Effector function of anti-pyroglutamate-3 Aβ antibodies affects cognitive benefit, glial activation and amyloid clearance in Alzheimer's-like mice.
Alzheimer Disease
Alzheimer Vaccines
/ pharmacology
Amyloid beta-Peptides
/ antagonists & inhibitors
Animals
Antibodies, Monoclonal
/ pharmacology
Cognition
/ drug effects
Disease Models, Animal
Immunization, Passive
/ methods
Immunoglobulin G
Mice
Mice, Transgenic
Neuroglia
/ drug effects
Protein Processing, Post-Translational
Pyrrolidonecarboxylic Acid
/ metabolism
APPSWE/PS1ΔE9
Immunotherapy
Microhemorrhage
Phagocytosis
Pyroglutamate-3 amyloid-β
microPET
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
13 01 2020
13 01 2020
Historique:
received:
23
10
2019
accepted:
30
12
2019
entrez:
15
1
2020
pubmed:
15
1
2020
medline:
12
1
2021
Statut:
epublish
Résumé
Pyroglutamate-3 Aβ (pGlu-3 Aβ) is an N-terminally truncated and post-translationally modified Aβ species found in Alzheimer's disease (AD) brain. Its increased peptide aggregation propensity and toxicity make it an attractive emerging treatment strategy for AD. We address the question of how the effector function of an anti-pGlu-3 Aβ antibody influences the efficacy of immunotherapy in mouse models with AD-like pathology. We compared two different immunoglobulin (Ig) isotypes of the same murine anti-pGlu-3 Aβ mAb (07/1 IgG1 and 07/2a IgG2a) and a general N-terminal Aβ mAb (3A1 IgG1) for their ability to clear Aβ and protect cognition in a therapeutic passive immunotherapy study in aged, plaque-rich APP We demonstrated significant cognitive improvement, better plaque clearance, and more plaque-associated microglia in the absence of microhemorrhage in aged APP Our results suggest that attenuation of behavioral deficits and clearance of amyloid is associated with strong effector function of the anti-pGlu-3 Aβ mAb in a therapeutic treatment paradigm. We present evidence that antibody engineering to reduce CDC-mediated complement binding facilitates phagocytosis of plaques without inducing neuroinflammation in vivo. Hence, the results provide implications for tailoring effector function of humanized antibodies for clinical development.
Sections du résumé
BACKGROUND
Pyroglutamate-3 Aβ (pGlu-3 Aβ) is an N-terminally truncated and post-translationally modified Aβ species found in Alzheimer's disease (AD) brain. Its increased peptide aggregation propensity and toxicity make it an attractive emerging treatment strategy for AD. We address the question of how the effector function of an anti-pGlu-3 Aβ antibody influences the efficacy of immunotherapy in mouse models with AD-like pathology.
METHODS
We compared two different immunoglobulin (Ig) isotypes of the same murine anti-pGlu-3 Aβ mAb (07/1 IgG1 and 07/2a IgG2a) and a general N-terminal Aβ mAb (3A1 IgG1) for their ability to clear Aβ and protect cognition in a therapeutic passive immunotherapy study in aged, plaque-rich APP
RESULTS
We demonstrated significant cognitive improvement, better plaque clearance, and more plaque-associated microglia in the absence of microhemorrhage in aged APP
CONCLUSION
Our results suggest that attenuation of behavioral deficits and clearance of amyloid is associated with strong effector function of the anti-pGlu-3 Aβ mAb in a therapeutic treatment paradigm. We present evidence that antibody engineering to reduce CDC-mediated complement binding facilitates phagocytosis of plaques without inducing neuroinflammation in vivo. Hence, the results provide implications for tailoring effector function of humanized antibodies for clinical development.
Identifiants
pubmed: 31931873
doi: 10.1186/s13195-019-0579-8
pii: 10.1186/s13195-019-0579-8
pmc: PMC6958628
doi:
Substances chimiques
Alzheimer Vaccines
0
Amyloid beta-Peptides
0
Antibodies, Monoclonal
0
Immunoglobulin G
0
Pyrrolidonecarboxylic Acid
SZB83O1W42
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
12Subventions
Organisme : NIA NIH HHS
ID : RF1 AG058657
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG040092
Pays : United States
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