scholarly journals B-cell inhibition by cross-linking CD79b is superior to B-cell depletion with anti-CD20 antibodies in treating murine collagen-induced arthritis

2014 ◽  
Vol 45 (3) ◽  
pp. 705-715 ◽  
Author(s):  
Hilke Brühl ◽  
Josef Cihak ◽  
Yvonne Talke ◽  
Manuel Rodriguez Gomez ◽  
Fabian Hermann ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Depletion ◽  
Cross Linking ◽  
B Cell Depletion ◽  
Collagen Induced Arthritis ◽  
Anti Cd20 ◽  
Cell Inhibition ◽  
Cd20 Antibodies

scholarly journals Frequency of Regulatory T Cells is Not Affected by Transient B Cell Depletion Using Anti-CD20 Antibodies in Rheumatoid Arthritis

2009 ◽  
Vol 2 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Martin Feuchtenberger ◽  
Sabine Muller ◽  
Petra Roll ◽  
Anne Waschbisch ◽  
Arne Schafer ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Anti Cd20 ◽  
Cd20 Antibodies

scholarly journals The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy

2004 ◽  
Vol 199 (12) ◽  
pp. 1659-1669 ◽  
Author(s):  
Junji Uchida ◽  
Yasuhito Hamaguchi ◽  
Julie A. Oliver ◽  
Jeffrey V. Ravetch ◽  
Jonathan C. Poe ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Effector Cell ◽  
Fc Receptor ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Antibody Immunotherapy ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Cd20 Antibodies

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.

Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis

2006 ◽  
Vol 54 (8) ◽  
pp. 2377-2386 ◽  
Author(s):  
Petra Roll ◽  
Arumugam Palanichamy ◽  
Christian Kneitz ◽  
Thomas Dorner ◽  
Hans-Peter Tony
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
B Cell Subsets ◽  
Anti Cd20 ◽  
Cd20 Antibodies

Depletion of Chronic Lymphocytic Leukemia Cells From Whole Blood Samples Mediated by the Anti-CD20 Antibodies Rituximab and GA101.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2365-2365 ◽  
Author(s):  
Michaela Patz ◽  
Nche Forcob ◽  
Bianka Müller ◽  
Christian Klein ◽  
Pablo Umana ◽  
...  
Keyword(s):  
B Cell ◽  
Whole Blood ◽  
Annexin V ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Antibody Treatment ◽  
Blood Samples ◽  
Whole Blood Samples ◽  
Anti Cd20 ◽  
Cd20 Antibodies

Abstract Abstract 2365 Poster Board II-342 Introduction: Monoclonal antibodies against CD20 have great potential as therapeutics for the treatment of B-cell lymphomas and chronic lymphocytic leukemia (CLL), since CD20 is expressed on all mature B-cells except stem or plasma cells. Therefore treatment with anti-CD20 antibodies leads to both, direct cell death induction (DCD) by receptor engagement and to cell killing by Fc-mediated mechanisms, namely antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In a pre-clinical in vitro assessment we compared the effects of rituximab, which was approved for treatment of non-Hodgkin lymphoma more than a decade ago, with GA101, a third-generation glyco-engineered anti-CD20-antibody recognizing a type II epitope. Methods: CLL cells were isolated from blood samples by Ficoll gradient centrifugation after treatment with a RosetteSep antibody cocktail. The effects of antibody treatment on membrane integrity were assessed by annexin V binding. Antibody-mediated B cell depletion in whole blood samples was determined flow cytometrically by enumerating CD19- and CD3-positive B and T lymphocytes and by relating the B/T cell ratios after antibody treatment with those of the corresponding untreated samples. Whole blood samples from 25 patients were investigated. Significance thresholds were determined by unpaired Student's T-test and linear correlation analysis. Results: The average decreases in viability of freshly isolated CLL cells due to treatment with 10 μg/ml of anti-CD20 antibodies were 21 % for GA101 (n=8) and 6 % for rituximab (n=6), while the mean B cell depletion in whole blood samples from CLL patients was 32 % for GA101 (n=18) and 11 % for rituximab (n=17). Thus the whole blood assay indicated the antibody effects with greater sensitivity than analysis of annexin V binding in isolated cells. In both assays GA101 performed better than rituximab as evidenced by superior DCD (p=0.021) and antibody-dependent B cell depletion (p=0.001). In about two thirds of whole blood samples from CLL patients treatment with 1 μg/ml of GA101 led to more than 20 % antibody-mediated B-cell depletion. The maximum B-cell depletion observed among the investigated CLL samples after treatment with 10 μg/ml of antibody was 85 % for GA101 and 25 % for rituximab. The B cell depletion from whole blood samples mediated by GA101 and rituximab correlated with the CD20 surface expression on CLL cells from the same patients (r=0.643, n=15, p<0.01 and r=0.610, n=14, p<0.05). In contrast, CLL cell depletion in six whole blood samples did not correlate with the increases in annexin V binding of the corresponding isolated CLL cells. Conclusions: The size of GA101 effects observed in the present B cell depletion assay in a majority of whole blood samples encourages attempts to dissect antibody-mediated killing mechanisms in individual patient samples by specifically inhibiting ADCC or CDC to determine their contribution to B cell depletion. As compared to rituximab, GA101 had stronger effects on isolated CLL cells and, to an even higher degree, led to superior B cell depletion in whole blood samples. These pre-clinical in vitro data obtained with CLL cells indicate that many patients might benefit from this promising therapeutic agent. Disclosures: Klein: Roche: Employment, Equity Ownership, Patents & Royalties. Umana:Roche: Employment, Equity Ownership, Patents & Royalties. Hallek:Roche: Honoraria, Research Funding. Krause:Roche: Research Funding.

