Recent studies have shown that various drugs, including small molecules, opioids, and antibiotics, can activate MRGPRX2 (Mas-related G-protein coupled receptor X2), leading to mast cell degranulation and triggering drug hypersensitivity reactions. As a transmembrane protein predominantly expressed on mast cells (MCs), MRGPRX2 plays a key role in mediating inflammatory and allergic responses. Several clinical trials are underway to assess the therapeutic potential of inhibiting this receptor in chronic urticaria and eczema. Ongoing preclinical research also suggests a role of MRGPRX2 in chronic pain, potentially paving the way for breakthroughs in pain management where traditional treatments have failed.
KACTUS is the only producer of full-length mammalian-expressed MRGPRX2 protein as an off-the-shelf product, making MRGPRX2 membrane protein an easily accessible research target.
The Role of MRGPRX2 in Allergy and Pain
MRGPRX2 is a G-protein coupled receptor (GPCR) predominantly expressed on human mast cells, which are essential for mediating allergic and inflammatory reactions. Recent studies have also identified its expression in keratinocytes and sensory neurons. MRGPRX2 binds exogenous and endogenous ligands such as major basic protein, eosinophil peroxidase, and neuropeptides, as well as certain drugs including neuromuscular blocking agents, fluoroquinolones, and vancomycin.
Figure 1. MRGPRX2 signaling pathways resulting in mast cell degranulation and inflammatory responses. Source: https://www.mdpi.com/2073-4409/13/3/220
Allergic Reactions
Upon activation, MRGPRX2 triggers mast cell degranulation and anaphylactic reactions. MRGPRX2-mediated mast cell activation is IgE-independent, distinguishing it from typical allergic pathways [3]. These interactions often lead to rapid but transient inflammatory responses through pathways like phospholipase C-beta, resulting in the release of histamine and other mediators.
Chronic Pain
This receptor's involvement in neurogenic inflammation also opens potential avenues for addressing chronic pain where traditional treatments have been less effective. MRGPRX2 also influences pain perception, especially in chronic pain conditions where mast cells are known to contribute to hyperalgesia [4]. Activation of MRGPRX2 by neuropeptides like Substance P leads to inflammatory responses, further sensitizing pain receptors.
Clinical Trials Targeting MRGPRX2
Several clinical trials have begun exploring the therapeutic potential of targeting MRGPRX2 to treat conditions related to mast cell activation.
Evommune’s EVO756 Small Molecule Antagonist Targeting MRGPRX2
Evommune recently initiated a Phase 2 trial for their drug, EVO756, an oral small-molecule antagonist targeting MRGPRX2. EVO756 treats Chronic Inducible Urticaria (CIndU), also called Physical Urticaria. CIndU is a condition characterized by itchy welts or hives that recur for six weeks or longer. Evommune's preclinical data show that EVO756, by blocking MRGPRX2 activation across all relevant ligand types, can prevent mast cell degranulation. EVO756 has the potential to be a first-in-class oral treatment for various mast cell-mediated diseases and may also offer quick itch relief in inflammatory conditions like atopic dermatitis due to its effect on peripheral sensory neurons [5].
Figure 2. EVO756 blocks MRGPRX2 activation, subsequently blocking mast cell activation. Source: https://www.evommune.com/mrgprx2-antagonist/
Incyte’s Small Molecule Antagonist Targeting MRGPRX2
Escient Pharmaceuticals, recently acquired by Incyte, developed EP262, a first-in-class oral small molecule antagonist targeting MRGPRX2, a receptor associated with mast cell activation [6]. The drug works by selectively blocking MRGPRX2 to prevent mast cell degranulation, aiming to treat disorders such as chronic urticaria and atopic dermatitis. In Phase 1 trials, EP262 demonstrated a strong safety profile and supported once-daily dosing, paving the way for future clinical studies focused on mast cell-mediated conditions.
Figure 3. Benefits of EP262, another small molecule drug antagonist targeting MRGPRX2 for mast cell disorders. Source: https://www.escientpharma.com/programs/mrgprx2/
Pain Management: Emerging Avenue for MRXPRX2-Targeting Drugs
Although there are not currently clinical trials for MRGPRX2 drugs targeting pain management, the role of mast cells in pain has been increasingly recognized, especially in conditions like fibromyalgia and neuropathic pain [4]. MRGPRX2 is a key receptor in neurogenic inflammation, where sensory neurons release neuropeptides that activate mast cells. Antibodies or small molecules targeting MRGPRX2 could reduce mast cell-driven inflammation and offer a new avenue for managing chronic pain, particularly in patients unresponsive to conventional therapies.
