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

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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.

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Acknowledgments

This work was funded by the National Health and Medical Research Council of Australia (NHMRC) and we thank the AIBL Flagship Study of Aging for the provision of blood samples. Funding was also received from the Victorian Government Operational Infrastructure Support Scheme to St Vincent’s Institute. D.B.A was supported by a Victoria Fellowship from the Victorian Government and a Leslie (Les) J. Fleming Churchill Fellowship from The Winston Churchill Memorial Trust. M.W.P. is an NHMRC Research Fellow.

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Authors and Affiliations

  1. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia

    Andrew D. Watt, Russell A. Down, Adam Gunn, Keyla A. Perez, Catriona A. McLean, Victor L. Villemagne & Kevin J. Barnham

  2. Department of Pathology, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia

    Andrew D. Watt & Russell A. Down

  3. Neuroproteomics Platform, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia

    Andrew D. Watt, Russell A. Down, Adam Gunn, Keyla A. Perez & Kevin J. Barnham

  4. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia

    Michael W. Parker & Luke A. Miles

  5. Department of Pharmacology, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia

    Kevin J. Barnham

  6. Department of Medicine, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia

    Victor L. Villemagne

  7. ACRF Rational Drug Discovery Centre and Biota Structural Biology Laboratory, St. Vincent’s Institute of Medical Research, Fitzroy, VIC, 3056, Australia

    Gabriela A. N. Crespi, David B. Ascher, Michael W. Parker & Luke A. Miles

  8. Department of Anatomical Pathology, The Alfred Hospital, Melbourne, VIC, 3084, Australia

    Catriona A. McLean

  9. Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, 3084, Australia

    Victor L. Villemagne

Authors
  1. Andrew D. Watt
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  2. Gabriela A. N. Crespi
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  3. Russell A. Down
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  8. Victor L. Villemagne
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  11. Luke A. Miles
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Corresponding authors

Correspondence to Kevin J. Barnham or Luke A. Miles.

Additional information

K. J. Barnham and L. A. Miles contributed equally to this work.

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Watt, A.D., Crespi, G.A.N., Down, R.A. et al. Do current therapeutic anti-Aβ antibodies for Alzheimer’s disease engage the target?. Acta Neuropathol 127, 803–810 (2014). https://doi.org/10.1007/s00401-014-1290-2

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  • DOI: https://doi.org/10.1007/s00401-014-1290-2

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