Tezepelumab for severe refractory asthma
Tezepelumab is a fully human monoclonal antibody that binds to TSLP, thereby preventing its interaction with the thymic stromal lymphopoietin (TSLP) receptor complex
Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation
- released from airway epithelial cells upon tissue damage induced by several noxious agents including allergens, viruses, bacteria, and airborne pollutants, TSLP activates dendritic cells and group 2 innate lymphoid cells involved in the pathobiology of T2-high asthma (1,2)
- composed of thymic stromal lymphopoietin (TSLP), IL-33 and IL-25, high levels of these upstream cytokines are released from the epithelium in individuals with T-helper type (Th)-2 lymphocyte-high inflammation after exposure to irritants such as bacteria, viruses, allergens and environmental pollutants
- TSLP belongs to the family of alarmins
- an innate cytokine that is mostly released by airway epithelial cells as an alarm signal when tissue injury is triggered by several environmental insults such as allergens, cigarette smoke, airborne pollutants, viruses, bacteria, and chemical and physical irritants
- is an interleukin-7-like receptor family found on the epithelial layer of the lung that releases a cytokine cascade inducing eosinophilic inflammation, mucus production and airflow obstruction in asthmatics (2)
- TSLP is an innate pleiotropic cytokine belonging to the four-helix-bundle cytokine family and is distantly related to interleukin-7 (IL-7)
- two TSLP variants exist, including a long isoform (159 amino acids) and a short one (60 amino acids), whose expressions are respectively regulated by different gene promoters, which are responsive to distinct patterns of environmental agents
- short TSLP is constitutively present in many tissues where it plays a homeostatic role, whilst the production of the long isoform can be induced by proinflammatory stimuli and is increased in asthmatic patients
- long variant of TSLP exerts its biological functions by selectively binding to its cognate receptor (TSLPR), and this interaction is promoted by the electrostatic attraction occurring between the positive charges of TSLP surface and the negative charges of TSLPR
Tezepelumab received its first approval on 17 December 2021 as an add-on maintenance treatment for patients aged >= 12 years with severe asthma in the USA; it is the only biologic approved for severe asthma with no phenotype (e.g. eosinophilic or allergic) or biomarker limitations (3)
Australian guidance with respect to monoclonal antibodies (4):
- four monoclonal antibody therapies (benralizumab, mepolizumab, dupilumab and omalizumab) are available in Australia for the treatment of severe asthma in patients whose asthma is uncontrolled despite optimised standard treatment
Key Points
- monoclonal antibody therapy is an add-on treatment option for reducing severe flare-ups and improving symptom control in patients with severe allergic or eosinophilic asthma whose asthma is uncontrolled despite treatment with high-dose inhaled corticosteroids and long-acting beta2 agonists.
- these therapies target inflammatory pathways that activate type 2 immune responses leading to airway inflammation.
- patients using these treatments must keep taking their inhaled corticosteroid-containing preventers.
- after treatment has been initiated by a specialist, ongoing maintenance doses can be administered in primary care, or by the patient or carer, under specialist supervision.
- monoclonal antibody therapies currently available in Australia for severe asthma are generally well tolerated
- injection site reactions are among the most common adverse events. Systemic reactions, including anaphylaxis, are rare but can occur.
- like all patients with asthma, those using monoclonal antibody therapies need an up-to-date written asthma action plan.
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