KACTUS' MRGPRX2 Copolymer Nanodiscs and Custom Protein Services
The discovery of therapeutic small molecules or antibodies targeting MRGPRX2 holds immense potential for treating allergic reactions, drug hypersensitivity, and chronic pain. For researchers focused on small molecule or antibody drug development, the ability to work with properly folded and functional MRGPRX2 proteins is essential for generating high-quality therapeutics. Given the structural complexity of GPCRs and their transmembrane nature, presenting MRGPRX2 in a functional format is critical for downstream applications such as antibody screening, functional assays, and PK/PD studies.
Off-the-Shelf, Full-Length, Mammalian-Expressed MRPGRX2 Protein
KACTUS offers the only full-length mammalian-expressed off-the-shelf MRGPRX2 protein. Our MRGPRX2 copolymer nanodisc is designed to present the full-length MRGPRX2 protein in a membrane-mimicking environment, allowing researchers to study the receptor in its native conformation. Our copolymer nanodiscs are made with detergent-free extraction to maintain protein stability and functionality.
Figure 4. Immobilized Human MRGPRX2 Nanodisc, His Tag at 2ug/ml (100ul/well) on the plate. Dose response curve for Anti-MRGPRX2 Antibody, mFc Tag with the EC50 of 15.5ng/ml determined by ELISA (QC Test).
Custom MRPGRX2 Protein Expression Services
Additionally, we offer custom VLPs and Nanodiscs production services, with both platforms offering full-length proteins with detergent-free extraction. Our VLPs and Nanodiscs can be biotinylated or fluorescently-labeled and can be used in various applications including immunization, yeast display, phage display, ELISA, and SPR, among others.
Figure 5. Flow cytometry analysis of MRGPRX2 expression using VLP-displayed MRGPRX2 and anti-MRGPRX2 antibody detection. The left panel shows cells incubated with MRGPRX2 VLP alone, serving as a baseline for MRGPRX2 expression. The middle panel represents cells treated with control VLP plus anti-MRGPRX2 antibody, indicating background staining. The right panel shows cells incubated with MRGPRX2 VLP and anti-MRGPRX2 antibody, demonstrating specific binding of the antibody to the MRGPRX2 protein displayed on the VLP. The percentage of cells in each quadrant reflects the expression levels and binding specificity, with a notable increase in PE-positive cells (Q2-4) in the right panel, confirming specific antibody recognition of MRGPRX2.
Try our MRGPRX2 copolymer nanodisc or contact us at support@kactusbio.us today to learn more about our custom MRGPRX2 protein services.
References
- Porebski, G., Kwiecien, K., Pawica, M., & Kwitniewski, M. (2018). Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) in Drug Hypersensitivity Reactions. Frontiers in Immunology, 9, 412299. https://doi.org/10.3389/fimmu.2018.03027
- Kolkhir, P., Ali, H., Babina, M., Ebo, D., Sabato, V., Elst, J., Frischbutter, S., Pyatilova, P., & Maurer, M. (2023). MRGPRX2 in drug allergy: What we know and what we do not know. The Journal of allergy and clinical immunology, 151(2), 410–412. https://doi.org/10.1016/j.jaci.2022.09.004
- McNeil, B. D., Pundir, P., Meeker, S., Han, L., Undem, B. J., Kulka, M., & Dong, X. (2015). Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature, 519(7542), 237–241. https://doi.org/10.1038/nature14022
- Thapaliya, M., Chompunud Na Ayudhya, C., Amponnawarat, A., Roy, S., & Ali, H. (2021). Mast Cell-Specific MRGPRX2: a Key Modulator of Neuro-Immune Interaction in Allergic Diseases. Current allergy and asthma reports, 21(1), 3. https://doi.org/10.1007/s11882-020-00979-5
- Evommune. (2024, September 3). Evommune initiates Phase 2 trial of EVO756, an oral MRGPRX2 antagonist, in chronic inducible urticaria. PR Newswire. https://www.prnewswire.com/news-releases/evommune-initiates-phase-2-trial-of-evo756-an-oral-mrgprx2-antagonist-in-chronic-inducible-urticaria-302234547.html
- Escient Pharmaceuticals. (2023, June 20). Escient Pharmaceuticals announces positive results from Phase 1 study of EP262, a first-in-class oral MRGPRX2 antagonist for mast cell mediated disorders. Escient Pharmaceuticals. https://www.escientpharma.com/escient-pharmaceuticals-announces-positive-results-from-phase-1-study-of-ep262-a-first-in-class-oral-mrgprx2-antagonist-for-mast-cell-mediated-disorders/
- Allakos. (2024, February 27). Allakos presents preclinical data highlighting inhibition of MRGPRX2-mediated mast cell activation with AK006 at AAAAI 2024. Allakos Investor Relations. https://investor.allakos.com/news-releases/news-release-details/allakos-presents-preclinical-data-highlighting-inhibition
