Tezepelumab Overview

Introduction of Tezepelumab

Tezepelumab (formerly MEDI9929 and AMG 157) is a human monoclonal antibody (mAb) developed in collaboration by MedImmune (now part of AstraZeneca) and Amgen. It blocks thymic stromal lymphopoietin (TSLP) and was designed to for the treatment of asthma and atopic dermatitis (AD). It is in Phase III trials as of August 2019.

Mechanism of Action of Tezepelumab

TSLP is a pleiotropic cytokine originally characterized as a lymphocyte growth factor. TSLP, IL-33, and IL-25 are alarmins overexpressed in airway epithelial cells which have been associated with the pathogenesis of asthma. Human TSLP exerts its biological activities by binding to a high-affinity heteromeric receptor complex composed of TSLPR and IL-7 receptor-α (IL-7Rα). Human TSLP, positively charged, binds to TSLPR, negatively charged, with high affinity; then, IL-7Rα binds to the TSLP:TSLPR binary complex. The ternary complex, TSLPR:TSLP:IL-7Rα, initiates signaling in cells co-expressing TSLPR and IL7Rα. TSLP is expressed predominantly by lung and gut epithelial cells, keratinocytes and dendritic cells (DCs). TSLP can be produced also by airway smooth muscle (ASM) cells, human DCs and mast cells, human monocytes, macrophages and granulocytes, and murine basophils. At the barrier surfaces (e.g., airway epithelium) TSLP is an upstream cytokine that activates TSLPR+ DCs to induce functional T helper type 2 (Th2) cells and T follicular helper (Tfh) cells. TSLP also possesses a plethora of pleiotropic properties mediated by the activation of a broad range of immune and non-immune cells. A wide spectrum of stimuli involved in the pathogenesis of different phenotypes/endotypes of asthma such as allergens, cytokines (e.g., TNF-α, IL-1β), respiratory viruses, bacterial and fungal products, cigarette smoke extracts and tryptase induce the expression of TSLP from different target cells.

TSLP-activated DCs prime CD4+ T cells to polarize toward Th2 cells (e.g., production of IL4, IL-5, and IL-13). TSLP produced by activated lung epithelial cells can cause goblet cell hyperplasia and mucus production. TSLP targets group 2 innate lymphoid cells (ILC2s) and drives the development of Th2 cells. TSLP also provides critical signals for human B cell proliferation and T follicular helper cells (Tfh) differentiation. Human monocytes do not express TSLPR and IL-7Rα but their stimulation with lipopolysaccharide (LPS) induces the expression of TSLPR complex on a percentage of monocytes. TSLP activates human eosinophils through the engagement of TSLPR and IL-7Rα. TSLP promoted peripheral basophilia and that TSLPR-expressing basophils play a role in Th2-dependent immunity in mice. Collectively, these findings demonstrate that TSLP might orchestrate a plethora of immune cells involved in the pathogenesis of different phenotypes/endotypes of asthma.

By binding to TSLP, tezepelumab prevents its interaction with the TSLP receptor complex and inhibits multiple downstream inflammatory pathways. Preclinical data support the role of TSLP in both asthma and AD, indicating that tezepelumab may be effective as a treatment in both diseases.

Mechanism of Action of Tezepelumab Fig.1 Mechanism of Action of Tezepelumab

Table 1. Clinical Projects of Tezepelumab*

NCT ID Status Conditions Lead Sponsor Update Time
NCT04362410 Recruiting Healthy Subjects AstraZeneca April 24, 2020
NCT03968978 Active, not recruiting Asthma AstraZeneca May 30, 2019
NCT04039113 Active, not recruiting Chronic Obstructive Pulmonary Disease (COPD) AstraZeneca July 31, 2019
NCT03809663 Recruiting Atopic Dermatitis Amgen January 18, 2019
NCT03927157 Active, not recruiting Asthma AstraZeneca April 25, 2019
NCT04048343 Active, not recruiting Severe Asthma AstraZeneca August 7, 2019
NCT03347279 Active, not recruiting Asthma AstraZeneca November 20, 2017
NCT03688074 Active, not recruiting Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; AstraZeneca September 28, 2018
NCT03706079 Enrolling by invitation Asthma AstraZeneca October 15, 2018
NCT03406078 Active, not recruiting Asthma AstraZeneca January 23, 2018

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References
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Tezepelumab


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