scholarly journals Vaccine Efficacy after Rituximab Exposure: First Interim Analysis of Virtue Project on Behalf of West Midlands Research Consortium, UK

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 196-196
Author(s):  
Adrian M Shields ◽  
Srinivasan Venkatachalam ◽  
Shankara Paneesha ◽  
Mark Ford ◽  
Tom Sheeran ◽  
...  
Keyword(s):  
B Cell ◽  
Vaccine Efficacy ◽  
Haematological Malignancy ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Spike Glycoprotein ◽  
Secondary Immunodeficiency ◽  
Haematology Patients ◽  
Anti Cd20 ◽  
Kinetics Of

Abstract Background: Anti-CD20 B cell depleting agents are amongst the most commonly used immunotherapeutics employed in the treatment of haematological malignancy and autoimmune diseases. By inducing peripheral B cell aplasia, anti-CD20 depleting agents are hypothesised to significantly impair serological responses to neoantigens, including the SARS-CoV-2 spike glycoprotein within SARS-CoV-2 vaccines. Seropositivity following SARS-CoV-2 is the strongest, measurable correlate of protection from severe COVID-19. Understanding the kinetics of B cell reconstitution and vaccine responsiveness following exposure to B cell depleting agents is essential to maximise vaccine efficacy in patients vulnerable to severe COVID-19. Methods: 80 patients with underlying haematological malignancy and 38 patients with underlying rheumatological disease previously treated with anti-CD20 B cell depleting agents were studied following their second dose of a SARS-CoV-2 vaccine (median time to sampling: 46.5d, IQR: 33.8-63.3). Lymphocyte subset (CD4, CD8, CD19, CD56/16) enumeration was performed using 6 colour flow cytometry (BD Trucount). Total anti-SARS-CoV-2 spike glycoprotein antibodies were measured by enzyme-linked immunosorbent assay (The Binding Site, Human Anti-IgG/A/M SARS-CoV-2-ELISA). The relationship between immune reconstitution following B cell depletion and vaccine responsiveness was explored. Results: In the haematology cohort (median age 70y, IQR 60.3-76.0, 62.5% male), overall seropositivity following vaccination was 60.0%. Individuals on active chemotherapy had significantly lower seroprevalence than those vaccinated following the completion of chemotherapy (22.7% vs 74.1%, p&lt;0.0001). In the rheumatology cohort (median age 65y, IQR 58.3-70.8, 39.9% male), overall seropositivity was 69.4%. In both cohorts, vaccine non-responders had significantly smaller populations of peripheral CD19+ B cells (haematology: 0.20 vs 0.02 x10 9/L, p=0.004, rheumatology: 0.07 vs 0.01 x10 9/L, p=0.03). The magnitude of the antibody response following vaccination did not differ between recipients of Tozinameran and Vaxzeveria in either cohort. Vaccine responsiveness was lower in the first 6 months following B cell depletion therapy; 42.9% in the haematology cohort and 33.3% in the rheumatology cohort, increasing to 100% and 75% respectively in individuals receiving their second dose 6-12 months following B cell depletion (Figure 1). B cell reconstitution in the 7-12 month window following B cell depletion was faster in haematology compared to rheumatology patients (77.8% v 22.2% achieving normal B cell count, p=0.005) and associated with improved vaccine responsiveness. However, persistent immunodeficiency occurred in some haematology patients following completion of treatment: 25% of patients who had completed therapy at least 36 months previously failed to respond to vaccination. In this cohort of vaccine non-responders, 83.3% of individuals had B cell numbers within the normal range. These patients had all previously been treated for follicular lymphoma suggesting a specific mechanism for long-range secondary immunodeficiency in these patients. Conclusions: Serological responsiveness to SARS-CoV-2 vaccines is poor during active chemotherapy for haematological malignancy and in the first 6 months following B cell depletion, regardless of underlying disease. Vaccine responsiveness significantly improves in the 7-12 month window following B cell depletion. Compared to haematology patients, B cell reconstitution is slower in rheumatology patients and associated with reduced vaccine responsiveness, possibly due to the use of additional concurrent disease-modifying anti-rheumatic therapies. Furthermore, long-term secondary immunodeficiency occurs in a minority of haematology patients. To maximise the efficacy from SARS-CoV-2 booster vaccination and optimal utilisation of available vaccine doses, immunisations should be delivered at least 6 months following the administration of anti-CD20 depleting drugs. Figure 1: Kinetics of return of vaccine responsiveness following B cell depletion in haematology and rheumatology patients. Figure 1 Figure 1. Disclosures Paneesha: Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company.

scholarly journals B cell depletion with anti-CD20 mAb exacerbates anti-donor CD4+ T cell responses in highly sensitized transplant recipients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asuka Tanaka ◽  
Kentaro Ide ◽  
Yuka Tanaka ◽  
Masahiro Ohira ◽  
Hiroyuki Tahara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Responses ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Transplant Recipients ◽  
Cell Responses ◽  
Anti Cd20

AbstractPretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients’ immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4+ T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4+ T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4+ T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4+ T cell response. The depletion of the CD5+ B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10+ CD5+ B cells suppress the excessive response of anti-donor CD4+ T cells responses in sensitized recipients.

scholarly journals B Cell Depletion With an Anti-CD20 Antibody Enhances Alloreactive Memory T Cell Responses After Transplantation

2015 ◽  
Vol 16 (2) ◽  
pp. 672-678 ◽  
Author(s):  
J. Marino ◽  
J. T. Paster ◽  
A. Trowell ◽  
L. Maxwell ◽  
K. H. Briggs ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Responses ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Memory T Cell ◽  
Cell Responses ◽  
Cd20 Antibody ◽  
Anti Cd20

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.

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