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A recent review explores mast cell silencing as a novel therapeutic approach for urticaria. New experimental mast cell silencers like Siglec-targeted monoclonal antibodies (e.g., lirentelimab, AK006) might revolutionize the management of mast cell-dependent diseases, including urticaria.

Urticaria is a complex, chronic skin health issue. Its underlying mechanism is not fully understood, posing treatment challenges. Urticaria primarily occurs due to IgE-mediated mast cell (MC) activation. Hence, there are two current treatment approaches to the condition: the first is influencing immune cells, and the second is affecting released mediators such as cytokines and histamine. 

However, despite the use of high-dose antihistamines, short-duration corticosteroids, or implementing second-line therapy using the anti-IgE monoclonal antibody (mAb) omalizumab, many individuals still continue to experience disease-related distress. Considering the significant number of non-responders, finding a novel therapeutic approach is vital. 

A review article published in the journal Allergy explores the utility of MC silencing in managing urticaria. 

Early Studies Using Mast Cell-Silencing Approach Offer Hope

In addition to urticaria, MC activation and degranulation play a significant role in a variety of conditions, including asthma, nasal polyps, and food allergies. MC silencing could be helpful in a range of MC-dependent disease conditions.

At present, there are few ways to counter MC activation. These include MC stabilizers (disodium cromoglycate and nedocromil sodium), immunosuppressants, antagonists of MC activation (omalizumab), inhibitors of MC mediators (H1 antihistamines, leukotriene receptor antagonists), and MC depletion (KIT inhibitors such as imatinib).

However, researchers are developing a new and highly promising class of drugs called MC silencers. MC silencers work by engaging specific transmembrane receptors to broadly inhibit MC activation, thereby blocking multiple pathways involved in this process. Siglecs, a family of Type I transmembrane proteins with immunoreceptor tyrosine-based inhibitory motifs (ITIMs), play a key role in the development of MC silencers. Monoclonal antibodies against Siglec-8 and Siglec-6, among others, have shown promise in preclinical studies and are advancing to clinical trials for MC-related diseases. 

Preclinical findings of the novel drug lirentelimab, a Siglec-8 agonist antibody, demonstrate its inhibitory effects across various MC activation pathways. Another emerging therapeutic approach is AK006, a Siglec-6 agonist antibody expected to enter human clinical trials in the second half of 2023. In preclinical studies, Siglec-6, primarily expressed on MCs and basophils, has demonstrated potent inhibitory activity. 

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Another potential target for MC silencing therapies is LY3454738, an anti-CD200R antibody that inhibits MC degranulation and cytokine secretion. While early studies showed promise, a Phase 2 study in CSU was terminated due to lack of efficacy.

The Bottom Line

This review highlights the potential advantages of using MC silencers as a novel therapeutic approach, emphasizing their potential to regulate MC activity in various diseases. The findings from early clinical trials suggest a promising avenue for improving treatments and enhancing the quality of life for individuals with MC-dependent diseases like urticaria.

Source:

Metz, M., Kolkhir, P., Altrichter, S., Siebenhaar, F., Levi-Schaffer, F., Youngblood, B. A., Church, M. K., & Maurer, M. (2024). Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases. Allergy, 79(1), 37–51. https://doi.org/10.1111/all.15850