| Download | - View accepted manuscript: A novel platform for engineering blood-brain barrier-crossing bispecific biologics (PDF, 3.3 MiB)
|
|---|
| DOI | Resolve DOI: https://doi.org/10.1096/fj.14-253369 |
|---|
| Author | Search for: Farrington, Graham K.; Search for: Caram-Salas, Nadia1; Search for: Haqqani, Arsalan S.1; Search for: Brunette, Eric1; Search for: Eldredge, John; Search for: Pepinsky, Blake; Search for: Antognetti, Giovanna; Search for: Baumann, Ewa1; Search for: Ding, Wen1; Search for: Garber, Ellen; Search for: Jiang, Susan1; Search for: Delaney, Christie1; Search for: Boileau, Eve1; Search for: Sisk, William P.; Search for: Stanimirovic, Danica B.1 |
|---|
| Affiliation | - National Research Council of Canada. Human Health Therapeutics
|
|---|
| Format | Text, Article |
|---|
| Subject | single-domain antibody; neuropeptides; drug delivery; blood-brain barrier |
|---|
| Abstract | The 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 | 2014-07-28 |
|---|
| In | |
|---|
| Language | English |
|---|
| Peer reviewed | Yes |
|---|
| NRC number | NRC-HHT-53254 |
|---|
| NPARC number | 21275155 |
|---|
| Export citation | Export as RIS |
|---|
| Report a correction | Report a correction (opens in a new tab) |
|---|
| Record identifier | 710861bf-e0dc-46d5-a21b-110ea6a6997b |
|---|
| Record created | 2015-05-21 |
|---|
| Record modified | 2020-06-04 |
|---|
