Am“B”valent: anti-CD20 antibodies unravel the dual role of B cells in immunopathogenesis

Blood ◽  
2010 ◽  
Vol 116 (4) ◽  
pp. 515-521 ◽  
Author(s):  
Olivier Thaunat ◽  
Emmanuel Morelon ◽  
Thierry Defrance
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Cell Depletion ◽  
Cell Compartment ◽  
Wide Range ◽  
Basic Studies ◽  
Anti Cd20 ◽  
Regulatory Properties ◽  
Cd20 Antibodies

Abstract Accumulating evidence has designated B cells as central players in the pathogenesis of immune diseases. In the late 1990s, anti-CD20 monoclonal antibodies were developed for the treatment of B-cell non-Hodgkin lymphomas, offering the opportunity to efficiently deplete the B-cell compartment for therapeutic immunointerventions. Several studies have since established the beneficial effect of this drug on the course of a wide range of immune diseases. However, paradoxically, it has also been reported that rituximab sometimes worsens the symptoms of the very same conditions. The explanation that reconciles such apparently conflicting results has recently emerged from basic studies, which demonstrate that (1) B cells are also endowed with immune-regulatory properties and (2) the opposing contributions of B cells may overlap during the course of the disease. Caution should therefore be exercised when considering B-cell depletion because the therapeutic effect will depend on the relative contributions of the opposing B-cell activities at the time of the drug administration.

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.

B-cell treatment in ANCA-associated vasculitis

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_3) ◽  
pp. iii68-iii73
Author(s):  
Alexandre Karras ◽  
Hélène Lazareth ◽  
Sophie Chauvet
Keyword(s):  
B Cells ◽  
B Cell ◽  
Optimal Dose ◽  
B Cell Depletion ◽  
Anca Vasculitis ◽  
Anca Associated Vasculitis ◽  
Cell Subpopulations ◽  
Anti Cd20

Abstract The pivotal role of B-cells in ANCA-associated vasculitis has been suggested by experimental data that demonstrate the direct pathogenicity of ANCAs. Rituximab (RTX), an anti-CD20 monoclonal antibody that targets B-cells, has proven its efficacy for induction of remission in severe ANCA vasculitis. RTX is equivalent to CYC for induction of remission, and is probably superior in relapsing patients. Long-term B cell depletion by prolonged RTX treatment has been shown to significantly reduce the relapse rate, when compared with AZA maintenance therapy. Biomarkers, such as B-cell subpopulations or ANCA monitoring, may help the clinician to determine the optimal dose and duration of RTX therapy.

B lymphocytes inactivation by Ibrutinib limits endometriosis progression in mice

2019 ◽  
Vol 34 (7) ◽  
pp. 1225-1234 ◽  
Author(s):  
L G C Riccio ◽  
M Jeljeli ◽  
P Santulli ◽  
S Chouzenoux ◽  
L Doridot ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peritoneal Cavity ◽  
B Cell Depletion ◽  
Regulatory B Cells ◽  
Btk Inhibitor ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
And Control

