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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.
The amyloid hypothesis posits that Aβ-related toxicity is the primary cause of synaptic dysfunction and subsequent neurodegeneration that underlies the progression characteristic of AD1,2. Genetic, neuropathological, and cell biological evidence strongly suggest that targeting Aβ could be beneficial for patients with AD3,4. So far, attempts at therapeutically targeting Aβ have not been successful5-7, casting doubt on the validity of the amyloid hypothesis. However, the lack of success may have been due to the inability of the antibodies to adequately engage their target or the proper target in the brain, or selecting the wrong patient population.
We describe the development of an antibody-based immunotherapeutic approach by selecting human B-cell clones triggered by neo-epitopes present in pathological Aβ aggregates. The screening of libraries of human memory B cells for reactivity against aggregated Aβ led to molecular cloning, sequencing, and recombinant expression of aducanumab (BIIB037), a human monoclonal antibody that selectively reacts with Aβ aggregates, including soluble oligomers and insoluble fibrils. In preclinical studies, we show that an analogue of aducanumab is capable of crossing the blood-brain barrier, engaging its target, and clearing Aβ from plaque-bearing transgenic mouse brains. These results prompted the start of clinical trials8.
We report here interim results from...