Validation of Endogenous Human Antibodies That are Correlated With Avoiding Alzheimer’s Disease and Their Corresponding Antigens, for Immunotherapeutic Development

Immunotherapy is a leading strategy for preventing cognitive decline in Alzheimer’s disease. In 2015,
the first disease-modifying treatment that prevented cognitive decline in human trials was reported. The trial showed that high doses (10 mg/kg) of a monoclonal antibody that targets amyloid beta-amyloid aggregates, Aducanumab, prevented cognitive decline in mild cognitively impaired patients over a one-year period. While this is an exciting breakthrough, there are a number of problems that need to be overcome before this therapy is widely available. A number of side effects were noted that may be associated with the high amount of antibody administered and the high costs associated with the amount of antibody required will interfere with its widespread utilization. More effective antibodies and cheaper treatments would be a great benefit to AD patients.

In the previous award period, we identified an antibody,mH, which is highly correlated with avoiding AD or having AD (P < .005) by using the immunoreactivity of human serum samples on a microarray of 458 different amyloid binding sites that are called epitopes or antigens. We hypothesize mH is protective against disease and we will test this hypothesis in this proposal.

We will test whether mH prevents AD pathology and improves cognitive performance in transgenic mouse models of AD pathology. Since the peptide epitope or antigen for this antibody is a non-natural random peptide sequence, it is unlikely to have the side effects previously observed for immunization against human amyloid beta, so we also will test whether active immunization with the mH antigen elicits a protective immune response in transgenic mouse models. The results of these investigations have the potential of leading to the development of more effective antibodies or active vaccines as a cost-effective therapy that can be widely administered. Other potential outcomes and deliverables include diagnostics that can detect onset of disease before cognitive deficits, and the ability to distinguish different subtypes of disease, such as vascular AD and AD with Lewy body disease. A “theranostic” approach to AD treatment, where antibodies or vaccines are tailored to a patient’s disease type based on microarray screening of patient serum samples, is also possible. The theranostic approach also can be used to monitor patient immune response to active vaccination and either change antigens or supplement antibody levels with monoclonal antibody administration for individuals with low immune response.