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Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies.
Immunotherapy 2012; 4(2):213-38I

Abstract

The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Aβ. The most innovative of the pharmacological approaches was the stimulation of Aβ clearance from the brain of AD patients via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination). Several active and passive anti-Aβ vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with bapineuzumab and solanezumab will tell us if monoclonal anti-Aβ antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD.

Authors+Show Affiliations

Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy. geriat.dot@geriatria.uniba.it.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

22339463

Citation

Panza, Francesco, et al. "Immunotherapy for Alzheimer's Disease: From Anti-β-amyloid to Tau-based Immunization Strategies." Immunotherapy, vol. 4, no. 2, 2012, pp. 213-38.
Panza F, Frisardi V, Solfrizzi V, et al. Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies. Immunotherapy. 2012;4(2):213-38.
Panza, F., Frisardi, V., Solfrizzi, V., Imbimbo, B. P., Logroscino, G., Santamato, A., ... Pilotto, A. (2012). Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies. Immunotherapy, 4(2), pp. 213-38. doi:10.2217/imt.11.170.
Panza F, et al. Immunotherapy for Alzheimer's Disease: From Anti-β-amyloid to Tau-based Immunization Strategies. Immunotherapy. 2012;4(2):213-38. PubMed PMID: 22339463.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies. AU - Panza,Francesco, AU - Frisardi,Vincenza, AU - Solfrizzi,Vincenzo, AU - Imbimbo,Bruno P, AU - Logroscino,Giancarlo, AU - Santamato,Andrea, AU - Greco,Antonio, AU - Seripa,Davide, AU - Pilotto,Alberto, PY - 2012/2/21/entrez PY - 2012/2/22/pubmed PY - 2012/6/9/medline SP - 213 EP - 38 JF - Immunotherapy JO - Immunotherapy VL - 4 IS - 2 N2 - The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Aβ. The most innovative of the pharmacological approaches was the stimulation of Aβ clearance from the brain of AD patients via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination). Several active and passive anti-Aβ vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with bapineuzumab and solanezumab will tell us if monoclonal anti-Aβ antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD. SN - 1750-7448 UR - https://www.unboundmedicine.com/medline/citation/22339463/Immunotherapy_for_Alzheimer's_disease:_from_anti_β_amyloid_to_tau_based_immunization_strategies_ L2 - http://www.futuremedicine.com/doi/full/10.2217/imt.11.170?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -