Immunotherapy Targeting Amyloid-ß Peptides in Alzheimer’s Disease

Abstract

Neurodegenerative diseases, in particular Alzheimer' s disease, represent significant unmet medical needs due to a lack of effective therapeutic treatment options and cause a substantial burden for health care systems. Accumulation of β-amyloid peptides within the brain is believed to be an initial trigger of the disease process. In the last 20 years, immunotherapy has emerged as a promising target-directed strategy to develop efficient treatment options with disease-modifying potential. Unfortunately, either active vaccination against β-amyloid or its fragments, as well as passive immunization using monoclonal antibodies, have largely failed to show a clinical benefit in a variety of clinical trials. This chapter addresses progress and developments with regard to active and passive immunization against Aβ and summarizes the current state of clinical trials.

Review of Advanced Drug Trials Focusing on the Reduction of Brain Beta-Amyloid to Prevent and Treat Dementia

“…Active immunization functions by introducing Aβ peptides as the antigen to the host, which then mounts an immune response against Aβ monomers and/or multimers that results in the production of antibodies specifically targeting Aβ. 88 , 89 The goal of active Aβ immunotherapy is to program the patient’s immune system to eliminate endogenous Aβ. 90 Active immunization for AD in humans was first tested in 2002 in a study where participants were immunized with full-length Aβ42 peptides (named AN1792; Elan Pharmaceuticals) along with the immunological adjuvant QS-21 (NCT00021723).…”

“…4. mAbs interact with Aβ in the peripheral blood and form a concentration gradient that causes Aβ to flow out from the brain; this process is referred to as the “sink effect.” 88 , 90 , 99 …”

“… 97 Another 2 potential benefits to passive versus active immunization are (i) the possibility to target specific conformations of Aβ peptides, which could then be used to remove specific forms of Aβ such as monomers, oligomers, or fibrils; and (ii) the potential ability to rapidly clear administered antibodies in case of adverse reactions. 88 …”

“…mAbs interact with Aβ in the peripheral blood and form a concentration gradient that causes Aβ to flow out from the brain; this process is referred to as the "sink effect." 88,90,99 This form of therapy allows for direct disassembly of Aβ in the brain. The use of mAbs is also one of the easiest ways to provide anti-Aβ antibodies without increasing the likelihood of an uncontrolled Th-1 mediated antibody response.…”

Amyloid-β targeting immunisation in aged non-human primate (Microcebus murinus)

“…Many antibodies have been tested clinically to date and a few of these studies are still ongoing ; however, results over the past two decades have been disappointing 5 , with the possible recent exception of aducanumab, which is an antibody specific to insoluble fibrillary and oligomeric forms of Aβ 6 , and Eli Lilly’s anti-pGlu3 Aβ antibody, donanemab 7 . A few vaccine trials remain active 8 , but this approach is not without challenges.…”