Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer's disease.
Alzheimer’s disease (AD)
Amyloid-β (Aβ)
Blood–brain barrier (BBB)
Immunotherapy
Monoclonal antibody
Transferrin receptor (TfR)-mediated transcytosis
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
02 05 2023
02 05 2023
Historique:
received:
01
03
2023
accepted:
23
04
2023
medline:
4
5
2023
pubmed:
3
5
2023
entrez:
2
5
2023
Statut:
epublish
Résumé
Brain-directed immunotherapy is a promising strategy to target amyloid-β (Aβ) deposits in Alzheimer's disease (AD). In the present study, we compared the therapeutic efficacy of the Aβ protofibril targeting antibody RmAb158 with its bispecific variant RmAb158-scFv8D3, which enters the brain by transferrin receptor-mediated transcytosis. App Neither RmAb158-scFv8D3 nor RmAb158 reduced soluble Aβ protofibrils or insoluble Aβ1-42 after a single injection treatment. After three successive injections, Aβ1-42 was reduced in mice treated with RmAb158, with a similar trend in RmAb158-scFv8D3-treated mice. Bispecific antibody immunogenicity was somewhat reduced by directed mutations, but CD4 Both RmAb158 and its bispecific variant RmAb158-scFv8D3 achieved positive effects of long-term treatment. Despite its ability to efficiently enter the brain, the benefit of using the bispecific antibody in chronic treatment was limited by its reduced plasma exposure, which may be a result of interactions with TfR or the immune system. Future research will focus in new antibody formats to further improve Aβ immunotherapy.
Sections du résumé
BACKGROUND
Brain-directed immunotherapy is a promising strategy to target amyloid-β (Aβ) deposits in Alzheimer's disease (AD). In the present study, we compared the therapeutic efficacy of the Aβ protofibril targeting antibody RmAb158 with its bispecific variant RmAb158-scFv8D3, which enters the brain by transferrin receptor-mediated transcytosis.
METHODS
App
RESULTS
Neither RmAb158-scFv8D3 nor RmAb158 reduced soluble Aβ protofibrils or insoluble Aβ1-42 after a single injection treatment. After three successive injections, Aβ1-42 was reduced in mice treated with RmAb158, with a similar trend in RmAb158-scFv8D3-treated mice. Bispecific antibody immunogenicity was somewhat reduced by directed mutations, but CD4
CONCLUSIONS
Both RmAb158 and its bispecific variant RmAb158-scFv8D3 achieved positive effects of long-term treatment. Despite its ability to efficiently enter the brain, the benefit of using the bispecific antibody in chronic treatment was limited by its reduced plasma exposure, which may be a result of interactions with TfR or the immune system. Future research will focus in new antibody formats to further improve Aβ immunotherapy.
Identifiants
pubmed: 37131196
doi: 10.1186/s13195-023-01236-3
pii: 10.1186/s13195-023-01236-3
pmc: PMC10152635
doi:
Substances chimiques
Iodine-125
GVO776611R
Amyloid beta-Peptides
0
Antibodies
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
90Informations de copyright
© 2023. The Author(s).
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