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Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies

Linse, Sara LU ; Scheidt, Tom ; Bernfur, Katja LU ; Vendruscolo, Michele ; Dobson, Christopher M. ; Cohen, Samuel I.A. ; Sileikis, Eimantas ; Lundqvist, Martin LU ; Qian, Fang and O’Malley, Tiernan , et al. (2020) In Nature Structural and Molecular Biology 27(12). p.1125-1133
Abstract

The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer’s disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the... (More)

The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer’s disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Structural and Molecular Biology
volume
27
issue
12
pages
9 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85091607188
  • pmid:32989305
ISSN
1545-9993
DOI
10.1038/s41594-020-0505-6
language
English
LU publication?
yes
id
9c67d6aa-7f70-4533-9716-c3a7a987f226
date added to LUP
2020-10-28 07:51:44
date last changed
2021-01-26 03:52:02
@article{9c67d6aa-7f70-4533-9716-c3a7a987f226,
  abstract     = {<p>The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer’s disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.</p>},
  author       = {Linse, Sara and Scheidt, Tom and Bernfur, Katja and Vendruscolo, Michele and Dobson, Christopher M. and Cohen, Samuel I.A. and Sileikis, Eimantas and Lundqvist, Martin and Qian, Fang and O’Malley, Tiernan and Bussiere, Thierry and Weinreb, Paul H. and Xu, Catherine K. and Meisl, Georg and Devenish, Sean R.A. and Knowles, Tuomas P.J. and Hansson, Oskar},
  issn         = {1545-9993},
  language     = {eng},
  number       = {12},
  pages        = {1125--1133},
  publisher    = {Nature Publishing Group},
  series       = {Nature Structural and Molecular Biology},
  title        = {Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies},
  url          = {http://dx.doi.org/10.1038/s41594-020-0505-6},
  doi          = {10.1038/s41594-020-0505-6},
  volume       = {27},
  year         = {2020},
}