Therapeutics

ADEL-Y01

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Overview

Name: ADEL-Y01
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: ADEL, Inc., Oscotec Inc.

Background

ADEL-Y01 is a humanized IgG1 monoclonal antibody that binds tau protein modified by acetylation at lysine residue 280. Tau acetylation at lysine residues is associated with protein aggregation and pathology in various tauopathies, including Alzheimer’s disease (e.g. Min et al., 2010; Cohen et al., 2011). K280 lies in a region critical for tau aggregation, and acetyl-K280 has been detected in AD and other human tauopathies (Irwin et al., 2012; Wesseling et al., 2020).

In preclinical work, an acetylated tau fragment spanning K280 was able to seed and accelerate aggregation of tau in vitro and in cells, and was more neurotoxic than the non-acetylated version. Mutational analysis suggested that K280 acetylation accounted for the enhanced toxicity. In the P301L mouse model of tau pathology, immunization with a tau 275-286 peptide, acetylated at K280, decreased the levels of phosphorylated and acetylated tau in brain, and improved cognitive and motor performance. The Y01 monoclonal antibody raised to this peptide interacted with acetylated K280 and surrounding residues in intact tau, inhibited aggregation and propagation of acetylated tau, and promoted tau uptake by microglia. The antibody detected K280-acetylated tau in human AD brain sections and CSF, and in P301L mouse brain lysates. Treatment of P301L mice with the antibody reduced memory impairment, behavioral deficits, and tau pathology (Song et al., 2023). A different group reported comparable effects on tau pathology and behavior after treatment of tauopathy mice with an antibody to acetylated tau K174 (Parra Bravo et al., 2024).

Findings

In February 2024, ADEL and Oscotec began a first-in-human Phase 1 study of ADEL-Y01. Forty healthy participants are to receive single intravenous infusions of antibody at 2.5, 7.5, 20, 50, or 100 mg/kg, or placebo. After that, a multiple-ascending-dose study is planned for 33 participants with MCI or mild AD who are to receive six doses of 7.5, 20, and 50 mg/kg, or placebo, given every two weeks. Primary outcomes include adverse events and clinical safety assessments; secondary outcomes span pharmacokinetics, immunogenicity, CSF exposure, and, in the patients, preliminary clinical measures of the CDR-SB and MMSE. The study will also assess CSF and plasma biomarkers of Aβ, phosphorylated tau and acetylated tau, as well as markers related to neurodegeneration and inflammation. CSF will be assayed for tau aggregates and tau seeding potential. The trial will run by a clinical CRO in Anaheim, California, through May 2026.

For details on ADEL-Y01 trials, see clinicaltrials.gov

Last Updated: 02 Aug 2024

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References

Paper Citations

  1. Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, Meyers D, Cole PA, Ott M, Gan L. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010 Sep 23;67(6):953-66. PubMed.
  2. Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, Lee VM. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun. 2011;2:252. PubMed.
  3. Irwin DJ, Cohen TJ, Grossman M, Arnold SE, Xie SX, Lee VM, Trojanowski JQ. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies. Brain. 2012 Mar;135(Pt 3):807-18. PubMed.
  4. Wesseling H, Mair W, Kumar M, Schlaffner CN, Tang S, Beerepoot P, Fatou B, Guise AJ, Cheng L, Takeda S, Muntel J, Rotunno MS, Dujardin S, Davies P, Kosik KS, Miller BL, Berretta S, Hedreen JC, Grinberg LT, Seeley WW, Hyman BT, Steen H, Steen JA. Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease. Cell. 2020 Dec 10;183(6):1699-1713.e13. Epub 2020 Nov 13 PubMed.
  5. Song HL, Kim NY, Park J, Kim MI, Jeon YN, Lee SJ, Cho K, Shim YL, Lee KH, Mun YS, Song JA, Kim MS, Pack CG, Jung M, Jang H, Na DL, Hong M, Kim DH, Yoon SY. Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280-acetylated tau in cell and mouse models. J Clin Invest. 2023 Apr 17;133(8) PubMed.
  6. Parra Bravo C, Krukowski K, Barker S, Wang C, Li Y, Fan L, Vázquez-Rosa E, Shin MK, Wong MY, McCullough LD, Kitagawa RS, Choi HA, Cacace A, Sinha SC, Pieper AA, Rosi S, Chen X, Gan L. Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury. Mol Neurodegener. 2024 Jun 24;19(1):51. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading