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Open Access 01-12-2018 | Research

Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody

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

Published in: Alzheimer's Research & Therapy | Issue 1/2018

Abstract

Background

Amyloid-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.

Methods

Aβ 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.

Results

ELISA 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.

Conclusions

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.

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Title: Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody
Authors: Stina Syvänen
Greta Hultqvist
Tobias Gustavsson
Astrid Gumucio
Hanna Laudon
Linda Söderberg
Martin Ingelsson
Lars Lannfelt
Dag Sehlin
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Alzheimer's Research & Therapy / Issue 1/2018
Electronic ISSN: 1758-9193
DOI: https://doi.org/10.1186/s13195-018-0377-8

At a glance: The STEP trials

Springer Medicine

Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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