# Accelerated dissociation of IgE receptor complexes

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $390,943

## Abstract

Project Summary
IgE antibodies bind the high affinity IgE Fc receptor (FcεRI), found primarily on mast cells and basophils, and
trigger inflammatory cascades of the allergic response. Potent inhibitors of IgE:FcεRI binding have been
identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma.
Omalizumab is also being used experimentally for the treatment of food allergies. However, improved
therapeutics are needed for the treatment of allergies. With current anti-IgE therapy, IgE remains bound to
receptors on mast cells in peripheral tissues for months, maintaining these cells in a sensitized state and
highlighting the high affinity and low turnover of the preformed IgE receptor complexes. Our studies of anti-IgE
DARPin inhibitors have revealed that these inhibitors can rapidly dissociate IgE:FcεRI complexes, with the
potential for greater therapeutic efficacy than the current anti-IgE therapy. We refer to these inhibitors as
“disruptive” since they are able to accelerate the dissociation of preformed receptor complexes. Our results
with the DARPins demonstrate that macromolecular inhibitors can accelerate the dissociation of receptor
complexes and raises the possibility that other macromolecules, such as antibodies, can be found that have
similar activity. The ability to disrupt preformed receptor complexes represents a previously unappreciated
potential function for macromolecular inhibitors in general and raises the possibility of developing novel
research tools and biological therapeutics. In this proposal, we are exploring multiple approaches to better
understanding the mechanism of the disruptive DARPin inhibitors and how to improve their activities further.
Since these synthetic proteins are not likely to replace current anti-IgE therapy, as they may induce immune
responses in humans, we also propose to indentify an anti-IgE antibody that exhibits similar disruptive inhibitor
activity as the DARPins. The potential overall impact of this proposal is high, given the possibility of improving
anti-IgE antibody therapeutics and also by providing foundational approaches for developing disruptive
macromolecular inhibitors for other receptor-ligand complexes.

## Key facts

- **NIH application ID:** 10071123
- **Project number:** 5R01AI115469-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Theodore S Jardetzky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,943
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071123

## Citation

> US National Institutes of Health, RePORTER application 10071123, Accelerated dissociation of IgE receptor complexes (5R01AI115469-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10071123. Licensed CC0.

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