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Identification of proteins that specifically recognize and bind protofibrillar aggregates of amyloid-?.

ABSTRACT: Protofibrils of the 42 amino acids long amyloid-? peptide are transient pre-fibrillar intermediates in the process of peptide aggregation into amyloid plaques and are thought to play a critical role in the pathology of Alzheimer's disease. Hence, there is a need for research reagents and potential diagnostic reagents for detection and imaging of such aggregates. Here we describe an in vitro selection of Affibody molecules that bind to protofibrils of A?₄₂cc, which is a stable engineered mimic of wild type A?₄₂ protofibrils. Several binders were identified that bind A?₄₂cc protofibrils with low nanomolar affinities, and which also recognize wild type A?₄₂ protofibrils. Dimeric head-to-tail fusion proteins with subnanomolar binding affinities, and very slow dissociation off-rates, were also constructed. A mapping of the chemical properties of the side chains onto the Affibody scaffold surface reveals three distinct adjacent surface areas of positively charged surface, nonpolar surface and a polar surface, which presumably match a corresponding surface epitope on the protofibrils. The results demonstrate that the engineered A?₄₂cc is a suitable antigen for directed evolution of affinity reagents with specificity for wild type A?₄₂ protofibrils.

SUBMITTER: Wahlberg E

PROVIDER: S-EPMC5519597 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Identification of proteins that specifically recognize and bind protofibrillar aggregates of amyloid-β.

Wahlberg Elisabet E Rahman M Mahafuzur MM Lindberg Hanna H Gunneriusson Elin E Schmuck Benjamin B Lendel Christofer C Sandgren Mats M Löfblom John J Ståhl Stefan S Härd Torleif T

Scientific reports 20170720 1

Protofibrils of the 42 amino acids long amyloid-β peptide are transient pre-fibrillar intermediates in the process of peptide aggregation into amyloid plaques and are thought to play a critical role in the pathology of Alzheimer's disease. Hence, there is a need for research reagents and potential diagnostic reagents for detection and imaging of such aggregates. Here we describe an in vitro selection of Affibody molecules that bind to protofibrils of Aβ<sub>42</sub>cc, which is a stable engineer ...[more]

PMID: 28729665

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Project description:BackgroundAnti-amyloid β (Aβ) immunotherapy represents a major area of drug development for Alzheimer's disease (AD). However, Aβ peptide adopts multiple conformations and the pathological forms to be specifically targeted have not been identified. Aβ immunotherapy-related vasogenic edema has also been severely dose limiting for antibodies with effector functions binding vascular amyloid such as bapineuzumab. These two factors might have contributed to the limited efficacy demonstrated so far in clinical studies.MethodsTo address these limitations, we have engineered SAR228810, a humanized monoclonal antibody (mAb) with limited Fc effector functions that binds specifically to soluble protofibrillar and fibrillar forms of Aβ peptide and we tested it together with its murine precursor SAR255952 in vitro and in vivo.ResultsUnlike gantenerumab and BAN2401, SAR228810 and SAR255952 do not bind to Aβ monomers, low molecular weight Aβ oligomers or, in human brain sections, to Aβ diffuse deposits which are not specific of AD pathology. Both antibodies prevent Aβ42 oligomer neurotoxicity in primary neuronal cultures. In vivo, SAR255952, a mouse aglycosylated IgG1, dose-dependently prevented brain amyloid plaque formation and plaque-related inflammation with a minimal active dose of 3 mg/kg/week by the intraperitoneal route. No increase in plasma Aβ levels was observed with SAR255952 treatment, in line with its lack of affinity for monomeric Aβ. The effects of SAR255952 translated into synaptic functional improvement in ex-vivo hippocampal slices. Brain penetration and decoration of cerebral amyloid plaques was documented in live animals and postmortem. SAR255952 (up to 50 mg/kg/week intravenously) did not increase brain microhemorrhages and/or microscopic changes in meningeal and cerebral arteries in old APPSL mice while 3D6, the murine version of bapineuzumab, did. In immunotolerized mice, the clinical candidate SAR228810 demonstrated the same level of efficacy as the murine SAR255952.ConclusionBased on the improved efficacy/safety profile in non-clinical models of SAR228810, a first-in-man single and multiple dose administration clinical study has been initiated in AD patients.

Dataset Information

Identification of proteins that specifically recognize and bind protofibrillar aggregates of amyloid-?.

Publications

Identification of proteins that specifically recognize and bind protofibrillar aggregates of amyloid-β.

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