Passive Aβ Immunotherapy: Current Achievements and Future Perspectives

Abstract

Passive immunotherapy has emerged as a very promising approach for the treatment of Alzheimer’s disease and other neurodegenerative disorders, which are characterized by the misfolding and deposition of amyloid peptides. On the basis of the amyloid hypothesis, the majority of antibodies in clinical development are directed against amyloid β (Aβ), the primary amyloid component in extracellular plaques. This review focuses on the current status of Aβ antibodies in clinical development, including their characteristics and challenges that came up in clinical trials with these new biological entities (NBEs). Emphasis is placed on the current view of common side effects observed with passive immunotherapy, so-called amyloid-related imaging abnormalities (ARIAs), and potential ways to overcome this issue. Among these new ideas, a special focus is placed on molecules that are directed against post-translationally modified variants of the Aβ peptide, an emerging approach for development of new antibody molecules.

Keywords: amyloid-β; drug development; monoclonal antibodies; posttranslational modifications.

Figure 1

Schematic depiction of prominent posttranslational modifications of Aβ. Modifications appearing within the peptide chain and those addressing amino acid side chains (in triangles) are highlighted. APP: amyloid precursor protein; iD: isoaspartate; NO₂: nitration pE: pyroglutamate; P: phosphorylation site.