A novel platform for engineering blood-brain barrier-crossing bispecific biologics

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DOIResolve DOI: http://doi.org/10.1096/fj.14-253369
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TypeArticle
Journal titleThe FASEB Journal
ISSN0892-6638
1530-6860
Volume28
Issue11
Pages47644778; # of pages: 15
Subjectsingle-domain antibody; neuropeptides; drug delivery; blood-brain barrier
AbstractThe blood-brain barrier (BBB) prevents the access of therapeutic antibodies to central nervous system (CNS) targets. The engineering of bispecific antibodies in which a therapeutic “arm” is combined with a BBB-transcytosing arm can significantly enhance their brain delivery. The BBB-permeable single-domain antibody FC5 was previously isolated by phenotypic panning of a naive llama single-domain antibody phage display library. In this study, FC5 was engineered as a mono- and bivalent fusion with the human Fc domain to optimize it as a modular brain delivery platform. In vitro studies demonstrated that the bivalent fusion of FC5 with Fc increased the rate of transcytosis (Papp) across brain endothelial monolayer by 25% compared with monovalent fusion. Up to a 30-fold enhanced apparent brain exposure (derived from serum and cerebrospinal fluid pharmacokinetic profiles) of FC5- compared with control domain antibody-Fc fusions after systemic dosing in rats was observed. Systemic pharmacological potency was evaluated in the Hargreaves model of inflammatory pain using the BBB-impermeable neuropeptides dalargin and neuropeptide Y chemically conjugated with FC5-Fc fusion proteins. Improved serum pharmacokinetics of Fc-fused FC5 contributed to a 60-fold increase in pharmacological potency compared with the single-domain version of FC5; bivalent and monovalent FC5 fusions with Fc exhibited similar systemic pharmacological potency. The study demonstrates that modular incorporation of FC5 as the BBB-carrier arm in bispecific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for CNS indications.
Publication date
PublisherFederation of American Societies for Experimental Biology
LanguageEnglish
AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NRC numberNRC-HHT-53254
NPARC number21275155
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Record identifier710861bf-e0dc-46d5-a21b-110ea6a6997b
Record created2015-05-21
Record modified2016-05-09
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