作者: Song, Xiaomin ; Guo, Xiaoxiao ; Zou, Xuan ; Wang, Jing ; Liu, Yonglin ; Ge, Weipeng ; Gao, Ran ; Pang, Junling ; Li, Zhengqing ; Niu, Yongliang ; Zhao, Hongmei

Abstract:

Aims:

Hypertension is the major cause of cardiovascular diseases and global mortality. Immunoglobulin E (IgE), which plays crucial roles in allergic diseases, has been implicated in the pathogenesis of vascular and cardiac remodelling via its receptor (FcεR1). In this study, we aimed to reveal the role of IgE and FcεR1 in hypertension.

Methods and results:

Herein, we reported that IgE levels were significantly increased in hypertensive patients as well as in hypertensive mice induced by angiotensin II (Ang II). Ang II-induced vascular remodelling and hypertension were significantly alleviated in FcεR1 genetic knockout mice or in mice treated with anti-IgE monoclonal antibody. Similarly, treatment with omalizumab (a clinical IgE antagonist) also markedly inhibited Ang II-induced hypertension. Furthermore, the cellular contribution of IgE–FcεR1 in hypertension was evaluated in mice with FcεR1 conditional knockout in mast cell (MC), smooth muscle cell (SMC), or endothelial cell (EC). Our data revealed that IgE-mediated hypertension is largely dependent on FcεR1 in MCs but not SMCs and ECs. Finally, RNA-seq and signalling pathway analyses of mouse bone marrow-derived MCs suggested that interleukin 6 (IL-6) is one of critical mediators in IgE-mediated hypertension. IL-6 derived from IgE-stimulated MCs promoted reactive oxygen species production and decreased the levels of phosphorylated endothelial nitric oxide synthase in ECs, leading to endothelial dysfunction.

Conclusion:

Our findings reveal that IgE contributes to the pathogenesis of hypertension, at least partially through activating the IgE–FcεR1 signalling in MCs. Thus, IgE may represent a new therapeutic target for IgE-mediated hypertension.

2021-10-01·The Journal of allergy and clinical immunology1区 · 医学

Structure-guided design of ultrapotent disruptive IgE inhibitors to rapidly terminate acute allergic reactions

1区 · 医学

Article

作者: Pennington, Luke F ; Brigger, Daniel ; Jardetzky, Theodore S ; Gasser, Pascal ; Eggel, Alexander ; Guntern, Pascal

BACKGROUND:

Anaphylaxis represents one of the most severe and fatal forms of allergic reactions. Like most other allergies, it is caused by activation of basophils and mast cells by allergen-mediated cross-linking of IgE bound to its high-affinity receptor, FcεRI, on the cell surface. The systemic release of soluble mediators induces an inflammatory cascade, rapidly causing symptoms with peak severity in minutes to hours after allergen exposure. Primary treatment for anaphylaxis consists of immediate intramuscular administration of adrenaline.

OBJECTIVE:

While adrenaline alleviates life-threatening symptoms of an anaphylactic reaction, there are currently no disease-modifying interventions available. We sought to develop potent and fast-acting IgE inhibitors with the potential to rapidly terminate acute allergic reactions.

METHODS:

Using affinity maturation by yeast display and structure-guided molecular engineering, we generated 3 optimized disruptive IgE inhibitors based on designed ankyrin repeat proteins and assessed their ability to actively remove IgE from allergic effector cells in vitro as well as in vivo in mice.

RESULTS:

The engineered IgE inhibitors rapidly dissociate preformed IgE:FcεRI complexes, terminate IgE-mediated signaling in preactivated human blood basophils in vitro, and shut down preinitiated allergic reactions and anaphylaxis in mice in vivo.

CONCLUSIONS:

Fast-acting disruptive IgE inhibitors demonstrate the feasibility of developing kinetically optimized inhibitors for the treatment of anaphylaxis and the rapid desensitization of allergic individuals.

2021-06-11·Advances in clinical and experimental medicine : official organ Wroclaw Medical University4区 · 医学

Investigating the inflammatory cascade effect of basophil activation in children with allergic rhinitis or asthma, via the IgE-FcεRI-NF-κB signaling pathway

4区 · 医学

Article

作者: Qiao, Yi ; Chen, Jie

BACKGROUND:

Allergic rhinitis (AR) is a type I allergic reaction mediated by serum immunoglobulin E (IgE).

