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AADvac1, an Active Immunotherapy for Alzheimer’s Disease and Non Alzheimer Tauopathies: An Overview of Preclinical and Clinical Development

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Abstract

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

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References

  1. Grundke–Iqbal, I., et al., Microtubule–associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem, 1986. 261(13): p. 6084–9.

    PubMed  Google Scholar 

  2. Wischik, C.M., et al., Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A, 1988. 85(12): p. 4506–10.

    Article  CAS  Google Scholar 

  3. Poorkaj, P., et al., Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol, 1998. 43(6): p. 815–25.

    Article  CAS  Google Scholar 

  4. Spillantini, M.G. and M. Goedert, Tau pathology and neurodegeneration. Lancet Neurol, 2013. 12(6): p. 609–22.

    Article  CAS  Google Scholar 

  5. Whitwell, J.L., et al., MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel–based morphometry study. Neurology, 2008. 71(10): p. 743–9.

    Article  CAS  Google Scholar 

  6. Nelson, P.T., et al., Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol, 2012. 71(5): p. 362–81.

    Article  Google Scholar 

  7. Murray, M.E., et al., Clinicopathologic and 11C–Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum. Brain, 2015. 138(Pt 5): p. 1370–81.

    Google Scholar 

  8. Braak, H. and E. Braak, Neuropathological stageing of Alzheimer–related changes. Acta Neuropathol, 1991. 82(4): p. 239–59.

    Article  CAS  Google Scholar 

  9. Kontsekova, E., et al., First–in–man tau vaccine targeting structural determinants essential for pathological tau–tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther, 2014. 6(4): p. 44.

    Google Scholar 

  10. Iqbal, K., F. Liu, and C.X. Gong, Tau and neurodegenerative disease: the story so far. Nat Rev Neurol, 2016. 12(1): p. 15–27.

    Article  CAS  Google Scholar 

  11. Li, C. and J. Gotz, Tau–based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov, 2017. 16(12): p. 863–883.

    Article  CAS  Google Scholar 

  12. Guo, T., W. Noble, and D.P. Hanger, Roles of tau protein in health and disease. Acta Neuropathol, 2017. 133(5): p. 665–704.

    Article  CAS  Google Scholar 

  13. Sotiropoulos, I., et al., Atypical, non–standard functions of the microtubule associated Tau protein. Acta Neuropathol Commun, 2017. 5(1): p. 91.

    Google Scholar 

  14. Violet, M., et al., A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front Cell Neurosci, 2014. 8: p. 84.

    Google Scholar 

  15. Paholikova, K., et al., N–terminal Truncation of Microtubule Associated Protein Tau Dysregulates its Cellular Localization. J Alzheimers Dis, 2014.

    Google Scholar 

  16. Zilka, N., et al., Who fans the flames of Alzheimer’s disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways. J Neuroinflammation, 2012. 9: p. 47.

    Google Scholar 

  17. Alonso, A.C., et al., Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A, 1994. 91(12): p. 5562–6.

    Article  CAS  Google Scholar 

  18. Alonso, A.C., I. Grundke–Iqbal, and K. Iqbal, Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med, 1996. 2(7): p. 783–7.

    Article  CAS  Google Scholar 

  19. Kovacech, B. and M. Novak, Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer’s disease. Curr Alzheimer Res, 2010. 7(8): p. 708–16.

    Article  CAS  Google Scholar 

  20. Grundke–Iqbal, I., et al., Abnormal phosphorylation of the microtubuleassociated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A, 1986. 83(13): p. 4913–7.

    Article  Google Scholar 

  21. Zilka, N., et al., The self–perpetuating tau truncation circle. Biochemical Society transactions, 2012. 40(4): p. 681–6.

    Article  CAS  Google Scholar 

  22. Skrabana, R., et al., Neuronal Expression of Truncated Tau Efficiently Promotes Neurodegeneration in Animal Models: Pitfalls of Toxic Oligomer Analysis. J Alzheimers Dis, 2017. 58(4): p. 1017–1025.

    Article  CAS  Google Scholar 

  23. Al–Hilaly, Y.K., et al., Alzheimer’s Disease–like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking. Journal of molecular biology, 2017. 429(23): p. 3650–3665.

    Article  Google Scholar 

  24. Alonso, A., et al., Hyperphosphorylation induces self–assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A, 2001. 98(12): p. 6923–8.

