Identification of long-term therapeutic strategy in IgE-mediated allergy by leveraging humanized models and patient samples

Projektinformationen

HumanIgE

ID Finanzhilfevereinbarung: 101043749

DOI

10.3030/101043749

EK-Unterschriftsdatum 2 Mai 2022

Startdatum 1 März 2023

Enddatum 29 Februar 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 999 431,00

EU-Beitrag

€ 1 999 431,00

Koordiniert durch

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - HumanIgE (Identification of long-term therapeutic strategy in IgE-mediated allergy by leveraging humanized models and patient samples)

Berichtszeitraum: 2023-03-01 bis 2025-08-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

IgE antibodies are key drivers of allergic diseases, which affect approximately one-third of the world’s population. Monoclonal antibodies (mAbs) targeting IgE are approved for the treatment of allergic asthma, and show clinical benefit in a number of other allergic diseases. Yet, a sizable portion of patients do not respond to the drug despite high levels of IgE. There is a clear need to better define which allergy features depend (or not) on IgE, and to find predictive biomarkers in order to identify patients who will benefit from anti-IgE therapy. In addition, use of anti-IgE mAbs is limited by very high cost and the need to perform frequent reinfusion to maintain clinical efficiency.
Combining unique mouse models humanized for IgE and its two receptors FceRI and CD23 and clinical samples from patients undergoing FDA-approved anti-IgE therapy, the project addresses three key questions:
(1) Which IgE features distinguish responders vs. non-responders to anti-IgE therapy, and can it be used as predictive biomarker?
(2) Which key allergy features depend on IgE, and through which mechanisms?
(3) Can we induce long-term protection against IgE-mediated allergies with a vaccine approach?
This translational project will increase our understanding of the basic mechanisms underlying allergic diseases, and has the potential to identify important new therapeutic strategies.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We have already made important progress in our three work packages.
In WP1: our main goal is to identify biomarkers which can help predicting clinical response to the anti-IgE mAb omalizumab in patients suffering from severe asthma. We have designed and validated a multiparametric flow cytometry antibody panel which now permits us to assess frequency and activation status for major T cell and B cell subsets in PBMCs. This includes the following T cell subsets known to play important roles in the regulation of IgE production: T helper 2 (Th2), follicular T helper 2 subset (TFH2), follicular T helper 13 subset (TFH13), follicular regulatory T cells (TFR) and regulatory T cells (Treg). Our panel has been fully validated using PBMCs from non-atopic controls and severe asthma subjects (which have higher frequency of Th2, TFH2, TFH13 and lower frequencies of TFR and Treg). Our study is linked to a phase 4 clinical trial (predictumab) from which we now got close to 80 blood samples from severe asthmatic subjects before initiation of anti-IgE therapy omalizumab (in half of the subjects). We stored PBMCs from all subjects and started to analyse them using this multiparametric flow cytometry panel. The trial is now completed and will be unblinded this summer (07/2025), so we will be able to stratify our results based on the clinical response (or lack of response) to omalizumab. This will permit us to identify key T cell and B cell signature that could help predicting clinical response to omalizumab.

In WP2, we proposed to generate a novel mouse model humanized for IgE and its two receptor FceRI and CD23, and use this model to better understand which asthma features depend (or not) on human IgE. We have now obtained and characterized mice knocked-in for human IgE, human FceRI and human CD23. We have confirmed expression of the human transgenes by ELISA and flow cytometry. We also started in vivo assays to confirm the functionnality of these human transgenes. In addition, we produced and cloned omalizumab in a mouse IgG1 backbone (to avoid immunogenicity issues when using it in vivo in our humanized mice). Our preliminary data indicate that omalizumab can neutralize human IgE in vivo in these humanized mice, leading to markedly reduced human IgE at the surface of circulating blood basophils. We also performed a pilot experiments showing that these humanized mice can develop key features of allergic asthma when exposed to house dust mite. Our preliminary data suggest that omalizumab therapy can partially reduce airway hyperresponsiveness and eosinophilia in this asthma model.

In WP3, we proposed to assess whether a novel anti-human IgE vaccine can protect from anaphylaxis (the most dramatic clinical manifestation of allergy) and for how long. We have now demonstrated that the vaccine can induce long-term production of neutralizing anti-human IgE antibodies (for up to one year, the longest time-point we assessed), and fully protect from IgE-mediated anaphylaxis for at least one year.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

In WP1 we propose to identify cellular biomarkers which could be used to identify asthma patients likely to respond to anti-IgE therapy omalizumab. Within the next 12 months, we will be able to analyse more than 40 clinical samples from severe asthma patients (PBMCs) collecting just before initiation of omalizumab therapy. This should permit us to define whether there is a T and/or B cell signature that could help predicting clinical response to the drug. If so, this flow cytometry panel could be easily standardized and used in clinical practice in the future.

The novel humanized mouse model we generated (WP2) is the first humanized model in which human IgE can signal through its two receptors FceRI and CD23. Data from these mice will help us to better understand the respective role of both receptors in IgE biology, as well as in the efficacy of the anti-IgE therapy omalizumab. We anticipate that this model will be key for preclinical testing of novel therapies targeting human IgE or its human receptors.

The anti-IgE vaccine we developped and tested in WP3 already demonstrated its efficacy at blocking anaphylaxis for at least one year in mice. In 2024, the anti-IgE omalizumab became the first monoclonal antibody approved for the treatment of food allergy (in the US). We thus anticipate that this vaccine which also targets human IgE could induce long-term protection from food allergic reactions, and especially from food-induced anaphylaxis.