Insights into the Mechanisms of the Therapeutic Efficacy of Alemtuzumab in Multiple Sclerosis.

The pathogenesis of multiple sclerosis (MS) is thought to involve peripheral activation of immune cells against central nervous system (CNS) antigens and their migration across the blood-brain barrier, leading to CNS inflammation and neurodegeneration. Alemtuzumab, a humanized anti-CD52 monoclonal antibody that rapidly depletes CD52-expressing cells from the circulation, is being investigated as a new treatment option in relapsing-remitting MS (RRMS). Clinical and radiologic results indicate robust suppression of inflammation related to the depletion of T and B lymphocytes during each treatment course of alemtuzumab. Furthermore, several lines of evidence suggest that the long-term clinical effects of alemtuzumab are attributable to qualitative changes in repopulating lymphocyte subsets potentially leading to a rebalancing of the immune system. Here, we review the contribution of data from animal models, ex vivo human studies, and clinical trials to the understanding of the mechanisms underlying the therapeutic effect of alemtuzumab in patients with RRMS.

[1]  Jeffrey A. Cohen,et al.  Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. , 2014, Immunotherapy.

[2]  J. Kaplan,et al.  Immune status following alemtuzumab treatment in human CD52 transgenic mice , 2013, Journal of Neuroimmunology.

[3]  G. Ingram,et al.  Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis , 2013, Neurology.

[4]  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.

[5]  Christian Confavreux,et al.  Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial , 2012, The Lancet.

[6]  F. Deisenhammer,et al.  Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial , 2012, Neurology.

[7]  Sambasiva P Rao,et al.  Human Peripheral Blood Mononuclear Cells Exhibit Heterogeneous CD52 Expression Levels and Show Differential Sensitivity to Alemtuzumab Mediated Cytolysis , 2012, PloS one.

[8]  S. Markovic‐Plese,et al.  Alemtuzumab (Anti-CD52 mAb) Induces Expansion of Treg and Th2 Cells and Inhibits Th1 and Th17 Cells in Treated Patients with Relapsing Remitting Multiple Sclerosis (RRMS) (P02.119) , 2012 .

[9]  R. Clark,et al.  Skin Effector Memory T Cells Do Not Recirculate and Provide Immune Protection in Alemtuzumab-Treated CTCL Patients , 2012, Science Translational Medicine.

[10]  H. Sullivan,et al.  A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. , 2011, Blood.

[11]  C. Wegner,et al.  Insight into the mechanism of laquinimod action , 2011, Journal of the Neurological Sciences.

[12]  K. Selmaj,et al.  Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes , 2011, The Lancet Neurology.

[13]  D. R. Allington,et al.  New approaches in the management of multiple sclerosis , 2010, Drug design, development and therapy.

[14]  K. Selmaj,et al.  Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. , 2010, Brain : a journal of neurology.

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

[16]  A. Compston,et al.  Predicting Autoimmunity Following Treatment of Multiple Sclerosis with Alemtuzumab , 2010 .

[17]  A. Weetman.  Immune reconstitution syndrome and the thyroid. , 2009, Best practice & research. Clinical endocrinology & metabolism.

[18]  Yanping Hu,et al.  Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model , 2009, Immunology.

[19]  M. Ban,et al.  IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). , 2009, The Journal of clinical investigation.

[20]  F. Fahoum,et al.  Interferon-β therapy up-regulates BDNF secretion from PBMCs of MS patients through a CD40-dependent mechanism , 2009, Journal of Neuroimmunology.

[21]  Laura Conti,et al.  T‐helper 17 cells expand in multiple sclerosis and are inhibited by interferon‐β , 2009, Annals of neurology.

[22]  A. Coles,et al.  B-Cell Reconstitution and BAFF After Alemtuzumab (Campath-1H) Treatment of Multiple Sclerosis , 2009, Journal of Clinical Immunology.

[23]  K. Selmaj,et al.  Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. , 2008, The New England journal of medicine.

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

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

[26]  M. Clatworthy,et al.  Anti-glomerular basement membrane disease after alemtuzumab. , 2008, The New England journal of medicine.

[27]  K. Venken,et al.  Compromised CD4+ CD25high regulatory T‐cell function in patients with relapsing‐remitting multiple sclerosis is correlated with a reduced frequency of FOXP3‐positive cells and reduced FOXP3 expression at the single‐cell level , 2008, Immunology.

