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Molecular basis for passive immunotherapy of Alzheimer's disease

Gardberg, Anna S. and Dice, Lezlee T. and Ou, Susan and Rich, Rebecca L. and Helmbrecht, Elizabeth and Ko, Jan and Wetzel, Ronald and Myszka, David G. and Patterson, Paul H. and Dealwis, Chris (2007) Molecular basis for passive immunotherapy of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 104 (40). pp. 16659-16664. ISSN 0027-8424. PMCID PMC1994138. https://resolver.caltech.edu/CaltechAUTHORS:GARpnas07

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Abstract

Amyloid aggregates of the amyloid-{beta} (A{beta}) peptide are implicated in the pathology of Alzheimer's disease. Anti-A{beta} 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-A{beta} mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize A{beta} monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the A{beta}(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 A{beta}(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 A{beta} with improved specificity and higher affinity.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994138/PubMed CentralArticle
https://doi.org/10.1073/pnas.0705888104DOIUNSPECIFIED
https://doi.org/10.1073/pnas.0705888104DOIUNSPECIFIED
Additional Information:Copyright © 2007 by the National Academy of Sciences. Freely available online through the PNAS open access option. Edited by David R. Davies, National Institutes of Health, Bethesda, MD, and approved August 15, 2007 (received for review June 22, 2007). This article is a PNAS Direct Submission. Published online before print September 25, 2007. We thank Angela Williams (University of Tennessee) for providing disaggregated peptides and CLC-Aβ protofibrils, Dr. Elias Fernandez for useful suggestions, Dr. Hai Xu (University of Tennessee) for assistance with crystallography of PFA2-pep, and Lauren Cagliuso for assistance. We also thank BioCARS at the Advanced Photon Source. This work was supported by National Institutes of Health Grants NS46356 (to R.W., P.H.P., and C.D.) and R01 AG018416 (to R.W. and D.G.M.). Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 2IPT, 2IPU, 2IQ9, 2IQA, 2ROZ, and 2ROW). Author contributions: R.W., D.G.M., and C.D. designed research; A.S.G., L.T.D., S.O., R.L.R., E.H., J.K., and C.D. performed research; A.S.G., L.T.D., S.O., R.L.R., J.K., R.W., D.G.M., and C.D. analyzed data; and A.S.G., R.W., P.H.P., and C.D. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/cgi/content/full/0705888104/DC1.
Funders:
Funding AgencyGrant Number
NIHNS46356
NIHR01 AG018416
Subject Keywords:amyloid, crystal structure, EFRH, monoclonal antibody, EFRHD
Issue or Number:40
PubMed Central ID:PMC1994138
Record Number:CaltechAUTHORS:GARpnas07
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:GARpnas07
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8910
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:26 Sep 2007
Last Modified:02 Oct 2019 23:55

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