# Protein depleting pre-existing antibodies for viral gene therapy

> **NIH NIH R44** · NEUROGT, INC. · 2024 · $1,000,000

## Abstract

Project Summary:
This is a fast-track SBIR grant proposal. As effective gene therapy (GT) products using adeno-associated
viral (AAV) vectors advance to clinical applications, the translation faces critical challenge of high prevalence
of αAA) antibodies (Abs) in humans. Currently, only individuals negative of αAAV-Abs are eligible for AAV GT
treatment. The goal of this SBIR project is to develop a therapeutic product capable of effectively depleting
Abs towards clinical application and commercialization, in order to make potentially life-saving AAV GT
products available to all patients in need of administration and re-administration.
To address the challenge of pre-existing αAAV-Abs, we have developed a new effective Ab-depleting protein
product, antibody cleaver (AbC), based on the demonstrated IgG degrading enzymes of Streptococci (IdeS).
IdeS specifically cleaves IgG of humans, primate, sheep and rabbit (but not mouse) origin. Numerous studies
demonstrate effective transient IgG degradation by IdeS in animals and humans, with no detectable dose
limiting toxicity. Our preliminary studies showed effective Ab depletion by an IV AbC infusion, leading to the
transient clearance of pre-existing αAAV9-Abs and allowing effective transduction in rabbitized αAAV9-Abs-
positive MPS IIIA mice after an IV scAAV9-hSGSH delivery. We believe that IV AbC administration offers a
great tool to overcome the pre-existing αAAV-Abs for the translation of rAAV GT to treat diseases in humans.
This proposal is to further develop and establish an optimal AbC Ab-depletion regimen for systemic rAAV9
gene delivery. In Phase I studies, we will identify optimal AbC product. Once validated, in Phase II, the
optimal Ab-C product will be evaluated in pre-clinical studies in animal models (Aim #2, 3), to assess the
efficacy and therapeutic potential of transient Ab-depletion by AbC. In Phase II, we will also optimize the
AbC production procedures for scale-up manufacture towards clinical application and commercialization (Aim
#4). Notably, The Phase II studies will lead to an IND and subsequent clinical trials to bridge the AbC
administration with systemic scAAV9-hSGSH gene replacement therapy clinical trials in patients with MPS
IIIA, for which an IND were recently submitted. More importantly, the AbC Ab depletion may offer the answer
to the challenge posed by pre-existing Abs to gene therapy products using AAV and other viral vectors in
general.

## Key facts

- **NIH application ID:** 11113670
- **Project number:** 4R44AI172670-02
- **Recipient organization:** NEUROGT, INC.
- **Principal Investigator:** Douglas M McCarty
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,000,000
- **Award type:** 4N
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11113670

## Citation

> US National Institutes of Health, RePORTER application 11113670, Protein depleting pre-existing antibodies for viral gene therapy (4R44AI172670-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11113670. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*