Superior efficacy to its rival antibodies
The microtubule-binding protein, tau, is the main component of neurofibrillary tangles that are pathologic hallmarks of neurodegenerative tauopathies including Alzheimer's disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).
Given that tau proteins within neurofibrillary tangles are hyperphosphorylated on serine and threonine residues, the therapeutic interventions like kinase inhibitors have aimed at reducing the phosphorylation of tau.
However, the mechanisms of hyperphosphorylation, aggregation, and dysfunction of tau in AD remain still unknown. Post-translational modifications other than phosphorylation, such as acetylation, O-GlcNAcylation, and ubiquitination are also involved in tau pathology.
Recently, the acetylation of tau at lysine residues has emerged as one of modifications that are associated with hyperphosphorylation and modulate tau pathology. Actually, the acetylation of tau inhibited its function and promoted its aggregation.
Interestingly, the serine/threonine residues where tau hyperphosphorylation occurs exist outside the microtubule-binding repeat domain. On the contrary, the lysine residues specific for tau acetylation reside within the microtubule-binding motif located in the mid-region of tau.
As tau-targeted antibodies for AD (gosuranemab, semorinemab, tilavonemab, and zagotenemab) that bind the N-terminal region of tau protein have recently come up short, the advanced versions of anti-tau antibodies are aiming at the midsection of tau.
These second-generation antibodies or other molecules that can inhibit the acetylation of tau in the mid-region would be a promising approach for the treatment of tauopathies.
ADEL, headquartered in Seoul, is a cutting-edge biotech company specialized in the diagnosis and treatment of neurodegenerative dementias.
The company developed its innovative antibody named ‘ADEL-Y01’ targeting the tau acetylated at lysine-280 (K280), a key determinant of tau-aggregation. In the preclinical studies, ADEL-Y01 inhibited the aggregation and propagation of tau and promoted the clearance of tau by microglia. According to the company, these effects were superior to those of antibodies which have reached the clinical trial stage.
ADEL-Y01 is evolving into its engineered version ‘ADEL-Y02’ to enhance the BBB-crossing efficiency. The company is also developing its novel anti-beta-2-microglubulin antibody (ADEL-Y03) based on that beta-2-microglubulin impairs cognition and neurogenesis. Grounded on that ApoE4 exacerbates the tau-mediated neurodegeneration and increases the risk of AD, anti-ApoE4 antibody is now under development as well.
Meanwhile, ADEL is planning to commence its phase 1 clinical study of ADEL-Y01 for the treatment of AD next year.