Abstract STUDY QUESTION What are the effects of B lymphocyte inactivation or depletion on the progression of endometriosis? SUMMARY ANSWER Skewing activated B cells toward regulatory B cells (Bregs) by Bruton’s tyrosine kinase (Btk) inhibition using Ibrutinib prevents endometriosis progression in mice while B cell depletion using an anti-CD20 antibody has no effect. WHAT IS KNOWN ALREADY A polyclonal activation of B cells and the presence of anti-endometrial autoantibodies have been described in a large proportion of women with endometriosis though their exact role in the disease mechanisms remains unclear. STUDY DESIGN, SIZE, DURATION This study included comparison of endometriosis progression for 21 days in control mice versus animals treated with the anti-CD20 depleting antibody or with the Btk inhibitor Ibrutinib that prevents B cell activation. PARTICIPANTS/MATERIALS, SETTING, METHODS After syngeneic endometrial transplantation, murine endometriotic lesions were compared between treated and control mice using volume, weight, ultrasonography, histology and target genes expression in lesions. Phenotyping of activated and regulatory B cells, T lymphocytes and macrophages was performed by flow cytometry on isolated spleen and peritoneal cells. Cytokines were assayed by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE Btk inhibitor Ibrutinib prevented lesion growth, reduced mRNA expression of cyclooxygenase-2, alpha smooth muscle actin and type I collagen in the lesions and skewed activated B cells toward Bregs in the spleen and peritoneal cavity of mice with endometriosis. In addition, the number of M2 macrophages decreased in the peritoneal cavity of Ibrutinib-treated mice compared to anti-CD20 and control mice. Depletion of B cells using an anti-CD20 antibody had no effect on activity and growth of endometriotic lesions and neither on the macrophages, compared to control mice. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION It is still unclear whether B cell depletion by the anti-CD20 or inactivation by Ibrutinib can prevent establishment and/or progression of endometriosis in humans. WIDER IMPLICATIONS OF THE FINDINGS Further investigation may contribute to clarifying the role of B cell subsets in human endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by a grant of Institut National de la Santé et de la Recherche Médicale and Paris Descartes University. None of the authors has any conflict of interest to disclose.

scholarly journals B-cell–targeted therapies in relapsing forms of MS

2017 ◽  
Vol 4 (6) ◽  
pp. e405 ◽  
Author(s):  
Divyanshu Dubey ◽  
Thomas Forsthuber ◽  
Eoin P. Flanagan ◽  
Sean J. Pittock ◽  
Olaf Stüve
Keyword(s):  
Clinical Trials ◽  
B Cells ◽  
B Cell ◽  
Therapeutic Strategies ◽  
Phase Iii ◽  
B Cell Depletion ◽  
Pathogenic Role ◽  
Phase Iii Clinical Trials ◽  
Anti Cd20

In recent years, there has been a significant increase in the therapeutic options available for the management of relapsing forms of MS. Therapies primarily targeting B cells, including therapeutic anti-CD20 monoclonal antibodies, have been evaluated in phase I, phase II, and phase III clinical trials. Results of these trials have shown their efficacy and relatively tolerable adverse effect profiles, suggesting a favorable benefit-to-risk ratio. In this review, we discuss the pathogenic role of B cells in MS and the rationale behind the utilization of B-cell depletion as a therapeutic cellular option. We also discuss the data of clinical trials for anti-CD20 antibodies in relapsing forms of MS and existing evidence for other B-cell–directed therapeutic strategies.

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.

Non-Cognate Cytotoxic T Cells Can Be Retargeted Against CD20 Positive Tumour Cells Using [Fab' × MHC Class I/Peptide] Conjugates.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2838-2838
Author(s):  
Angela D Hamblin ◽  
Ben CR King ◽  
Ruth R French ◽  
Claude H Chan ◽  
Alison L Tutt ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Mhc Class I ◽  
Peripheral Blood ◽  
Class I ◽  
B Cell Depletion ◽  
Cytokine Release ◽  
Anti Cd20

