Therapeutics

PNT001

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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 (Inactive), Traumatic Brain Injury (Inactive)
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, vascular dementia, 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., 2006; Hamdane 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. In humans, its levels in CSF correlate with severity of brain injury (Sisakht et al., 2022). 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).

Cis pTau appears to contribute to vascular dementia. It was found to be elevated in brains of people with vascular dementia, who lacked tau tangles. In mouse models of vascular dementia, a cis-tau targeted monoclonal antibody reduced neurodegeneration and improved cognitive impairment. The cis mAb ameliorated progression of AD-like neurodegeneration and cognitive impairment in mice expressing human tau (Qui et al., 2021).

Findings

In September 2019, Pinteon began a Phase 1 safety and tolerability study of PNT001 in healthy adults. In the trial, 49 people received single doses of 33, 100, 300, 900, 2,700, or 4,000 mg antibody or placebo, infused over 30 to 60 minutes. Primary outcomes were adverse events and abnormalities on clinical and laboratory measures after 16 weeks. Other outcomes included 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. According to data presented at AD/PD 2021, the antibody produced dose-linear blood and CSF concentrations that stayed constant for 28 days, and was well tolerated. For doses of 900 mg and above, CSF antibody concentrations exceeded the minimum required for tau binding (Mar 2021 conference news).

In March 2021, the company began a Phase 1 study of multiple ascending doses in 64 hospitalized patients with acute traumatic brain injury. Each patient was to receive three doses of 1,000 or 4,000 mg, or placebo. The first dose was planned to occur within 24 hours of injury; the time frame for subsequent doses was not specified. Safety, tolerability, pharmacokinetic, biomarker, imaging and cognitive data were to be collected over 12 weeks. The trial was terminated for non-safety reasons shortly after it began, and enrolled only one patient.

For details on PNT001 trials, see clinicaltrials.gov.

Last Updated: 28 Jun 2024

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References

News Citations

  1. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore

Paper Citations

  1. Galas MC, Dourlen P, Bégard S, Ando K, Blum D, Hamdane M, Buée L. 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. Hamdane M, Dourlen P, Bretteville A, Sambo AV, Ferreira S, Ando K, Kerdraon O, Bégard S, Geay L, Lippens G, Sergeant N, Delacourte A, Maurage CA, Galas MC, Buée L. 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. Mohsenian Sisakht A, Karamzade-Ziarati N, Jahanbakhshi A, Shahpasand K, Aghababaei S, Ahmadvand O, Azar M, Fattahi A, Zamanzadeh S. Pathogenic cis p-tau levels in CSF reflects severity of traumatic brain injury. Neurol Res. 2022 Jun;44(6):496-502. Epub 2022 Jan 3 PubMed.
  4. Nakamura K, Greenwood A, Binder L, Bigio EH, Denial S, Nicholson L, Zhou XZ, Lu KP. Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease. Cell. 2012 Mar 30;149(1):232-44. PubMed.
  5. Lu KP, Kondo A, Albayram O, Herbert MK, Liu H, Zhou XZ. 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.
  6. Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen CH, Yao Y, Lin YM, Driver JA, Sun Y, Wei S, Luo ML, Albayram O, Huang P, Rotenberg A, Ryo A, Goldstein LE, Pascual-Leone A, McKee AC, Meehan W, Zhou XZ, Lu KP. 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.
  7. Albayram O, Kondo A, Mannix R, Smith C, Tsai CY, Li C, Herbert MK, Qiu J, Monuteaux M, Driver J, Yan S, Gormley W, Puccio AM, Okonkwo DO, Lucke-Wold B, Bailes J, Meehan W, Zeidel M, Lu KP, Zhou XZ. 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.
  8. Albayram O, MacIver B, Mathai J, Verstegen A, Baxley S, Qiu C, Bell C, Caldarone BJ, Zhou XZ, Lu KP, Zeidel M. 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.
  9. Qiu C, Albayram O, Kondo A, Wang B, Kim N, Arai K, Tsai CY, Bassal MA, Herbert MK, Washida K, Angeli P, Kozono S, Stucky JE, Baxley S, Lin YM, Sun Y, Rotenberg A, Caldarone BJ, Bigio EH, Chen X, Tenen DG, Zeidel M, Lo EH, Zhou XZ, Lu KP. Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice. Sci Transl Med. 2021 Jun 2;13(596) PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Lanni C, Masi M, Racchi M, Govoni S. Cancer and Alzheimer's disease inverse relationship: an age-associated diverging derailment of shared pathways. Mol Psychiatry. 2020 May 7; PubMed.
  2. Wang L, Zhou Y, Chen D, Lee TH. Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer's Disease. Front Cell Dev Biol. 2020;8:355. Epub 2020 May 15 PubMed.
  3. Albayram O, Angeli P, Bernstein E, Baxley S, Gao Z, Lu KP, Zhou XZ. Targeting Prion-like Cis Phosphorylated Tau Pathology in Neurodegenerative Diseases. J Alzheimers Dis Parkinsonism. 2018;8(3) Epub 2018 Jun 29 PubMed.