scholarly journals A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis

2020 ◽  
pp. 135245852091837 ◽  
Author(s):  
Edward Fox ◽  
Amy E Lovett-Racke ◽  
Matthew Gormley ◽  
Yue Liu ◽  
Maria Petracca ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibody ◽  
B Cell ◽  
Optimal Dose ◽  
Cell Depletion ◽  
Controlled Study ◽  
Lesion Volume ◽  
B Cell Depletion ◽  
Phase 2 ◽  
Anti Cd20

Background: Ublituximab, a novel monoclonal antibody (mAb) targeting a unique epitope on the CD20 antigen, is glycoengineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity (ADCC). Greater ADCC may allow lower doses and shorter infusion times versus other anti-CD20 mAbs. Objective: The objective was to determine optimal dose, infusion time, and activity of ublituximab in relapsing multiple sclerosis. Methods: This is a phase 2, placebo-controlled study. Patients received three ublituximab infusions (150 mg over 1–4 hours on day 1 and 450–600 mg over 1–3 hours on day 15 and week 24) in six dosing cohorts. The primary endpoint was B-cell depletion. Results: In all cohorts ( N = 48), median B-cell depletion was >99% by week 4, maintained at weeks 24 and 48. Most common adverse events (AEs) were infusion-related reactions (all grade 1–2), with no apparent increased incidence at shorter infusion times. There were no AE-related discontinuations. At weeks 24 and 48, no T1 gadolinium-enhancing lesions ( p = 0.003) and a 10.6% decrease in T2 lesion volume ( p = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA). Conclusion: Ublituximab was safely infused as rapid as 1 hour, producing robust B-cell depletion and profound reductions in magnetic resonance imaging (MRI) activity and relapses.

scholarly journals Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study

2021 ◽  
pp. 135245852110444
Author(s):  
Amit Bar-Or ◽  
Heinz Wiendl ◽  
Xavier Montalban ◽  
Enrique Alvarez ◽  
Maria Davydovskaya ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cell ◽  
Geometric Mean ◽  
Cell Depletion ◽  
Maximum Plasma ◽  
B Cell Depletion ◽  
Phase 2 ◽  
Cell Counts ◽  
Phase 2 Study ◽  
Relapsing Multiple Sclerosis

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUC τ) and maximum plasma concentration ( Cmax) for Weeks 8–12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUC τ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.

scholarly journals 133 B cell depletion therapy resulting in sustained remission of severe autoimmune complications following alemtuzumab treatment of multiple sclerosis

2019 ◽  
Vol 90 (e7) ◽  
pp. A43.2-A43
Author(s):  
Jennifer Massey ◽  
Ian Sutton
Keyword(s):  
Multiple Sclerosis ◽  
B Cell ◽  
Autoimmune Encephalitis ◽  
Time Frame ◽  
Cell Depletion ◽  
Sustained Remission ◽  
B Cell Depletion ◽  
Autoimmune Thyroid ◽  
Acquired Haemophilia ◽  
Anti Cd20

IntroductionAlemtuzumab is a pan-lymphocyte ablating anti CD-52 monoclonal antibody licensed for the treatment of relapsing remitting multiple sclerosis (RRMS). Despite being classified as a high efficacy therapy, clinical application of alemtuzumab has been hampered by the frequent occurrence of secondary autoimmune disease (AID), with clinical trials and single-centre follow up cohorts estimating an incidence of up to 50% at seven years post treatment. Despite the establishment of pharmacovigilance programs to monitor for common complications of alemtuzumab, management guidelines for these conditions are lacking.MethodsHere, we report a series of cases of female patients treated with alemtuzumab for RRMS who developed treatment refractory secondary AID complications; specifically acquired haemophilia A (AHA) and an autoimmune encephalitis (AIE).ResultsWe report the sustained remission of these severe autoimmune disorders following administration of anti-CD20 therapy. This supports the current understanding of alemtuzumab associated AIDs, which occur in a time frame in which B-cell hyperpopulation and peripheral expansion occurs following initial lymphoablation.ConclusionsThus, we suggest that B-cell depletion should be initiated early in patients with severe, refractory complications of alemtuzumab. Furthermore, we suggest vigilant monitoring of patients with a preceding history of autoimmune thyroid disease following alemtuzumab treatment, as our experience suggests these patients have already demonstrated the potential to develop secondary AID.

scholarly journals Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study

2007 ◽  
Vol 156 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Mario Salvi ◽  
Guia Vannucchi ◽  
Irene Campi ◽  
Nicola Currò ◽  
Davide Dazzi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Thyroid Function ◽  
Cell Depletion ◽  
Clinical Activity ◽  
Graves Disease ◽  
B Cell Depletion ◽  
Muscle Involvement ◽  
Inflammatory Phase ◽  
Anti Cd20

