Targeted Hydrolysis of Beta-Amyloid with Engineered Antibody Fragments

Accumulation and deposition of beta amyloid (Aβ) play a critical role in the pathogenesis of Alzheimer's Disease (AD), and numerous approaches to control Aβ aggregation are being actively pursued. Brain Aβ 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 Aβ in transgenic mouse models of AD, these enzymes have other natural substrates and multiple cleavage sites in Aβ complicating their use for treating AD. Alternatively, immunotherapeutic approaches to clear Aβ are gaining interest. Active and passive immunization studies with Aβ 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 Aβ, 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 Aβ. A potentially non-inflammatory approach to facilitate Aβ clearance and reduce toxicity is to promote hydrolysis of Aβ at its α-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 α-secretase activity and to target toxic Aβ 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.