Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies

2017 ◽  
Vol 24 (9) ◽  
pp. 1224-1233 ◽  
Author(s):  
Nicky Dunn ◽  
Alexander Juto ◽  
Malin Ryner ◽  
Ali Manouchehrinia ◽  
Luca Piccoli ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cell ◽  
Clinical Outcomes ◽  
Clinical Relevance ◽  
Cell Depletion ◽  
Enzyme Linked Immunosorbent Assay ◽  
B Cell Depletion ◽  
Serum Samples ◽  
Cross Sectional ◽  
Cell Counts

Background: Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown. Objective: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients. Methods: Cross-sectional study with collection of serum samples from 339 MS patients immediately before a scheduled rituximab infusion. ADAs were detected using an in-house–validated electrochemiluminescent immunoassay and a commercial enzyme-linked immunosorbent assay (ELISA) to compare methods. Data on patient demographics and clinical outcomes were retrieved from the Swedish MS Registry and patient records. Results: ADAs were detected in 37% of relapsing–remitting MS and 26% in progressive forms of MS. Presence of ADAs decreased with increasing number of rituximab infusions. There was a significant association between both presence and titres of ADAs and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. Only five patients terminated rituximab during follow-up, four of which were ADA positive. Conclusion: Rituximab treatment is associated with a high degree of ADAs, which correlates with efficacy of B-cell depletion; however, the clinical relevance of ADAs remains uncertain.

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.

B-Cell Depletion and COVID-19 Severity in Multiple Sclerosis: Remaining Challenges

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012754
Author(s):  
Joep Killestein ◽  
Menno M. Schoonheim ◽  
Rhonda R. Voskuhl
Keyword(s):  
Multiple Sclerosis ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion

Sustained Depletion of B-Cells by a Humanized, Fc-Engineered Anti-CD20 Antibody, AME-133v, in Patients with Relapsed Follicular Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4977-4977
Author(s):  
Jennifer Wayne ◽  
Kristen N. Ganjoo ◽  
Andres Forero ◽  
Brad Pohlman ◽  
Sven de Vos ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cells ◽  
Phase I ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cell Counts ◽  
Evaluable Population ◽  
Anti Cd20

