2. Academic Validation
  3. Preclinical characterization and IND-enabling safety studies for PNT001, an antibody that recognizes cis-pT231 tau

Preclinical characterization and IND-enabling safety studies for PNT001, an antibody that recognizes cis-pT231 tau

  • Alzheimers Dement. 2023 Oct;19(10):4662-4674. doi: 10.1002/alz.13028.
Kelly Foster 1,  Matteo Manca 2,  Kim McClure 1,  Pyry Koivula 3,  John Q Trojanowski 3,  Daniel Havas 4,  Sarah Chancellor 5,  Lee Goldstein 5,  Kurt R Brunden 3,  Allison Kraus 2,  Michael K Ahlijanian 1
Affiliations

Affiliations

  • 1 Pinteon Therapeutics, Inc., Discovery Biology, Newton, Massachusetts, USA.
  • 2 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  • 3 Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 4 Psychogenics, Inc, Biology Paramus, New Jersey, USA.
  • 5 Molecular Aging & Development Laboratory, Boston University School of Medicine, USA.
PMID: 37002928 DOI: 10.1002/alz.13028
Abstract

Background: The cis-conformer of tau phosphorylated at threonine-231 (cis-pT231 tau) is hypothesized to contribute to tauopathies. PNT001 is a humanized, monoclonal antibody that recognizes cis-pT231 tau. PNT001 was characterized to assess clinical development readiness.

Methods: Affinity and selectivity were assessed by surface plasmon resonance and enzyme-linked immunosorbent assay. Immunohistochemistry (IHC) was performed with brain sections from human tauopathy patients and controls. Real-time quaking-induced conversion (RT-QuIC) was used to assess whether PNT001 reduced tau seeds from Tg4510 transgenic mouse brain. Murine PNT001 was evaluated in vivo in the Tg4510 mouse.

Results: The affinity of PNT001 for a cis-pT231 peptide was 0.3 to 3 nM. IHC revealed neurofibrillary tangle-like structures in tauopathy patients with no detectable staining in controls. Incubation of Tg4510 brain homogenates with PNT001 lowered seeding in RT-QuIC. Multiple endpoints were improved in the Tg4510 mouse. No adverse findings attributable to PNT001 were detected in Good Laboratory Practice safety studies.

Discussion: The data support clinical development of PNT001 in human tauopathies.

Keywords

RT-QuIC; Tg4510 mouse; cis-pT231 tau; tau aggregation; tauopathy.

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