Tezepelumab API Manufacturers

General Description:

Tezepelumab, identified by CAS number 1572943-04-4, is a notable compound with significant therapeutic applications. 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. 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. As existing asthma treatments such as , , , , and act on specific downstream mediators of the inflammatory response, they are mostly limited to treating T2 asthma. Conversely, tezepelumab, which targets the upstream master regulator TSLP, has the potential to be effective across asthma endotypes. 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.

Indications:

This drug is primarily indicated for: Tezepelumab is indicated as an add-on maintenance treatment for patients aged 12 years and older with severe asthma. Tezepelumab is not indicated for the relief of acute bronchospasm or status asthmaticus. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tezepelumab undergoes metabolic processing primarily in: As a human monoclonal antibody, tezepelumab is expected to be degraded by various proteolytic enzymes throughout the body. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tezepelumab are crucial for its therapeutic efficacy: When administered subcutaneously, tezepelumab reaches C_max in approximately 3-10 days with an estimated absolute bioavailability of 77%, regardless of injection site choice. 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 C_trough accumulation ratio. There are no clinically meaningful changes expected for tezepelumab pharmacokinetics in patients across patient populations, including those with renal or hepatic impairment. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tezepelumab is an important consideration for its dosing schedule: Tezepelumab has an elimination half-life of ~26 days. This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Tezepelumab from the body primarily occurs through: As a human monoclonal antibody, tezepelumab is eliminated primarily through catabolism; there is no evidence of target-mediated clearance at the therapeutic dose. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tezepelumab is distributed throughout the body with a volume of distribution of: Tezepelumab has a central V_d of 3.9 L and a peripheral V_d of 2.2 L (for a 70 kg individual). This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tezepelumab is a critical factor in determining its safe and effective dosage: Tezepelumab has an estimated clearance of 0.17 L/d (for a 70 kg individual). It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tezepelumab exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tezepelumab functions by: 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. 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. 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 (_K__D of 32 nM and _k__a 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 (_K__D of 29 nM and _k__a 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. 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. 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. Tezepelumab is a human monoclonal IgG2λ antibody that binds to TSLP with a dissociation constant of 15.8 pM. Specifically, the variable heavy chain domain (V_H) 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. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Tezepelumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Blood Proteins, Drugs for Obstructive Airway Diseases, Globulins, Immunoglobulins, Immunoproteins, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Tezepelumab include:

• Molecular Weight: 147000.0
• Molecular Formula: C6400H9844N1732O1992S52