Abstract Abstract 4977 Sustained Depletion of B-Cells by a Humanized, Fc-Engineered Anti-CD20 Antibody, AME-133v, in Patients with Relapsed Follicular Lymphoma J Wayne,1 K Ganjoo,2 A Forero,3 B Pohlman,4 S de Vos,5 S Carpenter,6 J Wooldridge,6 S Marulappa,1 V Jain11Mentrik Biotech, LLC, Dallas, TX, 2Standford University Medical Center, Stanford, CA, 3Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL,4Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 5David Geffen School of Medicine at University of California, Los Angeles, CA, 6Eli Lilly and Company, Indianapolis, Indiana Introduction AME-133v is a humanized anti-CD20 monoclonal antibody that has a 13 to 20-fold increase in binding affinity and approximately 6-fold more potent effector function in antibody-dependent cell-mediated cytotoxicity (ADCC) compared to rituximab. Phase I/II clinical trials of AME-133v in patients with relapsed follicular lymphoma have demonstrated an overall response rate of greater than 30% with a complete response rate of 16%. The extent and duration of depletion of CD19+ B-cells in peripheral blood was used as a surrogate of therapeutic levels of AME-133v. Analysis from the Phase I/II clinical trials is presented in this report. Methods CD-19 positive B-cells in peripheral blood were measured in 77 patients with relapsed follicular lymphoma enrolled in two phase I/II clinical trials of AME-133v. These studies assessed five different doses of AME-133v (from 2 mg/m2 to 375 mg/m2). AME-133v was administered intravenously four times at weekly intervals in both trials. Blood samples were taken at multiple time points throughout the trial and a central lab measured levels of circulating CD19+ B-cells using fluorescence-activated cell sorting (FACS). Results Excluding the four patients enrolled in the 2 mg/m2 dose cohort, depletion of peripheral B-cells occurred in all patients and was sustained over time (Table 1). Baseline levels of B-cell counts ranged from 4 × 103 to 1,187 × 103 cells/μL, with an average of 102 × 103 cells/μL and a median of 60 × 103 cells/μL. Within 24 hours of the first infusion, all patients had depletion of circulating B-cells; ninety-six percent of patients had less than 10 × 103 cells/μL and two patients had less than 20 × 103 cells/μL. Interestingly, AME-133v was effective at depleting B-cells even at doses as low as 7.5 mg/m2. To assess sustainability of B-cell depletion after four doses of AME-133v, CD19+ cell counts were evaluated at nine weeks after the fourth infusion and every three months thereafter. Complete depletion of CD19+ lymphocytes was sustained for nine weeks. At five months after the last infusion of AME-133v, nearly two-thirds of patients had no detectable circulating B-cells. Sustained B-cell depletion lasted for at least eight months following the last infusion in 63% of patients. Table 1. B-cell counts for all patients in 7.5, 30, 100 and 375 mg/m2 cohorts. Percentages are cumulative Time Point Cell Count (x 103 cells/μL) 0 < 1 2 to 10 11 to 30 31 to 50 < 100 Day 1 (24 hours after last infusion) 62 % 66 % 96 % 100 % 100% 100% Day 7 (day of infusion 2) 75% 80% 95% 97% 97% 98% Day 28 (1 week after last infusion) 78 % 87% 95% 98% 98% 100% Day 84 (9 weeks after last infusion) 78% 87% 91% 96% 96% 98% Day 174 (5 months after last infusion) 60% 60% 70% 86% 93% 100% Day 264 (8 months after last infusion) 26% 26% 41% 63% 81% 89% Day 354 (11 months after last infusion) 0% 0% 15% 40% 55% 80% DEMOGRAPHIC CHARACTERISTICS (EVALUABLE POPULATION) “\f C \l 1 Demographic and Disease Characteristics on evaluable population (N=30) Conclusion The rapid and sustained effect of AME-133v on B-cell depletion, even in low-affinity FcγRIIIa patients, indicates a potentially relevant biological activity of the antibody in treating B-cell non-Hodgkin lymphoma. Notably, this depletion occurred even at very low doses of drug administration and persisted over time. This may be related to its higher affinity for CD20, increased ADCC, or both. The sustained B-cell depletion may result in prolonged clinical response and might mitigate the need for maintenance therapy. A randomized trial is being planned to compare efficacy of AME-133v vs. rituximab. Disclosures: No relevant conflicts of interest to declare.

Blinatumomab exposure and pharmacodynamic response in patients with non-Hodgkin lymphoma (NHL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3051-3051 ◽  
Author(s):  
Youssef Hijazi ◽  
Matthias Klinger ◽  
Andrea Schub ◽  
Benjamin Wu ◽  
Min Zhu ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Phase 1 ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Dose Requirement ◽  
Time Curve ◽  
Cell Counts ◽  
Dose Dependent

3051 Background: Blinatumomab (AMG 103) is an investigational, bispecific, T cell engaging (BiTE) antibody targeting CD19-expressing B cells. We describe the exposure-pharmacodynamic (PD) response of blinatumomab in patients with NHL, using a quantitative pharmacology approach. Methods: In a phase 1 study, 76 patients with NHL received blinatumomab by continuous intravenous infusion (cIV) at doses of 0.5 to 90 μg/m2/d in 4- or 8-week cycles. Pharmacokinetics (PK) was determined. PD responses evaluated included lymphocytes and cytokines measured during treatment, and sum of the products of the greatest diameters of tumor size in lymph nodes (SPD) at the end of treatment. Blinatumomab concentration at steady state (Css) and the cumulative area under the concentration (AUCcum)–time curve over the period before the evaluation of SPD were used to evaluate the exposure-SPD relationship. Results: Blinatumomab showed linear PK. Early PD responses were characterized by B cell depletion, T cell redistribution, and transient cytokine release. Following cIV at doses from 0.5 to 90 μg/m2/d, B cells declined at a first-order rate with a dose-dependent rate constant, ranging from 0.16 to 1.0 h-1. Complete B cell depletion was achieved within 48 hours at doses ≥5 μg/m2/d. A dose-independent decrease in T cell counts was observed within 24 hours after dosing, and T cells returned to baseline within 2 weeks of treatment. Cytokine elevation occurred in some patients and was dose-dependent. Blinatumomab exposure-SPD relationship was best described by an inhibitory Emax model (E = E0-(Imax*C)/(IC50+C)). According to the model estimation, a 50% reduction in SPD would be achieved when Css is 2141 pg/mL and AUCcum is 1381 h*μg/L, equivalent to a blinatumomab dose of 54 µg/m2/d given over 27 days. Conclusions: B lymphocytes were completely depleted from the circulation at blinatumomab doses ≥5 μg/m2/d. Depletion was faster at higher doses. Higher blinatumomab Css and AUCcum were associated with better tumor reduction. Tissue accessibility may explain the higher dose requirement for SPD reduction versus peripheral B cell depletion. The PK/PD model has utility for the design of future studies of blinatumomab in NHL. Clinical trial information: NCT00274742.

