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.
journal_name
Neuronjournal_title
Neuronauthors
Demattos RB,Lu J,Tang Y,Racke MM,Delong CA,Tzaferis JA,Hole JT,Forster BM,McDonnell PC,Liu F,Kinley RD,Jordan WH,Hutton MLdoi
10.1016/j.neuron.2012.10.029subject
Has Abstractpub_date
2012-12-06 00:00:00pages
908-20issue
5eissn
0896-6273issn
1097-4199pii
S0896-6273(12)00950-6journal_volume
76pub_type
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