Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics

Abstract

Two anti-amyloid monoclonal antibodies (MABs)-lecanemab (Leqembi ® ) and aducanumab (Aduhelm ® )-have been approved in the USA for the treatment of Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies are the first disease-modifying therapies for AD that achieve slowing of clinical decline by intervening in the basic biological processes of the disease. These are breakthrough agents that can slow the inevitable progression of AD into more severe cognitive impairment. The results of trials of anti-amyloid MABs support the amyloid hypothesis and amyloid as a target for AD drug development. The success of MABs reflects a relentless application of neuroscience knowledge to solving major challenges facing humankind. The success of these transformative agents will foster the development of more anti-amyloid MABs, other types of anti-amyloid therapies, treatments of other targets of AD biology, and new approaches to therapies for an array of neurodegenerative disorders. Monoclonal antibodies have side effects and, during the period of treatment initiation, patients must be closely monitored for the occurrence of amyloid-related imaging abnormalities (ARIA) and infusion reactions. A successful first step in the development of disease-modifying therapy for AD defines desirable features for the next phase of therapeutic development including less frequent ARIA, more convenient administration, and greater efficacy. Unprecedented agents make new demands on patients and care partners, clinicians, payers, and health care systems. Collaboration among stakeholders is essential to take advantage of the therapeutic benefits offered by these agents and to make them widely available. Monoclonal antibodies usher in a new era in AD therapy and define a new landscape of what is possible for therapeutic development for neurodegenerative disorders.

Targeting misfolding and aggregation of the amyloid-β peptide and mutant p53 protein using multifunctional molecules

“…While the insoluble amyloid aggregates are considered a disease hallmark, soluble oligomeric species are however better correlated with memory impairment and AD progression. 33,38 The recent FDA approval of Lecanemab and Aducanumab, 13 antibodies which target Ab aggregates in the brain, has resulted in renewed interest in the development of small-molecules that target this disease pathway. 14 AD is also associated with an increase in reactive oxygen species (ROS), with early pathological changes indicating oxidative damage in the brain.…”

“…The recent FDA approval of antibodies targeting this pathway, has renewed interest in the development of small molecule agents that modulate Ab aggregation. 13 In addition, new work has shown that protein aggregates (Ab and tau) increase levels of neuron-specific maternally expressed gene 3 (MEG3) which induces necroptosis in human neurons in vitro. 133 MEG3 is also upregulated in AD patients thus providing a link to the neuronal toxicity of these aggregates.…”

Imaging of Amyloid-Related Imaging Abnormalities (ARIA)

“…The monoclonal antibodies aducanumab (Biogen), gantenerumab (Roche), crenezumab (Roche), sola- nezumab (Eli Lilly), lecanemab (Eisai, Biogen), and donanemab (Eli Lilly) have been examined in various phase III studies. Overviews of these studies are provided in [27][28][29][30]. After the EMERGE and ENGAGE studies by Biogen were terminated due to a lack of efficacy, an analysis of the final examinations with a treatment duration that was 6 months longer on average showed that patients treated for a longer time with higher doses of aducanumab experienced a significant delay in cognitive decline and a decrease in amyloid deposits on amyloid PET.…”

Bioactive Isoquinoline Alkaloids with Diverse Skeletons from Fissistigma polyanthum

“…The process of amyloid-β protein (Aβ) fibrillogenesis is responsible for triggering a cascade of physiological events that contribute directly to the initiation and progression of AD . This hypothesis led to the FDA approval of the anti-amyloid antibody Aduhelm (aducanumab-avwa) to treat mild to moderate stages of AD and more recently Leqembi (lecanemab-irmb), the second in a new category of medications . Nevertheless, disease-modifying therapies by small molecules are still considered quite challenging.…”

“…3 This hypothesis led to the FDA approval of the anti-amyloid antibody Aduhelm (aducanumab-avwa) to treat mild to moderate stages of AD and more recently Leqembi (lecanemab-irmb), the second in a new category of medications. 4 Nevertheless, disease-modifying therapies by small molecules are still considered quite challenging. Tau is a microtubule-associated protein mostly found in neuronal axons in the central nervous system.…”