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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 γ-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 Aβ 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.
Footnotes
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Citation: J. K. Atwal, Y. Chen, C. Chiu, D. L. Mortensen, W. J. Meilandt, Y. Liu, C. E. Heise, K. Hoyte, W. Luk, Y. Lu, K. Peng, P. Wu, L. Rouge, Y. Zhang, R. A. Lazarus, K. Scearce-Levie, W. Wang, Y. Wu, M. Tessier-Lavigne, R. J. Watts, A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β Production in Vivo. Sci. Transl. Med. 3, 84ra43 (2011).
- Copyright © 2011, American Association for the Advancement of Science
