Development of AFFITOPE vaccines for Alzheimer’s disease (AD) — From concept to clinical testing

  • A. Schneeberger
  • M. Mandler
  • O. Otava
  • W. Zauner
  • F. Mattner
  • W. Schmidt
Second Generation AD Vaccines

Abstract

Based on the notion that cerebral accumulation of certain Aβ species is central to AD pathogenesis and endowed with the knowledge that emerged during clinical testing of the first human Alzheimer vaccine, AN1792, we designed a new generation of Alzheimer vaccines. Rather than relying on full-length Aβ itself or fragments thereof, AFFITOPE vaccines use short peptides, mimicking parts of the native Aβ sequence, as their antigenic component. The technology created to identify these peptides, termed AFFITOPE-technology, at the same time provides the basis for the multi-component safety concept realized in AFFITOPE vaccines. First, as they are non-self, AFFITOPES don’t need to break tolerance typically established against self proteins. This allows us to use aluminium hydroxide, the agent first approved as immunological adjuvant for human use and, thus, exhibiting an excellent safety profile. Second, AFFITOPES employed in Alzheimer vaccines are only 6 amino acids in length, which precludes the activation of Aβ-specific autoreactive T cells. Third, and above all, the AFFITOPE technology allows for controlling the specificity of the vaccine-induced antibody response focusing it exclusively on Aβ and preventing crossreactivity with APP. In a program based on two AFFITOPES allowing neoepitope targeting of Aβ (free N-terminus), this approach was taken all the way from concept to clinical application. Early clinical data support the safety concept inherent to AFFITOPE Alzheimer vaccines. Further clinical testing will focus on the identification of the optimal vaccine dose and immunization schedule. Together, result of these trials will provide a solid basis for clinical POC studies.

Key words

Alzheimer vaccine immunotherapy disease modification clinical study 

Abbreviations

Aa

amino acid

amyloid β

Ab

antibody

AD

Alzheimer’s disease

AD

adverse event

APP

Amyloid Precursor Protein

BBB

blood brain barrier

CMI

cell mediated immunity

FDA

Federal Drug Agency

IFN

Interferon

ME

meningoencephalitis

NINCDS/ADRDA

National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria

POC

Proof of concept

SUSAR

suspected unexpected serious adverse reaction

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References

  1. 1.
    Schenk, D., R. Barbour, W. Dunn, G. Gordon, H. Grajeda, T. Guido, K. Hu, J. Huang, K. Johnson-Wood, K. Khan, D. Kholodenko, M. Lee, Z. Liao, I. Lieberburg, R. Motter, L. Mutter, F. Soriano, G. Shopp, N. Vasquez, C. Vandevert, S. Walker, M. Wogulis, T. Yednock, D. Games, and P. Seubert. 1999. Immunization with amyloidbeta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177.PubMedCrossRefGoogle Scholar
  2. 2.
    Janus, C., J. Pearson, J. McLaurin, P. M. Mathews, Y. Jiang, S. D. Schmidt, M. A. Chishti, P. Horne, D. Heslin, J. French, H. T. Mount, R. A. Nixon, M. Mercken, C. Bergeron, P. E. Fraser, P. St George-Hyslop, and D. Westaway. 2000. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408:979–982.PubMedCrossRefGoogle Scholar
  3. 3.
    Sigurdsson, E. M., H. Scholtzova, P. D. Mehta, B. Frangione, and T. Wisniewski. 2001. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am J Pathol 159:439–447.PubMedGoogle Scholar
  4. 4.
    Wilcock, D. M., G. DiCarlo, D. Henderson, J. Jackson, K. Clarke, K. E. Ugen, M. N. Gordon, and D. Morgan. 2003. Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci 23:3745–3751.PubMedGoogle Scholar
  5. 5.
    Morgan, D., D. M. Diamond, P. E. Gottschall, K. E. Ugen, C. Dickey, J. Hardy, K. Duff, P. Jantzen, G. DiCarlo, D. Wilcock, K. Connor, J. Hatcher, C. Hope, M. Gordon, and G. W. Arendash. 2000. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408:982–985.PubMedCrossRefGoogle Scholar
  6. 6.
    Orgogozo, J. M., S. Gilman, J. F. Dartigues, B. Laurent, M. Puel, L. C. Kirby, P. Jouanny, B. Dubois, L. Eisner, S. Flitman, B. F. Michel, M. Boada, A. Frank, and C. Hock. 2003. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61:46–54.PubMedGoogle Scholar
  7. 7.
    Vitaliani, R., M. Zoccarato, M. Vianello, and B. Giometto. 2008. Clinical, immunological and therapeutic aspects of autoimmune encephalitis. Recent Patents CNS Drug Discov 3:16–22.CrossRefGoogle Scholar
  8. 8.
    Gilman, S., M. Koller, R. S. Black, L. Jenkins, S. G. Griffith, N. C. Fox, L. Eisner, L. Kirby, M. B. Rovira, F. Forette, and J. M. Orgogozo. 2005. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553–1562.PubMedCrossRefGoogle Scholar
  9. 9.
    Grundman, M. 2008. 10th International Springfield Symposium, Hong Kong.Google Scholar
  10. 10.
    Nicoll, J. A., D. Wilkinson, C. Holmes, P. Steart, H. Markham, and R. O. Weller. 2003. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452.PubMedCrossRefGoogle Scholar
  11. 11.
    Ferrer, I., M. Boada Rovira, M. L. Sanchez Guerra, M. J. Rey, and F. Costa-Jussa. 2004. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 14:11–20.PubMedGoogle Scholar
  12. 12.
    Masliah, E., L. Hansen, A. Adame, L. Crews, F. Bard, C. Lee, P. Seubert, D. Games, L. Kirby, and D. Schenk. 2005. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64:129–131.PubMedGoogle Scholar
  13. 13.
    Holmes, C., D. Boche, D. Wilkinson, G. Yadegarfar, V. Hopkins, A. Bayer, R. W. Jones, R. Bullock, S. Love, J. W. Neal, E. Zotova, and J. A. Nicoll. 2008. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223.PubMedCrossRefGoogle Scholar
  14. 14.
    Le Poole, I. C., and R. M. Luiten. 2008. Autoimmune etiology of generalized vitiligo. Curr Dir Autoimmun 10:227–243.PubMedCrossRefGoogle Scholar
  15. 15.
    Rudolph. 2006. How TCRs bind MHCs, peptides and coreceptors. Ann Review Immunol 24:419–466.CrossRefGoogle Scholar
  16. 16.
    Sakaguchi, S., T. Yamaguchi, T. Nomura, and M. Ono. 2008. Regulatory T cells and immune tolerance. Cell 133:775–787.PubMedCrossRefGoogle Scholar

Copyright information

© Serdi and Springer Verlag France 2009

Authors and Affiliations

  • A. Schneeberger
    • 1
  • M. Mandler
    • 1
  • O. Otava
    • 1
  • W. Zauner
    • 1
  • F. Mattner
    • 1
  • W. Schmidt
    • 1
  1. 1.AFFiRiSViennaAustria

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