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General Description:

Tebentafusp, identified by CAS number 1874157-95-5, is a notable compound with significant therapeutic applications. Tebentafusp is a gp100 peptide-HLA-directed CD3 T cell engager. It is a bispecific, fusion protein and first-in-class drug of immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs), a recently developed cancer immunotherapy with a novel mechanism of action. ImmTACs bind to target cancer cells that express a specific antigen of interest and recruit cytotoxic T cells to lyse the cells, such as melanocytes. Uveal melanoma is a rare ocular tumour with often poor prognosis and limited treatment options. Even after surgical ablation or removal of the ocular tumour, almost 50% of patients with uveal melanoma develop metastatic disease. On January 26, 2022, tebentafusp was first approved by the FDA for the treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma. This approval marks the first bispecific T cell engager to be approved by the FDA to treat a solid tumour and being the first and only therapy for the treatment of unresectable or metastatic uveal melanoma to be approved by the FDA. Tebentafusp was subsequently approved for the same indication in the EU in April 2022.

Indications:

This drug is primarily indicated for: Tebentafusp is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tebentafusp undergoes metabolic processing primarily in: Tebentafusp is expected to be catabolized into small peptides and amino acids. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tebentafusp are crucial for its therapeutic efficacy: After a single dose administration, C_max and AUC_0-7d increased dose-proportionally from 20 to 68 mg (0.3 to 1 times the approved recommended dose). Following administration of the approved recommended dosage in patients with metastatic uveal melanoma, the steady-state geometric mean (% CV) C_max of tebentafusp was 13 ng/mL (34.6%) and AUC_0-7d was 4.6 ng.day/mL (23%) with no accumulation. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tebentafusp is an important consideration for its dosing schedule: The median terminal half-life is 7.5 hours, with a range of 6.8 to 7.5 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tebentafusp exhibits a strong affinity for binding with plasma proteins: There is 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 Tebentafusp from the body primarily occurs through: There is no information available. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tebentafusp is distributed throughout the body with a volume of distribution of: The geometric mean (%CV) steady-state volume of distribution is 7.56 L (24%). This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tebentafusp is a critical factor in determining its safe and effective dosage: The geometric mean clearance (%CV) of tebentafusp is 16.4 L/d (24.5%). It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tebentafusp exerts its therapeutic effects through: Tebentafusp is novel immunotherapy that causes cytotoxicity of cancer cells. Tebentafusp increased the serum levels of cytokines (IFN-γ, TNFα, IL-2, IL-6, IL-10 and IL-1RA) and chemokines (CXCL9, CXCL10, CXCL11, hepatocyte growth factor, and monocyte chemoattractant protein-1) during the first three doses. The levels of cytokines and chemokines peaked between eight to 24 hours after treatment, and levels returned to baseline before subsequent doses. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity than the first three doses. Tebentafusp also reduced lymphocyte counts after the first three doses, which returned to baseline before subsequent doses. In phase III clinical trials, patients treated with tebentafusp showed a better overall survival rate compared to , , or . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tebentafusp functions by: Glycoprotein 100 (gp100) is a transmembrane glycoprotein highly expressed in melanoma cells and weakly expressed by normal melanocytes or other tissues. Gp100 is presented as a human leukocyte antigen (HLA)-peptide complex on the cell surface. Gp100 has a particularly high affinity for the HLA-A subtype HLA-A*02:01. HLAs are part of a protein complex that normally regulates immune function: natural T cell responses are initiated by the interaction between the T-cell receptor (TCR) and its peptide antigen, such as gp100, presented by HLA on the surface of a target cell. Tebentafusp is a bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor CD3 T cell engager. It consists of a TCR targeting domain - or a TCR arm - fused to a single-chain variable fragment (scFv) anti-CD3 effector domain. The TCR arm binds to a gp100 peptide bound to HLA-A on the uveal melanoma tumour cell surface. The anti-CD3 effector domain of tebentafusp engages and activates CD3+ T cells to inflammatory cytokines and cytolytic proteins, which results in direct lysis of uveal melanoma tumour cells. The anti-CD3 fragment of the drug has a lower affinity, so the T cells are not stimulated unless tebentafusp has detected gp100. Tebentafusp is only effective in HLA-A*02:01-positive patients. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Tebentafusp is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antineoplastic Agents, Bispecific gp100 Peptide-HLA-directed CD3 T Cell Engager, Cancer immunotherapy, Immunotherapy, Melanoma, therapy, 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 Tebentafusp include:

• Molecular Weight: 77000.0
• Molecular Formula: C3344H5121O1069N928S22