Ocrelizumab: a B-cell depleting therapy for multiple sclerosis

ABSTRACT Introduction. Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown.

[1]  D. Ramasamy,et al.  Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: A retrospective, pilot, observational longitudinal study , 2017, Multiple sclerosis.

[2]  M. Triassi,et al.  Predictors of the 10‐year direct costs for treating multiple sclerosis , 2017, Acta neurologica Scandinavica.

[3]  D. Ramasamy,et al.  Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up? , 2017, Multiple sclerosis.

[4]  K. Schmierer,et al.  Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis , 2017, EBioMedicine.

[5]  A. Traboulsee,et al.  Ocrelizumab versus Interferon Beta‐1a in Relapsing Multiple Sclerosis , 2017, The New England journal of medicine.

[6]  Bernhard Hemmer,et al.  Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis , 2017, The New England journal of medicine.

[7]  P. Parren,et al.  Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells , 2016, The Journal of Immunology.

[8]  G. Tsay,et al.  Developing Connections among B Lymphocytes and Deregulated Pathways in Autoimmunity , 2016, Molecular medicine.

[9]  Alyssa H. Zhu,et al.  Long‐term evolution of multiple sclerosis disability in the treatment era , 2016, Annals of neurology.

[10]  R. Zivadinov,et al.  Use of natalizumab in multiple sclerosis: current perspectives , 2016, Expert opinion on biological therapy.

[11]  Mondher Toumi,et al.  The payer’s perspective: What is the burden of MS and how should the patient’s perspective be integrated in health technology assessment conducted for taking decisions on access to care and treatment? , 2016, Multiple sclerosis.

[12]  Ludwig Kappos,et al.  Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial , 2016, The Lancet.

[13]  E. Frohman,et al.  B cells from relapsing remitting multiple sclerosis patients support neuro-antigen-specific Th17 responses , 2016, Journal of Neuroimmunology.

[14]  M. Ramanathan,et al.  Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS , 2016, Neurology: Neuroimmunology & Neuroinflammation.

[15]  L. Wilkins,et al.  The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail? , 2015, Neurology.

[16]  K. Alexanderson,et al.  Cost of Illness of Multiple Sclerosis - A Systematic Review , 2015, PloS one.

[17]  J. Kremer,et al.  Considerations on the appropriateness of the John Cunningham virus antibody assay use in patients with rheumatoid arthritis. , 2015, Seminars in arthritis and rheumatism.

[18]  P. Parren,et al.  Complement in therapy and disease: Regulating the complement system with antibody-based therapeutics. , 2015, Molecular immunology.

[19]  D. Reich,et al.  Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis , 2015, Neurology.

[20]  C. English,et al.  New FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis. , 2015, Clinical therapeutics.

[21]  H. Weiner,et al.  Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. , 2015, JAMA neurology.

[22]  S. Hauser.  The Charcot Lecture | Beating MS: A story of B cells, with twists and turns , 2015, Multiple sclerosis.

[23]  Gregory F. Wu,et al.  B cell antigen presentation is sufficient to drive neuro-inflammation in an animal model of multiple sclerosis , 2014, Journal of Neuroimmunology.

[24]  L. Chan,et al.  Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. , 2014, Archives of physical medicine and rehabilitation.

[25]  L. Kappos,et al.  Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial , 2014, The Lancet Neurology.

[26]  M. Filippi,et al.  Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis , 2014, Neurology.

[27]  P. Tak,et al.  Safety with Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III Program , 2014, PloS one.

[28]  R. Maciuca,et al.  Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. , 2013, Arthritis and rheumatism.

[29]  C. Sautès-Fridman,et al.  Preclinical study of Ublituximab, a Glycoengineered anti-human CD20 antibody, in murine models of primary cerebral and intraocular B-cell lymphomas. , 2013, Investigative ophthalmology & visual science.

[30]  P. Sørensen,et al.  Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression , 2013, PloS one.

[31]  C. Klein,et al.  Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties , 2013, mAbs.

[32]  Jeffrey A. Cohen,et al.  Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial , 2012, The Lancet.

[33]  M. Krumbholz,et al.  B cells and antibodies in multiple sclerosis pathogenesis and therapy , 2012, Nature Reviews Neurology.

[34]  R. Reynolds,et al.  Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. , 2012, Brain : a journal of neurology.

[35]  G. Nakamura,et al.  The assay design used for measurement of therapeutic antibody concentrations can affect pharmacokinetic parameters , 2012, mAbs.

[36]  F. Barkhof,et al.  Long-Term Efficacy and Safety of Ocrelizumab in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS): Week 96 Results of a Phase II, Randomized, Multicenter Trial (S30.006) , 2012 .

[37]  J. Kremer,et al.  Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight–week randomized, double-blind, placebo-controlled, parallel-group phase III trial. , 2012, Arthritis and rheumatism.

[38]  C. Zerbini,et al.  Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial , 2012, Annals of the rheumatic diseases.

[39]  B. Combe,et al.  Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial. , 2012, Arthritis and rheumatism.

