Lirentelimab for severe and chronic forms of allergic conjunctivitis

Anesi, Stephen D; Tauber, Joseph; Nguyen, Quan Dong; Chang, Peter Y.; Berdy, Gregg J.; Lin, Charles C.; Chu, David; Levine, H Terry; Fernandez, Andrew; Roy, Neeta S.; Asbell, Penny A.; Kantor, Andrea; Chang, Ansi; Singh, Bhupinder; Youngblood, Brad; Jeng, Bennie H.; Jhanji, Vishal; Rasmussen, Henrik; Foster, C. Stephen

doi:10.1016/j.jaci.2022.03.021

Cited by 25 publications

(14 citation statements)

References 32 publications

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“…In addition, ligation of CD33 with ligand coated liposomes or Siglec-8 with a monoclonal antibody (mAb) reduces inflammation in vivo 22,23 . Indeed, lirentelimab (AK002), a humanized Siglec-8 mAb has shown beneficial activity in multiple clinical studies by depleting eosinophils and inhibiting MCs, suggesting Siglecs can modulate MC activation in humans [24][25][26] .…”

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confidence: 99%

Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells

et al. 2022

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Mast cells (MC) are key drivers of allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 is an immunoregulatory receptor found on MCs. While it is recognized that engaging Siglecs with antibodies mediates inhibition across immune cells, the mechanisms that govern this agonism are not understood. Here we generated Siglec-6 mAb clones (AK01 to AK18) to better understand Siglec-6-mediated agonism. Siglec-6 mAbs displayed epitope-dependent receptor internalization and inhibitory activity. We identified a Siglec-6 mAb (AK04) that required Fc-mediated interaction for receptor internalization and induced inhibition and antibody-dependent cellular phagocytosis against MCs. AK04-mediated MC inhibition required Siglec-6 immunoreceptor tyrosine-based inhibitory motif (ITIM) and ITIM-like domains and was associated with receptor cluster formation containing inhibitory phosphatases. Treatment of humanized mice with AK04 inhibited systemic anaphylaxis with a single dose and reduced MCs with chronic dosing. Our findings suggest Siglec-6 activity is epitope dependent and highlight an agonistic Siglec-6 mAb as a potential therapeutic approach in allergic disease.

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confidence: 99%

Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells

et al. 2022

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“…19 Patients with concomitant atopic comorbidities, also showed a reduction in symptoms of −55%, −50%, and −63% for AD, allergic asthma, and allergic rhinitis, respectively. 19 Across all studies to date, lirentelimab has been well tolerated, the most common adverse events (AEs) being infusion-related reactions typically associated with the initial infusion. 18,19,114 Subcutaneously…”

Section: Clinical Studies Of Lirentelimabmentioning

confidence: 94%

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell‐mediated diseases

Metz,

Kolkhir,

Altrichter

et al. 2023

Allergy

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Chronic urticaria (CU) is a mast cell (MC)‐dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE‐mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation—including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators—strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid‐binding immunoglobulin‐like lectin8 ‐[Siglec‐8] [lirentelimab/AK002], Siglec‐6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on‐ or off‐target, immunosuppressive adverse effects.

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“…Moreover, lirentelimab inhibits mast cell activation, thereby reducing degranulation, the secretion of inflammatory mediators, and the recruitment of additional mast cells, eosinophils, and other immune cells to the tissues. Open-label clinical studies of lirentelimab have proved its activity in various allergic diseases, such as chronic urticaria (Clinical-Trials.gov number, NCT03436797) and severe allergic conjunctivitis (NCT03379311) [ 131 ]. Recently, in patients with eosinophilic gastritis or duodenitis, lirentelimab was shown to reduce gastrointestinal eosinophils and their symptoms [ 132 ].…”

Section: Anti-eosinophil Targeted Therapy In Asthmamentioning

confidence: 99%

Subsets of Eosinophils in Asthma, a Challenge for Precise Treatment

Novosad

Krčmová

Souček

et al. 2023

IJMS

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The existence of eosinophils was documented histopathologically in the first half of the 19th century. However, the term “eosinophils” was first used by Paul Ehrlich in 1878. Since their discovery and description, their existence has been associated with asthma, allergies, and antihelminthic immunity. Eosinophils may also be responsible for various possible tissue pathologies in many eosinophil-associated diseases. Since the beginning of the 21st century, the understanding of the nature of this cell population has undergone a fundamental reassessment, and in 2010, J. J. Lee proposed the concept of “LIAR” (Local Immunity And/or Remodeling/Repair), underlining the extensive immunoregulatory functions of eosinophils in the context of health and disease. It soon became apparent that mature eosinophils (in line with previous morphological studies) are not structurally, functionally, or immunologically homogeneous cell populations. On the contrary, these cells form subtypes characterized by their further development, immunophenotype, sensitivity to growth factors, localization, role and fate in tissues, and contribution to the pathogenesis of various diseases, including asthma. The eosinophil subsets were recently characterized as resident (rEos) and inflammatory (iEos) eosinophils. During the last 20 years, the biological therapy of eosinophil diseases, including asthma, has been significantly revolutionized. Treatment management has been improved through the enhancement of treatment effectiveness and a decrease in the adverse events associated with the formerly ultimately used systemic corticosteroids. However, as we observed from real-life data, the global treatment efficacy is still far from optimal. A fundamental condition, “sine qua non”, for correct treatment management is a thorough evaluation of the inflammatory phenotype of the disease. We believe that a better understanding of eosinophils would lead to more precise diagnostics and classification of asthma subtypes, which could further improve treatment outcomes. The currently validated asthma biomarkers (eosinophil count, production of NO in exhaled breath, and IgE synthesis) are insufficient to unveil super-responders among all severe asthma patients and thus give only a blurred picture of the adepts for treatment. We propose an emerging approach consisting of a more precise characterization of pathogenic eosinophils in terms of the definition of their functional status or subset affiliation by flow cytometry. We believe that the effort to find new eosinophil-associated biomarkers and their rational use in treatment algorithms may ameliorate the response rate to biological therapy in patients with severe asthma.

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Lirentelimab for severe and chronic forms of allergic conjunctivitis

Cited by 25 publications

References 32 publications

Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells

Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell‐mediated diseases

Subsets of Eosinophils in Asthma, a Challenge for Precise Treatment

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