Epitopes described in "A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo."

Article Authors:Jasvinder K Atwal; Yongmei Chen; Cecilia Chiu; Deborah L Mortensen; William J Meilandt; Yichin Liu; Christopher E Heise; Kwame Hoyte; Wilman Luk; Yanmei Lu; Kun Peng; Ping Wu; Lionel Rouge; Yingnan Zhang; Robert A Lazarus; Kimberly Scearce-Levie; Weiru Wang; Yan Wu; Marc Tessier-Lavigne; Ryan J Watts
Article Title:A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo.
Reference Detail
Reference ID:1022165
Abstract:Reducing production of amyloid- (A) 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 -secretase (BACE1) and -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 A 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 A peptide concentrations. Anti-BACE1 also reduces central nervous system A 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.
Affiliations:Neurodegeneration Labs, Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Reference Type:Literature
PubMed ID:21613622
Journal:Sci Transl Med
Journal Volume:3
Article Pages:84ra43
Journal ISSN:1946-6242
Article Chemical List:Amyloid beta-Peptides;Antibodies;Peptide Library;Amyloid Precursor Protein Secretases;Aspartic Acid Endopeptidases;BACE1 protein, human;Bace1 protein, mouse
Article MeSH List:Amino Acid Sequence; Amyloid Precursor Protein Secretases(antagonists & inhibitors; chemistry; deficiency; metabolism); Amyloid beta-Peptides(biosynthesis; cerebrospinal fluid); Animals; Antibodies(chemistry; metabolism; pharmacology; therapeutic use); Aspartic Acid Endopeptidases(antagonists & inhibitors; chemistry; deficiency; metabolism); Biological Assay; Brain(drug effects; metabolism; pathology); Crystallography, X-Ray; Endocytosis(drug effects); Humans; Macaca fascicularis; Mice; Models, Molecular; Molecular Sequence Data; Neurons(drug effects; metabolism); Peptide Library; Protein Binding(drug effects); Treatment Outcome
Curation Last Updated:2014-10-03 22:21:53