Introduction: Hyperthyroid Graves’ disease (GD) is a B-cell-mediated condition caused by TSH receptor antibodies (TRAb), which decline when GD remits. Anti-CD20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophthalmopathy (TAO). Methods: Nine patients with GD, (seven with active TAO, two with mild lid signs) were studied. The trial was only approved as an open pilot study; thus we compared the effect of RTX therapy to that of i.v. glucocorticoids (IVGC) in 20 consecutive patients. Patients were treated with RTX (1000 mg i.v. twice at 2-week interval) or with IVGC (500 mg i.v. for 16 weeks). TAO was assessed by the clinical activity score (CAS) and severity was classified using NOSPECS (No signs or symptoms; Only signs (lid); Soft tissue involvement; Proptosis, Extraocular muscle involvement; Corneal involvement; Sight loss). Thyroid function and lymphocyte count were measured by standardized methods. Results: All patients attained peripheral B-cell depletion with the first RTX infusion. Minor side effects were reported in three patients. Thyroid function was not affected by RTX therapy and hyperthyroid patients required therapy with methimazole. After RTX, the changes in the levels of thyroglobulin antibodies, thyroperoxidase antibodies and TRAb were neither significant nor correlated with CD20+ depletion (P = NS). CAS values before RTX were 4.7 ± 0.5 and decreased to 1.8 ± 0.8 at the end of follow-up (P < 0.0001) and more significantly compared with IVGC (P < 0.05). Proptosis decreased significantly after RTX both in patients with active TAO (ANOVA; P < 0.0001) and those with lid signs (ANOVA; P < 0.003). The degree of inflammation (class 2) decreased significantly in response to RTX (ANOVA; P < 0.001). Relapse of active TAO was not observed in patients treated with RTX, but occurred in 10% of those treated with IVGC, who also experienced adverse effects more frequently (45 vs 33% of patients). Conclusions: RTX positively affects the clinical course of TAO, independently of either thyroid function or circulating antithyroid antibodies, including TRAb. If our findings are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO.

Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4424-4428 ◽  
Author(s):  
Roberto Stasi ◽  
Maurizio Brunetti ◽  
Elisa Stipa ◽  
Sergio Amadori
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Complete Response ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Acquired Hemophilia ◽  
Durable Response ◽  
Fviii Inhibitor ◽  
Fviii Activity ◽  
Anti Cd20

Abstract The activity and safety profile of selective B-cell depletion with rituximab, an anti-CD20 monoclonal antibody, were evaluated in 10 patients with acquired hemophilia. Rituximab was given intravenously at the dose of 375 mg/m2 once weekly for 4 consecutive weeks. Infusion-related side effects were observed in 3 patients but were of mild intensity and did not require discontinuation of treatment. Eight patients with Factor VIII (FVIII) inhibitor titers between 4 and 96 Bethesda units per milliliter (BU/mL) achieved a complete remission, which was defined as a return to normal FVIII activity and undetectable FVIII inhibitor titers. Two more patients with inhibitor levels greater than 100 BU/mL experienced only a partial transient decrease of the inhibitor after rituximab alone, but they achieved a complete response after being challenged with a combination of rituximab plus pulse intravenous cyclophosphamide. With a median follow-up of 28.5 months (range, 12-41 months), 3 patients have thus far relapsed. Retreatment with the monoclonal antibody at the same dose and schedule resulted in a new sustained response in all these patients. In conclusion, rituximab appears an effective and well-tolerated treatment for patients with acquired hemophilia and low inhibitor titers. A reinforcement of therapy with other agents seems to be required to achieve a full and durable response in those patients with high inhibitor levels. (Blood. 2004;103:4424-4428)

scholarly journals POS1226 THE COURSE OF CORONAVIRUS DISEASE 2019 (COVID-19) IN PATIENTS WITH SJOGREN’S SYNDROME TREATED WITH ANTI-CD20 MONOCLONAL ANTIBODY (RITUXIMAB)

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 896.3-897
Author(s):  
E. Sokol ◽  
A. Torgashina ◽  
B. Chalcev ◽  
J. Khvan ◽  
O. Golovina
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Rheumatic Diseases ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Lung Involvement ◽  
Anti Cd20 ◽  
Sjögren‘S Syndrome

Background:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) raised concern for the outcomes in people with different rheumatic diseases and management of these patients. There was an anxiety that biologic therapies, especially anti-B-cell depletion strategies, could lead to more severe disease course and lack of protective antibodies formation. Information about the course of COVID-19 in patients with certain rheumatic diseases is still lacking.Objectives:To examine clinical course of COVID-19 in patients with Sjogren’s syndrome treated with anti-CD20 monoclonal antibody (rituximab).Methods:Single center observational study. Diagnosis of SjS was based on ECR/EULAR 2016 criteria. COVID-19 diagnosis was based on positive PCR test even without clinical symptoms and/or typical clinical features (CT signs, fever and anosmia). Rituximab was administrated in two 1000 mg infusions 14 days apart for the 1st course, then 500 mg every 6 months.Results:19 patients were included, 18 women and 1 man. Median age was 55 years (29-70 years), and median rituximab treatment duration was 24 months (1-48 months). Five patients had concomitant RA (2 patients), SLAE (1 pt), Systemic sclerosis (2 patients). Patients with RA took baricitinib and methotrexate as well. 3 patients had MALT-lymphoma anamnesis (24, 38 and 24 months before the diagnosis of COVID-19). Only 3 patients had chronic ischemic heart disease and/or arterial hypertension. 12 patients were PCR positive, 6 negative and in 1 the test was not done. 11 patients had full and 4 partial B-cell depletion in peripheral blood. Five patients had <20% lung involvement on CT, 2 patients – 20-40% and 4 patients – 40-60%. Three patients with 40-60% lung involvement required hospitalization due to marked shortness of breath and long febrile period, 2 of them received anti-IL6 treatment and neither of them required mechanical lung ventilation (either non-invasive or invasive). Seventeen patients were treated at home and recovered in 10-24 days. Anti-SARS-CoV-2 IgG were measured in 9 patients, 6 (66.7%) of them were positive.Conclusion:It seems that neither SjS itself nor anti-CD20 therapy predisposes patients to severe course of COVID-19. Presumably risk factors such as age, diabetes or anamnesis of cardiovascular diseases have far more significant impact on COVID-19 severity. Data hints that anti-CD20 therapy might negatively affect the formation of specific anti-SARS-CoV-2 humoral immunity, but further investigation is required to determine that with any degree of certainty.Disclosure of Interests:None declared

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