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A therapeutic antibody targeting BACE1 inhibits amyloid- beta production in vivo

Reducing production of amyloid- beta (A beta ) 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 beta -secretase (BACE1) and gamma -secretase APP proce... Full description

Journal Title: Assay and drug development technologies 2011-08-01, Vol.9 (4), p.336-337
Main Author: Atwal, J K
Other Authors: Chen, Y , Chiu, C , Mortensen, D L , Meilandt, W J , Liu, Y , Heise, CE , Hoyte, K , Luk, W , Lu, Y , Peng, K , Wu, P , Rouge, L , Zhang, Y
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
ID: ISSN: 1540-658X
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recordid: cdi_proquest_miscellaneous_893269937
title: A therapeutic antibody targeting BACE1 inhibits amyloid- beta production in vivo
format: Article
creator:
  • Atwal, J K
  • Chen, Y
  • Chiu, C
  • Mortensen, D L
  • Meilandt, W J
  • Liu, Y
  • Heise, CE
  • Hoyte, K
  • Luk, W
  • Lu, Y
  • Peng, K
  • Wu, P
  • Rouge, L
  • Zhang, Y
subjects:
  • Primates
ispartof: Assay and drug development technologies, 2011-08-01, Vol.9 (4), p.336-337
description: Reducing production of amyloid- beta (A beta ) 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 beta -secretase (BACE1) and gamma -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 beta 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 beta peptide concentrations. Anti-BACE1 also reduces central nervous system A beta 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 1540-658X
fulltext: fulltext
issn:
  • 1540-658X
  • 1557-8127
url: Link


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titleA therapeutic antibody targeting BACE1 inhibits amyloid- beta production in vivo
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descriptionReducing production of amyloid- beta (A beta ) 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 beta -secretase (BACE1) and gamma -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 beta 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 beta peptide concentrations. Anti-BACE1 also reduces central nervous system A beta 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.
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abstractReducing production of amyloid- beta (A beta ) 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 beta -secretase (BACE1) and gamma -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 beta 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 beta peptide concentrations. Anti-BACE1 also reduces central nervous system A beta 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.