Efficient clearance of A\u03b2 protofibrils in A\u03b2PP-transgenic mice treated with a brain-penetrating bifunctional antibody

Stina Syvänen,Martin Ingelsson,Hanna Laudon,Lars Lannfelt,Greta Hultqvist,Astrid Gumucio,Linda Söderberg,Dag Sehlin,Tobias Gustavsson

doi:10.1186/s13195-018-0377-8

Stina Syvänen, Martin Ingelsson + Show 7 more

Open Access

https://doi.org/10.1186/s13195-018-0377-8

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Abstract

BackgroundAmyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer’s disease (AD). Despite recent progress targeting aggregated forms of Aβ, low antibody brain penetrance remains a challenge. In the present study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed Aβ protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble Aβ protofibrils.MethodsAβ protein precursor (AβPP)-transgenic mice (tg-ArcSwe) were given a single dose of mAb158, modified for TfR-mediated transcytosis (RmAb158-scFv8D3), in comparison with an equimolar dose or a tenfold higher dose of unmodified recombinant mAb158 (RmAb158). Soluble Aβ protofibrils and total Aβ in the brain were measured by enzyme-linked immunosorbent assay (ELISA). Brain distribution of radiolabeled antibodies was visualized by positron emission tomography (PET) and ex vivo autoradiography.ResultsELISA analysis of Tris-buffered saline brain extracts demonstrated a 40% reduction of soluble Aβ protofibrils in both RmAb158-scFv8D3- and high-dose RmAb158-treated mice, whereas there was no Aβ protofibril reduction in mice treated with a low dose of RmAb158. Further, ex vivo autoradiography and PET imaging revealed different brain distribution patterns of RmAb158-scFv8D3 and RmAb158, suggesting that these antibodies may affect Aβ levels by different mechanisms.ConclusionsWith a combination of biochemical and imaging analyses, this study demonstrates that antibodies engineered to be transported across the blood-brain barrier can be used to increase the efficacy of Aβ immunotherapy. This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs.

Highlights

Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer’s disease (AD)
With a combination of biochemical and imaging analyses, this study demonstrates that antibodies engineered to be transported across the blood-brain barrier can be used to increase the efficacy of Aβ immunotherapy
This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs

Summary

Introduction

Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer’s disease (AD). We used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed Aβ protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble Aβ protofibrils. Numerous preclinical studies have shown significant effects of treatment with monoclonal Aβ antibodies in transgenic mouse models [4,5,6,7], in terms of both reduced Aβ pathology and behavioral improvement. Several of these antibodies have been further developed and studied in clinical trials, where many of them have failed to reduce cognitive decline and Aβ pathology. Some of the evaluated antibodies bind soluble forms of AβPP, which further increases the peripheral depletion of free antibody available for Aβ clearance

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