Fusion Antibody for Alzheimer's Disease with Bidirectional Transport Across the Blood−Brain Barrier and Aβ Fibril Disaggregation

Abstract

Delivery of monoclonal antibody therapeutics across the blood−brain barrier is an obstacle to the diagnosis or therapy of CNS disease with antibody drugs. The immune therapy of Alzheimer's disease attempts to disaggregate the amyloid plaque of Alzheimer's disease with an anti-Aβ monoclonal antibody. The present work is based on a three-step model of immune therapy of Alzheimer's disease: (1) influx of the anti-Aβ monoclonal antibody across the blood−brain barrier in the blood to brain direction, (2) binding and disaggregation of Aβ fibrils in brain, and (3) efflux of the anti-Aβ monoclonal antibody across the blood−brain barrier in the brain to blood direction. This is accomplished with the genetic engineering of a trifunctional fusion antibody that binds (1) the human insulin receptor, which mediates the influx from blood to brain across the blood−brain barrier, (2) the Aβ fibril to disaggregate amyloid plaque, and (3) the Fc receptor, which mediates the efflux from brain to blood across the blood−brain barrier. This fusion protein is a new antibody-based therapeutic for Alzheimer's disease that is specifically engineered to cross the human blood−brain barrier in both directions.