Identification

Summary

Tezepelumab is a human monoclonal IgG2λ thymic stromal lymphopoietin (TSLP)-blocking antibody for add-on maintenance therapy in severe asthma.

Brand Names
Tezspire
Generic Name
Tezepelumab
DrugBank Accession Number
DB15090
Background

Asthma is a heterogeneous chronic obstructive respiratory disease with both "type 2" (T2) and T2-low endotypes characterized by reduced airflow, chronic inflammation, and airway remodelling.1,2 Thymic stromal lymphopoietin (TSLP), an innate pleiotropic IL-2-family cytokine, has emerged as a key upstream regulator of chronic inflammation across asthma endotypes. Blocking the interaction of TSLP with the receptors TSLPR and IL-7Rα improves asthma-associated biomarkers including eosinophil counts and IgE, FeNO, IL-5, and IL-13 levels.1,2,3 As existing asthma treatments such as omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab act on specific downstream mediators of the inflammatory response, they are mostly limited to treating T2 asthma.2 Conversely, tezepelumab, which targets the upstream master regulator TSLP, has the potential to be effective across asthma endotypes.1,2,3

Tezepelumab is a human monoclonal IgG2λ antibody directed against TSLP produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. It was granted FDA approval on December 17, 2021, and is currently marketed under the trademark TEZSPIRE by Amgen/AstraZeneca.5

Type
Biotech
Groups
Approved, Investigational
Synonyms
  • AMG 157
  • AMG-157
  • MEDI9929
  • Tezepelumab

Pharmacology

Indication

Tezepelumab is indicated as an add-on maintenance treatment for patients aged 12 years and older with severe asthma.5

Tezepelumab is not indicated for the relief of acute bronchospasm or status asthmaticus.5

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Tezepelumab is a human monoclonal IgG2λ antibody blocking thymic stromal lymphopoietin (TSLP). Tezepelumab treatment in asthmatic patients improves disease markers, including blood and airway submucosal eosinophils and IgE, FeNO, IL-5, and IL-13 levels. Despite an excellent safety profile, tezepelumab may be associated with hypersensitivity reactions and increased risk of infection, especially by parasitic helminths. Patients receiving tezepelumab should not discontinue systemic or inhaled corticosteroids, and any reduction in these drugs should be performed cautiously.5

Mechanism of action

Asthma is a heterogeneous chronic obstructive respiratory disease characterized by reduced airflow, chronic inflammation, and airway remodelling. Generally, asthma can be divided into "type 2" (T2, including allergic and eosinophilic presentations) and T2-low (including neutrophilic and paucigranulocytic presentations) endotypes, each driven by distinct underlying pathways.1,2 Thymic stromal lymphopoietin (TSLP) is an innate pleiotropic IL-2-family cytokine distantly related to IL-7; two forms of TSLP exist, with a short isoform (sfTSLP, 60 amino acids long) and a long isoform (lfTSLP, 159 amino acids long). The short isoform appears to be constitutively expressed, especially by lung and gut epithelial cells, while lfTSLP is upregulated in response to proinflammatory stimuli. While the role of sfTSLP is still unclear, lfTSLP has emerged as an upstream alarmin central to the pathophysiology of inflammatory disorders including asthma, atopic rhinitis, chronic obstructive pulmonary disease, eosinophilic esophagitis, and atopic dermatitis.1,2,3

Under normal conditions, lfTSLP interacts with its cognate receptor TSLPR, and IL-7Rα in a ternary complex with three contact sites labelled site I (TSLP:TSLPR), site II (TSLP:IL-7Rα), and site III (TSLPR:IL-7Rα). The assembly of the ternary complex is stepwise, as TSLP does not interact appreciably with IL-7Rα until after it has bound TSLPR. Complementary electrostatic surfaces on TSLP and TSLPR mediate initial high affinity formation of a TSLP:TSLPR complex (KD of 32 nM and ka of 1.7 x 105 M-1s-1). This initial binding induces a restructuring of the π-helical turn in the TSLP αA helix and structuring of the AB loop to facilitate binding of TSLP to a hydrophobic patch on IL-7Rα to form the ternary complex (KD of 29 nM and ka of 1.23 x 105 M-1s-1). The complete ternary complex is stabilized by additional interactions between TSLPR and IL-7Rα at site III near the transmembrane domain of each receptor.4

Formation of the ternary complex activates JAK1/2, which, through downstream pathways involving STAT3/5, NF-κB, PI3K, and MAPK, induces the expression of Th2 cytokines including IL-4, IL-5, IL-9, and IL-13.1 TSLP can induce Th2 cytokine production by stimulating dendritic cells and ILC2 cells (primarily in T2 asthma). Furthermore, TSLP has been implicated in steroid resistance of ILC2 cells. In neutrophilic asthma, TSLP induces dendritic cells to drive the development of Th17 cells, which secrete IL-17A to recruit neutrophils and drive inflammation. In paucigranulocytic asthma, TSLP mediates cross-talk between mast cells, smooth muscle cells, and fibroblasts. Hence, despite different underlying pathways, TSLP appears to function as a critical upstream driver across asthma endotypes.1,2,3

Tezepelumab is a human monoclonal IgG2λ antibody that binds to TSLP with a dissociation constant of 15.8 pM.4,5 Specifically, the variable heavy chain domain (VH) complementarity determining regions (CDRs) of tezepelumab bind TSLP at the AB-loop region and C-terminal region of the αD helix, obstructing the TSLPR binding region while leaving the IL-7Rα binding region unobstructed. As TSLP is incapable of binding IL-7Rα prior to its inclusion in the TSLP:TSLPR dimer, tezepelumab effectively blocks the assembly of the ternary complex and resulting downstream signalling.4 Furthermore, unlike existing therapies that act on specific downstream effector molecules, targeting TSLP ensures effective upstream blockade and is expected to be efficacious against multiple asthma endotypes.1,2,3

