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

被引：107

作者：

Farrington, Graham K. ^{[1
]}

Caram-Salas, Nadia ^{[2
]}

Haqqani, Arsalan S. ^{[2
]}

Brunette, Eric ^{[2
]}

Eldredge, John ^{[1
]}

Pepinsky, Blake ^{[1
]}

Antognetti, Giovanna ^{[1
]}

Baumann, Ewa ^{[2
]}

Ding, Wen ^{[2
]}

Garber, Ellen ^{[1
]}

Jiang, Susan ^{[2
]}

Delaney, Christie ^{[2
]}

Boileau, Eve ^{[2
]}

Sisk, William P. ^{[1
]}

Stanimirovic, Danica B. ^{[2
]}

机构：

[1] Biogen Idec Inc, Cambridge, MA USA

[2] Natl Res Council Canada, Ottawa, ON K1A 0R6, Canada

来源：

FASEB JOURNAL | 2014年 / 28卷 / 11期

关键词：

single-domain antibody; neuropeptides; drug delivery; OPIOID RECEPTOR DESENSITIZATION; SINGLE-DOMAIN ANTIBODIES; HUMAN INSULIN-RECEPTOR; CENTRAL-NERVOUS-SYSTEM; NEONATAL FC-RECEPTOR; CEREBROSPINAL-FLUID; DRUG-DELIVERY; RAT-BRAIN; MONOCLONAL-ANTIBODY; INTERSTITIAL FLUID;

D O I：

10.1096/fj.14-253369

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (P-app) 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.Farrington, G. K., Caram-Salas, N., Haqqani, A. S., Brunette, E., Eldredge, J., Pepinsky, B., Antognetti, G., Baumann, E., Ding, W., Garber, E., Jiang, S., Delaney, C., Boileau, E., Sisk, W. P., Stanimirovic, D. B. A novel platform for engineering blood-brain barrier-crossing bispecific biologics.

引用

页码：4764 / 4778

页数：15

共 59 条

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