scholarly journals A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20—Yet Progress Continues

2021 ◽  
Author(s):  
Esther S. Frisch ◽  
Roxanne Pretzsch ◽  
Martin S. Weber
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibodies ◽  
B Cells ◽  
B Cell ◽  
Current Knowledge ◽  
Disease Onset ◽  
Chronic Inflammatory Disease ◽  
Targeting Therapy ◽  
Long Term Treatment ◽  
Anti Cd20

AbstractMultiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute inflammation and relapse biology. These results paved the way for further research on the implication of B cells in the pathogenesis of MS. Besides controlling relapse development in RMS, ocrelizumab (OCR) also showed clinical benefits in patients with PPMS and became the first approved drug for this disease course. In this review, we provide an overview of the current anti-CD20 mabs used or tested for the treatment of MS—namely rituximab (RTX), OCR, ofatumumab (OFA), and ublituximab (UB). Besides their effectiveness, we also discuss possible limitations and safety concerns especially in regard to long-term treatment, both for this class of drugs overall as well as for each anti-CD20 mab individually. Additionally, we elucidate to what extent anti-CD20 therapy may alter the function of other immune cells, both directly or indirectly. Finally, we cover the current knowledge on repopulation of CD20+ cells after cessation of anti-CD20 treatment and discuss future aspirations towards alternative, further developed B cell silencing therapies.

A type II anti-CD20 monoclonal antibody efficiently depletes CNS B cells in a mouse model of multiple sclerosis

2021 ◽  
Author(s):  
Sabine Tacke ◽  
Rittika Chunder ◽  
Verena Schropp ◽  
Philipp Kirchner ◽  
Arif B. Ekici ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Total Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Type Ii ◽  
Cns Pathology ◽  
Anti Cd20

Abstract BackgroundSuccessful therapy with anti-CD20 monoclonal antibodies (mAbs) has reinforced the key role of B cells in the immunopathology of multiple sclerosis. While treatment with currently available anti-CD20 mAbs results in rapid and robust elimination of vascular B cells, B cells residing within compartments of the central nervous system (CNS) are not well targeted. The aim of this study was to determine the effects of a novel class of anti-CD20 mAbs on vascular and extravascular CNS-infiltrating B cells in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. MethodsMale double transgenic hCD20xhIgR3 mice and male wild-type C57BL/6 (B6) mice were injected with human myelin oligodendrocyte glycoprotein (MOG)1–125 to induce chronic EAE. On days 19, 22, and 25 after immunization, the hCD20xhIgR3 mice were injected intravenously with an anti-human CD20 mAb (5 mg/kg), either rituximab (a type I anti-CD20 mAb) or obinutuzumab (a type II humanized anti-CD20 mAb). The B6 mice received a dose of the murine anti-mouse CD20 antibody 18B12. Development of EAE was assessed daily. Seven days after the last injection, mice were euthanized, splenic B-cell subsets were analyzed by flow cytometry, and differential gene expression determined by single-cell RNA sequencing. Total serum immunoglobulin (Ig)G and anti-MOG1–125 IgG titers were measured by enzyme-linked immunosorbent assay. Reduction in CNS-infiltrated CD19+ and CD3+ cells was analyzed by immunohistochemistry, and ultrastructural CNS pathology was studied by transmission electron microscopy. ResultsTreatment with either anti-CD20 mAb had no effect on the clinical course of the disease, animal weight, or serum antibody levels. Obinutuzumab was superior to rituximab in reducing both splenic and CNS-infiltrated B cells. At the single-cell level, obinutuzumab showed pronounced effects on germinal center B cells as well as on CD4+ T cells, which acquired a regulatory-gene signature. In addition, obinutuzumab had beneficial effects on spinal cord myelination. B-cell depletion rates in the 18B12/B6 model were comparable with those observed in obinutuzumab-treated hCD20xhIgR3 mice. ConclusionsOur results demonstrate differential effects of anti-CD20 mAbs on peripheral immune response and CNS pathology, with type II antibodies potentially being superior to type I in the depletion of tissue-infiltrating B cells.

scholarly journals 3285 Toxicity of Released B Cell Products in Multiple Sclerosis: Effects on Neurons and Oligodendrocytes

