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Immunotherapy and Biomarkers in Neurodegenerative Disorders pp 51–60Cite as

Immunotherapy Against Amyloid-β Protofibrils: Opportunities and Challenges

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Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

Immunotherapy has emerged as a promising treatment option for Alzheimer’s disease (AD). Although many challenges still remain, data from drug programs within the immunotherapy area indicate that targeting amyloid β peptide (Aβ) with monoclonal antibodies might lead to positive treatment effects. Antibodies can be made highly specific for their target and monoclonal antibodies usually have a more favorable safety profile as compared to small molecules. Results from previous immunotherapy trials have indicated the importance of targeting early AD. Some of the anti-Aβ immunotherapy studies indicate that positive effects in the clinic are possible, which is encouraging for continued research. Promisingly, the monoclonal antibody aducanumab had dose-dependent effects both on cognitive measures and on amyloid PET imaging following 12 months of treatment. This is the first time a candidate drug targeting Aβ has shown a clinical effect. Our finding of the Arctic AD mutation in the amyloid β precursor protein (AβPP) gene led us to consider large soluble oligomers, i.e., protofibrils, of Aβ as particularly toxic and a promising target for immunotherapy. Furthermore, both preclinical and clinical data suggest that Aβ protofibrils have particular neurotoxic properties. Our research efforts lead to the isolation of mAb158, an antibody highly selective for these Aβ species. However, several of the antibodies in clinical trials have caused amyloid-related imaging abnormalities (ARIAs), side effects that pose a problem for the development of this class of drugs. BAN2401 is the humanized version of mAb158 and the antibody is now in a large phase 2b trial. The safety profile has so far been satisfactory.

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Abbreviations

A4:

Anti-amyloid treatment in Alzheimer’s disease prevention trial

Aβ:

Amyloid β

AD:

Alzheimer’s disease

API:

Alzheimer’s prevention initiative

ARIA-E:

Amyloid-related imaging abnormalities with edema

ARIA-H:

Amyloid-related imaging abnormalities with microhemorrhages

BACE:

Beta-secretase

CSF:

Cerebrospinal fluid

DIAN:

Dominantly inherited Alzheimer network trial

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Acknowledgements

Hans Basun, Gunilla Osswald, Christer Möller, Dag Sehlin, and Anna Lord for helpful comments on the manuscript.

Competing Interests:

Lars Lannfelt is co-founder of BioArctic Neuroscience AB.

Author information

Authors and Affiliations

  1. Department of Public Health & Caring Sciences/Geriatrics, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden

    Lars Lannfelt

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  1. Lars Lannfelt
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Correspondence to Lars Lannfelt .

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Editors and Affiliations

  1. Dept Public Health & Caring Sci Ger, Uppsala University, Uppsala, Sweden

    Martin Ingelsson

  2. Dept Public Health & Caring Sci Ger, Uppsala University, Uppsala, Sweden

    Lars Lannfelt

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Lannfelt, L. (2016). Immunotherapy Against Amyloid-β Protofibrils: Opportunities and Challenges. In: Ingelsson, M., Lannfelt, L. (eds) Immunotherapy and Biomarkers in Neurodegenerative Disorders. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3560-4_4

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  • DOI: https://doi.org/10.1007/978-1-4939-3560-4_4

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3558-1

  • Online ISBN: 978-1-4939-3560-4

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