Brain delivery of an amyloid-β oligomer (AβO)-targeting peptide-therapeutic by a novel blood-brain barrier (BBB)-crossing domain antibody

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DOIResolve DOI: http://doi.org/10.1016/j.jalz.2017.06.703
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TypeArticle
Journal titleAlzheimer's & Dementia
ISSN1552-5260
Volume13
Issue7
AbstractWe have identified an amyloid-ß (Aß) binding peptide (ABP) that selectively bound pathological Aß1-42 oligomers and reduced Aß- mediated cell toxicity1. ABP also bound Aß deposits in brains of AD transgenic mice and Alzheimer’s disease (AD) patients in vitro, and when directly injected into live transgenic mice (APPSwe and ΔPS1) brain2, suggesting that, when delivered to the brain, ABP can engage Aß and facilitate its clearance. Present study shows brain-delivery of ABP by a novel BBB-crossing domain antibody, and targeting and clearance of Aß in transgenic mice. Recombinant ABP-BBB carrier fusion construct (ABP-BBB) were produced in CHO cells. BBB-permeability of the construct was assessed using in vitro BBB (formed by rat or human brain endothelial cells) and in vivo (rat and mouse) models. Aß binding was determined by ELISA and Western blot overlay assays. For PK/PD studies, serum, CSF and brain levels of ABP-BBB construct and Aß were assessed following iv injection by nanoLC- MRM, ELISA and Western blot methods. ABP-BBB bi-functional fusion protein was successfully expressed in CHO cells. The fusion protein retained both Aß-oligomer binding activity and BBB-permeability in vitro. ABP-BBB transmigrated the in vitro BBB, in contrast to ABP without BBB carrier. When injected iv into rats, ABP-BBB appeared in the CSF in a dose- and time-dependent manner indicating transport of ABP across BBB in vivo. Apparent CNS exposure (Expapp), calculated as CSF[AUC]/serum[AUC], indicated a 15-20-fold increase in Expapp for ABP-BBB compared to non-BBB permeable ABP. This was further confirmed in mouse model wherein following iv injection, the fusion protein was detected in the CSF, and cortical and hippocampal regions of wild type and Tg mice. More importantly, in Tg mice ABP treatment resulted in a significant (∼50%) reduction of Aß levels in the CSF, and brain cortex and hippocampus within 4-weeks.
Publication date
PublisherElsevier
LanguageEnglish
AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NPARC number23002450
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Record identifier16c5c6bb-33b2-4d89-a2ed-f5f67cceeacd
Record created2017-11-10
Record modified2017-11-10
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