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

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.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0447-y) contains supplementary material, which is available to authorized users.

In Vivo Detection of Amyloid Plaques by Gadolinium-Stained MRI Can Be Used to Demonstrate the Efficacy of an Anti-amyloid Immunotherapy

“…For example, some of them clear aggregated forms of Aβ ( Demattos et al, 2012 ), whereas others focus on inhibiting amyloid seeding to prevent amyloid deposition propagation ( Golde, 2003 ) or target soluble forms of Aβ to shift the equilibrium between soluble and fibrillar Aβ to favor plaque dissolution ( DeMattos et al, 2001 ). The SAR255952 anti-amyloid antibody used in this study targets both protofibrillar and fibrillar amyloid forms ( Schupf et al, 2008 ; Pradier et al, 2013 ). Our data show that IgG (presumably SAR255952) is homogeneously distributed in the brain of SAR255952-treated APP/PS1 mice while DM4-treated APP/PS1 mice did not display any IgG immunoreactivity.…”

“…SAR255952 is a mouse monoclonal aglycosylated IgG1 antibody engineered to reduce the risk of vasogenic edemas and microhemorrhages that have been associated to anti-amyloid immunotherapies ( Pradier et al, 2013 ). These potential side effects of immunotherapies have been revealed by clinical trials that highlighted signal changes on MR images [also called amyloid imaging related abnormalities (ARIA); Sperling et al, 2011 ].…”

“…SAR255952 was designed on the basis of an antibody (13C3) that binds to soluble protofibrillar and fibrillar forms of Aβ ( Schupf et al, 2008 ), the most synaptotoxic forms of Aβ ( Haass and Selkoe, 2007 ). 13C3 do not target soluble Aβ monomers or low molecular weight Aβ complexes ( Schupf et al, 2008 ), which limits peripheral sink effects that can lead to microhemorrhages ( Pradier et al, 2013 ). SAR255952 is an aglycosyled form of 13C3.…”

“…These effector functions of antibodies are linked to their glycosylated states ( Jefferis, 2009 ). Aglycosylation limits the activation of Fc-γ receptors and C1q component of complement and preclude the risk of vasogenic edemas and microhemorrhages ( Pradier et al, 2013 ). A phase 1 clinical trial is ongoing using a humanized version of this antibody 1 .…”

Tetravalent Bispecific Tandem Antibodies Improve Brain Exposure and Efficacy in an Amyloid Transgenic Mouse Model

“…The construct affinity for TfR can be modulated by the positional effect of the two paratopes, with the internal position displaying, generally, a poorer affinity 26 than the parent TfR antibody. We chose to illustrate the potential of such constructs for brain enhancement and brain parenchymal target engagement using the anti-amyloid-beta (Aβ) antibody 13C3 27 as a tool (specific for protofibrillar and fibrillar Aβ and therefore without any target in wild-type [WT] animals) and the highly published murine anti-TfR monoclonal antibody (mAb) 8D3 28 to allow direct comparison with previous literature. In addition to the positional TfR paratope affinity modulation, we engineered a series of structure-based mutations in the complementarity determining regions (CDRs) of the anti-TfR paratopes to further lower their affinity.…”