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

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.