# Designer covalent heterobivalent inhibitors to prevent IgE-dependent allergic reactions

> **NIH NIH R01** · UNIVERSITY OF NOTRE DAME · 2020 · $449,325

## Abstract

Project Summary:
 Allergic reactions are elicited by the allergen-mediated-clustering of the immunoglobulin E (IgE) antibodies
on the surface of mast cells, which is “the key event” in initiation of the systemic reaction. Allergic diseases are
increasing health concerns in developed nations. Depending on the severity of the allergic reaction, the results
can vary from a simple itch to anaphylactic shock, which results in 1,500 deaths each year in the US. There
are no cures for allergies, and current therapies focus on treatment of acute symptoms or chronic immune
suppression. Even with the most restricted diets, accidental exposure is very frequent for food allergies, putting
patients at risk for life threatening anaphylaxis. Thus, there is a need for more effective, alternative treatments
for IgE-mediated allergic responses. The objective of this application is to develop allergen-specific IgE
inhibitors (cHBI: covalent heterobivalent inhibitor) that target allergen-binding IgE, and prevent it from
recognizing the allergen. This approach inhibits the allergic reaction before it starts with specific targeting but
without broad immune suppression. Naturally occurring allergens are typically complex, structurally
heterogenous proteins with multiple allergy-inducing epitopes. Historically it has been a challenge to identify
contributions from individual allergen epitopes to the overall allergic reaction. During the previous funding
cycle, we addressed this problem by developing a multicomponent epitope presentation platform that we
named nanoallergens. Using nanoallergen screening, we can study the immunogenicity of individual allergen
epitopes, and identify immunodominant epitopes. Using the identified immunodominant epitope, we synthesize
cHBI inhibitors that mimic the epitope and block the IgE antibodies that recognize the specific epitope. This
method inhibits the IgE from recognizing the allergen when it enters the system and prevents the initiation of
the allergic reaction. We have recently demonstrated that using a cocktail of cHBIs, we can block peanut
allergic reactions using patient samples in an in vitro cellular degranulation method. In the current application,
we will evaluate the peanut allergy inhibition in vivo using a humanized mice model. Simultaneously, we will
exploit the potential of the cHBI as a platform to block other allergens including shellfish, dust mite and
hazelnut. The proposed work is innovative and significant because it (i) offers a novel molecular design
approach to inhibit “the key event” triggering an allergic response with potential long-term clinical applications
in food, environmental and drug allergies, (ii) it does so without any non-specific suppression of immune
system components, and (iii) develops a much needed, physiologically relevant, easily adjustable and
reproducible platform (nanoallergens), which will be used in identifying immunodominant public allergen
epitopes and their relative significance du...

## Key facts

- **NIH application ID:** 9973687
- **Project number:** 2R01AI108884-06
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Zihni Basar Bilgicer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,325
- **Award type:** 2
- **Project period:** 2014-12-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973687

## Citation

> US National Institutes of Health, RePORTER application 9973687, Designer covalent heterobivalent inhibitors to prevent IgE-dependent allergic reactions (2R01AI108884-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973687. Licensed CC0.

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