Abstract
Levels of amyloid-beta monomer and deposited amyloid-beta in the Alzheimer’s disease brain are orders of magnitude greater than soluble amyloid-beta oligomer levels. Monomeric amyloid-beta has no known direct toxicity. Insoluble fibrillar amyloid-beta has been proposed to be an in vivo mechanism for removal of soluble amyloid-beta and exhibits relatively low toxicity. In contrast, soluble amyloid-beta oligomers are widely reported to be the most toxic amyloid-beta form, both causing acute synaptotoxicity and inducing neurodegenerative processes. None of the amyloid-beta immunotherapies currently in clinical development selectively target soluble amyloid-beta oligomers, and their lack of efficacy is not unexpected considering their selectivity for monomeric or fibrillar amyloid-beta (or both) rather than soluble amyloid-beta oligomers. Because they exhibit acute, memory-compromising synaptic toxicity and induce chronic neurodegenerative toxicity and because they exist at very low in vivo levels in the Alzheimer’s disease brain, soluble amyloid-beta oligomers constitute an optimal immunotherapeutic target that should be pursued more aggressively.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60% to 80% of all dementias [1,2]
Aβ antibodies optimized to bind soluble Aβ oligomers selectively are much more likely to succeed in AD clinical trials and should be aggressively pursued
The prediction that immunotherapies targeting soluble Aβ oligomers will elicit clinical benefit is supported by studies of human Aβ autoantibodies, of which only a subset appears to be disease-protective [221,222,223]
Summary
Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60% to 80% of all dementias [1,2]. Because bapineuzumab binds monomeric Aβ with similar affinity to soluble Aβ oligomers and fibrillar Aβ and because Aβ soluble oligomer levels are orders of magnitude less than Aβ monomer and fibrils levels in the AD brain [58,59,60,61,62,63,64,65], it is clear that bapineuzumab was not dosed high enough in the pivotal phase 3 trials to effectively sequester soluble Aβ oligomers. Explicit details of the binding characteristics of BiiB037 have not been publicly disclosed, results reported by Dunstan and colleagues [209] and data in the patent covering BiiB037 [208] suggest that BiiB037 is very similar, or identical, to antibody NI-101.11, which binds with high affinity to Aβ plaques in human AD brain tissue samples [208] Such binding is not blocked by monomeric Aβ(1-16) or Aβ(1-42), showing selective affinity for fibrillar Aβ versus Aβ monomers [208]. The reported data suggest that 13C3/SAR228810 is very similar to mAb158/ BAN2401 and binds higher-molecular-weight soluble Aβ oligomers (referred to as protofibrils in the 13C3/ SAR228810 literature) and fibrillar Aβ with high affinity and has low affinity for binding monomeric Aβ and lower-molecular-weight soluble Aβ oligomers
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