scholarly journals Monitoring B-cell repopulation after depletion therapy in neurologic patients

2018 ◽  
Vol 5 (4) ◽  
pp. e463 ◽  
Author(s):  
Erik Ellwardt ◽  
Lea Ellwardt ◽  
Stefan Bittner ◽  
Frauke Zipp
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Depletion ◽  
Close Monitoring ◽  
B Cell Depletion ◽  
Cell Recovery ◽  
Cell Counts ◽  
White Blood Cell Counts ◽  
Anti Cd20 ◽  
Cell Repopulation

ObjectiveTo determine the factors that influence B-cell repopulation after B-cell depletion therapy in neurologic patients and derive recommendations for monitoring and dosing of patients.MethodsIn this study, we determined the association of body surface area (BSA; calculated by body weight and height with the Dubois formula), sex, pretreatment therapy, age, CSF data, and white blood cell counts with the risk and timing of B-cell repopulation, defined as 1% CD19+ cells (of total lymphocytes), following 87 B cell–depleting anti-CD20 treatment cycles of 45 neurologic patients (28 women; mean age ± SD, 44.5 ± 15.0 years).ResultsPatients with a larger BSA had a higher probability to reach 1% CD19+ cells than those with a smaller BSA (p < 0.05) following B-cell depletion therapy, although those patients had received BSA-adapted doses of rituximab (375 mg/m2). Sex, pretreatment, age, CSF data, or absolute lymphocyte and leukocyte counts during treatment did not significantly influence CD19+ B-cell recovery in the fully adjusted models. Intraindividual B-cell recovery in patients with several treatment cycles did not consistently change over time.ConclusionsB-cell repopulation after depletion therapy displays both high inter- and intra-individual variance. Our data indicate that a larger BSA is associated with faster repopulation of B cells, even when treatment is adapted to the BSA. A reason is the routinely used Dubois formula, underestimating a large BSA. In these patients, there is a need for a higher therapy dose. Because B-cell count–dependent therapy regimes are considered to reduce adverse events, B-cell monitoring will stay highly relevant. Patients' BSA should thus be determined using the Mosteller formula, and close monitoring should be done to avoid resurgent B cells and disease activity.

scholarly journals Use of B-Cell–Depleting Therapy in Women of Childbearing Potential With Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

2022 ◽  
pp. 10.1212/CPJ.0000000000001147
Author(s):  
Alexandra Galati ◽  
Thomas McElrath ◽  
Riley Bove
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibodies ◽  
B Cell ◽  
Neuromyelitis Optica ◽  
Spectrum Disorder ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Neuromyelitis Optica Spectrum Disorder ◽  
Childbearing Potential ◽  
Pregnancy And Postpartum

AbstractPurposeof Review: There is considerable heterogeneity in the use of B cell depletion in women of childbearing age, likely driven at least in part by the discrepancy between the product labels and what is known about the physiology of IgG1, including breastmilk and placental transfer.Recent Findings:We provide practical considerations on the use of this medication class in women of childbearing potential. We discuss pre-pregnancy planning including vaccinations, safety of B cell depletion during pregnancy as well as postpartum considerations including breastfeeding.Summary:B cell depleting monoclonal antibodies have shown to be effective for pre-pregnancy and postpartum prevention of inflammatory activity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). B cell depleting therapies are large IgG1 monoclonal antibodies which have minimal transfer across the placenta and into breastmilk. Consideration of risks and benefits of these therapies should be considered in counseling women planning pregnancy and postpartum.

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