Therapeutics

PNT001

Overview

Name: PNT001
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Traumatic Brain Injury
U.S. FDA Status: Alzheimer's Disease (Phase 1), Traumatic Brain Injury (Phase 1)
Company: Pinteon Therapeutics

Background

PNT001 is a monoclonal antibody to the cis isomer of tau phosphorylated at threonine 231, a form of pathological tau suspected to play a role in traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease.

Phosphorylated T231 tau exists in cis and trans conformations, as modulated by the peptidyl-prolyl cis/trans isomerase Pin1 (Galas et al., 2006Hamdane et al, 2006). Cis pT231 has been detected in brain tissue from people with AD and CTE and increases acutely after traumatic brain injury in humans and rodent models. Cis pT231 is resistant to dephosphorylation and degradation, and promotes aggregation (Nakamura et al., 2012; reviewed in Lu et al., 2016). 

In preclinical models of brain injury, a mouse monoclonal antibody to cis pT231 prevented axonal pathology, astrogliosis, tau oligomerization and tangle formation, brain atrophy, and behavioral and other deficits (Kondo et al., 2015; Albayram et al., 2017; Albayram et al., 2019).

Findings

In September 2019, Pinteon began a Phase 1 safety and tolerability study of PNT001 in healthy adults. In the trial, 48 people will receive single doses of 33, 100, 300, 900, or 2,700 mg antibody or placebo, infused over 30 minutes. Primary outcomes are adverse events and abnormalities on clinical and laboratory measures after 16 weeks. Other outcomes include antibody concentration in serum and CSF, measures of total tau, cis pT231 tau, pT231 tau, and NfL in CSF, as well as serum NfL and antidrug antibodies. The trial will run through November 2020.

For details on the trial, see clinicaltrials.gov.

Last Updated: 25 Jun 2020

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References

Paper Citations

  1. . The peptidylprolyl cis/trans-isomerase Pin1 modulates stress-induced dephosphorylation of Tau in neurons. Implication in a pathological mechanism related to Alzheimer disease. J Biol Chem. 2006 Jul 14;281(28):19296-304. Epub 2006 May 3 PubMed.
  2. . Pin1 allows for differential Tau dephosphorylation in neuronal cells. Mol Cell Neurosci. 2006 May-Jun;32(1-2):155-60. Epub 2006 May 11 PubMed.
  3. . Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease. Cell. 2012 Mar 30;149(1):232-44. PubMed.
  4. . Potential of the Antibody Against cis-Phosphorylated Tau in the Early Diagnosis, Treatment, and Prevention of Alzheimer Disease and Brain Injury. JAMA Neurol. 2016 Nov 1;73(11):1356-1362. PubMed.
  5. . Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature. 2015 Jul 23;523(7561):431-6. Epub 2015 Jul 15 PubMed.
  6. . Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae. Nat Commun. 2017 Oct 17;8(1):1000. PubMed.
  7. . Traumatic Brain Injury-related voiding dysfunction in mice is caused by damage to rostral pathways, altering inputs to the reflex pathways. Sci Rep. 2019 Jun 14;9(1):8646. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Cancer and Alzheimer's disease inverse relationship: an age-associated diverging derailment of shared pathways. Mol Psychiatry. 2020 May 7; PubMed.
  2. . Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer's Disease. Front Cell Dev Biol. 2020;8:355. Epub 2020 May 15 PubMed.
  3. . Targeting Prion-like Cis Phosphorylated Tau Pathology in Neurodegenerative Diseases. J Alzheimers Dis Parkinsonism. 2018;8(3) Epub 2018 Jun 29 PubMed.