Drug Development

Area of Science:

• Neuroscience
• Immunology
• Biochemistry

Background:

• Tau protein abnormalities are central to Alzheimer's disease (AD) and other tauopathies.
• Previous tau antibodies have failed due to insufficient affinity or specificity for pathogenic tau species.
• The humanized monoclonal antibody TBL-100 targets tauC3, a toxic C-terminal fragment with high affinity and specificity.

Purpose of the Study:

• To investigate the binding characteristics of TBL-100 to tauC3.
• To determine if TBL-100 binds an inaccessible epitope or a neoepitope created by tau cleavage.
• To assess TBL-100's potential for targeting toxic tau species and oligomers.

Main Methods:

• Enzyme-linked immunosorbent assay (ELISA) to determine TBL-100 affinity for monomeric and oligomeric tauC3.
• Surface plasmon resonance (SPR) to assess TBL-100 binding to synthetic tau peptides.
• Comparison of TBL-100 binding to tauC3 versus full-length tau (FLT).

Main Results:

• TBL-100 demonstrated exquisite end specificity for tauC3, binding preferentially to the sequence ending at Asp421.
• Binding affinity was significantly reduced for peptides with additional C-terminal amino acids.
• TBL-100 bound both monomeric and oligomeric tauC3 with picomolar affinity, but not FLT.

Conclusions:

• TBL-100 exhibits high affinity and specificity for the pathogenic tauC3 fragment.
• Its ability to bind oligomeric tauC3 suggests potential to inhibit pathology spread.
• TBL-100 represents a promising therapeutic candidate for tauopathies.