title: Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab.
abstract: BACKGROUND
  Gantenerumab is a fully human anti-Aβ monoclonal antibody in clinical development for the treatment of Alzheimer disease (AD).
  
  
  OBJECTIVE
  To investigate whether treatment with gantenerumab leads to a measurable reduction in the level of Aβ amyloid in the brain and to elucidate the mechanism of amyloid reduction.
  
  
  METHODS
  A multicenter, randomized, double-blind, placebo-controlled, ascending-dose positron emission tomographic study. Additionally, ex vivo studies of human brain slices from an independent sample of patients who had AD were performed.
  
  
  METHODS
  Three university medical centers.
  
  
  METHODS
  Patients with mild-to-moderate AD.
  
  
  METHODS
  Two consecutive cohorts of patients received 2 to 7 infusions of intravenous gantenerumab (60 or 200 mg) or placebo every 4 weeks. Brain slices from patients who had AD were coincubated with gantenerumab at increasing concentrations and with human microglial cells.
  
  
  METHODS
  Percent change in the ratio of regional carbon 11-labeled Pittsburgh Compound B retention in vivo and semiquantitative assessment of gantenerumab-induced phagocytosis ex vivo.
  
  
  RESULTS
  Sixteen patients with end-of-treatment positron emission tomographic scans were included in the analysis. The mean (95% CI) percent change from baseline difference relative to placebo (n = 4) in cortical brain amyloid level was -15.6% (95% CI, -42.7 to 11.6) for the 60-mg group (n = 6) and -35.7% (95% CI, -63.5 to -7.9) for the 200-mg group (n = 6). Two patients in the 200-mg group showed transient and focal areas of inflammation or vasogenic edema on magnetic resonance imaging scans at sites with the highest level of amyloid reduction. Gantenerumab induced phagocytosis of human amyloid in a dose-dependent manner ex vivo.
  
  
  CONCLUSIONS
  Gantenerumab treatment resulted in a dose-dependent reduction in brain amyloid level, possibly through an effector cell-mediated mechanism of action.
authors: F. Hoffmann-La Roche Ltd, Neuroscience, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors: Susanne
authors: S
authors: Ostrowitzki
authors: Dennis
authors: D
authors: Deptula
authors: Lennart
authors: L
authors: Thurfjell
authors: Frederik
authors: F
authors: Barkhof
authors: Bernd
authors: B
authors: Bohrmann
authors: David J
authors: DJ
authors: Brooks
authors: William E
authors: WE
authors: Klunk
authors: Elizabeth
authors: E
authors: Ashford
authors: Kisook
authors: K
authors: Yoo
authors: Zhi-Xin
authors: ZX
authors: Xu
authors: Hansruedi
authors: H
authors: Loetscher
authors: Luca
authors: L
authors: Santarelli
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000532:radiotherapy; D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001923:Brain Chemistry / Q000187:drug effects; D002452:Cell Count; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D017628:Microglia / Q000502:physiology; D008875:Middle Aged; D010587:Phagocytosis / Q000502:physiology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D018401:Sample Size; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D019275:Radiopharmaceuticals; D013844:Thiazoles; C571128:gantenerumab