title: A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo.
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.
authors: Neurodegeneration Labs, Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Jasvinder K
authors: JK
authors: Atwal
authors: Yongmei
authors: Y
authors: Chen
authors: Cecilia
authors: C
authors: Chiu
authors: Deborah L
authors: DL
authors: Mortensen
authors: William J
authors: WJ
authors: Meilandt
authors: Yichin
authors: Y
authors: Liu
authors: Christopher E
authors: CE
authors: Heise
authors: Kwame
authors: K
authors: Hoyte
authors: Wilman
authors: W
authors: Luk
authors: Yanmei
authors: Y
authors: Lu
authors: Kun
authors: K
authors: Peng
authors: Ping
authors: P
authors: Wu
authors: Lionel
authors: L
authors: Rouge
authors: Yingnan
authors: Y
authors: Zhang
authors: Robert A
authors: RA
authors: Lazarus
authors: Kimberly
authors: K
authors: Scearce-Levie
authors: Weiru
authors: W
authors: Wang
authors: Yan
authors: Y
authors: Wu
authors: Marc
authors: M
authors: Tessier-Lavigne
authors: Ryan J
authors: RJ
authors: Watts