O2–06–03: ACU‐193: A candidate therapeutic antibody that selectively targets soluble beta‐amyloid oligomers
Year: 2013
Type: article
Abstract: Soluble beta-amyloid oligomers are widely recognized as the key molecular pathogens in Alzheimer's disease. Because these non-fibrillar beta-amyloid assemblies inhibit synaptic function, trigger early memory deficits and initiate neurodegeneration, they represent a highly attractive intervention target for Alzheimer's disease. In this presentation we describe ACU-193, a promising new drug candidate with high binding selectivity for soluble beta-amyloid oligomers, and with potent capability to block their synaptotoxicity. ACU-193 is a humanized, affinity matured IgG2 monoclonal antibody that has been engineered to minimize cellular effector functions and immunogenicity. It binds to soluble beta-amyloid oligomers with low nanomolar affinity, exhibits >500-fold selectivity for soluble beta-amyloid oligomers versus beta-amyloid monomer and fibrillic beta-amyloid, and does not exhibit cross-reactive binding to other proteins. ACU-193 potently blocks synaptic binding of soluble beta-amyloid oligomers in cultured hippocampal neurons (IC 50 = 17 nM), and its efficacy does not diminish in the presence of excess beta-amyloid monomer. In vivo ACU-193 target engagement and behavioral efficacy were demonstrated by administration to Tg-AD mice, which afforded dose-dependent complex formation with soluble beta-amyloid oligomers in brain tissue, reduction in plaque deposition, and significantly reduced abnormal nocturnal hyperactivity. ACU-193 exhibited linear, dose-dependent pharmacokinetics, biodistribution, and brain penetration in mice, rats, dogs, and monkeys, typical of other CNS-directed antibody drugs. ACU-193 has an overall excellent safety profile, and high-yielding, stable cell lines have been established for efficient production. Human dosing is expected to deliver brain levels of ACU-193 >200-fold higher than measured soluble beta-amyloid oligomer levels in AD CSF; thus ACU-193 is expected improve synaptic and cognitive function in AD patients. Biomarker assays to measure the drug-target complex and levels of soluble beta-amyloid oligomers in CSF have been developed to support clinical studies of ACU-193. These assays should allow patient selection and stratification and serve as a companion diagnostic. ACU-193 is expected to deliver acute behavioral benefits and chronic disease modification benefits. Clinical develop plans reflect the availability of biomarker assays and the expectation that behavioral efficacy is achieved relatively quickly. It is anticipated that initial evidence for efficacy will be obtained in a phase Ib study of relatively short duration and cost.
Source: Alzheimer s & Dementia
Institution: Acumen Pharmaceuticals (United States)
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1983250356