[40]  R. Sudlow,et al.  Single- versus dual-infusion of B-cell-depleting antibody ocrelizumab in rheumatoid arthritis: results from the Phase III FEATURE trial , 2011 .

[41]  F. Barkhof,et al.  Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial , 2011, The Lancet.

[42]  R. Reynolds,et al.  Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. , 2011, Brain : a journal of neurology.

[43]  G. Silverman,et al.  Development of anti-CD20 therapy for multiple sclerosis. , 2011, Experimental cell research.

[44]  M. Shlomchik,et al.  B-Cell Depletion In Vitro and In Vivo with an Afucosylated Anti-CD19 Antibody , 2010, Journal of Pharmacology and Experimental Therapeutics.

[45]  B. Coiffier,et al.  Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[46]  E. Coccia,et al.  Epstein-Barr Virus Latent Infection and BAFF Expression in B Cells in the Multiple Sclerosis Brain: Implications for Viral Persistence and Intrathecal B-Cell Activation , 2010, Journal of neuropathology and experimental neurology.

[47]  P. Calabresi,et al.  Abnormal B‐cell cytokine responses a trigger of T‐cell–mediated disease in MS? , 2010, Annals of neurology.

[48]  P. Calabresi,et al.  Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double‐blind placebo‐controlled multicenter trial , 2009, Annals of neurology.

[49]  Peter K. Stys,et al.  Gray matter pathology in (chronic) MS: Modern views on an early observation , 2009, Journal of the Neurological Sciences.

[50]  Jianping Ding,et al.  Structure of the Fab fragment of therapeutic antibody Ofatumumab provides insights into the recognition mechanism with CD20. , 2009, Molecular immunology.

[51]  D. Hafler,et al.  Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid , 2009, Annals of neurology.

[52]  D. Bourdette,et al.  B-cell depletion with rituximab in relapsing-remitting multiple sclerosis , 2008, Current neurology and neuroscience reports.

[53]  E. Frohman,et al.  Impact of myelin-specific antigen presenting B cells on T cell activation in multiple sclerosis. , 2008, Clinical immunology.

[54]  M. Krumbholz,et al.  Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. , 2008, Brain : a journal of neurology.

[55]  D. Arnold,et al.  Rituximab in relapsing‐remitting multiple sclerosis: A 72‐week, open‐label, phase I trial , 2008, Annals of neurology.

[56]  Jianping Ding,et al.  Structural Basis for Recognition of CD20 by Therapeutic Antibody Rituximab* , 2007, Journal of Biological Chemistry.

[57]  Hans Lassmann,et al.  The Immunopathology of Multiple Sclerosis: An Overview , 2007, Brain pathology.

[58]  P. Narayana,et al.  Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double‐blind, placebo‐controlled trial , 2007, Annals of neurology.

[59]  Amanda L. Cox,et al.  Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis , 2005, European journal of immunology.

[60]  A. Rosenwald,et al.  BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma , 2005, The Journal of experimental medicine.

[61]  I. Sanz,et al.  B lymphocytes in systemic lupus erythematosus: lessons from therapy targeting B cells , 2004, Lupus.

[62]  B. Serafini,et al.  Detection of Ectopic B‐cell Follicles with Germinal Centers in the Meninges of Patients with Secondary Progressive Multiple Sclerosis , 2004, Brain pathology.

[63]  M. Cragg,et al.  Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. , 2003, Blood.

[64]  G. Salles,et al.  Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. , 2002, Blood.

[65]  J. Maroun,et al.  The standardization of NK cell assays for use in studies of biological response modifiers. , 1984, Journal of immunological methods.

[66]  L. Nadler,et al.  Characterization of a human B lymphocyte-specific antigen. , 1980, Journal of immunology.

[67]  R. Bakshi,et al.  Use of Magnetic Resonance Imaging to Visualize Leptomeningeal Inflammation in Patients With Multiple Sclerosis: A Review , 2017, JAMA neurology.

[68]  D. Arnold,et al.  Evaluation of no evidence of progression using composite outcome measures, in patients with primary progressive multiple sclerosis in the ORATORIO trial , 2016 .

[69]  D. Goodin.  The epidemiology of multiple sclerosis: insights to disease pathogenesis. , 2014, Handbook of clinical neurology.

[70]  K. Kolasa.  How much is the cost of multiple sclerosis--systematic literature review. , 2013, Przeglad epidemiologiczny.

[71]  J. Leusen,et al.  Mechanisms of action of CD20 antibodies. , 2012, American journal of cancer research.

[72]  D. Maloney.  Follicular NHL: from antibodies and vaccines to graft-versus-lymphoma effects. , 2007, Hematology. American Society of Hematology. Education Program.

[73]  R. Reynolds,et al.  Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. , 2007, Brain : a journal of neurology.

[74]  J. Newcombe,et al.  Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. , 2006, Brain : a journal of neurology.

[75]  M. Cragg,et al.  The biology of CD20 and its potential as a target for mAb therapy. , 2005, Current directions in autoimmunity.

[76]  M. Filippi,et al.  Primary Progressive Multiple Sclerosis , 2002, Topics in Neuroscience.

[77]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.