Characterization of tau binding by gosuranemab

Area of Science:

• Neuroscience
• Immunology
• Biochemistry

Background:

• Tau aggregate deposition is a hallmark of neurodegenerative tauopathies, including Alzheimer's disease (AD).
• Transcellular spread of pathological tau contributes to disease progression, making immunotherapy a potential therapeutic strategy.

Purpose of the Study:

• To biochemically and biophysically characterize gosuranemab, a monoclonal antibody targeting N-terminal tau.
• To evaluate gosuranemab's efficacy in reducing tau aggregation and its potential as an Alzheimer's disease treatment.

Main Methods:

• Binding experiments to assess gosuranemab affinity for different tau species (monomer, fibrils, insoluble tau).
• X-ray crystallography and mutagenesis for epitope mapping.
• Immunodepletion assays, tau biosensor cell studies, and primary neuronal cultures to evaluate aggregation inhibition.
• Measurement of N-terminal tau levels in cerebrospinal fluid (CSF) and interstitial fluid (ISF) in patients and animal models.

Main Results:

• Gosuranemab demonstrated high affinity for monomeric, fibrillar, and insoluble tau.
• Epitope mapping identified the binding site to human tau residues 15-22.
• Gosuranemab reduced tau aggregation in vitro and in vivo, and decreased unbound N-terminal tau in biological fluids.
• High target engagement (>90%) was observed in the CSF of clinical trial participants.

Conclusions:

• Gosuranemab effectively binds pathological tau species and inhibits tau aggregation.
• These findings support gosuranemab's potential as a therapeutic agent for Alzheimer's disease and other tauopathies.