The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

• Published in: Nature (London) 2016-09, Vol.537 (7618), p.50-56
• Main Authors: Sevigny, Jeff, Chiao, Ping, Bussière, Thierry, Weinreb, Paul H., Williams, Leslie, Maier, Marcel, Dunstan, Robert, Salloway, Stephen, Chen, Tianle, Ling, Yan, O’Gorman, John, Qian, Fang, Arastu, Mahin, Li, Mingwei, Chollate, Sowmya, Brennan, Melanie S., Quintero-Monzon, Omar, Scannevin, Robert H., Arnold, H. Moore, Engber, Thomas, Rhodes, Kenneth, Ferrero, James, Hang, Yaming, Mikulskis, Alvydas, Grimm, Jan, Hock, Christoph, Nitsch, Roger M., Sandrock, Alfred
• Format: Article
• Language: English
• Subjects: 692/308/153; 692/699/375/132; Aged; Aged, 80 and over; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - psychology; Amyloid - drug effects; Amyloid - metabolism; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Animals; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Brain - drug effects; Brain - metabolism; Clinical Trials, Phase III as Topic; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humanities and Social Sciences; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Models, Biological; multidisciplinary; Plaque, Amyloid - drug therapy; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Protein Aggregation, Pathological - drug therapy; Science; Solubility
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature19323

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. Aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ, reduces soluble and insoluble Aβ in the brain, an action accompanied by a dose-dependent slowing of clinical decline in treated patients. A prospect for amyloid-β-removal therapy Aducanumab is a recombinant human monoclonal antibody that selectively targets the amyloid-β (Aβ) peptide aggregates thought to play a part in the neurodegenerative process in Alzheimer's disease. Several Alzheimer's disease drugs have failed in development in recent years — including other anti-amyloid antibodies — so there is intense interest in any new developments. A new study reports interim results from a clinical trial of monthly infusions of aducanumab in subjects with prodromal or mild Alzheimer's disease. Treatment with aducanumab reduced brain Aβ plaques, an action accompanied by a dose-dependent slowing of clinical decline. The trial data support further development of aducanumab as an Aβ-removing therapy.