Research into treatments for Alzheimer's disease (AD) has reached impressive milestones this year. AD affects over 55 million individuals globally and while there is no cure, the first treatment to reduce disease progression rate was the antibody therapy Leqembi, which received full FDA approval in 2023.
AD is a progressive neurodegenerative disease marked by progressive dementia, starting with mild memory loss which can lead to loss of the ability to carry out simple, daily tasks. The main pathological features of AD involve the presence of abnormal amyloid protein plaques and tau tangles in the brain.
The amyloid hypothesis suggests that the accumulation of amyloid beta (Aβ) deposits, resulting from excessive cleavage of amyloid precursor protein (APP), leads to synaptic and neuronal loss and ultimately causing brain atrophy. However, AD's exact origins remain unknown.
Source: Alzheimer’s Association
Traditionally, Alzheimer's treatments have focused on symptom management, with drugs like donepezil, rivastigmine, and galantamine seeking to improve cognitive function by enhancing brain acetylcholine levels. Memantine, an NMDA receptor antagonist, was introduced later to curb the harmful effects of excess glutamate. However, while these drugs offer symptomatic relief, they do not arrest or reverse disease progression.
In a groundbreaking achievement this year, lecanemab became the first amyloid beta-directed antibody for AD approved by the FDA. Developed by Eisai and Biogen, Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, thus reducing the formation of amyloid plaques in the brain. The Phase III Clarity-AD study demonstrated a 27% reduction in clinical decline compared to placebo after 18 months of treatment.
Lecanemab’s approval comes as a big win for the healthcare industry, as many antibody drugs with potential did not perform well in clinical studies. Just this week, a study was published on the phase II trial results for gosuranemab, a humanized IgG4 monoclonal antibody to N-terminal tau, for patients with early AD. Gosuranemab binds to tau monomers and fibrils to remove N-terminal tau from brain interstitial fluid, with the intention of reducing tau aggregation in cells. However, it did not meet its primary efficacy endpoint of change from baseline.
Source: Eisai
As of now, research efforts are ongoing for more potential antibody therapeutics to target AD. For instance, donanemab, an antibody developed by Eli Lilly, showed positive results, particularly in early symptomatic AD. Unlike lecanemab, donanemab binds to amyloid once the fibres have clumped together to become a larger build-up of plaque in the brain.
Another recent paper describes a novel antibody 7C11, which was developed to bind to ApoE4, a key risk factor for sporadic AD. The APOE3 Christchurch (APOE3Ch) variant may provide resistance to AD from reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans. As the 7C11 antibody was shown to reduce APOE-mediated toxicity and tau phosphorylation, its potential in clinical applications is highly valuable for patients.
Bispecific antibodies are rapidly transforming the therapeutic landscape, especially in oncology and autoimmune diseases. Such recombinant molecules can bind to two different antigens at the same time, offering greater specificity in targeting disease pathways. Since their introduction, the area of bispecifics has held tremendous promise in oncological cancers like multiple myeloma and lymphomas.
A common theme emerging from recent antibody research is the development and validation of advanced diagnostic tools based on antibody detection. Multiple studies highlight the creation of novel biosensors and assays designed to enhance the sensitivity, specificity, and efficiency of detecting antibodies across various diseases.
T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is an immune receptor that plays a key role in suppressing T-cell activation and proliferation. As a newly identified checkpoint, it is highly expressed on various immune cells, including CD4+ and CD8+ T cells, NK cells.
