A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice

Bibliographic

Year of Publication: 
2012
Contact PI Name: 
Ronald B. DeMattos
Contact PI Affiliation: 
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Co-Authors: 
Jirong Lu, Ying Tang, Margaret M. Racke, Cindy A. DeLong, John A. Tzaferis, Justin T. Hole, Beth M. Forster, Peter C. McDonnell, Feng Liu, Robert D. Kinley, William H. Jordan, Michael L. Hutton
Primary Reference (PubMED ID): 
Funding Source:
Study Goal and Principal Findings: 

This study tests the hypothesis that antibody specificity for deposited beta amyloid plaque is critical for plaque removal since soluble Abeta peptide would block recognition of deposited forms. In order to test this hypothesis, the authors developed and engineered high affinity murine monoclonal antibodies that selectively target deposited plaque in an AD brain. Mouse Mabs were generated that were specific for Abetap3-x with either minimal (mE8-IgG1) or maximal (mE8-IgG2a) effector function. These antibodies robustly labeled deposited plaque in both AD and PDAPP brain sections and led to a significant reduction of deposited Abeta  in an ex vivo phagocytosis assay. Therapeutic plaque-lowering studies performed with the anti-Abp3-42 antibodies in extremely aged PDAPP mice (23 to 26 months of age) demonstrated that mE8 on either maximal or minimal effector function significantly lowered deposited Abeta, whereas mice treated with the N-terminal antibody 3D6 (mIgG2b), which binds both soluble and insoluble Abeta, lacked efficacy. The underlying mechanism of action responsible for these contrasting results was identified as a differential target engagement for the antibodies; the Abp3-42 antibodies crossed the blood-brain barrier and bound to the deposited Abeta, whereas the 3D6 antibody lacked plaque binding, a finding thought to be due to its saturation with soluble Abeta in the brain. Importantly, micro hemorrhage analyses demonstrated that the Abp3-42 antibodies did not increase this adverse event, whereas mice treated with 3D6 had extensive micro bleeds. These studies have profound implications for the development of therapeutic Abeta antibodies for Alzheimer’s disease.

Therapeutic Agent

Therapeutic Information: 
Therapy Type:
Therapy Type:
Therapy Type:

Animal Model

Model Information: 
Species:
Model Type:
Strain/Genetic Background: 
 C57B6 x DBA2

Experimental Design

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

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Histopathology
  • beta Amyloid Load
  • Activated Microglia
  • Biochemical
  • Brain-beta Amyloid Peptide 40
  • Brain-beta Amyloid Peptide 42
  • Pharmacokinetics
  • Antibody Concentration-Plasma
  • Antibody Concentration-CSF
  • Pharmacodynamics
  • Target Engagement (binding abeta antibodies to beta amyloid deposits)
  • Toxicology
  • Microhemorrhage