Brain pharmacokinetics of mono- and bispecific amyloid-β antibodies in wild-type and Alzheimer's disease mice measured by high cut-off microdialysis.
Amyloid-β
Bispecific antibody
Blood–brain barrier
Microdialysis
Transferrin receptor
Journal
Fluids and barriers of the CNS
ISSN: 2045-8118
Titre abrégé: Fluids Barriers CNS
Pays: England
ID NLM: 101553157
Informations de publication
Date de publication:
12 Dec 2022
12 Dec 2022
Historique:
received:
14
08
2022
accepted:
05
12
2022
entrez:
12
12
2022
pubmed:
13
12
2022
medline:
15
12
2022
Statut:
epublish
Résumé
Treatment with amyloid-β (Aβ) targeting antibodies is a promising approach to remove Aβ brain pathology in Alzheimer's disease (AD) and possibly even slow down or stop progression of the disease. One of the main challenges of brain immunotherapy is the restricted delivery of antibodies to the brain. However, bispecific antibodies that utilize the transferrin receptor (TfR) as a shuttle for transport across the blood-brain barrier (BBB) can access the brain better than traditional monospecific antibodies. Previous studies have shown that bispecific Aβ targeting antibodies have higher brain distribution, and can remove Aβ pathology more efficiently than monospecific antibodies. Yet, there is only limited information available on brain pharmacokinetics, especially regarding differences between mono- and bispecific antibodies. The aim of the study was to compare brain pharmacokinetics of Aβ-targeting monospecific mAb3D6 and its bispecific version mAb3D6-scFv8D3 that also targets TfR. High cut-off microdialysis was used to measure intravenously injected radiolabelled mAb3D6 and mAb3D6-scFv8D3 antibodies in the interstitial fluid (ISF) of hippocampus in wild-type mice and the App Brain concentrations of the bispecific antibody were elevated compared to the monospecific antibody in the hippocampal ISF measured by microdialysis and in the brain tissue at 4-6 h after an intravenous injection. The concentration of the bispecific antibody was approximately twofold higher in the ISF dialysate compared to the concentration of monospecific antibody and eightfold higher in brain tissue 6 h post-injection. The ISF dialysate concentrations for both antibodies were similar in both wild-type and App The BBB-penetrating bispecific antibody displayed higher ISF concentrations than the monospecific antibody. The concentration difference between the two antibodies was even larger in the whole brain than in the ISF. Further, the bispecific antibody, but not the monospecific antibody, displayed higher total brain concentrations than ISF concentrations, indicating association to brain tissue.
Sections du résumé
BACKGROUND
BACKGROUND
Treatment with amyloid-β (Aβ) targeting antibodies is a promising approach to remove Aβ brain pathology in Alzheimer's disease (AD) and possibly even slow down or stop progression of the disease. One of the main challenges of brain immunotherapy is the restricted delivery of antibodies to the brain. However, bispecific antibodies that utilize the transferrin receptor (TfR) as a shuttle for transport across the blood-brain barrier (BBB) can access the brain better than traditional monospecific antibodies. Previous studies have shown that bispecific Aβ targeting antibodies have higher brain distribution, and can remove Aβ pathology more efficiently than monospecific antibodies. Yet, there is only limited information available on brain pharmacokinetics, especially regarding differences between mono- and bispecific antibodies.
METHODS
METHODS
The aim of the study was to compare brain pharmacokinetics of Aβ-targeting monospecific mAb3D6 and its bispecific version mAb3D6-scFv8D3 that also targets TfR. High cut-off microdialysis was used to measure intravenously injected radiolabelled mAb3D6 and mAb3D6-scFv8D3 antibodies in the interstitial fluid (ISF) of hippocampus in wild-type mice and the App
RESULTS
RESULTS
Brain concentrations of the bispecific antibody were elevated compared to the monospecific antibody in the hippocampal ISF measured by microdialysis and in the brain tissue at 4-6 h after an intravenous injection. The concentration of the bispecific antibody was approximately twofold higher in the ISF dialysate compared to the concentration of monospecific antibody and eightfold higher in brain tissue 6 h post-injection. The ISF dialysate concentrations for both antibodies were similar in both wild-type and App
CONCLUSION
CONCLUSIONS
The BBB-penetrating bispecific antibody displayed higher ISF concentrations than the monospecific antibody. The concentration difference between the two antibodies was even larger in the whole brain than in the ISF. Further, the bispecific antibody, but not the monospecific antibody, displayed higher total brain concentrations than ISF concentrations, indicating association to brain tissue.
Identifiants
pubmed: 36510227
doi: 10.1186/s12987-022-00398-w
pii: 10.1186/s12987-022-00398-w
pmc: PMC9743601
doi:
Substances chimiques
Antibodies, Bispecific
0
Amyloid beta-Peptides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
99Subventions
Organisme : Vetenskapsrådet
ID : 2021-03524
Organisme : Vetenskapsrådet
ID : 2021-01083
Organisme : VINNOVA
ID : 2016-04050
Organisme : VINNOVA
ID : 2016-04050
Organisme : EU Innovative Medicines Initiative 2
ID : 807015
Organisme : EU Innovative Medicines Initiative 2
ID : 807015
Informations de copyright
© 2022. The Author(s).
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