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Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2017 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 7, no 2, 308-318 p.Article in journal (Refereed) Published
Abstract [en]

The blood-brain barrier (BBB) is an obstacle for antibody passage into the brain, impeding the development of immunotherapy and antibody-based diagnostics for brain disorders. In the present study, we have developed a brain shuttle for active transport of antibodies across the BBB by receptor-mediated transcytosis. We have thus recombinantly fused two single-chain variable fragments (scFv) of the transferrin receptor (TfR) antibody 8D3 to the light chains of mAb158, an antibody selectively binding to A beta protofibrils, which are involved in the pathogenesis of Alzheimer's disease (AD). Despite the two TfR binders, a monovalent interaction with TfR was achieved due to the short linkers that sterically hinder bivalent binding to the TfR dimer. The design enabled efficient receptor-mediated brain uptake of the fusion protein. Two hours after administration, brain concentrations were 2-3% of the injected dose per gram brain, comparable to small molecular drugs and 80-fold higher than unmodified mAb158. After three days, fusion protein concentrations in AD transgenic mouse brains were 9-fold higher than in wild type mice, demonstrating high in vivo specificity. Thus, our innovative recombinant design markedly increases mAb158 brain uptake, which makes it a strong candidate for improved Aa immunotherapy and as a PET radioligand for early diagnosis and evaluation of treatment effect in AD. Moreover, this approach could be applied to any target within the brain.

Place, publisher, year, edition, pages
IVYSPRING INT PUBL , 2017. Vol. 7, no 2, 308-318 p.
Keyword [en]
BBB shuttle, TfR, antibodies, Alzheimer's disease, immunotherapy, PET
National Category
Geriatrics
Identifiers
URN: urn:nbn:se:uu:diva-319779DOI: 10.7150/thno.17155ISI: 000396555900006PubMedID: 28042336OAI: oai:DiVA.org:uu-319779DiVA: diva2:1088273
Funder
Swedish Research Council, 2012-1593 2012-2172The Swedish Brain FoundationStiftelsen Gamla TjänarinnorMagnus Bergvall Foundation
Available from: 2017-04-12 Created: 2017-04-12 Last updated: 2017-04-12Bibliographically approved

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Hultqvist, GretaSyvänen, StinaFang, Xiaotian T.Lannfelt, LarsSehlin, Dag
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