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General Description:

Tremelimumab, identified by CAS number 745013-59-6, is a notable compound with significant therapeutic applications. Tremelimumab, formerly known as ticilimumab, is a fully human IgG2 monoclonal antibody directed against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). CTLA-4 is a cell surface receptor expressed on activated T cells to act as a negative regulator for T cells. By binding to CTLA-4, tremelimumab enhances T cell-mediated killing of tumours and reduces tumour growth. Because CTLA-4 is an immune checkpoint that plays a vital role in regulating T cell-mediated immune response, tremelimumab is considered an immune checkpoint inhibitor, which is an emerging cancer immunotherapy drug class. Tremelimumab was first approved by the FDA in October 2022 to be used in combination with to treat hepatocellular carcinoma. It is also being investigated in other cancers, such as colon cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), and malignant melanoma.

Indications:

This drug is primarily indicated for: Tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma in combination with . It is also indicated in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Absorption:

The absorption characteristics of Tremelimumab are crucial for its therapeutic efficacy: In patients with solid tumours who received tremelimumab doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) once every four weeks for four doses, the AUC of tremelimumab increased proportionally and steady-state was achieved at approximately 12 weeks. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tremelimumab is an important consideration for its dosing schedule: The geometric mean (CV%) terminal half-life of tremelimumab was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady-state. This determines the duration of action and helps in formulating effective dosing regimens.

Volume of Distribution:

Tremelimumab is distributed throughout the body with a volume of distribution of: The geometric mean (% coefficient of variation ) of tremelimumab for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tremelimumab is a critical factor in determining its safe and effective dosage: The geometric mean (CV%) clearance of tremelimumab was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady-state. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tremelimumab exerts its therapeutic effects through: Tremelimumab is a cytotoxic agent that works to decrease tumour growth. It binds to its target, human CTLA-4, with high selectivity and subnanomolar affinity. Tremelimumab caused increased IL-2 production in a dose-dependent manner in _ex-vivo_ blood stimulation assays using peripheral blood mononuclear cells (PBMCs) from healthy volunteers and patients with cancer, indicating that tremelimumab stimulated T cell-mediated cytotoxicity. Tremelimumab also increased the proliferation of effector T cells. _In vitro_, there was no evidence of nonspecific cytokine release induced by tremelimumab or drug binding to Fc receptors. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tremelimumab functions by: T cell activation is influenced by several processes. T cell receptors (TCR), which are expressed on T cells, bind to the cognate antigen processed and presented by major histocompatibility complex (MHC) expressed on antigen-presenting cells (APC). This interaction generates a TCR signal to activate T cells. In addition to the TCR signal, optimal T cell activation requires a costimulatory signal, produced when CD80 and CD86, expressed on the surface of APCs, bind to receptors expressed on T cells. CD80 and CD86 are also referred to together as B7 molecules. In response to these signals, activated T cells can be further differentiated into specific T cell subtypes with specialized functions. Immune checkpoints are proteins that control the intensity and duration of T cell activation and response. CD28 and CTLA-4 are homologous receptors expressed on CD4⁺ and CD8⁺ T cell surface. These immune checkpoints have opposing regulatory functions on T cell activity: CD28 is a positive regulator of T cell activity, while CTLA-4 is a negative regulator suppressing T cell activation and proliferation, as well as IL-2 gene transcription. B7 molecules act as ligands to both of these receptors, and the balance between CD28 and CTLA-4 expression and signalling influence the extent of T cell activation. In cancer immunotherapy, CTLA-4 has been investigated as a therapeutic target as blocking this receptor can enhance the activation of tumour-specific T cells, allowing them to exert cytotoxic effects on tumour cells. Tremelimumab is an antibody directed against CTLA-4. By binding to CTLA-4, tremelimumab blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, limiting its negative regulatory effect on T cell activation. Inhibition of CTLA-4 leads to increased proliferation of T cells in tumours and promotes T cell-mediated cytotoxicity. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Tremelimumab 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:

Tremelimumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antineoplastic Agents, Blood Proteins, CTLA-4-directed Blocking Antibody, Globulins, Immune Checkpoint Inhibitors, 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 Tremelimumab include:

• Molecular Weight: 149000.0
• Molecular Formula: C6500H9974N1726O2026S52