Immunotherapy Against Amyloid-β Protofibrils: Opportunities and Challenges
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.
Key wordsAlzheimer’s disease Amyloid-β Aβ Protofibril Oligomer Immunotherapy BAN2401 mAb158 ARIA
List of Abbreviations
Anti-amyloid treatment in Alzheimer’s disease prevention trial
Alzheimer’s prevention initiative
Amyloid-related imaging abnormalities with edema
Amyloid-related imaging abnormalities with microhemorrhages
Dominantly inherited Alzheimer network trial
Hans Basun, Gunilla Osswald, Christer Möller, Dag Sehlin, and Anna Lord for helpful comments on the manuscript.
Lars Lannfelt is co-founder of BioArctic Neuroscience AB.
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