title: The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL.
abstract: OBJECTIVE
  To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab.
  
  
  METHODS
  In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INF beta]1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies (>or=0.5 microg/mL) at a single time point or "persistently positive" if they had antibodies at two or more time points >or=6 weeks apart.
  
  
  RESULTS
  In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p <or= 0.05), relapse rate (p = 0.009), and MRI (p <or= 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant.
  
  
  CONCLUSIONS
  The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing.
authors.affiliation: Johns Hopkins Multiple Sclerosis Center, Baltimore, MD, USA. Calabresi@jhmi.edu
authors.forename: P A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: G
authors.initials: G
authors.lastname: Giovannoni
authors.forename: C
authors.initials: C
authors.lastname: Confavreux
authors.forename: S L
authors.initials: SL
authors.lastname: Galetta
authors.forename: E
authors.initials: E
authors.lastname: Havrdova
authors.forename: M
authors.initials: M
authors.lastname: Hutchinson
authors.forename: L
authors.initials: L
authors.lastname: Kappos
authors.forename: D H
authors.initials: DH
authors.lastname: Miller
authors.forename: P W
authors.initials: PW
authors.lastname: O'Connor
authors.forename: J T
authors.initials: JT
authors.lastname: Phillips
authors.forename: C H
authors.initials: CH
authors.lastname: Polman
authors.forename: E-W
authors.initials: EW
authors.lastname: Radue
authors.forename: R A
authors.initials: RA
authors.lastname: Rudick
authors.forename: W H
authors.initials: WH
authors.lastname: Stuart
authors.forename: F D
authors.initials: FD
authors.lastname: Lublin
authors.forename: A
authors.initials: A
authors.lastname: Wajgt
authors.forename: B
authors.initials: B
authors.lastname: Weinstock-Guttman
authors.forename: D R
authors.initials: DR
authors.lastname: Wynn
authors.forename: F
authors.initials: F
authors.lastname: Lynn
authors.forename: M A
authors.initials: MA
authors.lastname: Panzara
mesh_terms: D019138:Antibodies, Blocking / Q000032:analysis / Q000097:blood* / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity / Q000276:immunology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004185:Disability Evaluation; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D000069442:Natalizumab; D015990:Placebo Effect; D055502:Secondary Prevention; D016896:Treatment Outcome
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D016899:Interferon-beta; D000068556:Interferon beta-1a