2019 ◽  
Vol 3 (s1) ◽  
pp. 116-116
Author(s):  
Leah Zuroff ◽  
Hanane Touil ◽  
Micah Romer ◽  
Liljana Nedelkoska ◽  
Joyce A. Benjamins ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Chronic Inflammatory Disease ◽  
Conditioned Media ◽  
Pathogenic Potential ◽  
Cytotoxic Factor ◽  
B Cell Subsets ◽  
Normal Controls ◽  
Age And Sex

OBJECTIVES/SPECIFIC AIMS: We previously demonstrated that products released by cultured B cells from patients with Multiple Sclerosis (MS) are cytotoxic to neurons and oligodendrocytes, while minimal toxicity was observed in response to B cell secretory products from age- and sex-matched normal controls. The goal of this proposal is to identify the range of brain cells susceptible to MS B cell-mediated cytotoxicity, to define the cytotoxic factor(s) released by MS B cells, and to determine whether particular subset(s) of MS B cells harbor the greatest pathogenic potential. METHODS/STUDY POPULATION: The toxicity of B cell products will be demonstrated by incubating primary rat cultures of neurons, oligodendrocytes, and oligodendrocyte progenitor cells (OPCs) with B cell supernatants. B cells will be isolated from the peripheral circulation of untreated relapse-remitting MS (RRMS) patients and age- and sex-matched normal controls. The identification of specific toxic factor(s) in MS B cell supernatants will be achieved through a combination of exosome-depletion/enrichment of conditioned media, proteomics, next generation sequencing, and lipidomics. Determining pathogenic B cell subsets will be achieved by cell sorting into memory and naïve B cell subsets prior to collection of supernatants. RESULTS/ANTICIPATED RESULTS: We hypothesize that the toxicity of MS B cell products is mediated, at least in part, by extracellular vesicles, such as exosomes. We expect depletion of these exosomes from the B cell conditioned media or inhibition of their biogenesis will mitigate the observed toxicity. Furthermore, differences in B cell-derived exosomal content, such as proteins, (mi)RNAs, or lipids, likely explain the differences in observed toxicity. Lastly, we hypothesize that memory B cells, which are enriched in the CNS of MS patients and demonstrate a more pro-inflammatory profile than naïve B cells, are responsible for the toxicity observed in supernatants of total B cells. DISCUSSION/SIGNIFICANCE OF IMPACT: MS is the most prevalent chronic inflammatory disease of the CNS, affecting more than 2 million people worldwide. Although over a dozen disease-modifying therapies are approved for the treatment of RRMS, none are meaningfully effective at limiting disease progression. This proposal will provide new insight into immune-CNS interactions in progressive MS and provide much-needed novel targets for therapeutic intervention, either via blocking identified toxic molecule(s) or by selectively depleting pathogenic B cell subsets.

scholarly journals It is time to individualize anti-CD20 therapies in multiple sclerosis

2021 ◽  
Author(s):  
Jagannadha Avasarala
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Current Knowledge ◽  
Dosing Interval ◽  
Know How ◽  
Financial Perspective ◽  
Fda Approval ◽  
Anti Cd20

Anti-CD20 therapies in multiple sclerosis (MS) have become central to management of the disease since their FDA approval in 2017. As their role in MS management continues to grow, it is also increasingly important to know how such drugs can be better administered using current knowledge of how B cells repopulate after their depletion. To this end, individualizing therapy needs to be prioritized since a timed-dosing interval is perhaps not required based on evidence and it certainly unwelcome from a financial perspective.

scholarly journals Monitoring anti-B cell immunotherapies in autoimmune diseases: Go with the flow. A Position Paper of the Italian Society for Clinical Cell Analysis (ISCCA)

2019 ◽  
Vol 1 (2) ◽  
pp. 52-62
Author(s):  
Bruno Brando ◽  
Arianna Gatti ◽  
Alfredo Maria Lurati ◽  
Paola M.L. Faggioli
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cells ◽  
Autoimmune Diseases ◽  
B Cell ◽  
Cell Activation ◽  
Biological Effects ◽  
Individual Response ◽  
Anti Cd20

