| DOI | Resolve DOI: https://doi.org/10.1096/fj.201500078 |
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| Author | Search for: Webster, Carl I.; Search for: Caram-Salas, Nadia1; Search for: Haqqani, Arsalan S.1; Search for: Thom, George; Search for: Brown, Lee; Search for: Rennie, Kerry1; Search for: Yogi, Alvaro1; Search for: Costain, Willard1; Search for: Brunette, Eric1; Search for: Stanimirovic, Danica B.1 |
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| Affiliation | - National Research Council of Canada. Human Health Therapeutics
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| Format | Text, Article |
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| Subject | Pain; Receptor-mediated transcytosis; Brain endothelial cells; Mass spectrometry |
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| Abstract | 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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| Publication date | 2016-02-02 |
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| Publisher | Federation of American Societies for Experimental Biology |
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| In | |
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| Language | English |
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| Peer reviewed | Yes |
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| NPARC number | 23000385 |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | 73a5d42c-7e5f-4e65-836d-407585a2631b |
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| Record created | 2016-07-12 |
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| Record modified | 2020-03-16 |
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