Specific amyloid β clearance by a catalytic antibody construct

Area of Science:

• Immunology
• Neuroscience
• Biochemistry

Background:

• Classical immunization fails to produce catalytic antibodies (catabodies).
• The innate antibody repertoire is a potential source for catabodies.
• Amyloid beta (Aβ) is implicated in Alzheimer disease pathogenesis.

Purpose of the Study:

• To engineer and characterize a catabody with specificity for amyloid beta (Aβ).
• To evaluate the Aβ-clearing efficacy and therapeutic potential of the engineered catabody.

Main Methods:

• Engineering a catabody construct based on innate immunity principles.
• Assessing catabody specificity and catalytic activity against Aβ.
• Evaluating the catabody's effect on preformed Aβ aggregates and Aβ aggregation.
• Administering the catabody intravenously in a mouse model of Alzheimer disease.

Main Results:

• The engineered catabody recognized and rapidly hydrolyzed the Aβ C terminus.
• The catabody showed high specificity, with no reactivity to related proteins or off-target sequences.
• It effectively dissolved preformed Aβ aggregates and inhibited further aggregation.
• Intravenous administration reduced brain Aβ deposits in a mouse Alzheimer disease model without inducing inflammation or hemorrhage.

Conclusions:

• Specific Aβ hydrolysis is a potential innate immune function.
• Engineered catabodies derived from innate immunity principles offer a promising therapeutic strategy for Aβ removal in Alzheimer disease.
• This approach demonstrates potential for safe and effective Aβ clearance.