Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis

Dellon, Evan S.; Peterson, Kathryn A.; Murray, Joseph A.; Falk, Gary W.; Gonsalves, Nirmala; Chehade, Mirna; Genta, Robert M.; Leung, John; Khoury, Paneez; Klion, Amy D.; Hazan, Sabine; Vaezi, Michael F.; Bledsoe, Adam C.; Durrani, Sandy; Wang, Chao; Shaw, Camilla; Chang, Ansi; Singh, Bhupinder; Kamboj, Amol P.; Rasmussen, Henrik; Rothenberg, Marc E.; Hirano, Ikuo

doi:10.1056/nejmoa2012047

Cited by 205 publications

(149 citation statements)

References 35 publications

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“…These receptors and/or their tissue and cellular ligands may identify novel targets for therapeutic modulation of eosinophil activation, survival and function. To this end, a humanized afucosylated antibody against Siglec 8, demonstrated to induce eosinophil death and inhibit mast cell degranulation, is in clinical development for eosinophil-mediated diseases [ 113 , 114 , 115 ].…”

Section: Heterogeneity Of Intestinal Tissue Eosinophilsmentioning

confidence: 99%

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

Masterson

Menard‐Katcher

Larsen

et al. 2021

Cells

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Eosinophils are implicated in the pathophysiology of a spectrum of eosinophil-associated diseases, including gastrointestinal eosinophilic diseases (EGIDs). Biologics that target the IL-5 pathway and are intended to ablate eosinophils have proved beneficial in severe eosinophilic asthma and may offer promise in treating some endotypes of EGIDs. However, destructive effector functions of eosinophils are only one side of the coin; eosinophils also play important roles in immune and tissue homeostasis. A growing body of data suggest tissue eosinophils represent a plastic and heterogeneous population of functional sub-phenotypes, shaped by environmental (systemic and local) pressures, which may differentially impact disease outcomes. This may be particularly relevant to the GI tract, wherein the highest density of eosinophils reside in the steady state, resident immune cells are exposed to an especially broad range of external and internal environmental pressures, and greater eosinophil longevity may uniquely enrich for co-expression of eosinophil sub-phenotypes. Here we review the growing evidence for functional sub-phenotypes of intestinal tissue eosinophils, with emphasis on the multifactorial pressures that shape and diversify eosinophil identity and potential targets to inform next-generation eosinophil-targeting strategies designed to restrain inflammatory eosinophil functions while sustaining homeostatic roles.

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Section: Heterogeneity Of Intestinal Tissue Eosinophilsmentioning

confidence: 99%

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

Masterson

Menard‐Katcher

Larsen

et al. 2021

Cells

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“…However, larger controlled studies to confirm the safety and efficacy of the drug in the treatment of CSU are still pending. Initial recently published findings on the safety of this antibody were demonstrated in a study of the therapy of eosinophilic gastritis and duodenitis [ 9 ].…”

Section: Antibodies That Bind To Inhibitory Receptors On Mcsmentioning

confidence: 99%

Use of biologics in chronic spontaneous urticaria – beyond omalizumab therapy?

Metz

Maurer

2021

ALS

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In chronic spontaneous urticaria (CSU), itchy wheals, angioedema, or both occur regularly, often daily, and for years. An effective therapy for CSU aims at achieving complete symptom control. The current guideline for the management of CSU patients recommends non-sedative anthistamines in standard or up to 4-fold higher dosages as 1 and 2 line treatment. For most CSU patients this treatment is not sufficient; for them, the anti-IgE antibody omalizumab is the therapy of choice. Although good to very good symptom control can be achieved in most cases, there are many patients with insufficient response. For these patients, but also as an alternative to therapy with omalizumab, numerous other biologicals are currently under development. In this review, we provide an overview of possible future biologic therapies for chronic urticaria.

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“…Most recently, lirentelimab was evaluated in ENIGMA, a multi-center, randomized, double-blind, placebo-controlled phase 2 study in patients with active eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD) [ 71 ]. EG/EoD is characterized by gastrointestinal mucosal eosinophilia, chronic gastrointestinal symptoms, impaired quality of life, and a lack of adequate treatments.…”

Section: Ak002 Efficacy In Eosinophil- and Mast Cell-mediated Disementioning

confidence: 99%

Discovery, Function, and Therapeutic Targeting of Siglec-8

Youngblood

Leung

Falahati

et al. 2020

Cells

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Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases.

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Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis

Cited by 205 publications

References 35 publications

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

Use of biologics in chronic spontaneous urticaria – beyond omalizumab therapy?

Discovery, Function, and Therapeutic Targeting of Siglec-8

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