Accumulation of amyloid ? peptide (A?) aggregates in the brain is thought to be a central event leading to neurodegenerative changes observed in Alzheimer disease (AD). There is consensus that immunoglobulins (Igs) with specific A? binding activity are viable candidates for AD therapy. We propose to develop novel catalytic Igs with improved efficacy and safety as candidate immunotherapeutic agents for AD. Our experimental approach is based on these considerations. A single catalytic Ig molecule hydrolyzes thousands of A? molecules over its lifetime, which should confer superior efficacy to catalytic Igs in removing A? oligomers compared to conventional stoichiometrically binding Igs. The catalysts do not form stable immune complexes with A?, reducing the likelihood of inflammatory reactions. Deposition of A? in blood vessels observed using conventional Igs is unlikely because of A? digestion by the catalytic Igs. We have identified catalytic Ig variable domains (IgVs) suitable for further development as AD drugs. We will apply protein engineering methods to prepare catalytic IgV derivatives with improved stability and reduced immunogenicity suitable for administration to humans. The resultant Igs will be characterized with respect to catalytic rates and specificity. They will then be tested for efficacy (A? clearance, behavioral improvement) and safety using a transgenic mouse model of AD. If our hypotheses are correct, these studies will validate catalytic Igs as agents suitable for AD therapy.

Public Health Relevance

Finding an effective and safe treatment for Alzheimer disease is an important public health need. We plan to test and develop catalytic antibodies that clear amyloid beta peptide for immunotherapy of Alzheimer disease.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG033183-05
Application #
8728715
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Planque, Stephanie A; Nishiyama, Yasuhiro; Hara, Mariko et al. (2014) Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J Biol Chem 289:13243-58
Nishiyama, Yasuhiro; Taguchi, Hiroaki; Hara, Mariko et al. (2014) Metal-dependent amyloid ?-degrading catalytic antibody construct. J Biotechnol 180:17-22