Opportunities for Conformation-Selective Antibodies in Amyloid-Related Diseases

Abstract

Assembly of misfolded proteins into fibrillar deposits is a common feature of many neurodegenerative diseases. Developing effective therapies to these complex, and not yet fully understood diseases is currently one of the greatest medical challenges facing society. Slow and initially asymptomatic onset of neurodegenerative disorders requires profound understanding of the processes occurring at early stages of the disease including identification and structural characterisation of initial toxic species underlying neurodegeneration. In this review, we chart the latest progress made towards understanding the multifactorial process leading to amyloid formation and highlight efforts made in the development of therapeutic antibodies for the treatment of amyloid-based disorders. The specificity and selectivity of conformational antibodies make them attractive research probes to differentiate between transient states preceding formation of mature fibrils and enable strategies for potential therapeutic intervention to be considered.

Immunoaffinity extraction using conformation-dependent antibodies coupled to SE-HPLC for the development of stability and potency-indicating assay for quadrivalent human papillomavirus vaccine

“…In contrast, a conformational epitope has a specific three-dimensional shape specific to a folded protein structure. Thus, conformation-dependent antibodies can differentiate between correctly folded forms and misfolded or denatured proteins [5,22]. In this study, a set of type-specific, conformation-dependent antibodies were employed in order to isolate each type of the VLPs from quadrivalent HPV vaccine preparations.…”

New tool to tackle Alzheimer's disease: amyloid‐β protofibril‐selective antibody AbSL

“…). Schematic representation illustrates the Aβ aggregation process initiated by misfolded, monomeric proteins, which undergo several conformational transitions and aggregation before they reach mature fibril states (Westwood and Lawson ).…”

“…Due to their selectivity, conformation‐specific antibodies are currently the best tools for the detection of particular transient states of Aβ in Alzheimer's disease. These antibodies may also enable the development of highly targeted immunotherapeutic interventions (Westwood and Lawson ). Indeed, there are a number of antibody‐based immunotherapies targeting Aβ currently in clinical trials (Westwood and Lawson ; Cummings et al .…”

“…These antibodies may also enable the development of highly targeted immunotherapeutic interventions (Westwood and Lawson ). Indeed, there are a number of antibody‐based immunotherapies targeting Aβ currently in clinical trials (Westwood and Lawson ; Cummings et al . ) and this approach could be improved by immunoreagents that are selective for a particular Aβ conformation.…”

“…). Therefore, the new antibody, in combination with other previously developed immunoreagents to other forms of Aβ (Westwood and Lawson ), will be useful for detecting Aβ42 protofibril formation in Alzheimer's disease as well as distinguishing between different forms of Aβ42. This study supports the notion that there are significant structural differences between Aβ protofibrils and other Aβ oligomers which can be detected with conformational epitope‐specific antibodies.…”