During the past decades autoimmune diseases have been usually treated with immunosuppressive drugs mostly active on T-Cell mediated responses. Only in recent years, with our extended knowledge of the pathogenic mechanisms of autoreactive disorders and the tremendous development of new therapeutic monoclonal antibodies, anti-B-Cell therapies have emerged as a new option for treating autoimmune diseases. The rationale for this changeover from T-Cell to B-Cell targeted therapies resides in the recently accumulated evidence of the role of B-Cells in the pathogenesis of autoimmune diseases and in the generation of tissue damage. Targeting memory and effector BCells may then disrupt the production of pathogenic antibodies, counteract the role of B-Cells in sustaining antigen presentation to T-Cells and block the synthesis of B-Cell activation cytokines. The anti-CD20 monoclonal antibody Rituximab was first introduced more than 20 years ago for the treatment of CD20+ chronic B-lymphoproliferative disorders, and was then successfully experimented in the treatment of an ever-increasing spectrum of autoimmune diseases. Newer anti-CD20 monoclonal antibodies have been introduced more recently, which vary in their biological effects. The need for laboratory indicators that may help the rational usage and follow-up of anti-CD20 treatments has now emerged, due to the high variability of individual response, to the markedly different outcomes in the various diseases and to the controversial role of pathogenic autoantibodies as indicators of disease activity. Flow cytometric (FCM) analyses to identify and enumerate the B-cell functional subsets in the peripheral blood have been developed in recent years. They can be used to assess the degree and the persistence of memory B-Cell depletion, the quality and the timing of B-Cell reconstitution, along with the highly sensitive FCM counting technique needed for the detection of extremely low cell levels. The long-term aim of this innovative approach is to provide clinicians with a tool for a safer and more rational usage of anti-CD20 agents.

scholarly journals Specific hypomethylation programs underpin B cell activation in early multiple sclerosis

2021 ◽  
Vol 118 (51) ◽  
pp. e2111920118
Author(s):  
Qin Ma ◽  
Stacy J. Caillier ◽  
Shaun Muzic ◽  
Michael R. Wilson ◽  
Roland G. Henry ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Disease Onset ◽  
Cell Types ◽  
B Cell Differentiation ◽  
Dna Hypomethylation

Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.

scholarly journals Anti-CD20 B Cell Treatment for Relapsing Multiple Sclerosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Charles A. Roach ◽  
Anne H. Cross
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
B Cells ◽  
B Cell ◽  
Clinical Success ◽  
Mechanisms Of Action ◽  
Cell Therapies ◽  
Anti Cd20 ◽  
Relapsing Multiple Sclerosis

Several clinical trials have demonstrated the efficacy of lytic therapies targeting B cells in the treatment of relapsing multiple sclerosis (MS). More modest efficacy has been noted in the primary progressive subtype of MS. Clinical success has increased interest in the role of B cells in the pathogenesis of MS and in ways to potentially improve upon current B cell therapies. In this mini review, we will critically review previous and ongoing clinical trials of anti-CD20 monoclonal antibodies in MS, including rituximab, ocrelizumab, ofatumumab, and ublituximab. Side effects and adverse event profiles will be discussed. Studies examining the proposed mechanisms of action of B cell depleting therapies will also be reviewed.

scholarly journals Determining the best window for BNT162b2 mRNA vaccination for SARS-CoV-2 in patients with multiple sclerosis receiving anti-CD20 therapy

2021 ◽  
Vol 7 (4) ◽  
pp. 205521732110621
Author(s):  
Audrey Rico ◽  
Laetitia Ninove ◽  
Adil Maarouf ◽  
Clémence Boutiere ◽  
Pierre Durozard ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Serologic Response ◽  
Cell Counts ◽  
Anti Cd20 ◽  
Cell Proportion ◽  
Cell Repopulation

We studied the serologic response to the BNT162b2 mRNA vaccine at four weeks after the second dose in patients with RRMS treated with rituximab with extended-interval dosing ( n = 26). At four weeks, 73% of patients were seropositive. No patient without B cells at the first dose ( n = 4) was seropositive. Four of seven (57%) patients with B-cell proportion >0% and ≤5% were seropositive. All patients with B-cell proportion >5% ( n = 15) were seropositive. In all patients, quantitative ELISA measures after vaccination were correlated with B-cell counts measured before vaccination. In patients receiving rituximab, seropositivity after BNT162b2 mRNA vaccination emerged only after B-cell repopulation.

scholarly journals Apoptosis of Malignant Human B Cells by Ligation of CD20 With Monoclonal Antibodies

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1644-1652 ◽  
Author(s):  
Daming Shan ◽  
Jeffrey A. Ledbetter ◽  
Oliver W. Press
Keyword(s):  
Cell Proliferation ◽  
Monoclonal Antibodies ◽  
B Cells ◽  
B Cell ◽  
Nuclear Dna ◽  
Chimeric Mouse ◽  
Anti Cd20 ◽  
Nuclear Dna Fragmentation ◽  
Cd20 Antibodies