Abstract Abstract 2838 To circumvent cytotoxic T lymphocyte (CTL) tolerance of tumour-associated antigens, the concept of redirecting CTLs against non-cognate targets has developed. One way of doing this is to use bispecific antibodies comprising anti-CD3 and anti-tumour antigen moieties. Unfortunately, this is frequently associated with unacceptable toxicity due to inflammatory cytokine release. As an alternative our approach has been to use a bivalent conjugate recognising a tumour antigen (through an antibody fragment) and a defined population of CTLs (specific for a single antigenic peptide e.g. viral epitope) through peptide presented in the context of recombinant MHC class I. We have produced a conjugate consisting of an anti-human CD20 Fab' fragment joined via a chemical crosslinker (succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate) to murine MHC class I/peptide (Kbα1-α3 domains/β2microglobulin presenting the ovalbumin-derived peptide SIINFEKL; expressed bacterially as a continuous polypeptide single chain trimer after Yu et al, J Immunol 2002). Size exclusion chromatography allowed purification of conjugates with [Fab':MHC class I/peptide] ratios of 1:1 and 2:1 (F2 and F3 respectively). In vitro both constructs were able to redirect the transgenic murine CTL line OT-1 (specific for KbSIINFEKL) to lyse human CD20+ tumour cells (lymphoblastoid Daudi cell line) at effector: target ratios of 10:1. This lysis could be blocked by the addition of 100 fold excess of either anti-CD20 F(ab')2 or the Kb/SIINFEKL-specific antibody 25D1. The constructs were also able to cause in vitro proliferation of naïve OT-1 cells (but not irrelevant CD8+ T cells) in the presence of human CD20+ cells in both thymidine incorporation and CFSE dilution assays. Using a human CD20 transgenic mouse model (Ahuja et al, J Immunol 2007) we have evaluated both constructs in vivo for their ability to redirect adoptively transferred OT-1 cells to deplete B cells from the peripheral blood. A single dose of 1 nmole F3 and 2 nmole F2 caused respectively up to 95% and 85% B cell depletion at day 7. The efficacy of lower doses suggested a dose: response relationship. As a marker of toxicity, we have measured cytokine levels at 2, 8 and 24 hours following a dose of 1 nmole F3 and compared them to those seen after administration of an [anti-CD3 × anti-CD20] bispecific F(ab')2 at a dose (0.5 nmole) which produced similar day 7 peripheral blood B cell depletion: phosphate-buffered saline was given as a negative control. Maximal cytokine release was seen at 2 hours with the levels of IL-4, IL-5, KC, IL-2 and IL-10 being lower after administration of the F3 than after the bispecific F(ab')2. However, interestingly, the F3 resulted in greater IL-12 release. Overall these data suggest that [Fab' × MHC class I/peptide] constructs have the potential to redirect non-cognate CTLs to deplete CD20+ malignant B cells from the peripheral blood and that this is associated with a lower level of cytokine release than a similarly efficacious dose of an anti-CD3-containing bispecific F(ab')2. Furthermore, the ability of [Fab' × MHC class I/peptide] constructs to cause proliferation of OT-1 cells in vitro suggests it may be possible to use a single molecule to both generate a secondary cytotoxic T cell response and subsequently to retarget it, increasing the viability of the approach if adopted in the clinic. Disclosures: No relevant conflicts of interest to declare.

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.

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 The Influence of B Cell Depletion Therapy on Naturally Acquired Immunity to Streptococcus pneumoniae

2021 ◽  
Vol 11 ◽  
Author(s):  
Giuseppe Ercoli ◽  
Elisa Ramos-Sevillano ◽  
Rie Nakajima ◽  
Rafael Ramiro de Assis ◽  
Algis Jasinskas ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
B Cells ◽  
B Cell ◽  
Respiratory Infections ◽  
Serum Levels ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Protein Antigens ◽  
Antibody Recognition ◽  
Anti Cd20

The anti-CD20 antibody Rituximab to deplete CD20+ B cells is an effective treatment for rheumatoid arthritis and B cell malignancies, but is associated with an increased incidence of respiratory infections. Using mouse models we have investigated the consequences of B cell depletion on natural and acquired humoral immunity to Streptococcus pneumoniae. B cell depletion of naïve C57Bl/6 mice reduced natural IgM recognition of S. pneumoniae, but did not increase susceptibility to S. pneumoniae pneumonia. ELISA and flow cytometry assays demonstrated significantly reduced IgG and IgM recognition of S. pneumoniae in sera from mice treated with B cell depletion prior to S. pneumoniae nasopharyngeal colonization compared to untreated mice. Colonization induced antibody responses to protein rather than capsular antigen, and when measured using a protein array B cell depletion prior to colonization reduced serum levels of IgG to several protein antigens. However, B cell depleted S. pneumoniae colonized mice were still partially protected against both lung infection and septicemia when challenged with S. pneumoniae after reconstitution of their B cells. These data indicate that although B cell depletion markedly impairs antibody recognition of S. pneumoniae in colonized mice, some protective immunity is maintained, perhaps mediated by cellular immunity.

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