# Discovery and engineering of novel anti-IgE disruptive inhibitors

> **NIH NIH R21** · STANFORD UNIVERSITY · 2021 · $236,100

## Abstract

Project Summary
The majority of allergic reactions are caused by anti-allergen IgE antibodies, which sensitize allergic effector
cells such as mast cells and basophils. In contrast to IgG antibodies, IgE binds with subnanomolar affinity to
the high affinity IgE receptor (FceRI) and persists in a receptor-bound form on allergic effector cells for months
even in the presence of high affinity anti-IgE antibody inhibitors, such as omalizumab. We have shown that
both antibodies and Designed Ankyrin Repeat Proteins (DARPins) are able to kinetically accelerate the
dissociation of IgE from FceRI through two mechanisms: a facilitated dissociation mechanism that allows
receptor-adjacent inhibitors to promote receptor dissociation and an allosteric mechanism that restricts IgE to a
conformation incompatible with receptor binding. We have developed a yeast display approach to selecting
anti-IgE inhibitors capable of disrupting receptor complexes and demonstrated our ability to select more potent
anti-IgE variants of omalizumab. In addition, we have demonstrated pathways to engineering more potent
bivalent disruptive inhibitors consisting of a disruptive anti-IgE domain and a non-competitive IgE anchoring
domain. Here we propose to apply these approaches to interrogate an anti-IgE immune library, to isolate more
potent disruptive inhibitors, to explore the mechanistic diversity of disruptive inhibitors and to develop
ultrapotent bivalent anti-IgE inhibitors compatible with future clinical development.

## Key facts

- **NIH application ID:** 10353982
- **Project number:** 1R21AI166496-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Theodore S Jardetzky
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $236,100
- **Award type:** 1
- **Project period:** 2021-09-24 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353982

## Citation

> US National Institutes of Health, RePORTER application 10353982, Discovery and engineering of novel anti-IgE disruptive inhibitors (1R21AI166496-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10353982. Licensed CC0.

---

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