Pitrakinra

Last updated
Pitrakinra
Clinical data
Trade names Aerovant
Routes of
administration 		Inhalation, (subcutaneous injection)
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
  • L-methionyl-[121-aspartic acid, 124-aspartic acid]interleukin-4 [1]
ChemSpider
  • none
ChEMBL
Chemical and physical data
Formula C651H1054N190O200S8
Molar mass 14999.20 g·mol−1

Pitrakinra (trade name Aerovant) is a 15-kDa human recombinant protein of wild-type human interleukin-4 (IL-4). It is an IL-4 and IL-13 antagonist that has been studied in a phase IIb clinical trial for the treatment of asthma. Two point mutations on pitrakinra (position 121 mutated from arginine to aspartic acid and position 124 mutated from tyrosine to aspartic acid) confer its ability to block signaling of IL-4 and interleukin-13 (IL-13) by preventing assembly of IL-4 receptor alpha (IL-4Rα) with either IL-2Rγ or IL-13Rα. Upregulation of Th2 cytokines, including IL-4 and IL-13, is thought to be critical for the allergic inflammation associated with atopic diseases such as asthma and eczema. The targets of pitrakinra action are inflammatory cells (dendritic cells, Th2 cells, B cells) and structural cells (smooth muscle, endothelium, epithelium) that express IL-4Rα. [2] The drug has been applied both as a subcutaneous injection and as an inhalation, but the latter formulation proved to be more effective. [3]

Contents

Mechanism of action

Asthma results from a dysregulated, hyperresponsive immune response in the airways. Some immune cells in allergic asthmatics respond aggressively to foreign allergens with the release of IL-4 and 13, two key mediators that initiate a cycle of inflammation in the lung. Pitrakinra is an antagonist of the interleukin-4 receptor alpha chain, a protein that is also part of IL-13. It thereby blocks the inflammatory effects of IL-4 and IL-13, interrupting the Th2 lymphocyte immune response. [3] [4]

Pitrakinra protects allergic cynomolgus monkeys from allergen-induced airways hyper-responsiveness and lung eosinophilia in both prophylactic and therapeutic model settings. Subcutaneous injection of pitrakinra in human patients with severe atopic eczema for 4 weeks or more decreases the eczema clinical score and circulating IgE concentrations, and normalized T-cell subsets. Decreases in Forced Expiratory Volume in 1 s (FEV1) after allergen challenge after 4 weeks of inhalation of pitrakinra supports the hypothesis that dual inhibition of IL-4 and IL-13 can affect the course of the late asthmatic response after experimental allergen challenge. The reduced frequency of spontaneous asthma attacks requiring rescue medication use suggests that the use of pitrakinra improves the control over asthma symptoms. [5]

In addition to improvements in the late asthmatic response, measurement of Fractional Expiratory Nitric Oxide (FENO) indicates that the resting inflammatory status of the lungs is significantly attenuated after inhalation of pitrakinra for 4 weeks. This result supports observations that IL-4 and other pro-inflammatory mediators induce nitric oxide synthase (iNOS) through STAT1 and STAT6 in epithelial cells. Basal FENO could be more dependent on up-regulation of iNOS by IL-4 and IL-13, whereas the increase in FENO after allergen challenge could involve additional pathways in epithelial cells and perhaps macrophages that are not affected by the inhibition of IL-4Rα. Pitrakinra may down-regulate baseline Th2 inflammation in the asthmatic lung while not interfering with the lung’s natural defenses in contact with large amounts of foreign allergen. [5]

Adverse events

Pitrakinra is associated with few adverse effect, whether administered by subcutaneous injection or by inhalation in participants with atopic asthma or atopic eczema. The most common adverse event after subcutaneous administration is injection site-related discomfort, a common event with most injectable drugs. However, these events are neither associated with the development of antibodies nor with any discernible pattern (i.e., they were not more common at the end of the 4 weeks of exposure). There are also fewer spontaneous asthma attacks and respiratory-related adverse events that require rescue medication in participants who received pitrakinra subcutaneously than in those in the placebo group. [5]

Related Research Articles

Allergy Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, a runny nose, shortness of breath, or swelling. Food intolerances and food poisoning are separate conditions.

Corticosteroid

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

Eosinophil

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply. They form about 2 to 3% of WBC's.

Immunoglobulin E Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing 4 Ig-like constant domains (Cε1-Cε4). IgE's main function is immunity to parasites such as helminths like Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a last line of defense to protect against venoms.

Cromoglicic acid

Cromoglicic acid (INN) is traditionally described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium. This drug prevents the release of inflammatory chemicals such as histamine from mast cells.

Allergic conjunctivitis

Allergic conjunctivitis (AC) is inflammation of the conjunctiva due to allergy. Although allergens differ among patients, the most common cause is hay fever. Symptoms consist of redness, edema (swelling) of the conjunctiva, itching, and increased lacrimation. If this is combined with rhinitis, the condition is termed allergic rhinoconjunctivitis (ARC).

