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- Title
A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β Production in Vivo.
- Authors
Yongmei Chen; Cecilia Chiu; Mortensen, Deborah L.; Meilandt, William J.; Yichin Liu; Heise, Christopher E.; Kwame Hoyte; Wilman Luk; Yanmei Lu; Kun Peng; Ping Wu; Lionel Rouge; Yingnan Zhang; Lazarus, Robert A.; Scearce-Levie, Kimberly; Weiru Wang; Yan Wu; Tessier-Lavigne, Marc; Watts, Ryan J.
- Abstract
Reducing production of amyloid-β (Aβ) peptide by direct inhibition of the enzymes that process amyloid precursor protein (APP) is a central therapeutic strategy for treating Alzheimer's disease. However, small-molecule inhibitors of the β-secretase (BACE1) and g-secretase APP processing enzymes have shown a lack of target selectivity and poor penetrance of the blood-brain barrier (BBB). Here, we have developed a high-affinity, phage-derived human antibody that targets BACE1 (anti-BACE1) and is anti-amyloidogenic. Anti-BACE1 reduces endogenous BACE1 activity and Aβ production in human cell lines expressing APP and in cultured primary neurons. Anti-BACE1 is highly selective and does not inhibit the related enzymes BACE2 or cathepsin D. Competitive binding assays and x-ray crystallography indicate that anti-BACE1 binds noncompetitively to an exosite on BACE1 and not to the catalytic site. Systemic dosing of mice and nonhuman primates with anti-BACE1 resulted in sustained reductions in peripheral Aβ peptide concentrations. Anti-BACE1 also reduces central nervous system Ab concentrations in mouse and monkey, consistent with a measurable uptake of antibody across the BBB. Thus, BACE1 can be targeted in a highly selective manner through passive immunization with anti-BACE1, providing a potential approach for treating Alzheimer's disease. Nevertheless, therapeutic success with anti-BACE1 will depend on improving antibody uptake into the brain.
- Publication
Science Translational Medicine, 2011, Vol 3, Issue 84, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.3002254