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Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication

Munke, Anna; Persson, Jonas; Weiffert, Tanja LU ; De Genst, Erwin J.; Meisl, Georg; Arosio, Paolo; Carnerup, Anna LU ; Dobson, Christopher M; Vendruscolo, Michele and Knowles, Tuomas P J, et al. (2017) In Proceedings of the National Academy of Sciences of the United States of America 114(25). p.6444-6449
Abstract

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 A (A42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of A42. Starting from large phage display libraries of single-chain antibody fragments (scFvs), the three-stage approach that we describe includes (i) selection... (More)

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 A (A42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of A42. 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 A42 fibrils after removal of scFvs that bind A42 in its monomeric form; (ii) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the A42 fibrils; and (iii) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril-catalyzed secondary nucleation process in A42 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.

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publication status
published
subject
keywords
Alzheimer, Antibody, Drug development, Inhibitor, Self-assembly
in
Proceedings of the National Academy of Sciences of the United States of America
volume
114
issue
25
pages
6 pages
publisher
National Acad Sciences
external identifiers
  • scopus:85021181906
  • wos:000403687300022
ISSN
0027-8424
DOI
10.1073/pnas.1700407114
language
English
LU publication?
yes
id
da1b124e-0f97-42d7-955d-d8fef1eaac3e
date added to LUP
2017-07-11 14:33:58
date last changed
2017-09-18 11:38:09
@article{da1b124e-0f97-42d7-955d-d8fef1eaac3e,
  abstract     = {<p>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 A (A42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of A42. 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 A42 fibrils after removal of scFvs that bind A42 in its monomeric form; (ii) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the A42 fibrils; and (iii) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril-catalyzed secondary nucleation process in A42 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.</p>},
  author       = {Munke, Anna and Persson, Jonas and Weiffert, Tanja and De Genst, Erwin J. and Meisl, Georg and Arosio, Paolo and Carnerup, Anna and Dobson, Christopher M and Vendruscolo, Michele and Knowles, Tuomas P J and Linse, Sara},
  issn         = {0027-8424},
  keyword      = {Alzheimer,Antibody,Drug development,Inhibitor,Self-assembly},
  language     = {eng},
  month        = {06},
  number       = {25},
  pages        = {6444--6449},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication},
  url          = {http://dx.doi.org/10.1073/pnas.1700407114},
  volume       = {114},
  year         = {2017},
}