| Téléchargement | - Voir le manuscrit accepté : A novel platform for engineering blood-brain barrier-crossing bispecific biologics (PDF, 3.3 Mio)
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| DOI | Trouver le DOI : https://doi.org/10.1096/fj.14-253369 |
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| Auteur | Rechercher : Farrington, Graham K.; Rechercher : Caram-Salas, Nadia1; Rechercher : Haqqani, Arsalan S.1; Rechercher : Brunette, Eric1; Rechercher : Eldredge, John; Rechercher : Pepinsky, Blake; Rechercher : Antognetti, Giovanna; Rechercher : Baumann, Ewa1; Rechercher : Ding, Wen1; Rechercher : Garber, Ellen; Rechercher : Jiang, Susan1; Rechercher : Delaney, Christie1; Rechercher : Boileau, Eve1; Rechercher : Sisk, William P.; Rechercher : Stanimirovic, Danica B.1 |
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| Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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| Format | Texte, Article |
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| Sujet | single-domain antibody; neuropeptides; drug delivery; blood-brain barrier |
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| Résumé | 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. |
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| Date de publication | 2014-07-28 |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Numéro du CNRC | NRC-HHT-53254 |
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| Numéro NPARC | 21275155 |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | 710861bf-e0dc-46d5-a21b-110ea6a6997b |
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| Enregistrement créé | 2015-05-21 |
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| Enregistrement modifié | 2020-06-04 |
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