Targeted Hydrolysis of Beta-Amyloid with Engineered Antibody Fragments

Accumulation and deposition of beta amyloid (A beta) play a critical role in the pathogenesis of Alzheimer's Disease (AD), and numerous approaches to control A beta aggregation are being actively pursued. Brain A beta levels are controlled by the action of several proteolytic enzymes such as neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin. While up-regulation of these enzymes increased clearance of A beta in transgenic mouse models of AD, these enzymes have other natural substrates and multiple cleavage sites in A beta complicating their use for treating AD. Alternatively, immunotherapeutic approaches to clear A beta are gaining interest. Active and passive immunization studies with A beta can reduce plaque burden and memory loss, but clinical trials were stopped due to meningioencephalitis in some patients. Naturally occurring proteolytic antibodies have been shown to cleave A beta, and their serum titers are increased in patients with AD reflecting a protective autoimmune response. These antibodies however cannot cross the blood brain barrier and depend entirely on peripheral clearance to clear A beta. A potentially non-inflammatory approach to facilitate A beta clearance and reduce toxicity is to promote hydrolysis of A beta at its alpha-secretase site using affinity matured single chain antibody fragments (scFvs). Bispecific antibodies consisting of a proteolytic scFv and a targeting scFv can be engineered to selectively supplement and target extracellular alpha-secretase activity and to target toxic A beta forms facilitating their degradation and clearance without generating an immune response. This strategy represents a suitable paradigm for treating other neurological diseases such as Parkinson's Disease, Lou Gehrig's Disease, and spongiform encephalopathies.