Allergen immunotherapy Medical treatment for environmental allergies

Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies, such as insect bites, and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergen in an attempt to change the immune system's response.

Interleukin 4

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to interleukin 13.

Bronchoconstriction Constriction of the airways in the lungs

Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.

Acute severe asthma, also known as status asthmaticus, is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators (inhalers) and corticosteroids. Asthma is caused by multiple genes, some having protective effect, with each gene having its own tendency to be influenced by the environment although a genetic link leading to acute severe asthma is still unknown. Symptoms include chest tightness, rapidly progressive dyspnea(shortness of breath), dry cough, use of accessory respiratory muscles, fast and/or labored breathing, and extreme wheezing. It is a life-threatening episode of airway obstruction and is considered a medical emergency. Complications include cardiac and/or respiratory arrest. The increasing prevalence of atopy and asthma remains unexplained but may be due to infection with respiratory viruses.

Interleukin 13

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence homology to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterised by an exaggerated response of the immune system to the fungus Aspergillus. It occurs most often in people with asthma or cystic fibrosis. Aspergillus spores are ubiquitous in soil and are commonly found in the sputum of healthy individuals. A. fumigatus is responsible for a spectrum of lung diseases known as aspergilloses.

Ustekinumab, sold under the brand name Stelara®, is a monoclonal antibody medication developed by Janssen Pharmaceuticals, for the treatment of Crohn's disease, Ulcerative Colitis, Plaque Psoriasis and Psoriatic Arthritis, targeting both IL-12 and IL-23.

Prostaglandin DP<sub>2</sub> receptor

Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases.

Prostacyclin receptor

The Prostacyclin receptor , also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.

Thymic stromal lymphopoietin

Thymic stromal lymphopoietin (TSLP) is a protein belonging to the cytokine family. It is known to play an important role in the maturation of T cell populations through activation of antigen presenting cells.

Pathophysiology of asthma

Asthma is a common pulmonary condition defined by chronic inflammation of respiratory tubes, tightening of respiratory smooth muscle, and episodes of bronchoconstriction. The Centers for Disease Control and Prevention estimate that 1 in 11 children and 1 in 12 adults have asthma in the United States of America. According to the World Health Organization, asthma affects 235 million people worldwide. There are two major categories of asthma: allergic and non-allergic. The focus of this article will be allergic asthma. In both cases, bronchoconstriction is prominent.

Dupilumab, sold under the brand name Dupixent, is a monoclonal antibody used for allergic diseases such as eczema, asthma and nasal polyps which result in chronic sinusitis.

Chronic Mycoplasma pneumonia and Chlamydia pneumonia infections are associated with the onset and exacerbation of asthma. These microbial infections result in chronic lower airway inflammation, impaired mucociliary clearance, an increase in mucous production and eventually asthma. Furthermore, children who experience severe viral respiratory infections early in life have a high possibility of having asthma later in their childhood. These viral respiratory infections are mostly caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV). Although RSV infections increase the risk of asthma in early childhood, the association between asthma and RSV decreases with increasing age. HRV on the other hand is an important cause of bronchiolitis and is strongly associated with asthma development. In children and adults with established asthma, viral upper respiratory tract infections (URIs), especially HRVs infections, can produce acute exacerbations of asthma. Thus, Chlamydia pneumoniae, Mycoplasma pneumoniae and human rhinoviruses are microbes that play a major role in non-atopic asthma.

Setipiprant

Setipiprant (INN; developmental code names ACT-129968, KYTH-105) is an investigational drug developed for the treatment of asthma and scalp hair loss. It was originally developed by Actelion and acts as a selective, orally available antagonist of the prostaglandin D2 receptor 2 (DP2). The drug is being developed as a novel treatment for male pattern baldness by Allergan.

References

  1. ↑ "Recommended International Nonproprietary Names (rec. Inn): List 46". WHO Drug Information. 15 (3&4). 2001.
  2. ↑ Burmeister Getz E, Fisher DM, Fuller R (September 2009). "Human pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antagonist in asthma". Journal of Clinical Pharmacology. 49 (9): 1025–36. doi:10.1177/0091270009341183. PMID   19717725. S2CID   41101326.
  3. 1 2 Long AA (2009). "Monoclonal antibodies and other biologic agents in the treatment of asthma". mAbs. 1 (3): 237–46. doi:10.4161/mabs.1.3.8352. PMC   2726591 . PMID   20065638.
  4. ↑ Antoniu SA (November 2010). "Pitrakinra, a dual IL-4/IL-13 antagonist for the potential treatment of asthma and eczema". Current Opinion in Investigational Drugs. 11 (11): 1286–94. PMID   21157648.
  5. 1 2 3 Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M (October 2007). "Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies". Lancet. 370 (9596): 1422–31. doi:10.1016/S0140-6736(07)61600-6. PMID   17950857. S2CID   205949227.
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