Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab.

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Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L

Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab.

Arch Neurol. 2012 Feb;69(2):198-207. doi: 10.1001/archneurol.2011.1538. Epub 2011 Oct 10.

PubMed ID

21987394 [ View in PubMed

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Abstract

BACKGROUND: Gantenerumab is a fully human anti-Abeta monoclonal antibody in clinical development for the treatment of Alzheimer disease (AD). OBJECTIVES: To investigate whether treatment with gantenerumab leads to a measurable reduction in the level of Abeta amyloid in the brain and to elucidate the mechanism of amyloid reduction. DESIGN: 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. SETTING: Three university medical centers. PATIENTS: Patients with mild-to-moderate AD. INTERVENTION: 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. MAIN OUTCOME MEASURES: 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. CONCLUSION: Gantenerumab treatment resulted in a dose-dependent reduction in brain amyloid level, possibly through an effector cell-mediated mechanism of action.

DrugBank Data that Cites this Article

Drugs

Gantenerumab

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Gantenerumab	Amyloid beta A4 protein	Protein	Humans	Yes	Antagonist Binder Antibody	Details