Amyloid‐ß‐directed immunotherapy for Alzheimer's disease

L Lannfelt,N R Relkin,E R Siemers

doi:10.1111/joim.12168

Abstract

Lannfelt L, Relkin NR, Siemers ER (Uppsala University, Uppsala, Sweden; Weill Cornell Medical College, New York, NY; and Eli Lilly and Co., Indianapolis, IN, USA). Amyloid-ß-directed immunotherapy for Alzheimer’s disease. (Key Symposium). J Intern Med 2014; 275: 284–295.Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid-ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti-amyloid immunotherapy remains one of the most promising emerging strategies for developing disease-modifying treatments for AD. In this review, we examine the presently ongoing Aß-directed immunotherapies that have passed clinical development Phase IIa.

Highlights

Current treatment options for Alzheimer’s disease (AD) are limited to medications that reduce dementia symptoms but do not arrest or reverse the underlying neurodegenerative disorder
The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop
One strategy for improving immunotherapy studies is the use of newly approved positron emission tomography (PET) amyloid imaging technology as a means of identifying individuals who have measurable brain amyloid burden, and improving diagnostic accuracy, which is being done in the Alzheimer’s Disease Cooperative Study (ADCS) A4 trial

Summary

Introduction

Current treatment options for Alzheimer’s disease (AD) are limited to medications that reduce dementia symptoms but do not arrest or reverse the underlying neurodegenerative disorder. Ab oligomers and protofibrils have been shown to be toxic to neurons and synapses and to inhibit mechanisms associated with memory For these and other reasons, the soluble and highly toxic forms of Ab such as oligomers and protofibrils may be more directly linked to cellular pathology and are appropriate targets for treatments; the equilibria between monomeric Ab, oligomers or protofibrils and insoluble Ab fibrils remain poorly understood. Adverse effects can occur after active vaccination, which may depend on the binding epitopes of the polyclonal antibodies produced; these adverse effects can be persistent, even lifelong For these reasons as well as others, the development of active immunization for AD has proceeded more slowly than that of passive immunization. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. Antibodies that block RAGE could in theory stimulate reduction in CSF Aß levels by

Aβ amyloid plaque

Conclusions

Findings

Conflict of interest statement