Drug Development.

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Alzheimer's disease (AD) immunotherapies face safety challenges due to amyloid-related imaging abnormalities (ARIA).
• Current treatments struggle with effective brain delivery and managing ARIA side effects.

Purpose of the Study:

• To develop an antibody transport vehicle (ATV) for improved brain delivery of amyloid beta (Aβ) antibodies.
• To reduce ARIA-like lesions and enhance Aβ plaque engagement in a mouse model.

Main Methods:

• An antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) was engineered.
• Asymmetrical Fc mutations (ATVcisLALA) were introduced to modulate effector function and mitigate TfR liabilities.
• The ATV carrying Aβ antibodies (ATVcisLALA:Aβ) was tested in a mouse model of amyloid deposition.

Main Results:

• ATVcisLALA:Aβ demonstrated broad brain parenchymal distribution, unlike conventional anti-Aβ IgG.
• ATVcisLALA:Aβ significantly reduced ARIA-like lesions and vascular inflammation.
• The engineered ATV improved Aβ plaque target engagement while mitigating hematological side effects.

Conclusions:

• ATVcisLALA enhances the biodistribution of Aβ antibodies across the blood-brain barrier.
• This approach holds potential for improving both safety and efficacy of Aβ immunotherapy for Alzheimer's disease.
• Targeting TfR with engineered antibodies offers a promising strategy for AD treatment.