title: Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis.
abstract: BACKGROUND
  Antibodies against natalizumab have been found in 4.5-14.1% of natalizumab-treated multiple sclerosis (MS) patients. If antibodies persist, they are associated with an adverse effect on treatment response. However, it has proved to be difficult to standardize anti-drug antibody measurements.
  
  
  OBJECTIVE
  The purpose of this study was to evaluate the clinical and radiological impact of serum natalizumab concentrations and their relation with anti-natalizumab antibodies in MS patients.
  
  
  METHODS
  In this prospective observational cohort study of 73 consecutive patients treated with natalizumab, we measured serum natalizumab levels and antibody titers before the start of natalizumab treatment, at weeks 12 and 24 and annually after natalizumab initiation. Antibodies against natalizumab were measured by radioimmunoassay and serum natalizumab concentrations using a newly developed enzyme linked immunosorbent assay (ELISA). Magnetic resonance imaging (MRI) scan and clinical evaluation were performed before the start of natalizumab treatment and subsequently every year.
  
  
  RESULTS
  Antibodies were detected in 58% of the natalizumab-treated patients. All patients developed their antibodies before week 24. The large majority of these patients reverted to neutralizing antibody (NAb) negative status during follow-up. The presence of antibodies was inversely correlated with serum natalizumab concentration (p<0.001). Only high antibody titers are associated with very low or undetectable serum natalizumab concentration. Both high antibody titers and low serum natalizumab concentrations are associated with relapses and gadolinium-enhancing lesions on MRI.
  
  
  CONCLUSIONS
  Our data show that both low natalizumab serum concentration and high antibody titers are associated with a lack of efficacy of natalizumab. Measuring serum natalizumab, using a highly specific assay, might lead to more enhanced precision using natalizumab in individual patients.
authors.affiliation: Department of Neurology, VU University Medical Center, The Netherlands. a.vennegoor@vumc.nl
authors.forename: Anke
authors.initials: A
authors.lastname: Vennegoor
authors.forename: Theo
authors.initials: T
authors.lastname: Rispens
authors.forename: Eva Mm
authors.initials: EM
authors.lastname: Strijbis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Seewann
authors.forename: Bernard Mj
authors.initials: BM
authors.lastname: Uitdehaag
authors.forename: Lisanne J
authors.initials: LJ
authors.lastname: Balk
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.forename: Gertjan
authors.initials: G
authors.lastname: Wolbink
authors.forename: Joep
authors.initials: J
authors.lastname: Killestein
mesh_terms: D000328:Adult; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood* / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000069442:Natalizumab; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D007155:Immunologic Factors; D000069442:Natalizumab