Acta Neuropathologica

, Volume 127, Issue 6, pp 803–810 | Cite as

Do current therapeutic anti-Aβ antibodies for Alzheimer’s disease engage the target?

  • Andrew D. Watt
  • Gabriela A. N. Crespi
  • Russell A. Down
  • David B. Ascher
  • Adam Gunn
  • Keyla A. Perez
  • Catriona A. McLean
  • Victor L. Villemagne
  • Michael W. Parker
  • Kevin J. Barnham
  • Luke A. Miles
Original Paper

Abstract

Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer’s disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.

Keywords

Alzheimer’s disease β-Amyloid Bapineuzumab Crenezumab Solanezumab Mass spectrometry 

Supplementary material

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Supplementary material 1 (TIFF 7223 kb)
401_2014_1290_MOESM2_ESM.doc (590 kb)
Supplementary material 2 (DOC 591 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Andrew D. Watt
    • 1
    • 2
    • 3
  • Gabriela A. N. Crespi
    • 7
  • Russell A. Down
    • 1
    • 2
    • 3
  • David B. Ascher
    • 7
  • Adam Gunn
    • 1
    • 3
  • Keyla A. Perez
    • 1
    • 3
  • Catriona A. McLean
    • 1
    • 8
  • Victor L. Villemagne
    • 1
    • 6
    • 9
  • Michael W. Parker
    • 4
    • 7
  • Kevin J. Barnham
    • 1
    • 3
    • 5
  • Luke A. Miles
    • 4
    • 7
  1. 1.Florey Institute of Neuroscience and Mental HealthThe University of MelbourneMelbourneAustralia
  2. 2.Department of PathologyThe University of MelbourneMelbourneAustralia
  3. 3.Neuroproteomics Platform, Bio21 Molecular Science and Biotechnology InstituteThe University of MelbourneMelbourneAustralia
  4. 4.Department of Biochemistry and Molecular BiologyThe University of MelbourneMelbourneAustralia
  5. 5.Department of PharmacologyThe University of MelbourneMelbourneAustralia
  6. 6.Department of MedicineThe University of MelbourneMelbourneAustralia
  7. 7.ACRF Rational Drug Discovery Centre and Biota Structural Biology LaboratorySt. Vincent’s Institute of Medical ResearchFitzroyAustralia
  8. 8.Department of Anatomical PathologyThe Alfred HospitalMelbourneAustralia
  9. 9.Department of Nuclear Medicine and Centre for PETAustin HealthHeidelbergAustralia

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