    Article  CAS  Google Scholar 

  25. Vechterova, L., et al., DC11: a novel monoclonal antibody revealing Alzheimer’s disease–specific tau epitope. Neuroreport, 2003. 14(1): p. 87–91.

    Article  CAS  Google Scholar 

  26. Kovacech, B., R. Skrabana, and M. Novak, Transition of tau protein from disordered to misordered in Alzheimer’s disease. Neurodegener Dis, 2010. 7(1–3): p. 24–7.

    Google Scholar 

  27. Novak, M., J. Kabat, and C.M. Wischik, Molecular characterization of the minimal protease resistant tau unit of the Alzheimer’s disease paired helical filament. EMBO J, 1993. 12(1): p. 365–70.

    Article  CAS  Google Scholar 

  28. Frost, B., et al., Conformational diversity of wild–type Tau fibrils specified by templated conformation change. J Biol Chem, 2009. 284(6): p. 3546–51.

    Article  CAS  Google Scholar 

  29. Skrabana, R., J. Sevcik, and M. Novak, Intrinsically disordered proteins in the neurodegenerative processes: formation of tau protein paired helical filaments and their analysis. Cellular and molecular neurobiology, 2006. 26(7–8): p. 1085–97.

    Google Scholar 

  30. Fitzpatrick, A.W.P., et al., Cryo–EM structures of tau filaments from Alzheimer’s disease. Nature, 2017. 547(7662): p. 185–190.

    Article  CAS  Google Scholar 

  31. Augustinack, J.C., et al., Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol, 2002. 103(1): p. 26–35.

    Article  CAS  Google Scholar 

  32. Goedert, M., D.S. Eisenberg, and R.A. Crowther, Propagation of Tau Aggregates and Neurodegeneration. Annual review of neuroscience, 2017. 40: p. 189–210.

    Google Scholar 

  33. Novak, M., Truncated tau protein as a new marker for Alzheimer’s disease. Acta Virol, 1994. 38(3): p. 173–89.

    CAS  PubMed  Google Scholar 

  34. Clavaguera, F., et al., Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol, 2009. 11(7): p. 909–13.

    Article  CAS  Google Scholar 

  35. Ahmed, Z., et al., A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol, 2014. 127(5): p. 667–83.

    Article  CAS  Google Scholar 

  36. Hu, W., et al., Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement, 2016. 12(10): p. 1066–1077.

    Article  Google Scholar 

  37. Zilka, N., M. Korenova, and M. Novak, Misfolded tau protein and disease modifying pathways in transgenic rodent models of human tauopathies. Acta Neuropathol, 2009. 118(1): p. 71–86.

    Article  CAS  Google Scholar 

  38. Masters, C.L., et al., Alzheimer’s disease. Nat Rev Dis Primers, 2015. 1: p. 15056.

    Google Scholar 

  39. Zilka, N., et al., Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett, 2006. 580(15): p. 3582–8.

    Article  CAS  Google Scholar 

  40. Koson, P., et al., Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. Eur J Neurosci, 2008. 28(2): p. 239–46.

    Article  Google Scholar 

  41. Zimova, I., et al., Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy. J Alzheimers Dis, 2016. 54(2): p. 831–43.

    Article  CAS  Google Scholar 

  42. Novak, P., et al., Stress–Induced Alterations of Immune Profile in Animals Suffering by Tau Protein–Driven Neurodegeneration. Cell Mol Neurobiol, 2018. 38(1): p. 243–259.

    Article  CAS  Google Scholar 

  43. Kovac, A., et al., Misfolded truncated protein tau induces innate immune response via MAPK pathway. J Immunol, 2011. 187(5): p. 2732–9.

    Article  CAS  Google Scholar 

  44. Cente, M., et al., Expression of a truncated human tau protein induces aqueous–phase free radicals in a rat model of tauopathy: implications for targeted antioxidative therapy. J Alzheimers Dis, 2009. 17(4): p. 913–20.

    Article  CAS  Google Scholar 

  45. Filipcik, P., et al., Cortical and hippocampal neurons from truncated tau transgenic rat express multiple markers of neurodegeneration. Cell Mol Neurobiol, 2009. 29(6–7): p. 895–900.

