title: ALAIN01--Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential.
abstract: BACKGROUND
  Alemtuzumab (Lemtrada®) is a newly approved therapeutic agent for relapsing-remitting multiple sclerosis (RRMS). In previous phase II and III clinical trials, alemtuzumab has proven superior efficacy to subcutaneous interferon beta-1a concerning relapse rate and disability progression with unprecedented durability and long-lasting freedom of disease activity. The humanized monoclonal antibody targets CD52, leading to a rapid and long-lasting depletion, especially of B and T cells. Arising from hematopoietic precursor cells a fundamental reprogramming of the immune system restores tolerogenic networks effectively suppressing autoimmune inflammatory responses in the central nervous system (CNS). Despite its favourable effects alemtuzumab holds a severe risk of side effects with secondary autoimmunity being the most considerable. Markers for risk stratification and treatment response improving patient selection and therapy guidance are a big unmet need for MS patients and health care providers.
  
  
  METHODS
  This is a mono center, single arm, explorative phase IV study including 15 patients with highly active RRMS designed for 3 years. Patients will be studied by a high-resolution analysis comprising a repertoire of various immunological assays for the detection of immune cells and their function in peripheral blood as well as the cerebrospinal fluid (CSF). These assays encompass a number of experiments investigating immune cell subset composition, activation status, cytokine secretion, migratory capacity, potential neuroprotective properties and cytolytic activity complemented by instrument-based diagnostics like MRI scans, evoked potentials and optical coherence tomography (OCT).
  
  
  CONCLUSIONS
  Our study represents the first in-depth and longitudinal functional analysis of key immunological parameters in the periphery and the CNS compartment underlying the fundamental effects of alemtuzumab in MS patients. By combining clinical, experimental and MRI data our study will provide a deeper understanding of alemtuzumab's mechanisms of action (MOA) potentially identifying immune signatures associated with treatment response or the development of secondary autoimmunity. After validation in larger cohorts this might help to improve efficacy and safety of alemtuzumab therapy in RRMS patients.
  
  
  BACKGROUND
  NCT02419378 (clinicaltrials.gov), registered 31 March 2015.
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany. tobias.ruck@ukmuenster.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ruck
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Ali Maisam
authors.initials: AM
authors.lastname: Afzali
authors.affiliation: Center for Clinical Studies, University of Münster, Münster, Germany.
authors.forename: Karl-Friedrich
authors.initials: KF
authors.lastname: Lukat
authors.affiliation: Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Eveslage
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Catharina C
authors.initials: CC
authors.lastname: Gross
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Pfeuffer
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Melzer
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
mesh_terms: D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018450:Disease Progression; D006801:Humans; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D018579:Patient Selection; D041623:Tomography, Optical Coherence / Q000379:methods
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074323:Alemtuzumab
keywords: Alemtuzumab; Disease-modifying therapy; Mechanism of action; Multiple sclerosis; Risk stratification; Secondary autoimmune disease