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Cited by 24Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsBarrier Structure and Function Studies

Fibrin-targeting immunotherapy for dementia

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Kantor, A.B., Akassoglou, K., Stavenhagen, Jeffrey B.·2023·The Journal of Prevention of Alzheimer's Disease
DOI 10.14283/jpad.2023.105PMC PMC11227370
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Abstract

Blood-brain barrier (BBB) disruption is an early event in the development of Alzheimer's disease. It precedes extracellular deposition of amyloid-β in senile plaques and blood vessel walls, the intracellular accumulation of neurofibrillary tangles containing phosphorylated tau protein, microglial activation, and neuronal cell death. BBB disruption allows the coagulation protein fibrinogen to leak from the blood into the brain, where it is converted by thrombin cleavage into fibrin and deposits in the parenchyma and CNS vessels. Fibrinogen cleavage by thrombin exposes a cryptic epitope termed P2 which can bind CD11b and CD11c on microglia, macrophages and dendritic cells and trigger an inflammatory response toxic to neurons. Indeed, genetic and pharmacological evidence demonstrates a causal role for fibrin in innate immune cell activation and the development of neurodegenerative diseases. The P2 inflammatory epitope is spatially and compositionally distinct from the coagulation epitope on fibrin. Mouse monoclonal antibody 5B8, which targets the P2 epitope without interfering with the clotting process, has been shown to reduce neurodegeneration and neuroinflammation in animal models of Alzheimer's disease and multiple sclerosis. The selectivity and efficacy of this anti-human fibrin-P2 antibody in animal models supports the development of a monoclonal antibody drug targeting fibrin P2 for the treatment of neurodegenerative diseases. THN391 is a humanized, affinity-matured antibody which has a 100-fold greater affinity for fibrin P2 and improved development properties compared to the parental 5B8 antibody. It is currently in a Phase 1 clinical trial.

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Cited by

Sorted by citations

Authors
Kantor, A. B., Akassoglou, K., & Stavenhagen, J. B.
Affiliations
Gladstone Institutes (US)
Corresponding author
Stavenhagen, Jeffrey B.
ORCID
Akassoglou, K.
Venue
The Journal of Prevention of Alzheimer's Disease
Publisher
Elsevier BV
Published
2023-11
Volume
10
Issue
4
Pages
647-660
ISSN
2274-5807 (ISSN-L)
DOI
10.14283/jpad.2023.105
PMC
PMC11227370
OpenAlex
W4387893293
Cited by
24
References
24
Citations by year
2026: 12 · 2025: 8 · 2024: 4
FWCI
4.26
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Prevention of Alzheimer s Disease (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
Funders
  • Gladstone Institutes
  • National Institutes of Health (1rf1ag064926-01)
  • National Institute on Aging (U01AG073125, RF1 (AG064926))
  • National Institute of Neurological Disorders and Stroke (R35NS097976)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
fibrinogen, fibrin, blood-brain barrier disruption, Alzheimer's disease, dementia, neuroinflammation, microglial activation, neurodegeneration, multiple sclerosis, humanized monoclonal antibody
MeSH terms
Alzheimer Disease, Animals, Antibodies, Monoclonal, Epitopes, Fibrin, Fibrinogen, Humans, Immunotherapy, Thrombin, Neurodegenerative Diseases, Mice

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