BACKGROUND: The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis. METHODS: In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability. RESULTS: A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group. CONCLUSIONS: Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

• MeSH
• antiflogistika nesteroidní terapeutické užití   MeSH
• dvojitá slepá metoda MeSH
• gadolinium terapeutické užití   MeSH
• hydroxybutyráty MeSH
• imunosupresiva terapeutické užití   MeSH
• krotonáty MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• monoklonální protilátky * terapeutické užití   MeSH
• nitrily MeSH
• relabující-remitující roztroušená skleróza * komplikace   diagnostické zobrazování   farmakoterapie   patologie   MeSH
• roztroušená skleróza komplikace   diagnostické zobrazování   farmakoterapie   patologie   MeSH
• toluidiny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

• Publikační typ
• zprávy MeSH

BACKGROUND: Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity. The phase 3 ULTIMATE I and II studies showed significant improvements in annualized relapse rate, total number of gadolinium-enhancing (Gd+) T1 lesions, and total number of new or enlarging T2 at Week 96, as well as improvement in the proportion of participants with no evidence of disease activity (NEDA) from Weeks 24-96 with ublituximab vs. teriflunomide. METHODS: In ULTIMATE I (NCT03277261; www.clinicaltrials.gov) (N = 549) and II (NCT03277248; www.clinicaltrials.gov) (N = 545), participants with relapsing multiple sclerosis received ublituximab 450 mg intravenous infusion every 24 weeks (following Day 1 infusion of 150 mg and Day 15 infusion of 450 mg) or teriflunomide 14 mg oral once daily for 96 weeks. Pooled post hoc analyses evaluated NEDA by treatment epoch and participant subtype: age ( ≤ 38 or >38 years), early or later disease (<3 or ≥3 years following diagnosis), treatment history (treatment naïve or previously treated), 0 or ≥1 Gd+ T1 lesions at baseline, and Expanded Disability Status Scale score ≤ 3.5 or >3.5 at baseline. NEDA was defined as no confirmed relapses, no Gd+ T1 lesions, no new or enlarging T2 lesions, and no disability progression confirmed for ≥12 weeks. RESULTS: NEDA rates in the ublituximab vs. teriflunomide cohorts by treatment epoch were: Weeks 0-96, 44.6% vs. 12.4% (3.6 × improvement); Weeks 24-96 (re-baselined), 82.1% vs. 22.5% (3.6 × improvement); and Weeks 48-96 (re-baselined), 88.2% vs. 30.4% (2.9 × improvement) (all p < 0.0001). The primary driver of disease activity in ublituximab-treated participants was new or enlarging T2 lesions during Weeks 0-24. 41.8% of ublituximab-treated participants who had evidence of disease activity in the first year (Weeks 0-48) experienced NEDA in the second year of treatment (Weeks 48-96) compared with 17.3% of teriflunomide-treated participants. At Weeks 24-96 (re-baselined), rates of NEDA were significantly higher with ublituximab than teriflunomide in all participant subtypes (all p < 0.0001). CONCLUSIONS: ULTIMATE I and II pooled post hoc analyses demonstrated a consistent NEDA benefit among ublituximab-treated participants across treatment epochs and key participant subpopulations.

• Publikační typ
• časopisecké články MeSH

Monoklonální protilátky se staly základem v léčbě pacientů s roztroušenou sklerózou. Jejich mechanismus účinku cílí na odlišné imunitní mechanismy patofyziologie roztroušené sklerózy. Natalizumab působí prostřednictvím vazby na buněčné povrchové receptory, a tím zabraňuje migraci leukocytů přes hematoencefalickou bariéru. Alemtuzumab, rituximab, okrelizumab, ofatumumab a ublituximab eliminují vybranou populaci patogenních buněk. Opicinumab působí jako antagonista transmembránového signálního proteinu (LINGO-1). Tato léčiva jsou významným pilířem v léčbě roztroušené sklerózy. Potenciální nežádoucí účinky však mohou být závažné a mohou vyžadovat přerušení léčby. Především jde o riziko oportunních infekcí, ale také sekundárních autoimunitních onemocnění nebo malignit. K léčbě a prevenci migrén se využívají monoklonální protilátky, které se váží na receptor calcitonin gene­‐related peptide (CGRP) a inhibují jej. CGRP monoklonální protilátky jsou první specifickou profylaxí založenou na znalostech patofyziologie migrény. Celá řada klinických studií naznačuje novou možnost v léčbě a profylaxi migrén, která by měla snížit rizika plynoucí z nadužívání jiných skupin léků, především pak nesteroidních protizánětlivých analgetik.

