Year-end Sale % OFF 
Abstract
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.
Highlights
Anti-amyloid β (Aβ) immunotherapy represents a major area of drug development for Alzheimer’s disease (AD)
Immunotherapy failures far have been attributed in part to: 1) the dose severely limited by safety issues (vasogenic edema/microhemorrhage associated with amyloid-related imaging abnormalities (ARIA) reported in clinical settings, preventing efficacious brain levels being reached); 2) not targeting the appropriate toxic Aβ species; and 3) intervention late in the disease continuum
SAR255952 maintained a higher affinity for soluble High molecular weight (HMW) Aβ protofibrils compared with low molecular weight (LMW) Aβ complexes with EC50 values of 36 ± 5.5 ng/ml (n = 6) and 3751 ± 130 ng/ml (n = 6), respectively, while the pan Aβ-conformer antibody 3D6 displayed similar affinities for both Aβ conformations (Fig. 1 and Table 1)
Summary
Anti-amyloid β (Aβ) immunotherapy represents a major area of drug development for Alzheimer’s disease (AD). Aβ immunotherapy-related vasogenic edema has 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. Immunotherapy failures far have been attributed in part to: 1) the dose severely limited by safety issues (vasogenic edema/microhemorrhage associated with amyloid-related imaging abnormalities (ARIA) reported in clinical settings, preventing efficacious brain levels being reached); 2) not targeting the appropriate toxic Aβ species; and 3) intervention late in the disease continuum. More promising results were recently generated with three antibodies binding to protofibrillar Aβ (aducanumab [7], gantenerumab [8, 9], and BAN2401 [10]) on biomarker endpoints that will need to be confirmed in larger ongoing clinical studies
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