Abstract CD20 is a nonglycosylated 33 to 37 kD phosphoprotein involved in B-cell signaling that subserves important functions in the regulation of B-cell proliferation and differentiation. In addition, this B-cell surface antigen has been shown recently to be an effective target for immunotherapy of B-cell malignancies using chimeric (mouse/human) or radiolabeled murine monoclonal anti-CD20 antibodies. In this report we show that extensive crosslinking of CD20 with murine anti-CD20 monoclonal antibodies (MoAbs) in the presence of either goat anti-mouse IgG or Fc receptor (FcR)-expressing cells directly inhibits B-cell proliferation, induces nuclear DNA fragmentation, and leads to cell death by apoptosis. The apoptotic effects of these MoAbs can be inhibited by chelation of extracellular or intracellular Ca2+ by EGTA or Bapta AM, indicating that anti-CD20–mediated apoptosis may be related to changes in Ca2+ concentration. These findings suggest that ligation of CD20 in vivo by anti-CD20 antibodies in the presence of FcR-expressing cells may initiate signal transduction events that induce elevation of [Ca2+]i and lead to apoptosis of malignant B cells, thereby contributing to the impressive tumor regressions observed in mouse models and clinical trials using anti-CD20 MoAbs.

scholarly journals Apoptosis of Malignant Human B Cells by Ligation of CD20 With Monoclonal Antibodies

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1644-1652 ◽  
Author(s):  
Daming Shan ◽  
Jeffrey A. Ledbetter ◽  
Oliver W. Press
Keyword(s):  
Cell Proliferation ◽  
Monoclonal Antibodies ◽  
B Cells ◽  
B Cell ◽  
Nuclear Dna ◽  
Chimeric Mouse ◽  
Anti Cd20 ◽  
Nuclear Dna Fragmentation ◽  
Cd20 Antibodies

CD20 is a nonglycosylated 33 to 37 kD phosphoprotein involved in B-cell signaling that subserves important functions in the regulation of B-cell proliferation and differentiation. In addition, this B-cell surface antigen has been shown recently to be an effective target for immunotherapy of B-cell malignancies using chimeric (mouse/human) or radiolabeled murine monoclonal anti-CD20 antibodies. In this report we show that extensive crosslinking of CD20 with murine anti-CD20 monoclonal antibodies (MoAbs) in the presence of either goat anti-mouse IgG or Fc receptor (FcR)-expressing cells directly inhibits B-cell proliferation, induces nuclear DNA fragmentation, and leads to cell death by apoptosis. The apoptotic effects of these MoAbs can be inhibited by chelation of extracellular or intracellular Ca2+ by EGTA or Bapta AM, indicating that anti-CD20–mediated apoptosis may be related to changes in Ca2+ concentration. These findings suggest that ligation of CD20 in vivo by anti-CD20 antibodies in the presence of FcR-expressing cells may initiate signal transduction events that induce elevation of [Ca2+]i and lead to apoptosis of malignant B cells, thereby contributing to the impressive tumor regressions observed in mouse models and clinical trials using anti-CD20 MoAbs.

scholarly journals Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

2016 ◽  
Vol 10 (1) ◽  
pp. 51-66 ◽  
Author(s):  
Stefan Bittner ◽  
Tobias Ruck ◽  
Heinz Wiendl ◽  
Oliver M. Grauer ◽  
Sven G. Meuth
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Demyelinating Disease ◽  
Current Knowledge ◽  
Clinical Results ◽  
Autoimmune Response ◽  
Clinical Phase

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that is caused by an autoimmune response against central nervous system (CNS) structures. Traditionally considered a T-cell-mediated disorder, the contribution of B cells to the pathogenesis of MS has long been debated. Based on recent promising clinical results from CD20-depleting strategies by three therapeutic monoclonal antibodies in clinical phase II and III trials (rituximab, ocrelizumab and ofatumumab), targeting B cells in MS is currently attracting growing interest among basic researchers and clinicians. Many questions about the role of B and plasma cells in MS remain still unanswered, ranging from the role of specific B-cell subsets and functions to the optimal treatment regimen of B-cell depletion and monitoring thereafter. Here, we will assess our current knowledge of the mechanisms implicating B cells in multiple steps of disease pathology and examine current and future therapeutic approaches for the treatment of MS.

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