Monoclonal antibodies have become a mainstay in the treatment of patients with multiple sclerosis. Their mechanism of action targets distinct immune mechanisms of multiple sclerosis pathophysiology. Natalizumab acts by binding to cell surface receptors and thus prevents the migration of leukocytes across the blood-brain barrier. Alemtuzumab, rituximab, ocrelizumab, ofatumumab and ublituximab eliminate a selected population of pathogenic cells. Opicinumab acts as a transmembrane signaling protein (LINGO-1) antagonist. These drugs are an important pillar in the treatment of scattered. However, potential side effects can be serious and may require discontinuation of treatment. Above all, it is a risk of opportunistic infections, but also of secondary autoimmune diseases or malignancies. Monoclonal antibodies that bind to and inhibit the calcitonin gene-related peptide (CGRP) receptor are used to treat and prevent migraines. CGRP monoclonal antibodies are the first specific prophylaxis based on knowledge of the pathophysiology of migraine. A whole series of clinical studies indicate a new possibility in the treatment and prophylaxis of migraines, which should reduce the risks resulting from the overuse of other groups of drugs, especially non-steroidal anti-inflammatory analgesics.

• MeSH
• lidé MeSH
• migréna farmakoterapie   patofyziologie   MeSH
• monoklonální protilátky * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• roztroušená skleróza farmakoterapie   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• Klíčová slova
• ruxolitinib, pegunigalsidáza alfa, vadadustat, Ivosidenib, mirikizumab, ublituximab, thiosulfát sodný,
• MeSH
• alfa-galaktosidasa terapeutické užití   MeSH
• anemie farmakoterapie   MeSH
• Fabryho nemoc farmakoterapie   MeSH
• inhibitory interleukinu terapeutické užití   MeSH
• inhibitory Janus kinas terapeutické užití   MeSH
• inhibitory prolylhydroxylas terapeutické užití   MeSH
• lidé MeSH
• mutantní proteiny terapeutické užití   MeSH
• myeloidní leukemie farmakoterapie   MeSH
• ototoxicita farmakoterapie   MeSH
• roztroušená skleróza farmakoterapie   MeSH
• schvalování léčiv * MeSH
• thiosírany terapeutické užití   MeSH
• vitiligo farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Geografické názvy
• Evropa MeSH

Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell-related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD), or are in advanced stages of clinical development. Currently, ocrelizumab, ofatumumab, and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This review focuses on the current state of knowledge about the role of B lymphocytes in immune-mediated pathophysiology and its implications for the mode of action. To understand the significance of this breakthrough in the context of the current MS therapeutic armamentarium, this review more closely examines the clinical development of CD20 depletion and the pioneering contribution of rituximab. Phase 3 and the recently published postmarketing studies will be highlighted to better understand the relevant efficacy data and safety aspects of long-term B-cell depletion.

• MeSH
• antigeny CD20 účinky léků   imunologie   MeSH
• B-lymfocyty účinky léků   imunologie   MeSH
• imunologické faktory farmakologie   MeSH
• lidé MeSH
• neuromyelitis optica farmakoterapie   imunologie   MeSH
• roztroušená skleróza farmakoterapie   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell-related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD) or are in advanced stages of clinical development. Currently, ocrelizumab and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This part of the review focuses on monoclonal antibody B cell-depleting strategies in NMOSD and the emerging related myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G-associated disease (MOGAD). Case series and phase 2/3 studies in these inflammatory disorders are assessed. The safety profile of long-term B-cell depletion in MS, NMOSD, and MOGAD will be highlighted. Finally implications of the current coronavirus disease 2019 pandemic on the management of patients with these disorders and the use of B cell-depleting agents will be discussed.

• MeSH
• akvaporin 4 MeSH
• B-lymfocyty MeSH
• COVID-19 * MeSH
• lidé MeSH
• neuromyelitis optica * farmakoterapie   MeSH
• SARS-CoV-2 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Monoclonal antibodies have become a mainstay in the treatment of patients with relapsing multiple sclerosis (RMS) and provide some benefit to patients with primary progressive MS. They are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. They not only differ in the target antigen they recognize but also by the mode of action that generates their therapeutic effect. Natalizumab, an [Formula: see text]4[Formula: see text]1 integrin antagonist, works via binding to cell surface receptors, blocking the interaction with their ligands and, in that way, preventing the migration of leukocytes across the blood-brain barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and ublituximab work via eliminating selected pathogenic cell populations. However, potential adverse effects may be serious and can necessitate treatment discontinuation. Most importantly, those are the risk for (opportunistic) infections, but also secondary autoimmune diseases or malignancies. Monoclonal antibodies also carry the risk of infusion/injection-related reactions, primarily in early phases of treatment. By careful patient selection and monitoring during therapy, the occurrence of these potentially serious adverse effects can be minimized. Monoclonal antibodies are characterized by a relatively long pharmacologic half-life and pharmacodynamic effects, which provides advantages such as permitting infrequent dosing, but also creates disadvantages regarding vaccination and family planning. This review presents an overview of currently available monoclonal antibodies for the treatment of RMS, including their mechanism of action, efficacy and safety profile. Furthermore, we provide practical recommendations for risk management, vaccination, and family planning.

• MeSH
• lidé MeSH
• monoklonální protilátky terapeutické užití   MeSH
• natalizumab terapeutické užití   MeSH
• protinádorové látky imunologicky aktivní * terapeutické užití   MeSH
• řízení rizik MeSH
• roztroušená skleróza * terapie   MeSH
• těhotenství MeSH
• vakcinace MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH