SAR228810: an antibody for protofibrillar amyloid β peptide designed to reduce the risk of amyloid-related imaging abnormalities (ARIA) | Alzheimer's Research & Therapy | Full Text

SAR228810: an antibody for protofibrillar amyloid β peptide designed to reduce the risk of amyloid-related imaging abnormalities (ARIA) | Alzheimer's Research & Therapy | Full Text



Alzheimer's Research & Therapy

SAR228810: an antibody for protofibrillar amyloid β peptide designed to reduce the risk of amyloid-related imaging abnormalities (ARIA)

• Laurent PradierEmail authorView ORCID ID profile,
• Véronique Blanchard-Brégeon,
• Andrees Bohme,
• Thomas Debeir,
• Jean Menager,
• Patrick Benoit,
• Pascal Barneoud,
• Véronique Taupin,
• Philippe Bertrand,
• Philippe Dugay,
• Béatrice Cameron,
• Yi Shi,
• Souad Naimi,
• Marc Duchesne,
• Marie Gagnaire,
• Tim Weeden,
• Tara Travaline,
• David Reczek,
• Leonard Khiroug,
• Mohamed Slaoui,
• Pascale Brunel,
• Hidehiro Fukuyama,
• Jeffrey Ravetch,
• Thierry Canton and
• Caroline Cohen

Alzheimer's Research & Therapy201810:117

https://doi.org/10.1186/s13195-018-0447-y

©  The Author(s). 2018

• Received: 11 April 2018
• Accepted: 4 November 2018
• Published: 28 November 2018

Abstract

Background

Anti-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.

Methods

To 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.

Results

Unlike 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.

Conclusion

Based 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.

Keywords

• Alzheimer’s disease
• Anti-Aβ immunotherapy
• Protofibrillar Aβ peptide