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Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Lund Univ, Chem Ctr, Dept Biochem & Struct Biol, SE-22100 Lund, Sweden.ORCID iD: 0000-0002-5510-2245
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Lund Univ, Chem Ctr, Dept Biochem & Struct Biol, SE-22100 Lund, Sweden.
Lund Univ, Chem Ctr, Dept Biochem & Struct Biol, SE-22100 Lund, Sweden.
Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England.; Astra Zeneca, Innovat Med, Discovery Sci, Cambridge CB4 0WG, England .
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 25, 6444-6449 p.Article in journal (Refereed) Published
Abstract [en]

The aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is a defining characteristic of Alzheimer’s disease. Because of the complexity of this aggregation process, effective therapeutic inhibitors will need to target the specific microscopic steps that lead to the production of neurotoxic species. We introduce a strategy for generating fibril-specific antibodies that selectively suppress fibril-dependent secondary nucleation of the 42-residue form of Aβ (Aβ42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of Aβ42. Starting from large phage display libraries of single-chain antibody fragments (scFvs), the three-stage approach that we describe includes (i) selection of scFvs with high affinity for Aβ42 fibrils after removal of scFvs that bind Aβ42 in its monomeric form; (ii) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the Aβ42 fibrils; and (iii) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril-catalyzed secondary nucleation process in Aβ42 aggregation. By applying this approach, we have identified four scFvs that inhibit specifically the fibril-dependent secondary nucleation process. Our method also makes it possible to discard antibodies that inhibit elongation, an important factor because the suppression of elongation does not target directly the production of toxic oligomers and may even lead to its increase. On the basis of our results, we suggest that the method described here could form the basis for rationally designed immunotherapy strategies to combat Alzheimer’s and related neurodegenerative diseases.

Place, publisher, year, edition, pages
2017. Vol. 114, no 25, 6444-6449 p.
Keyword [en]
Alzheimer, antibody, inhibitor, drug development, self-assembly
National Category
Physical Chemistry Biophysics
Identifiers
URN: urn:nbn:se:uu:diva-323432DOI: 10.1073/pnas.1700407114ISI: 000403687300022PubMedID: 28584111OAI: oai:DiVA.org:uu-323432DiVA: diva2:1114729
Funder
Swedish Research CouncilWellcome trust
Available from: 2017-06-25 Created: 2017-06-25 Last updated: 2017-09-26Bibliographically approved

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Munke, Anna

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