title: A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice.
abstract: Aβ Immunotherapy is a promising therapeutic approach for Alzheimer's disease. Preclinical studies demonstrate that plaque prevention is possible; however, the more relevant therapeutic removal of existing plaque has proven elusive. Monoclonal antibodies in development target both soluble and insoluble Aβ peptide. We hypothesized that antibody specificity for deposited plaque was critical for plaque removal since soluble Aβ peptide would block recognition of deposited forms. We developed a plaque-specific antibody that targets a modified Aβ peptide (Aβ(p3-42)), which showed robust clearance of pre-existing plaque without causing microhemorrhage. Interestingly, a comparator N-terminal Aβ antibody 3D6, which binds both soluble and insoluble Aβ(1-42), lacked efficacy for lowering existing plaque but manifested a significant microhemorrhage liability. Mechanistic studies suggested that the lack of efficacy for 3D6 was attributed to poor target engagement in plaques. These studies have profound implications for the development of therapeutic Aβ antibodies for Alzheimer's disease.
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. demattosrb@lilly.com
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Demattos
authors.forename: Jirong
authors.initials: J
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Racke
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Delong
authors.forename: John A
authors.initials: JA
authors.lastname: Tzaferis
authors.forename: Justin T
authors.initials: JT
authors.lastname: Hole
authors.forename: Beth M
authors.initials: BM
authors.lastname: Forster
authors.forename: Peter C
authors.initials: PC
authors.lastname: McDonnell
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Robert D
authors.initials: RD
authors.lastname: Kinley
authors.forename: William H
authors.initials: WH
authors.lastname: Jordan
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006470:Hemorrhage / Q000139:chemically induced; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D058225:Plaque, Amyloid / Q000276:immunology* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007074:Immunoglobulin G; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)