OBJECTIVES:

This study aimed to investigate the basophil activation rate and serum expression of inflammatory factors in AR patients and rats. The involvement of the IgE-FcεRI-nuclear factor kappa B (NF-κB) signaling pathway in the pathogenesis of AR was also explored.

MATERIAL AND METHODS:

Thirty patients with pediatric AR (or asthma; untreated) were enrolled in our hospital as the observation group. Fifteen healthy children were selected as the control group. The basophil activation and serum levels of interleukin (IL)-4, IL-5, IL-13, IgE, and prostaglandin D2 (PGD2) in 2 groups of children were detected. Forty-eight male Sprague Dawley rats were randomly divided into group A (AR model group), group B (AR model + IgE inhibitor), group C (AR model + omalizumab), and group D (control). The animal model was established by intraperitoneal injection of ovalbumin and nasal mucosa stimulation. The basophil activation rate, serum levels of IL-4, IL-5, IL-13, IgE, and PGD2 were analyzed.

RESULTS:

In children with AR, the blood samples contained mainly activated basophils, whereas the healthy group showed mainly non-activated basophils. The levels of IL-4, IL-5, IL-13, IgE and PGD2 in the serum of the AR group were higher than those in healthy subjects (p < 0.05). In animal studies, the blood samples collected from group A were mainly activated basophils, while the samples of the other groups were mainly non-activated basophils. The serum contents of IL-4, IL-5, IL-13, IgE, and PGD2 in group A were significantly higher than those in groups B and C (p < 0.05).

CONCLUSIONS:

Patients with AR showed increased activation of basophils and elevated expression of IL-4, IL-5, IL-13, IgE, and PGD2. The upregulation of FcεRI and NF-κB was involved in the pathogenesis of AR.

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2024-09-09

·Pharmaceutical Technology

Epsilogen secures additional funds in Series B for cancer treatment

The funds will support the trial of MOv18 IgE to potentially treat platinum-resistant ovarian cancer. Credit: Jo Panuwat D/Shutterstock. Epsilogen has completed a Series B expansion financing round, raising £12.5m ($16.4m) to progress the development of its immunoglobulin E (IgE) antibodies for cancer treatment. The investment was sourced entirely from existing backers British Patient Capital, the Novartis Venture Fund, Epidarex Capital, the 3B Future Health Fund and ALSA Ventures. The latest funding takes the total raised in the Series B financing round to £43.25m. The funds will primarily support the clinical proof of concept for MOv18 IgE, the company’s leading asset, in a Phase Ib trial targeting platinum-resistant ovarian cancer. MOv18 IgE, a therapeutic IgE antibody, is designed to target the folate receptor alpha (FRα) which is prevalent in various cancers. See Also: LACTIN-V by Osel for Human Papillomavirus Infections: Likelihood of Approval Cadisegliatin by VTv Therapeutics for Type 1 Diabetes (Juvenile Diabetes): Likelihood of Approval The Phase Ib trial of MOv18 IgE will have dose escalation and expansion parts, enrolling patients with FRα-positive PROC who have undergone up to four previous treatments. The trial follows a Phase I study where MOv18 IgE showed safety, tolerability and initial signs of clinical activity. MOv18 IgE’s unique mechanism of action is different from that of other clinical agents, due to its high-affinity binding to FcεR1 that promotes immunosurveillance and robust tumour cell destruction by myeloid cells. IgE antibodies have the potential to alter the tumour immune microenvironment, making it more pro-inflammatory, which results in higher levels of activated T cells and macrophages within the tumour, enhancing its destruction. Established in 2017, Epsilogen is a spin-out from King’s College London, UK. Its CEO Tim Wilson stated: “We are delighted to have received strong continued support from our existing investors, and we thank them. “The promise of IgE to treat cancer is based upon its unique mechanism of action and MOv18 IgE is the first ever to be tested in man. Everything is ready for phase Ib initiation which will occur shortly and we look forward to reporting progress from the trial.”

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