Targeted Hydrolysis of B-amyloid with Engineered Antibody Fragments

Project: Research project

Project Details

Description

Targeted Hydrolysis of B-amyloid with Engineered Antibody Fragments Targeted Hydrolysis of B-amyloid with Engineered Antibody Fragments Alzheimer's Disease (AD) is a debilitating neurodegenerative disease affecting a significant and growing portion of the elderly population. In transgenic mouse models of A plaque deposition, active and passive immunization against A delayed A deposition, dissolved existing extracellular plaques and reduced memory loss and behavioral impairment. Immunization trials in humans with AD showed decreased cognitive decline and reduced neuritic pathology, however the study was suspended due to occurrence of aseptic meningoencephalitis. In addition, increased cerebral hemorrhaging was observed in immunized mouse models. While A immunization has shown great promise for treatment of AD and further trials are currently underway, we do not fully understand how immunization works and what the various endpoints measured mean for AD treatment. The role of A in AD is still controversial, an issue that has been complicated greatly since A occurs in a variety of lengths and morphologies. Therefore multiple approaches to prevent A toxicity are needed. Our long term objective is to develop a series of novel recombinant antibodies that can be used as part of an effective passive immunization approach for treating or preventing AD while controlling potential inflammation in the CNS. Our hypothesis in this proposal is that multifunctional recombinant antibody constructs containing a proteolytic activity can be engineered to specifically target and hydrolyze A as part of a safe, effective therapeutic treatment for AD. The bispecific recombinant antibodies we will develop in this proposal will contain two different functionalities; first a single chain antibody fragment (scFv) possessing proteolytic activity designed to hydrolyze A at the alpha-secretase site, and second an scFv to target the diabody to different regions of A or APP with high specificity and affinity. We will address the following four specific aims to demonstrate the potential protective effects of the proteolytic diabodies for treating AD: 1) Increase the specificity of a proteolytic antibody light chain for the alpha-secretase site of A; 2) Increase the specificity of scFv's to different regions of A or APP; 3) Construct diabodies containing the proteolytic and A targeting scFv's and 4) Perform in vitro characterization of diabody function. This novel approach of engineering a proteolytic activity to very specifically target A will provide a complimentary approach to existing strategies to decrease A toxicity.2
StatusFinished
Effective start/end date1/1/0912/31/09

Funding

  • Institute for the Study of Aging: $100,000.00

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