1. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.
- Author
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Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, and Sandrock A
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid drug effects, Amyloid metabolism, Amyloid beta-Peptides chemistry, Animals, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Brain drug effects, Brain metabolism, Clinical Trials, Phase III as Topic, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Models, Biological, Plaque, Amyloid pathology, Protein Aggregation, Pathological drug therapy, Solubility, Alzheimer Disease drug therapy, Alzheimer Disease psychology, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides metabolism, Antibodies, Monoclonal, Humanized therapeutic use, Plaque, Amyloid drug therapy, Plaque, Amyloid metabolism
- Abstract
Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
- Published
- 2016
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