Week 5, October 2024: Anti-Amyloid Monoclonal Antibodies

Anti-amyloid antibodies are designed to target and remove amyloid-beta plaques in the brain, a hallmark of Alzheimer’s disease. These plaques are toxic protein clusters believed to disrupt communication between neurons, leading to cell death and cognitive decline. By binding to amyloid-beta, these antibodies aim to neutralize or clear the plaques, potentially slowing disease progression. 

This Monday, AbbVie announced it will acquire Aliada Therapeutics, a biotechnology company advancing therapies using a novel blood-brain barrier (BBB)-crossing technology to address challenging central nervous system (CNS) diseases. Aliada's lead investigational asset using this delivery technology, ALIA-1758, is an anti-pyroglutamate amyloid beta (3pE-Aβ) antibody in development for the treatment of Alzheimer's disease. 

High-affinity 3pE-Aβ binders enable lower predicted efficacious dosage levels compared to competitors, and target the plaque form of Aβ rather than earlier stages of aggregation. An optimized Fc domain increases half-life, reduces effector function, and leads to clearance of bound antibodies through a mechanism that reduces pro-inflammatory cytokine release and immune exhaustion. The anti-TfR Delivery Module transports 3pE-Aβ antibodies into the brain at a higher concentration than naked antibodies, leading to more efficient target clearance. The scFv design also confers increased stability, reduced aggregation and lower manufacturing cost. 

In a review published this week, researchers from Wayne State University and National Institute on Aging described how newer mAbs like donanemab and lecanemab demonstrate statistically significant, though modest, clinical benefits. These treatments moderately slowed cognitive decline on clinical scales (such as CDR-SB and ADAS-Cog) and significantly reduced amyloid burden on PET scans. However, these antibodies also increased the risk of brain swelling (ARIA-E) and microbleeds (ARIA-H), especially with certain drugs. The benefits of these antibodies were most notable for those that do not bind to amyloid monomers, suggesting that binding specificity might influence effectiveness. 

They suggest that cumulative benefits may emerge over time with prolonged use, potentially leading to more noticeable effects. Additionally, the moderate correlation between amyloid reduction and clinical benefits suggests a relevant target engagement, but there remains uncertainty about the true clinical importance of these findings across individual antibodies and trials. 

Meanwhile, another recent review focused on the safety and efficacy of treating Alzheimer’s disease with monoclonal antibodies. Lecanemab was found to be particularly effective at lowering brain amyloid plaques and delaying cognitive deterioration, while other antibodies, such as solanezumab and bapineuzumab, had little to no beneficial effects. However, the contradictory results of aducanumab indicate that further research is necessary to ascertain its actual efficacy. In addition, when administered at the earliest stages of Alzheimer’s disease or when used at a higher dose, crenezumab may be beneficial. This study emphasizes the necessity of ongoing research to discover trustworthy treatments for AD patients.