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General Description:

Tagraxofusp, identified by CAS number 2055491-00-2, is a notable compound with significant therapeutic applications. Tagraxofusp is a CD123-directed cytotoxin. It is a fusion protein composed of a human interleukin-3 (IL-3) that is genetically fused to the catalytic and translocation domains of truncated diphtheria toxin (DT) produced in _Escherichia coli_. Tagraxofusp received its first global approval by the FDA on December 21, 2018 as the first FDA-approved treatment for blastic plasmacytoid dendritic cell neoplasm, which is a myeloid malignancy in the dendritic cell lineage. It was also approved by the European Commission on January 7, 2021.

Indications:

This drug is primarily indicated for: Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). In the US, it is approved for use in adults and pediatric patients over 2 years old. In Europe, it is only approved for use in adults. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tagraxofusp undergoes metabolic processing primarily in: Tagraxofusp is expected to be degraded into peptides and its constituent amino acids through proteolysis, with no involvement of CYP or transporters. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tagraxofusp are crucial for its therapeutic efficacy: Following administration of tagraxofusp 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) area under the plasma drug concentration over time curve (AUC) was 231 (123) hr x mcg/L and maximum plasma concentration (C_max) was 162 (58.1) mcg/L. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tagraxofusp is an important consideration for its dosing schedule: The mean (SD) terminal half-life of tagraxofusp was 0.7 (0.3) hours in patients with BPDCN. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tagraxofusp exhibits a strong affinity for binding with plasma proteins: No information available. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Tagraxofusp from the body primarily occurs through: No information available. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tagraxofusp is distributed throughout the body with a volume of distribution of: Following administration of tagraxofusp 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) volume of distribution of tagraxofusp was 5.1 (1.9) L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tagraxofusp is a critical factor in determining its safe and effective dosage: Mean clearance (SD) clearance was 7.1 (7.2) L/hr in patients with BPDCN. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tagraxofusp exerts its therapeutic effects through: Tagraxofusp has potent antitumour activity against BPDCN cells in both _in vitro_ and _in vivo_ models. It is a cytotoxin that works to cause cell death in malignant cells that express CD123, which is a subunit of the interleukin 3 (IL-3) receptor. _In vitro_, tagraxofusp decreased cell proliferation and increased expression of apoptotic markers in BPDCN cell lines and in blasts from patients with BPDCN. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tagraxofusp functions by: Interleukin 3 (IL-3) is a cytokine and hematopoietic growth factor that promotes the differentiation of hematopoietic cells into various myeloid cells. It mediates its biological actions by binding to the IL-3 receptor, which is made up of two subunits: the alpha (α) subunit - also known as CD123 - is the site of ligand attachment and confers receptor specificity, while the beta (β) subunit, also known as CDw131 - plays a role in signal transduction, internalization of the ligand-receptor complexes, and activation of the Ras signalling pathway. The expression of the IL-3 receptor is prevalent in CD34⁺ hematopoietic cells as well as on granulocytes and monocyte precursors. CD123, the subunit of the IL-3 receptor, has also been implicated in the pathophysiology of BPDCN, as transformed plasmacytoid dendritic cells that overexpress CD123 are frequently observed. Tagraxofusp targets leukemic stem cells that express CD123. It is a fusion protein made up of diphtheria toxin (DT) and IL-3; therefore, it binds to the IL-3 receptor with high affinity. Upon binding to the IL-3 receptor on CD123-expressing cells, tagraxofusp is internalized via receptor-mediated endocytosis. The catalytic domain of DT is then cleaved and translocates from the endosome into the cytosol. The catalytic domain of DT irreversibly inhibits protein synthesis by inactivating elongation factor 2 (EF2), eventually inducing apoptosis. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Tagraxofusp belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Tagraxofusp is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, CD123 Interaction, CD123 Interactions, Cytotoxins, Narrow Therapeutic Index Drugs, Proteins, Recombinant Fusion Proteins, Recombinant Proteins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Tagraxofusp include:

• Molecular Weight: 57695.0
• Molecular Formula: C2553 H4026 N692 O798 S16