Tau antibody chimerization alters its charge and binding, thereby reducing its cellular uptake and efficacy.

Background: Bringing antibodies from pre-clinical studies to human trials requires humanization, but this process may alter properties that are crucial for efficacy. Since pathological tau protein is primarily intraneuronal in Alzheimer's disease, the most efficacious antibodies should work both intra- and extracellularly. Thus, changes which impact uptake or antibody binding will affect antibody efficacy.

Structural characterization of monoclonal antibodies targeting C-terminal Ser region of phosphorylated tau protein.

Targeting tau with immunotherapies is currently the most common approach taken in clinical trials of patients with Alzheimer's disease. The most prominent pathological feature of tau is its hyperphosphorylation, which may cause the protein to aggregate into toxic assemblies that collectively lead to neurodegeneration. Of the phospho-epitopes, the region around Ser/Ser has received particular attention for therapeutic targeting because of its prominence and stability in diseased tissue.

Tau Antibody Structure Reveals a Molecular Switch Defining a Pathological Conformation of the Tau Protein.

Tau antibodies have shown therapeutic potential for Alzheimer's disease and several are in clinical trials. As a microtubule-associated protein, tau relies on dynamic phosphorylation for its normal functions. In tauopathies, it becomes hyperphosphorylated and aggregates into toxic assemblies, which collectively lead to neurodegeneration.