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

STATEMENT: 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)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG033183-03
Application #
8320914
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6 (M1))
Program Officer
Petanceska, Suzana
Project Start
2010-09-15
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$511,111
Indirect Cost
$114,873
Name
University of Texas Health Science Center Houston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Meretoja, Ville V; Paul, Sudhir; Planque, Stephanie A (2017) Hydrolysis and Dissolution of Amyloids by Catabodies. Methods Mol Biol 1643:111-134
Planque, Stephanie A; Nishiyama, Yasuhiro; Sonoda, Sari et al. (2015) Specific amyloid ? clearance by a catalytic antibody construct. J Biol Chem 290:10229-41
Nishiyama, Yasuhiro; Taguchi, Hiroaki; Hara, Mariko et al. (2014) Metal-dependent amyloid ?-degrading catalytic antibody construct. J Biotechnol 180:17-22
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