Innate and vaccine-generated antibodies against transthyretin amyloids - Brian O'Nuallain
Aging is associated with the aberrant deposition of sticky extracellular aggregates of amyloid polypeptides in tissues and/or organs. The formation of amyloid is associated with a host of human diseases, including heart disease, Alzheimer’s disease, and diabetes. Unfortunately, amyloid diseases are currently incurable, and there is an urgent need for non-invasive diagnostics for timely patient treatment with current symptomatic or future disease-modifying therapies. To address this, we are investigating the therapeutic and diagnostic potential of innate and vaccine-generated antibodies that target toxic amyloid assemblies of a blood transport protein, transthyretin (TTR), the cause of senile systemic amyloidosis (SSA) – a disease that affects ~20% of humans over the age of 80 years. We will report progress on identifying antibodies that specifically catalyze the breakdown of toxic TTR assemblies. Our experimental approach is based on the hypothesis of covalent catalysis as a primordial immune mechanism that can be applied to identify an efficacious therapeutic agent for treating SSA. We have also vaccinated mice with non-native TTR and generated eight novel murine TTR-reactive monoclonal IgG antibodies that have diagnostic potential for SSA. These IgGs specifically target binding sites on soluble and insoluble non-native TTR assemblies, and can recognize patient-derived TTR amyloid but not native physiologically relevant TTR contained in normal human plasma. Taken together, these findings support further investigations on the therapeutic and diagnostic potential of the innate and vaccine-generated anti-TTR antibodies for SSA.