    Google Scholar 

  46. Cente, M., et al., Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J Neurosci, 2006. 24(4): p. 1085–90.

    Article  Google Scholar 

  47. Kontsekova, E., et al., Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res Ther, 2014. 6(4): p. 45.

    Google Scholar 

  48. Gilman, S., et al., Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 2005. 64(9): p. 1553–62.

    Article  CAS  Google Scholar 

  49. Vandenberghe, R., et al., Active Abeta immunotherapy CAD106 in Alzheimer’s disease: A phase 2b study. Alzheimers Dement (N Y), 2017. 3(1): p. 10–22.

    Google Scholar 

  50. Novak, P., et al., Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double–blind, placebocontrolled, phase 1 trial. Lancet Neurol, 2017. 16(2): p. 123–134.

    Article  CAS  Google Scholar 

  51. Lang, P.O., et al., Immune senescence and vaccination in the elderly. Curr Top Med Chem, 2013. 13(20): p. 2541–50.

    Article  CAS  Google Scholar 

  52. Hobart, J., et al., Putting the Alzheimer’s cognitive test to the test I: traditional psychometric methods. Alzheimers Dement, 2013. 9(1 Suppl): p. S4–9.

    Google Scholar 

  53. Hobart, J., et al., Putting the Alzheimer’s cognitive test to the test II: Rasch Measurement Theory. Alzheimers Dement, 2013. 9(1 Suppl): p. S10–20.

    Google Scholar 

  54. Raghavan, N., et al., The ADAS–Cog revisited: novel composite scales based on ADAS–Cog to improve efficiency in MCI and early AD trials. Alzheimers Dement, 2013. 9(1 Suppl): p. S21–31.

    Google Scholar 

  55. Gorno–Tempini, M.L., et al., Classification of primary progressive aphasia and its variants. Neurology, 2011. 76(11): p. 1006–14.

    Article  Google Scholar 

  56. Josephs, K.A., et al., Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol, 2011. 122(2): p. 137–53.

    Article  Google Scholar 

  57. Santos–Santos, M.A., et al., Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration. JAMA Neurol, 2016. 73(6): p. 733–42.

    Article  Google Scholar 

  58. Grossman, M., Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol, 2010. 6(2): p. 88–97.

    Article  Google Scholar 

  59. Rohrer, J.D., et al., Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology, 2016. 87(13): p. 1329–36.

    Article  CAS  Google Scholar 

  60. Steinacker, P., et al., Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias. Neurology, 2017. 88(10): p. 961–969.

    Article  CAS  Google Scholar 

  61. Semler, E., et al., A language–based sum score for the course and therapeutic intervention in primary progressive aphasia. Alzheimers Res Ther, 2018. 10(1): p. 41.

    Google Scholar 

  62. Knopman, D.S., et al., Development of methodology for conducting clinical trials in frontotemporal lobar degeneration. Brain, 2008. 131(Pt 11): p. 2957–68.

    Google Scholar 

  63. Sikkes, S.A., et al., Validation of the Amsterdam IADL Questionnaire(c), a new tool to measure instrumental activities of daily living in dementia. Neuroepidemiology, 2013. 41(1): p. 35–41.

    PubMed  Google Scholar 

  64. Rafii, M.S., et al., PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI, and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI). J Alzheimers Dis, 2017. 60(2): p. 439–450.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. AXON Neuroscience CRM Services SE, Dvorakovo nabrezie 10, 811 02, Bratislava, Slovakia

    P. Novak & M. Ondrus

  2. AXON Neuroscience R&D Services SE, Dvorakovo nabrezie 10, 811 02, Bratislava, Slovakia

    N. Zilka, M. Zilkova, B. Kovacech, R. Skrabana, L. Fialova & E. Kontsekova

  3. Ulm University, Department of Neurology, Oberer Eselsberg 45, 89081, Ulm, Germany

    M. Otto

  4. AXON Neuroscience SE, Arch. Makariou & Kalogreon 4, 6016, Larnaca, Cyprus

    M. Novak

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  1. P. Novak
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  2. N. Zilka
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  3. M. Zilkova
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Novak, P., Zilka, N., Zilkova, M. et al. AADvac1, an Active Immunotherapy for Alzheimer’s Disease and Non Alzheimer Tauopathies: An Overview of Preclinical and Clinical Development. J Prev Alzheimers Dis 6, 63–69 (2019). https://doi.org/10.14283/jpad.2018.45

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  • DOI: https://doi.org/10.14283/jpad.2018.45

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