TargetActionsOrganism
AThymic stromal lymphopoietin
binder
antibody
Humans
Absorption

When administered subcutaneously, tezepelumab reaches Cmax in approximately 3-10 days with an estimated absolute bioavailability of 77%, regardless of injection site choice.5

Tezepelumab displays dose-proportional pharmacokinetics over a range of 2.1-420 mg (0.01-2 times the recommended dose) following a single subcutaneous dose. With a 4-week dosing schedule, tezepelumab achieves steady-state kinetics after 12 weeks with a 1.86-fold Ctrough accumulation ratio.5

There are no clinically meaningful changes expected for tezepelumab pharmacokinetics in patients across patient populations, including those with renal or hepatic impairment.5

Volume of distribution

Tezepelumab has a central Vd of 3.9 L and a peripheral Vd of 2.2 L (for a 70 kg individual).5

Protein binding

Not Available

Metabolism

As a human monoclonal antibody, tezepelumab is expected to be degraded by various proteolytic enzymes throughout the body.5

Route of elimination

As a human monoclonal antibody, tezepelumab is eliminated primarily through catabolism; there is no evidence of target-mediated clearance at the therapeutic dose.5

Half-life

Tezepelumab has an elimination half-life of ~26 days.5

Clearance

Tezepelumab has an estimated clearance of 0.17 L/d (for a 70 kg individual).5

Adverse Effects
Adverseeffects
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Toxicity

Toxicity information regarding tezepelumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as opportunistic infections and other conditions related to immunosuppression. Symptomatic and supportive measures are recommended.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Tezepelumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Tezepelumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Tezepelumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Tezepelumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Tezepelumab.
AmivantamabThe risk or severity of adverse effects can be increased when Tezepelumab is combined with Amivantamab.
AnifrolumabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Tezepelumab.
AnsuvimabThe risk or severity of adverse effects can be increased when Tezepelumab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Tezepelumab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Tezepelumab.
Interactions
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TezspireInjection, solution210 mg/1.9mLSubcutaneousAmgen, Inc2021-12-17Not applicableUS flag
TezspireInjection, solution210 mg/1.9mLSubcutaneousAmgen, Inc2021-12-17Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
RJ1IW3B4QX
CAS number
1572943-04-4

References

Synthesis Reference

Michael R Comeau, James F Smothers, Bo-Rin P Yoon, Christopher Mehlin, "Antigen binding proteins capable of binding thymic stromal lymphopoietin." U.S. Patent US9284372B2, issued March 15, 2016.

General References
  1. Pelaia C, Pelaia G, Crimi C, Maglio A, Gallelli L, Terracciano R, Vatrella A: Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma. Int J Mol Sci. 2021 Apr 22;22(9). pii: ijms22094369. doi: 10.3390/ijms22094369. [Article]
  2. Marone G, Spadaro G, Braile M, Poto R, Criscuolo G, Pahima H, Loffredo S, Levi-Schaffer F, Varricchi G: Tezepelumab: a novel biological therapy for the treatment of severe uncontrolled asthma. Expert Opin Investig Drugs. 2019 Nov;28(11):931-940. doi: 10.1080/13543784.2019.1672657. Epub 2019 Oct 10. [Article]
  3. Nakajima S, Kabata H, Kabashima K, Asano K: Anti-TSLP antibodies: Targeting a master regulator of type 2 immune responses. Allergol Int. 2020 Apr;69(2):197-203. doi: 10.1016/j.alit.2020.01.001. Epub 2020 Jan 21. [Article]
  4. Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, Vandenberghe I, Pauwels K, Tavernier J, Lambrecht BN, Hammad H, De Winter H, Beyaert R, Lippens G, Savvides SN: Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat Commun. 2017 Apr 3;8:14937. doi: 10.1038/ncomms14937. [Article]
  5. FDA Approved Drug Products: TEZSPIRE (tezepelumab-ekko) injection [Link]
RxNav
2587789
Wikipedia
Tezepelumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAsthma1
3Active Not RecruitingTreatmentModerate to Severe Asthma1
3CompletedTreatmentAsthma3
3CompletedTreatmentSevere Asthma1
3RecruitingTreatmentAsthma1
3RecruitingTreatmentChronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP)1
2CompletedTreatmentAsthma2
2CompletedTreatmentAsthma / Bronchial Diseases / Coronavirus Disease 2019 (COVID‑19) / Hypersensitivity / Immune System Diseases / Lung Disorder / Obstructive Lung Diseases / Respiratory Hypersensitivity / Respiratory Tract Diseases / Type I Hypersensitivity1
2CompletedTreatmentAtopic Dermatitis1
2RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous210 mg/1.9mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Antibody
Curator comments
Tezepelumab binds TSLP with a dissociation constant of 15.8 pM, blocking its interaction with its cognate receptor TSLPR.
General Function
Isoform 1 Cytokine that induces the release of T-cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c(+) dendritic cells. Can induce allergic inflammation by directly activating mast cells.
Specific Function
Cytokine activity
Gene Name
TSLP
Uniprot ID
Q969D9
Uniprot Name
Thymic stromal lymphopoietin
Molecular Weight
18141.13 Da
References
  1. Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, Vandenberghe I, Pauwels K, Tavernier J, Lambrecht BN, Hammad H, De Winter H, Beyaert R, Lippens G, Savvides SN: Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat Commun. 2017 Apr 3;8:14937. doi: 10.1038/ncomms14937. [Article]
  2. FDA Approved Drug Products: TEZSPIRE (tezepelumab-ekko) injection [Link]

Drug created at May 20, 2019 14:49 / Updated at December 28, 2021 09:48