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[PMID]: | 26839377 |
[Au] Autor: | Webster CI; Caram-Salas N; Haqqani AS; Thom G; Brown L; Rennie K; Yogi A; Costain W; Brunette E; Stanimirovic DB |
[Ad] Endereço: | Antibody Discovery and Protein Engineering, MedImmune, Cambridge, United Kingdom; websterc@medimmune.com. |
[Ti] Título: | Brain penetration, target engagement, and disposition of the blood-brain barrier-crossing bispecific antibody antagonist of metabotropic glutamate receptor type 1. |
[So] Source: | FASEB J;30(5):1927-40, 2016 05. | [Is] ISSN: | 1530-6860 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | 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.-Webster, C. I., Caram-Salas, N., Haqqani, A. S., Thom, G., Brown, L., Rennie, K., Yogi, A., Costain, W., Brunette, E., Stanimirovic, D. B. Brain penetration, target engagement, and disposition of the blood-brain barrier-crossing bispecific antibody antagonist of metabotropic glutamate receptor type 1. |
[Mh] Termos MeSH primário: |
Anticorpos Biespecíficos/farmacologia Encéfalo/metabolismo Dor/tratamento farmacológico Receptores de Glutamato Metabotrópico/antagonistas & inibidores
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[Mh] Termos MeSH secundário: |
Analgésicos Animais Produtos Biológicos/metabolismo Transporte Biológico Barreira Hematoencefálica/metabolismo Encéfalo/efeitos dos fármacos Camelidae Membrana Celular Células HEK293 Temperatura Alta/efeitos adversos Seres Humanos Imunoconjugados/metabolismo Imunoglobulina G/imunologia Dor/etiologia Engenharia de Proteínas/métodos Ratos Receptores de Glutamato Metabotrópico/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Analgesics); 0 (Antibodies, Bispecific); 0 (Biological Products); 0 (Immunoconjugates); 0 (Immunoglobulin G); 0 (Receptors, Metabotropic Glutamate); 0 (metabotropic glutamate receptor type 1) |
[Em] Mês de entrada: | 1708 |
[Cu] Atualização por classe: | 171102 |
[Lr] Data última revisão:
| 171102 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 160204 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1096/fj.201500078 |
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