Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain

Area of Science:

• Biochemistry
• Immunology
• Neuroscience

Background:

• Amyloidosis is characterized by misfolded protein deposition, sharing common features despite diverse causes.
• Amyloid light chain (AL) amyloidosis and Alzheimer's disease involve amyloid light chain (AL) and beta-amyloid peptide (Aβ) respectively.
• Current therapeutic antibodies, like crenezumab (anti-Aβ), have limitations.

Purpose of the Study:

• To test the hypothesis that amyloid antibodies can be engineered via mutations to target different amyloid species.
• To computationally design and prepare crenezumab variants with high affinity for AL fibrils.
• To establish a platform for repurposing existing amyloid monoclonal antibodies.

Main Methods:

• Computational design of crenezumab variants.
• In vitro testing of antibody binding affinities to Aβ42 oligomers and AL fibrils.
• Assessment of antibody efficacy in reversing cytotoxicity induced by Aβ42 oligomers and AL fibrils.

Main Results:

• Successfully re-engineered crenezumab to bind both Aβ42 oligomers and AL fibrils with high affinity.
• Demonstrated reversal of Aβ42-oligomers-induced cytotoxicity.
• Showed decreased AL fibril formation and alleviated AL-fibrils-induced cytotoxicity in vitro.

Conclusions:

• A few mutations can engineer an amyloid antibody to bind new amyloid sequences.
• This approach provides an efficient method for repositioning therapeutic antibodies for different amyloid diseases.
• The engineered antibody shows potential for treating both Alzheimer's disease and AL amyloidosis.