# Development of Therapeutic Antibody for Traumatic Brain Injury

> **NIH NIH U01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $1,292,737

## Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability in children and young adults and one of
the best-known environmental risk factors for chronic traumatic encephalopathy (CTE) and even Alzheimer's
disease (AD). Despite the immense public health burden, targeted TBI therapies remain elusive and over 30
TBI drug trials have failed to mitigate the devastating short- and long-term sequelae of TBI. One putative target
after TBI is phosphorylated tau, a defining pathological signature of CTE and AD brains, however, the role of
tau-related pathology (tauopathy) in short and long term outcomes of TBI was unknown until lately.
 We have previously identified a unique prolyl isomerase, Pin1 that inhibits tauopathy in AD by
converting the phosphorylated T231-P motif in tau (P-tau) from the toxic cis isomer to the physiologic trans. By
developing the antibodies capable of distinguishing these two isomers, we find that cis P-tau is a precursor of
tauopathy that instigates and propagates neurodegeneration. Notably, prominent cis P-tau is localized to
axons diffusely in human CTE brains. Surprisingly, hours after single severe or repetitive mild closed head
injury (ssCHI or rmCHI) in mice, neurons robustly produce cis P-tau mainly at axons, which causes and
spreads “cistauosis”, leading to axonopathy and eventually CTE-like phenotypes. Treating ssCHI or rmCHI
mice with cis mAb not only blocks early cistauosis, but also prevents the later development of CTE-like
neuropathology and clinically relevant brain dysfunction. Our preliminary data also demonstrate that robust cis
P-tau is found at axons in several other CHI models that feature diffuse axon injury, as well as in human TBI
brains, and that cis mAb blocked purified TBI cis P-tau or human TBI CSF from causing neuron death and/or
brain dysfunction. Others have shown that tau knockout prevents axonopathy and memory deficits in rmCHI,
Thus, therapies targeting cis P-tau are most effective in preventing axonal injury mechanisms and cis mAb
therapy is a new targeted therapy for diffuse axon injury, a prominent feature and a therapeutic focus in TBI.
 We have assembled a multidisciplinary team to develop therapeutic cis mAb to treat or prevent
short- and long-term sequelae after TBI. First, we will humanize our murine cis mAb and use the unique
models and reagents that we have developed to identify humanized cis mAbs that have high affinity, specificity
and potency against cis P-tau and cistauosis, and the physicochemical properties as a therapeutic antibody.
Next, we will determine their PK/PD, efficacy, toxicology and safety profiles to select top 3 humanized mAb
candidates, followed by their efficacy evaluation in ssCHI and rmCHI, two CHI mouse models of diffuse axon
injury, and controlled cortical impact (CCI), one of severe focal injury, to assess TBI pathoanatomic subtypes
best amenable to cis mAb therapy. Finally, we will evaluate efficacy of CSF cis P-tau as a theranostic
biomarker. Th...

## Key facts

- **NIH application ID:** 9942525
- **Project number:** 5U01NS096835-04
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Mark L. Zeidel
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,292,737
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942525

## Citation

> US National Institutes of Health, RePORTER application 9942525, Development of Therapeutic Antibody for Traumatic Brain Injury (5U01NS096835-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9942525. Licensed CC0.

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