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Bivalent Brain Shut...
Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor
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- Hultqvist, Greta (author)
- Uppsala universitet,Geriatrik
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- Syvänen, Stina (author)
- Uppsala universitet,Geriatrik
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- Fang, Xiaotian T. (author)
- Uppsala universitet,Geriatrik
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- Lannfelt, Lars (author)
- Uppsala universitet,Geriatrik
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- Sehlin, Dag (author)
- Uppsala universitet,Geriatrik
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(creator_code:org_t)
- IVYSPRING INT PUBL, 2017
- 2017
- English.
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In: Theranostics. - : IVYSPRING INT PUBL. - 1838-7640. ; 7:2, s. 308-318
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.7...
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https://urn.kb.se/re...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Geriatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Geriatrics (hsv//eng)
Keyword
- BBB shuttle
- TfR
- antibodies
- Alzheimer's disease
- immunotherapy
- PET
Publication and Content Type
- ref (subject category)
- art (subject category)
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