[28]  Jia Newcombe,et al.  Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. , 2008, The American journal of pathology.

[29]  A. Coles,et al.  Campath-1H Treatment of Multiple Sclerosis , 2007, Neurodegenerative Diseases.

[30]  P. Krammer,et al.  Prevalence of Newly Generated Naive Regulatory T Cells (Treg) Is Critical for Treg Suppressive Function and Determines Treg Dysfunction in Multiple Sclerosis1 , 2007, The Journal of Immunology.

[31]  Aaron J. Johnson,et al.  The CD8 T cell in multiple sclerosis: suppressor cell or mediator of neuropathology? , 2007, International review of neurobiology.

[32]  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.

[33]  G. Freeman,et al.  Innate Immunity in Multiple Sclerosis: Myeloid Dendritic Cells in Secondary Progressive Multiple Sclerosis Are Activated and Drive a Proinflammatory Immune Response1 , 2006, The Journal of Immunology.

[34]  Tomoko Watanabe,et al.  CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells. , 2006, Clinical immunology.

[35]  T. Fry,et al.  Autoimmunity during lymphopenia: a two-hit model. , 2006, Clinical immunology.

[36]  T. Waldmann,et al.  Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Stefanelli,et al.  Journal of Autoimmune Diseases BioMed Central , 2005 .

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

[39]  A. Karni,et al.  Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: Reversal by glatiramer acetate , 2005, Journal of Neuroimmunology.

[40]  D. Hafler,et al.  Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein1 , 2005, The Journal of Immunology.

[41]  U. Frey,et al.  Alemtuzumab induces enhanced apoptosis in vitro in B-cells from patients with chronic lymphocytic leukemia by antibody-dependent cellular cytotoxicity. , 2005, European journal of pharmacology.

[42]  Andrew K. Brown,et al.  Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia , 2004, Arthritis research & therapy.

[43]  H. Waldmann,et al.  The window of therapeutic opportunity in multiple sclerosis , 2005, Journal of Neurology.

[44]  M. Hallek,et al.  Rituximab and alemtuzumab induce a nonclassic, caspase-independent apoptotic pathway in B-lymphoid cell lines and in chronic lymphocytic leukemia cells , 2004, Annals of Hematology.

[45]  Clare Baecher-Allan,et al.  Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis , 2004, The Journal of experimental medicine.

[46]  K. Rajewsky,et al.  Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Roland Martin,et al.  The immunopathogenesis of multiple sclerosis. , 2002, Journal of rehabilitation research and development.

[48]  W. Brück,et al.  BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? , 2002, Brain : a journal of neurology.

[49]  J. Goverman,et al.  A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis , 2001, The Journal of experimental medicine.

[50]  H. Neumann,et al.  Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. , 2001, The American journal of pathology.

[51]  W. Brück,et al.  Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. , 2000, Brain : a journal of neurology.

[52]  D. Clayton,et al.  Autoimmune disease in first-degree relatives of patients with multiple sclerosis. A UK survey. , 2000, Brain : a journal of neurology.

[53]  A. Compston,et al.  Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis , 1999, The Lancet.

[54]  Jingwu Z. Zhang,et al.  Impaired apoptotic deletion of myelin basic protein‐reactive T cells in patients with multiple sclerosis , 1999, European Journal of Immunology.

[55]  S. Kano,et al.  Characterization of the 4C8 Antigen Involved in Transendothelial Migration of CD26hi T Cells after Tight Adhesion to Human Umbilical Vein Endothelial Cell Monolayers , 1999, The Journal of experimental medicine.

[56]  C. Caltagirone,et al.  Impaired apoptosis in mitogen-stimulated lymphocytes of patients with multiple sclerosis. , 1999, Neuroreport.

[57]  M. Ferguson,et al.  Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchored glycoprotein which is an exceptionally good target for complement lysis. , 1993, The Biochemical journal.

[58]  J. Tite,et al.  Humanized monoclonal antibody CAMPATH‐1H: myeloma cell expression of genomic constructs, nucleotide sequence of cDNA constructs and comparison of effector mechanisms of myeloma and Chinese hamster ovary cell‐derived material , 1992, Clinical and experimental immunology.

[59]  J. Mussini,et al.  [Immunology of multiple sclerosis]. , 1982, La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris.

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