Tau-Targeting Agent ADEL-Y01 Gains FDA Clearance for Phase 1 Study

Seung-Yong Yoon, MD

According to a recent announcement, the FDA has cleared the investigational new drug application (IND) of ADELY01 (Oscotec/ADEL Inc), a novel disease-modifying immunotherapy, as a potential treatment for patients with Alzheimer disease (AD). The phase 1a/1b study is expected to assess the safety, tolerability, pharmacokinetics, and clinical activity of the agent in a cohort of healthy volunteers and those with mild cognitive impairment (MCI) because of AD.¹

ADEL-Y01 is a recombinant immunoglobulin-1 class type monoclonal humanized antibody that recognizes and binds to tau protein acetylated at lysine-280 (ack280) thus inhibiting aggregation and propagation of tau seeds and enhancing microglial tau clearance. In preclinical models, upon interaction with acetylated tau aggregates, ADEL-Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau-Tg mice through antibody-mediated neutralization and phagocytosis, respectively.

"We are convinced that ADEL-Y01 has the strong potential to be a much needed treatment option for patients with Alzheimer's disease based on its novel mechanism of action and the strength of preclinical data,” Taeyoung Yoon, chief executive officer and chief scientific officer, Oscotec, said in a statement.¹ "Initiating the first-in-human study of ADEL-Y01 is a significant milestone to the Oscotec-Adel partnership, which also serves as a vehicle for Oscotec in expanding its R&D horizon beyond small molecule."

In several neurodegenerative disease like AD, tau proteoforms cause irreversible conformational shifts from soluble monomers to laterally stackable aggregates. Following pathogenic posttranslational modifications, tau forms neurofibrils in brain regions including the transentorhinal cortex, and then spreads into connected recipient neurons in other brain areas, leading to progressive AD. ADEL-Y01, designed to target tau acetylated at ack280, is considered superior to other tau-targeting agents because of its anti-seeding, anti-propagation properties, as well as its ability to enhance microglial clearance of tau.

Earlier this year, in March, investigators published preclinical research in The Journal of Clinical Investigation on how tau initiates the formation of detrimental tauopathies at the molecular and cellular levels, and the potential efficacy of ADEL-Y01. To ensure the specific of the antibody, study authors prepared 2 full-length recombinant tau proteins, 2N4R, and a mutant, in which k280 was replaced by alanine, and treated them with P300 to induce in vitro acetylation. The binding of ADEL-Y01 was compared with Ac Lys, another tau antibody previously used to observe acetylated proteins.²

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While AC Lys bound both p300-treated tau proteins, 2N4R and 2N4Rk280A, ADEL-Y01 only interested with p300-treated 2N4R, not with 2N4R or 2N4RK280A, demonstrating selectivity toward tau-ack280. In a ThT assay, the addition of ADEL-Y01 dramatically decreased aggregation of p300-treated tau in a concentration-dependent manner, whereas IgG had no effect. In FRET experiments, ADEL-Y01 prevented cellular tau form aggregation induced by acetylated tau aggregates. The agent also inhibited seeding of tau aggregation in the sarkosyl-insoluble fraction of human AD brain. Overall, investigators concluded that the results indicated that ADEL-Y01 may have the potential to reduce the progression of tauopathy aggregation and seeding induced by in vitro p300 acetylation, as well as by in vivo human AD tau aggregates.

To assess the agent’s therapeutic potential, investigators performed intracerebroventricular infusion of the murine version of ADEL-Y01 (mY01) into the lateral ventricle of tau-P301L mice or the intraperitoneal injection of mY01. All told, improvements in behavorial tests, including nest building test, Y maze, and Morris water maze test, were observed following administration of ADEL-Y01. Western blots with anti-mouse IgG antibody revealed that both control IgG and ADEL-Y01 antibody were present in the brain, confirming that antibodies entered the brain even through the blood-to-brain ratio may have been low.

"The IND clearance by the FDA represents a major achievement for us, especially in light of our first candidate entering into clinical trials,” Seung-Yong Yoon, MD, chief executive office, ADEL, said in a statement. "We are enthusiastic about commencing the clinical trial, as it brings us closer to providing therapeutic solutions for the patients grappling with tauopathies including AD."

REFERENCES
1. Oscotec/ADEL announce FDA clearance of IND application of ADEL-Y01 for the treatment of Alzheimer’s disease. September 14, 2023. Accessed September 25, 2023. https://www.biospace.com/article/releases/oscotec-adel-announce-fda-clearance-of-ind-application-of-adel-y01-for-the-treatment-of-alzheimer-s-disease/
2. Song HL, Kim NY, Park J, et al. Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280-acetylated tau in cell and mouse models. J Clin Investig. Published online March 14, 2023. doi:10.1172/JCI156537