| DOI | Trouver le DOI : https://doi.org/10.1096/fj.201500078 |
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| Auteur | Rechercher : Webster, Carl I.; Rechercher : Caram-Salas, Nadia1; Rechercher : Haqqani, Arsalan S.1; Rechercher : Thom, George; Rechercher : Brown, Lee; Rechercher : Rennie, Kerry1; Rechercher : Yogi, Alvaro1; Rechercher : Costain, Willard1; Rechercher : Brunette, Eric1; 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 | Pain; Receptor-mediated transcytosis; Brain endothelial cells; Mass spectrometry |
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| Résumé | Receptor mediated transcytosis harnessing the cellular uptake and transport of natural ligands across the blood–brain barrier (BBB) has been identified as a means for antibody delivery to the CNS. In this study, we characterized bispecific antibodies in which a BBB-crossing antibody fragment FC5 was used as a BBB carrier. Cargo antibodies were either a high-affinity, selective antibody antagonist of the metabotropic glutamate receptor-1 (BBB-mGluR1), a widely abundant CNS target, or an IgG that does not bind the CNS target (BBB-NiP). Both BBB-NiP and BBB-mGluR1 demonstrated a similar 20-fold enhanced rate of transcytosis across an in vitro BBB model compared with mGluR1 IgG fused to a control antibody fragment. All 3 bispecific antibodies exhibited identical pharmacokinetics in vivo. Comparative assessment of BBB-NiP and BBB-mGluR1 revealed that, whereas their serum pharmacokinetics and BBB penetration were identical, their central disposition (brain levels) and elimination (cerebrospinal fluid levels) were widely different, due to central target-mediated removal of the mGluR1-engaging antibody. Central mGluR1 target engagement after systemic administration was demonstrated by a dose-dependent inhibition of mGluR-1-mediated thermal hyperalgesia and by colocalization of the antibody with thalamic neurons involved in mGluR1-mediated pain processing. We demonstrate the feasibility of targeting central G-protein-coupled receptors using a BBB-crossing bispecific antibody approach and emerging principles that govern brain distribution and disposition of these antibodies. These data will be important for designing safe and selective CNS antibody therapeutics. |
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| Date de publication | 2016-02-02 |
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| Maison d’édition | Federation of American Societies for Experimental Biology |
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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 NPARC | 23000385 |
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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 | 73a5d42c-7e5f-4e65-836d-407585a2631b |
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| Enregistrement créé | 2016-07-12 |
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| Enregistrement modifié | 2020-03-16 |
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