Journal
THERANOSTICS
Volume 7, Issue 2, Pages 308-318Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.17155
Keywords
BBB shuttle; TfR; antibodies; Alzheimer's disease; immunotherapy; PET
Categories
Funding
- Swedish Research Council [2012-1593, 2012-2172]
- Alzheimerfonden
- Swedish Brain Foundation
- Ahlen-stiftelsen
- Stohnes stiftelse
- Stiftelsen fur Gamla tjanarinnor
- Magnus Bergwalls stiftelse
- Uppsala Berzelii Technology Centre for Neurodiagnostics
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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.
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