Molecular basis for passive immunotherapy of Alzheimer's disease

Amyloid aggregates of the amyloid-β (Aβ) peptide are implicated in the pathology of Alzheimer's disease. Anti-Aβ monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer&#...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-10, Vol.104 (40), p.15659-15664
Main Authors: Gardberg, Anna S, Dice, Lezlee T, Ou, Susan, Rich, Rebecca L, Helmbrecht, Elizabeth, Ko, Jan, Wetzel, Ronald, Myszka, David G, Patterson, Paul H, Dealwis, Chris
Format: Article
Language:English
Subjects:
Alzheimer Disease - immunology
Alzheimer's disease
Alzheimers disease
Amyloid beta-Peptides - immunology
Amyloids
Antibodies
Antibodies, Monoclonal - therapeutic use
Antigens
Binding Sites, Antibody
Biochemistry
Biological Sciences
Cross Reactions
Enzyme-Linked Immunosorbent Assay
Epitopes
Epitopes - analysis
Humans
Hydrogen bonds
Immunotherapy
Immunotherapy - methods
Monoclonal antibodies
Monomers
Oligopeptides - immunology
Passive immunization
Peptides
Proteins
Solar fibrils
Surface Plasmon Resonance
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Summary:Amyloid aggregates of the amyloid-β (Aβ) peptide are implicated in the pathology of Alzheimer's disease. Anti-Aβ monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-Aβ mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize Aβ monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the Aβ(1-8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIP1 is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to Aβ(1-8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target Aβ with improved specificity and higher affinity.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0705888104