西亚试剂：A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β P

A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β Production in Vivo

Atwal, Jasvinder K.; Chen, Yongmei; Chiu, Cecilia; Mortensen, Deborah L.; Meilandt, William J.; Liu, Yichin; Heise, Christopher E.; Hoyte, Kwame; Luk, Wilman; Lu, Yanmei; Peng, Kun; Wu, Ping; Rouge, Lionel; Zhang, Yingnan; Lazarus, Robert A.; Scearce-Levie, Kimberly; Wang, Weiru; Wu, Yan; Tessier-Lavigne, Marc; Watts, Ryan J.

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-brainbarrier (BBB). Here, we have developed a high-affinity, phage-derived human antibody that targets BACE1 (anti-BACE1) and isanti-amyloidogenic. Anti-BACE1 reduces endogenous BACE1 activity and Aβ production in human cell lines expressing APP andin 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 BACE1and not to the catalytic site. Systemic dosing of mice and nonhuman primates with anti-BACE1 resulted in sustained reductionsin 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 throughpassive immunization with anti-BACE1, providing a potential approach for treating Alzheimer’s disease. Nevertheless, therapeuticsuccess with anti-BACE1 will depend on improving antibody uptake into the brain.