age and disease duration were 35.2 ± 7.1 and 9.2 ± 5.4 years, respectively. There was no history of hypertension or vascular events. Mean baseline SBP was 119.8 ± 15.1 mmHg, 118.8 ± 14.3 mmHg and 106.5 ± 6.1 mmHg whilst mean DBP was 75.3 ± 9.2 mmHg, 74.1 ± 12.4 mmHg and 69.2 ± 4.3 mmHg at doses 1, 6 and 9, respectively. During the first cycle, SBP increased by 19.2 ± 9.4 mmHg, with comparable percentage increases over the five infusions (16%, 22%, 17%, 11%, 13%, respectively). DBP increased by 6.2 ± 3.8 mmHg with similar percentage increases over the five infusions (8.4%, 11.5%, 5.5%, 7%, 3%). For the second cycle, SBP increased by 16.9 ± 3.2 mmHg, with similar increases over the 3 days (12%, 15%, 17%). DBP increased by 5.4 ± 4.2 mmHg (11%, 9%, 12.8%). The third cycle demonstrated increased mean and percentage of SBP and DBP by 8.9 ± 2.3 mmHg (10%, 70%, 11.8%) and 4.2 ± 1.9 mmHg (3%, 2%, 6.5%), respectively. Collectively, for 31 patients, in the first cycle, mean SBP increased from 119.8 ± 15.1 mmHg to 138.8 ± 13 mmHg (p ˂ 0.001), whilst mean DBP increased from 74.5 ± 9.2 mmHg to 79.2 ± 9.1 mmHg (p = 0.007). Overall, 17 (54.8%) patients had increasing BP by ≥20% and nine (29%) had increasing BP by ≥20 mmHg from baseline.
CONCLUSIONS
This demonstrates significant increases in BP during alemtuzumab infusions in PwMS.
Topics: Alemtuzumab; Blood Pressure; Female; Humans; Hypertension; Multiple Sclerosis; Retrospective Studies
PubMed: 33175474
DOI: 10.1111/ene.14633 -
CNS Drugs Jan 2017Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of... (Review)
Review
Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naïve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naïve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Europe; Humans; Multiple Sclerosis; Treatment Outcome
PubMed: 27882532
DOI: 10.1007/s40263-016-0394-8 -
Clinical Pharmacokinetics Feb 2018Alemtuzumab is a humanized monoclonal antibody against CD52 and causes depletion of T and B lymphocytes, monocytes, and NK cells. Alemtuzumab is registered for the... (Comparative Study)
Comparative Study
Alemtuzumab is a humanized monoclonal antibody against CD52 and causes depletion of T and B lymphocytes, monocytes, and NK cells. Alemtuzumab is registered for the treatment of multiple sclerosis (MS) and is also used in chronic lymphocytic leukemia (CLL). Alemtuzumab is used off-label in kidney transplantation as induction and anti-rejection therapy. The objective of this review is to present a review of the pharmacokinetics, pharmacodynamics, and use of alemtuzumab in kidney transplantation. A systematic literature search was conducted using Ovid Medline, Embase, and Cochrane Central Register of controlled trials. No pharmacokinetic or dose-finding studies of alemtuzumab have been performed in kidney transplantation. Although such studies were conducted in patients with CLL and MS, these findings cannot be directly extrapolated to transplant recipients, because CLL patients have a much higher load of CD52-positive cells and, therefore, target-mediated clearance will differ between these two indications. Alemtuzumab used as induction therapy in kidney transplantation results in a lower incidence of acute rejection compared to basiliximab therapy and comparable results as compared with rabbit anti-thymocyte globulin (rATG). Alemtuzumab used as anti-rejection therapy results in a comparable graft survival rate compared with rATG, although infusion-related side effects appear to be less. There is a need for pharmacokinetic and dose-finding studies of alemtuzumab in kidney transplant recipients to establish the optimal balance between efficacy and toxicity. Furthermore, randomized controlled trials with sufficient follow-up are necessary to provide further evidence for the treatment of severe kidney transplant rejection.
Topics: Alemtuzumab; Animals; Antineoplastic Agents, Immunological; Basiliximab; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Treatment Outcome
PubMed: 28669130
DOI: 10.1007/s40262-017-0573-x -
Scientific Reports Apr 2022Alemtuzumab is a monoclonal antibody targeting CD52, used as induction therapy after lung transplantation (LTx). Its engagement produces a long-lasting immunodepletion;...
Alemtuzumab is a monoclonal antibody targeting CD52, used as induction therapy after lung transplantation (LTx). Its engagement produces a long-lasting immunodepletion; however, the mechanisms driving cell reconstitution are poorly defined. We hypothesized that miRNAs are involved in this process. The expression of a set of miRNAs, cytokines and co-signaling molecules was measured with RT-qPCR and flow cytometry in prospectively collected serum samples of LTx recipients, after alemtuzumab or no induction therapy. Twenty-six LTx recipients who received alemtuzumab and twenty-seven matched LTx recipients without induction therapy were included in the analysis. One year after transplantation four miRNAs were differentially regulated: miR-23b (p = 0.05) miR-146 (p = 0.04), miR-155 (p < 0.001) and miR-486 (p < 0.001). Expression of 3 miRNAs changed within the alemtuzumab group: miR-146 (p < 0.001), miR-155 (p < 0.001) and miR-31 (p < 0.001). Levels of IL-13, IL-4, IFN-γ, BAFF, IL-5, IL-9, IL-17F, IL-17A and IL-22 were different one year after transplantation compared to baseline. In no-induction group, concentration of sCD27, sB7.2 and sPD-L1 increased overtime. Expression of miR-23b, miR-146, miR-486, miR-155 and miR-31 was different in LTx recipients who received alemtuzumab compared to recipients without induction therapy. The observed cytokine pattern suggested proliferation of specific B cell subsets in alemtuzumab group and co-stimulation of T-cells in no-induction group.
Topics: Alemtuzumab; Circulating MicroRNA; Cytokines; Induction Chemotherapy; Lung Transplantation; MicroRNAs
PubMed: 35490174
DOI: 10.1038/s41598-022-10866-w