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An anti-pyroglutamate-3 Abeta vaccine reduces plaques and improves cognition in APPswe/PS1dE9 mice


Year of Publication:
Contact PI Name:
Cynthia A. Lemere
Contact PI Affiliation:
Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Jeffrey L. Frost, Bin Liu, Jens-Ulrich Rahfeld, Martin Kleinschmidt, Brian O’Nuallain, Kevin X. Le, Inge Lues, Barbara J. Caldarone, Stephan Schilling, Hans-Ulrich Demuth
Primary Reference (PubMED ID):
Funding Source:
Harvard NeuroDiscovery Center
National Institute on Aging (NIA)
Study Goal and Principal Findings:

Pyroglutamate-3 amyloid-beta (pGlu-3 Aβ) is an N-terminally truncated Aβ isoform likely playing a decisive role in Alzheimer's disease pathogenesis. Here, we describe a prophylactic passive immunization study in APPswe/PS1ΔE9 mice using a novel pGlu-3 Aβ immunoglobulin G1 (IgG1) monoclonal antibody, 07/1 (150 and 500 μg, intraperitoneal, weekly) and compare its efficacy with a general Aβ IgG1 monoclonal antibody, 3A1 (200 μg, intraperitoneal, weekly) as a positive control. After 28 weeks of treatment, plaque burden was reduced and cognitive performance of 07/1-immunized Tg mice, especially at the higher dose, was normalized to wild-type levels in 2 hippocampal-dependent tests and partially spared compared with phosphate-buffered saline-treated Tg mice. Mice that received 3A1 had reduced plaque burden but showed no cognitive benefit. In contrast with 3A1, treatment with 07/1 did not increase the concentration of Aβ in plasma, suggesting different modes of Aβ plaque clearance. In conclusion, early selective targeting of pGlu-3 Aβ by immunotherapy may be effective in lowering cerebral Aβ plaque burden and preventing cognitive decline in the clinical setting. Targeting this pathologically modified form of Aβ thereby is unlikely to interfere with potential physiologic function(s) of Aβ that have been proposed.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
anti-Pyroglutamate-3 beta Amyloid Mab
Therapeutic Target:
pGlu-3 beta Amyloid Peptide
Therapeutic Notes:
Two antibodies were used in this study: 3A1, a general Abeta IgG1 mAb 07/1, a pGlu-3 Abeta IgG1 mAb. The 07/1 mAb was generated and provided by Probiodrug AG.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Experiment Notes

A group of age- and gender-matched Wt littermates were used in this study.


Outcome Measured
Outcome Parameters
Open Field Test
Contextual Fear Conditioning
Morris Water Maze
beta Amyloid Load
Fibrillar beta Amyloid Deposits
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Pyroglutamate Modified beta Amyloid Peptides
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Activated Microglia
Antibody Target Specificity
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Antibody Concentration-Plasma
Antibody Concentration-Brain
Target Engagement (Reduction pGlu-3 beta Amyloid-Brain)