title: New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.
abstract: The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens.
  
  
  
  We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy.
  
  
  
  In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro.
  
  
  
  Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.
authors.affiliation: Neuroimmunological Lab, Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany.|Multiple Sclerosis Center, Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Sehr
authors.affiliation: Neuroimmunological Lab, Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany.|Multiple Sclerosis Center, Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Proschmann
authors.affiliation: Neuroimmunological Lab, Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany.|Multiple Sclerosis Center, Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Neuroimmunological Lab, Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Marggraf
authors.affiliation: Neurology Outpatient Center Barsinghausen, Marktstrasse 27/29, Barsinghausen, 30890, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Straube
authors.affiliation: Multiple Sclerosis Center, Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Reichmann
authors.affiliation: Department of Neurology, University Hospital Bern and University of Bern, Freiburgstrasse, Bern, 3010, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Chan
authors.affiliation: Neuroimmunological Lab, Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany. Tjalf.Ziemssen@uniklinikum-dresden.de.|Multiple Sclerosis Center, Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl-Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307, Dresden, Germany. Tjalf.Ziemssen@uniklinikum-dresden.de.
authors.forename: T
authors.identifier: 0000-0001-8799-8202
authors.initials: T
authors.lastname: Ziemssen
mesh_terms: D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD; D004185:Disability Evaluation; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D039041:Integrin alpha4beta1 / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy; D000069442:Natalizumab / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D007155:Immunologic Factors; D039041:Integrin alpha4beta1; D000069442:Natalizumab; D019010:Vascular Cell Adhesion Molecule-1
keywords: CSF; Immunology; Multiple sclerosis; Natalizumab; Treatment monitoring; Tysabri