Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody.
Parkinson’s disease (PD)
alpha-synuclein (αSYN)
bispecific antibody
blood-brain barrier (BBB)
immunotherapy
monoclonal antibody
receptor-mediated transcytosis (RMT)
transferrin receptor (TfR)
Journal
Pharmaceutics
ISSN: 1999-4923
Titre abrégé: Pharmaceutics
Pays: Switzerland
ID NLM: 101534003
Informations de publication
Date de publication:
05 Jul 2022
05 Jul 2022
Historique:
received:
25
05
2022
revised:
28
06
2022
accepted:
01
07
2022
entrez:
27
7
2022
pubmed:
28
7
2022
medline:
28
7
2022
Statut:
epublish
Résumé
Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson's disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology.
Identifiants
pubmed: 35890306
pii: pharmaceutics14071412
doi: 10.3390/pharmaceutics14071412
pmc: PMC9318263
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Swedish Research Council
ID : 2017-02413
Organisme : Swedish Research Council
ID : 2018-02715
Organisme : Swedish Research Council
ID : 2021-03524
Organisme : Swedish Research Council
ID : 2021-01083
Organisme : Swedish Innovation Agency
ID : 2016-04050
Organisme : Swedish Innovation Agency
ID : 2019-00106
Organisme : Hjärnfonden
ID : n/a
Organisme : Torsten Söderbergs Stiftelse
ID : n/a
Organisme : Åke Wibergs Stiftelse
ID : n/a
Organisme : Petrus och Augusta Hedlunds Stiftelse
ID : n/a
Organisme : Åhlén-Stiftelsen
ID : n/a
Organisme : Parkinsonfonden
ID : n/a
Organisme : Magnus Bergvalls Stiftelse
ID : n/a
Organisme : Stiftelsen för Gamla Tjänarinnor
ID : n/a
Organisme : Stohnes stiftelse
ID : n/a
Organisme : Neurofonden
ID : n/a
Organisme : Demensfonden
ID : n/a
Organisme : Syskonen Inger och Sixten Norheds stiftelse
ID : n/a
Organisme : Konung Gustaf V:s och Drottning Victorias frimurarestiftelse
ID : n/a
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