# Temporal Biomarker-Powered Immunotherapy Targeting GFAP for Traumatic Brain Injury

> **NIH NIH R44** · GRYPHON BIO, INC. · 2021 · $499,065

## Abstract

ABSTRACT
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity in the US, with
over two million new patients each year and no FDA-approved therapeutics. TBI
induces an early, high concentration wave of cytotoxic glutamate into synapses that
exceeds the buffering capacity of astroglial glutamate transporters (e.g. GLT-1), causing
injury and death of brain cells. Under these neurotrauma conditions, the calpain-
generated, 38 kDa core breakdown product of glial fibrillary acidic protein (GBDP) was
released from injured astrocytes within hours to days post-injury. In parallel, other
protein “debris” are released from neuronal cell bodies (ubiquitin C terminal hydrolase 1
/UCH-L1) and injured axons (neurofilament-heavy /pNF-H and light /NF-L, Tau and
phosphorylated Tau /p-Tau). In fact, our most recent clinical data from TRACK-TBI and
CENTER-TBI multicenter consortium studies showed that GFAP/GDBPs are the most
the abundant protein debris released into the circulation after TBI. Significantly, we and
others discovered that GBDPs are prone to form protein aggregates that are neurotoxic
when externalized. Grus and coworkers reported that anti-GFAP antibodies have
neuroprotective effects on cultured neuro-retinal cells and on retinal ganglion cells in
organotypic culture under stress. Similarly, GBDP active immunization was
neuroprotective in a mouse model of TBI, including attenuation of GBDP levels,
reduction of key neuropathological biomarkers of TBI, and improvement of
neurofunctional outcomes. Therefore, our central hypothesis is that passive
immunotherapy with effector-competent IgG monoclonal antibodies (mAbs) against
GBDP will accelerate brain repair and improve cognition and other outcome measures
in TBI patients. Our proposed mechanism of action is the beneficial opsonization of
neurotoxic GBDP debris by anti-GBDP mAb (IgG), followed by accelerated
phagocytosis by activated FcγR+ phagocytes. Our content of use is TBI patients with a
significant injury, as defined by moderate to severe TBI patients with initial GCS of 6-12
and elevated levels of selected acute temporal predictive biomarkers for targeted
enrollment. Our proposed route of administration is intravenous multiday infusion of
anti-GBDP mAbs to maximize brain exposure, with subacute temporal
pharmacodynamic (PD) biomarkers (such as GBDP, NFL, Tau and p-Tau) to track
treatment response and adjust dosing. In this project, we leverage our synergistic
expertise to test our hypothesis with (Phase I) proof-of-concept in vitro and cell-based
studies prior to (Phase II) in vivo dose-ranging and efficacy studies to prioritize and
characterize our lead anti-GBDP mAb immunotherapy candidates. Our preliminary
preclinical studies now show that pre-injury, active immunization with GDBP AND post-
injury passive immunotherapy with anti-GBDP mAbs are safe and beneficial in TBI
mice. Moreover, we show how PD biomarkers might be employed to track treatment
response and adjust dosing ...

## Key facts

- **NIH application ID:** 10253356
- **Project number:** 1R44NS117221-01A1
- **Recipient organization:** GRYPHON BIO, INC.
- **Principal Investigator:** William E Haskins
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $499,065
- **Award type:** 1
- **Project period:** 2021-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10253356

## Citation

> US National Institutes of Health, RePORTER application 10253356, Temporal Biomarker-Powered Immunotherapy Targeting GFAP for Traumatic Brain Injury (1R44NS117221-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10253356. Licensed CC0.

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