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J Biol Chem. 2017 Jul 28;292(30):12713-12724. doi: 10.1074/jbc.M117.777839. Epub 2017 Jun 16.

Structural and functional analyses of pyroglutamate-amyloid-β-specific antibodies as a basis for Alzheimer immunotherapy.

Author information

1
From Probiodrug AG, Weinbergweg 22, 06120 Halle (Saale), Germany.
2
the Institute of Biotechnology, Martin Luther University, 06108 Halle-Wittenberg, Germany.
3
the Department of Molecular Drug Biochemistry and Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Weinbergweg 22, 06120 Halle, Germany, and.
4
SynAging SAS, 54518 Vandoeuvre-les-Nancy, France.
5
From Probiodrug AG, Weinbergweg 22, 06120 Halle (Saale), Germany, jens-ulrich.rahfeld@probiodrug.de.
6
the Institute of Biotechnology, Martin Luther University, 06108 Halle-Wittenberg, Germany, stubbs@biochemtech.uni-halle.de.

Abstract

Alzheimer disease is associated with deposition of the amyloidogenic peptide Aβ in the brain. Passive immunization using Aβ-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo Because N-terminally truncated pyroglutamate (pE)-modified Aβ species (AβpE3) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize AβpE3 with affinities of 1-10 nm and inhibit AβpE3 fibril formation in vitro. In vivo application of one of these resulted in improved memory in AβpE3 oligomer-treated mice. Crystal structures of Fab-AβpE3 complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the "pEF head") confers a pronounced bulky hydrophobic nature to the AβpE3 N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies.

KEYWORDS:

Alzheimer disease; amyloid-beta (Aβ); crystal structure; drug development; ligand binding; monoclonal antibody; thermodynamics

PMID:
28623233
PMCID:
PMC5535044
DOI:
10.1074/jbc.M117.777839
[Indexed for MEDLINE]
Free PMC Article

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