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Efficient clearence...
Efficient clearence of A beta protofibrils in A beta PP-transgenic mice treated with a brain-penetrating bifunctional antibody
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- Syvänen, Stina (author)
- Uppsala universitet,Geriatrik
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- Hultqvist, Greta, 1980- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Gustavsson, Tobias (author)
- Uppsala universitet,Geriatrik
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- Gumucio, Astrid (author)
- Uppsala universitet,Geriatrik
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- Laudon, Hanna (author)
- BioArctic AB, Stockholm, Sweden
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- Söderberg, Linda (author)
- BioArctic AB, Stockholm, Sweden
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- Ingelsson, Martin (author)
- Uppsala universitet,Geriatrik
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- Lannfelt, Lars (author)
- Uppsala universitet,Geriatrik,BioArctic AB, Stockholm, Sweden
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- Sehlin, Dag, 1976- (author)
- Uppsala universitet,Geriatrik
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(creator_code:org_t)
- BIOMED CENTRAL LTD, 2018
- 2018
- English.
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In: Alzheimer's Research & Therapy. - : BIOMED CENTRAL LTD. - 1758-9193. ; 10
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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Abstract
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- Background: Amyloid-beta (A beta) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer's disease (AD) Despite recent progress targeting aggregated forms of A beta, low antibody brain penetrance remains a challenge In the piesent study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed A beta protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble A beta protofibills. Methods: A beta protein precursor (A beta PP)-transgenic mice (tg-ArcSwe) were given a single dose of mAb158, modified for TfR-mediated transcytosis (RmAb158-scFvSDB), in companson with an equimolar dose or a tenfold higher dose of unmodified recombinant mAb158 (RmAb158) Soluble A beta protofibrills and total A beta 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 autoiadiography. Results: ELISA analysis of Tris-buffered saline brain extracts demonstrated a 40% reduction of soluble A beta protofibrils in both RmAb158-scFv8D3- and high-dose RmAb158-treated mice, whereas there was no A beta protofibril reduction in mice treated with a low dose of RmAb158. Further, ex vivo autoradiography and PET imaging revealed diffeient brain distribution patterns of RmAb158-scFv8D3 and RmAb158, suggesting that these antibodies may affect A beta 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 A beta immunotherapy. This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Geriatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Geriatrics (hsv//eng)
Keyword
- Alzheimer's disease (AD)
- Immunotherapy
- Amyloid-beta (A beta)
- Oligomers
- Protofibrils
- Monoclonal antibody
- Blood-brain barrier (BBB)
- Transferrin receptor (TfR)-mediated transcytosis
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Syvänen, Stina
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Hultqvist, Greta ...
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Gustavsson, Tobi ...
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Gumucio, Astrid
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Laudon, Hanna
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Söderberg, Linda
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show more...
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Ingelsson, Marti ...
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Lannfelt, Lars
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Sehlin, Dag, 197 ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Geriatrics
- Articles in the publication
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Alzheimer's Rese ...
- By the university
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Uppsala University