# Safety and Tolerability Studies for an Anti-Fibrin P2 Monoclonal Antibody for the Treatment of Alzheimer's Disease

> **NIH NIH U01** · THERINI BIO, INC. · 2023 · $966,254

## Abstract

ABSTRACT
Neuroinflammation is a significant driver of pathology in Alzheimer’s disease (AD) and Alzheimer’s disease
related dementia (ADRD). Multiple lines of evidence in patients and in animal models of AD/ADRD point to
vascular dysregulation and deposits of fibrin (FN) in the brain and cerebral blood vessels as significant sources
of this inflammation. In AD/ADRD patients localized BBB breakdown is an early event and increases with
disease progression. Vascular breakdown leads to the extravasation of blood proteins, including fibrinogen
(FGN), into the brain and the formation of FN clots in brain parenchyma and cerebral vasculature coincident with
Aβ plaques and inflammatory immune cells. In the conversion of FGN to FN a cryptic epitope is exposed on
the FN  chain This sequence (Fibγ377-395, also known as FN P2) is a ligand for the CD11b/CD18 receptor
on macrophages and microglia, triggering activation of these innate immune cells and secretion of inflammatory
mediators. Genetic or chemical depletion of FGN or genetic substitution of 6 key amino acids within FN P2 in
the 5xFAD mouse model of AD considerably reduces their level of inflammatory cytokines and the rate of
cognitive decline. A mouse monoclonal antibody (mAb), 5B8, discovered by Dr. Katerina Akassoglou (founder
of Therini Bio Inc.) binds this cryptic epitope and recapitulates the activity of the genetic FN P2 deletion. 5B8 is
highly selective for FN over FGN and does not interfere with normal coagulation. Therini Bio Inc. has humanized
5B8 and demonstrated that the lead humanized anti-FN P2 mAb, termed THN227, retains the selective binding
for FN over FGN and does not interfere with normal FN-mediated functions such as hemostasis. In an in vivo
fibrino(gen)-induced encephalomyelitis model of neuroinflammation, intravenous administration of THN227
reduced microglial activation, macrophage infiltration, and oxidative stress. In this proposal the lead humanized
anti-FN P2 mAb will be tested in several key preclinical and nonclinical safety studies to ensure that the antibody
is safe and tolerable for human clinical trials. Prior to the initiation of the proposed studies, we will have tested
THN227 and several back-up humanized or fully human anti-FN P2 mAbs in ex vivo assays of immunogenicity
and in rodent PK and dose range finding studies. In this proposal, we will first test whether our lead anti-FN P2
mAb induces microhemorrhages in a transgenic AD mouse model. This is an important safety test, as several
anti-Aβ mAbs induced amyloid related imaging abnormalities associated with hemorrhage (ARIA-H) in a subset
of AD patients in previous clinical trials. We will also establish the safe dose range in nonhuman primates (NHPs)
and assess the safety or repeated short-term and chronic dose regimens. These key safety studies will drive
the preclinical development of our novel anti-FN P2 mAb approach, establish important safety limitations,
supporting an IND application and informing the ra...

## Key facts

- **NIH application ID:** 10693372
- **Project number:** 5U01AG073125-03
- **Recipient organization:** THERINI BIO, INC.
- **Principal Investigator:** Aaron B Kantor
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $966,254
- **Award type:** 5
- **Project period:** 2021-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693372

## Citation

> US National Institutes of Health, RePORTER application 10693372, Safety and Tolerability Studies for an Anti-Fibrin P2 Monoclonal Antibody for the Treatment of Alzheimer's Disease (5U01AG073125-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693372. Licensed CC0.

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